Professional Documents
Culture Documents
Cardiovascular
Diseases
From Current Evidence
to Clinical Practice
Jadelson P. Andrade
Fausto J. Pinto
Donna K. Arnett
Editors
123
Prevention of Cardiovascular
Diseases
From Current Evidence to Clinical Practice
Editors
Jadelson P. Andrade, M.D.
Director, Hospital da Bahia
Salvador, Bahia, Brazil
Donna K. Arnett, M.S.P.H., Ph.D.
Professor and Chair of the Department
of Epidemiology
School of Public Health
University of Alabama School of Medicine
Birmingham, AL, USA
(eBook)
According to data released by the World Health Organization (WHO), 56.9 million
deaths were reported worldwide in 2008, and of these about 17 million were caused
by cardiovascular diseases.
From this alarming reported epidemiological reality, the WHO began to encourage all countries of the world to embrace the banner of cardiovascular prevention,
proposing an alliance between the nations, governments, civil society, and private
sectors to team up in your face.
The WHO proposal has the primary objective to promote working together to
modify these serious epidemiological data and the gloomy future outlook projected
for the following 30 years.
In line with the WHO global project, the Brazilian Society of Cardiology proposed an international partnership with the European Society of Cardiology and the
American Heart Association to prepare the book Cardiovascular Prevention A
Global Challenge. Three editors were invited, Jadelson P. Andrade, Donna
K. Arnett, and Fausto J. Pinto, then president and president-elect of the aforementioned institutions.
The work was developed in 28 chapters addressing different themes of cardiovascular prevention with the original version in Portuguese and this edition in
English with the title: Prevention of Cardiovascular Diseases: From Current
Evidence to Clinical Practice. The authors of the chapters were distributed among
Brazilian, European, and American experts, all with relevant scientic contributions
on the subject.
The ultimate purpose of the editors, in line with the recent proposal from WHO,
is to make available to the international medical community a valuable reference
tool for proper addressing the alarming epidemiological index.
Salvador, Brazil
viii
priority across the different countries. It is also important to recognize the need of a
tailored approach considering the differences among different countries, which
reinforces the importance of putting in place surveillance systems in place that may
be able to monitor properly the need and implementation of preventable measures.
This is of crucial importance for a successful ght against inequalities to access
to appropriate health care among the different countries. The role of scientic societies in the dissemination of information as well as in the promotion of different
activities towards the populations as well as the decision makers can ll in an important gap in this regard. This Book on Prevention, being a joint enterprise between
the Brazilian Society of Cardiology, European Society of Cardiology and American
Heart Association, will certainly t into this common goal of improving Prevention
of Cardiovascular Disease worldwide.
Cardiology Department, CCUL, CAML
University of Lisbon, Lisbon, Portugal
For those of us who have devoted our lives to studying and treating cardiovascular
disease (CVD), the idea that CVD prevention is critical is so obvious that further
exposition on the subject may seem gratuitous. It is decidedly not. The successes
that clinicians and public health practitioners have had in the realm of CVD prevention are not only reasons to exult, but also cause for redoubling our efforts with
some assurance that prevention is eminently possible and further progress can be
made. And although some of the more alarming trends observed in some parts of the
world (rising prevalence of obesity, for example) are cause for deep concern, they
are also cause for increased and improved preventive action. It is precisely this
changing landscape of CVD and its risk factors that makes continued assessment
and discussion of CVD-prevention strategies so critically important. Programs in
the USA such as the Centers for Disease Control and Preventions Million Hearts
Initiative and the American Heart Associations 2020 Impact Goal (to improve cardiovascular health by 20 % by 2020 while reducing CVD and stroke mortality by
20 %) and analogous efforts in other countries are tangible representations of population evaluation, goal setting, policy making, and program development that drive
progress in this realm. Each of the chapters in this book represents a primer in CVD
and its prevention. With its calculated mix of CVD and risk factor fundamentals and
trenchant foresight, this volume will be welcomed by all those around the globe
who aim to rise to the challenge of CVD prevention.
Birmingham, AL, USA
ix
Contents
13
21
29
41
49
59
69
81
91
xii
Contents
Contents
xiii
Advisory Board
Angelo Amato Vincenzo de Paola Full professor and chief of the discipline of
Cardiology; chief of the Arrhythmia and Electrophysiology Sector Federal
University of So Paulo (UNIFESP), Brazil. President of the Brazilian Society of
Cardiology (20142015)
Antonio Carlos de Carvalho Full professor of Cardiology Federal University of
So Paulo (UNIFESP)
Luiz Alberto Piva e Mattos Coordenator of hemodynamics and Cardiovascular
Intervention Rede DOr Hospitals, Brazil. Professor of the Port-Graduate Program
in Tecnology and Intevention in Cardiology Dante Pazzanese Cardiology Institute,
So Paulo, Brazil
Marcia de Melo Barbosa Director of Ecocenter, Hospital Socor Belo Horizonte,
Brazil. President of the Interamerican Society of Cardiology. PhD in Cardiology by
the University of So Paulo (USP), Brazil
xv
Contributors
xviii
Contributors
Marcia de Melo Barbosa, M.D., Ph.D. ECO Center, Hospital Socor, Belo
Horizonte, Brazil
Interamerican Society of Cardiology
Angelo A. V. de Paola, M.D., Ph.D. Paulista School of Medicine, Federal
University of So Paulo, So Paulo, Brazil
Arrhythmia Department of the Paulista School of Medicine, Federal University of
So Paulo, So Paulo, Brazil
Brazilian Society of Cardiology, Rio de Janeiro, Brazil
Andra Silvestre de Sousa, M.D., Ph.D. Federal University of Rio de Janeiro,
Rio de Janeiro, Brazil
Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
Joo Carlos Pinto Dias, M.D., Ph.D. School of Medicine, Federal University of
Minas Gerais, Belo Horizonte, Brazil
Neglected Diseases Committee of the World Health Organization, Geneva,
Switzerland
Maria do Carmo Pereira Nunes, M.D. School of Medicine, Federal University of
Minas Gerais, Belo Horizonte, Brazil
Donald Edmondson, M.P.H., Ph.D. Center for Behavioral Cardiovascular Health,
Columbia University Medical Center, New York, NY, USA
Gilson S. Feitosa, M.D., Ph.D. Bahia School of Medicine and Public Health,
Salvador, Brazil
Hospital Santa Isabel/Santa Casa da Bahia, Salvador, Brazil
Brazilian Society of Cardiology, Rio de Janeiro, Brazil
Roberto Ferrari, M.D. Department of Cardiology, LTTA Centre, University
Hospital of Ferrara and Maria Cecilia Hospital, GVM Care et Research, E. S. Health
Science Foundation, Cotignola, Italy
Renata Caruso Fialdini, M.D. University of Sao Paulo, Sao Paulo, Brazil
Dan Gaita, M.D. Cardiology inn Romanian, Bucharest, RomaniaRomanian Heart
Foundation, Bucharest, Romania
Pantaleo Giannuzzi, M.D. Cardiac Rehabilitation Department, Salvatori Maugeri
FoundationIRCCS, Scientic Institute of Veruno, Veruno, Italy
Stephan Gielen, M.D. University Hospital, Martin-Luther-University of Halle/
Wittenberg, Halle, Germany
Department of Internal Medicine III, University Hospital, Martin-Luther
University of Halle/Wittenberg, Halle, Germany
Contributors
xix
xx
Contributors
C. Noel Bairey Merz, M.D. Barbara Streisand Womens Heart Center, Preventive
and Rehabilitative Cardiac Center, Womens Guild Chair in Womens Health,
Los Angeles, CA, USA
Regina Mller, M.D., Ph.D. Working Group on Rheumatic Fever from the World
Heart Federation, Geneva, Switzerland
National Heart Institute of Rio de Janeiro, Rio de Janeiro, Brazil
Joep Perk, M.D., Ph.D. Linnaeus University, Kalmar, Sweden
Dalton Bertolim Prcoma, M.D., Ph.D. Catholic University of Parana, Curitiba,
Brazil
Brazilian Society of Cardiology, Rio de Janeiro, Brazil
Anis Rassi, M.D., Ph.D. Faculty of Medicine, Federal University of Goias,
Goiania, Goias, Brazil
Anis Rassi Jr. M.D., Ph.D. Anis Rassi Hospital, Goiania, Goias, Brazil
Amanda R. Ratigan, M.S. Joint Doctoral Program in Public Health Epidemiology,
University of California San Diego State University, San Diego, CA, USA
Department of Defense HIV/AIDS Prevention Program, Naval Research Center,
San Diego, CA, USA
Master of Public Health, Epidemiology, San Diego State University, San Diego,
CA, USA
Evangelista Rocha, M.D., Ph.D. Faculty of Medicine, Institute of Preventive
Medicine and Public Health, University of Lisbon, Lisbon, Portugal
Evgeny Shlyakhto, M.D., Ph.D. Federal Almazov Medical Research Center,
Saint-Petersburg, Russia
Russian Society of Cardiology, Moscow, Russia
Antonio Felipe Simo, M.D. Institute of Cardiology from Santa Catarina,
Florianpolis, Brazil
Brazilian Society of Cardiology, Rio de Janeiro, Brazil
Sidney C. SmithJr. M.D. Department of Medicine, University of North Carolina
at Chapel Hill School of Medicine, Chapel Hill, USA
Laurence Sperling, M.D. Emory University School of Medicine, Atlanta,
GA, USA
Gabriel Pelegrineti Targueta, M.D. Instituto Dante Pazzanese of Cardiology,
Federal University of Sao Paulo, Sao Paulo, Brazil
Lale Tokgzoglu, M.D. Hacettepe University in Ankara, Ankara, Turkey
Contributors
xxi
Lost (YLL) metric, which measures differences from the same potential life length
across populations to estimate burden, usually taken as the global mean life expectancy [3]. However, these measures do not account for the age- and sex-characteristics of different countries. Therefore, age-adjustment or -standardization to a global
population have been basic strategies to account for a populations age structure to
improve comparability across populations. Data are usually stratied by sex to
account for differences in the proportion of men and women among different
countries.
However, these approaches do not account for any measure of health during the
lifecourse. To overcome this limitation, the Global Burden of Disease team developed the Disability Adjusted Life Year (DALY) metric, which is equal to the sum of
Years of Life Lost (YLL) and Years Lived with Disability (YLD), or:
Disability Adjusted LifeYear = Years of Life Lost + Years Lived with Disability
The DALY metric was founded on the principles that: (1) everyone in the world has
right to best life expectancy, and (2) differences in the rating of a death or disability
should be due to age and sex and not to income, culture, location, social class.
It is also important to understand how Years Lived with Disability (YLD) is
dened, by whom, and at what time in the disease course [4]. First, disability represents an objective alteration of behavior or performance at the individual level.
Disability falls between impairment, which is dened by symptoms at an organ
level, and handicap, which is dened by changed interactions with others at the
social or environmental level due to disability. To illustrate, if an individual suffers
from a stroke, s/he might have symptoms of unilateral arm and leg weakness
(impairment), which limits her/his ability to walk independently (disability) and
her/his ability to work in a job that requires walking (handicap). Second, researchers
have typically surveyed medical professionals and public health experts to rank
symptom states to quantitatively estimate YLD for myriad disease states. Other
individuals, including but not limited to patients, families, caregivers, general public, insurance companies, and legal experts, might offer complementary perspectives on how YLDs should be estimated yet have not been incorporated in these
estimates to date. Third, YLD estimates can be sensitive to the time course of the
disease, particularly for non-communicable, chronic diseases, which can have long
periods of minimal to no symptoms followed by acute shocks and gradual recovery
to or near baseline. In the stroke example, the immediate post-stroke disability can
be substantially different than 3, 6, or 12 months later and can be dependent upon
access to rehabilitation and medical therapy. As such, YLD estimates may be susceptible to reporting bias by experts based on their previous clinical or health
experiences.
Newer estimates of disease burden incorporate costs and nancial risk through
measures such as catastrophic health spending (based on the proportion of health
spending relative to non-food expenditures) and distress nancing (based on risky
nancial activities to pay for health, including borrowing money or selling assets)
[5]. These complementary measures of nancial protection, or lack thereof, are
associated with individuals and families falling into poverty. Because health systems
are evaluated in terms of quality, access, and nancial protection [6], these measures
of disease burden will likely gain more attention.
Using the International Classification of Diseases framework, the Global
Burden of Disease project employed systematic searched published and unpublished data on causes of death through a variety of sources, including the World
Health Organization mortality database, national vital registration systems, verbal
autopsy-based sample registration systems, demographic surveillance systems,
cancer registers, crime reports, mortuary data, among others [3]. In the case of socalled garbage codes that have been deemed implausible causes of death, available data were used to reclassify the causes of death [1]. The project team then
incorporated these best available data into advanced, multi-level statistical models
and imputation methods to estimate the causes of death among all countries from
1980 through 2010.
The Global Burden of Disease project is not without its critics who express concern about the complex analytic methods and frequent use of imputation to estimate
data for countries that do not have accurate, updated mortality data. Some fear that
the Global Burden of Disease, which is largely funded by the Bill & Melinda Gates
Foundation, a private non-governmental organization, may lead to reduced public
investments in vital registration systems, a basic public health function that currently covers less than half of the worlds population [7]. Nevertheless, the Global
Burden of Disease project represents the most comprehensive and accessible summary of contemporary global disease burden, including providing estimates for
non-communicable, chronic diseases.
Table 1 All-cause and non-communicable, chronic disease (NCD)-specic deaths and death rates
in 1990 and 2010 estimated by the Global Burden of Disease Study [3]
1990 deaths
Deaths expected with 1990 population, 2010 population age structure,
1990 death rates
Deaths expected with 2010 population, 2010 population age structure,
1990 death rates
2010 deaths
Percentage change from 1990 due to population growth
Percentage change from 1990 due to population aging
Percentage change from 1990 due to change in death rates
Percentage change from 1990 to 2010
All causes
46,511,000
61,307,000
NCDs
26,560,000
32,647,000
70,316,000
43,062,000
52,770,000
31.8 %
19.4 %
37.7 %
13.5 %
34,540,000
22.9 %
39.2 %
32.1 %
30.0 %
Table 2 Global Burden of Disease 2010 estimates of deaths and age-standardized death rates per
100,000 in 1990 and 2010 across non-communicable, chronic diseases
All ages deaths (thousands)
1990
2010
All non26,560.3
34,539.9
communicable,
(25,843.4,
(33,164.7,
chronic diseases
27,249.3)
35,313.0)
Cardiovascular and 11,903.7
15,616.1
circulatory diseases (11,329.4,
(14,542.2,
12,589.3)
16,315.1)
Neoplasms
5779.1
7977.9
(5415.9,
(7337.1,
6201.9)
8403.8)
Chronic lung
3986.3
3776.3
diseases
(3914.3,
(3648.2,
4063.8)
3934.1)
Diabetes
1544.3
2726.2
(1420.0,
(2447.1,
1804.0)
2999.1)
Mental and
138.1 (95.2, 231.9 (176.3,
behavioral disorders 188.0)
329.1)
Musculoskeletal
69.5 (46.2, 153.5 (110.7,
disorders
89.6)
214.8)
18,893, 21,874) per 100,000 in 1990 to 19,502 (95 % UI: 17,997, 21,143) per
100,000 in 2010.
The death and disability burdens of specic NCDs are outlined below with
supporting data presented in Tables 2 and 3.
Table 3 Global Burden of Disease 2010 estimates of disability adjusted life years and disability
adjusted life years lost per 100,000 in 1990 and 2010 across non-communicable, chronic diseases
All noncommunicable,
chronic diseases
Cardiovascular
and circulatory
diseases
Neoplasms
Chronic lung
diseases
Diabetes
Mental and
behavioral
disorders
Musculoskeletal
disorders
Cardiovascular Diseases
Global cardiovascular disease deaths increased from 11.9 million (95 % UI: 11.2,
12.6) in 1990 to 15.6 million (95 % UI: 14.5, 16.3) in 2010, which represents a 31 %
increase. Age- and sex-adjusted rates of cardiovascular disease deaths decreased
from 298.1 (95 % UI: 283.9, 314.9) per 100,000 in 1990 to 234.8 (95 % UI: 218.7,
245.2) per 100,000 in 2010, which represents a 21 % decrease [3]. Ischemic heart
disease was the leading cause of cardiovascular deaths during both time periods.
The number of deaths increased from 5.2 million (95 % UI: 5.0, 5.6) ischemic heart
disease deaths in 1990 to 7.0 million (95 % UI: 6.6, 7.4), which represents a 35 %
increase. Age- and sex-adjusted death rates due to ischemic heart disease decreased
from 131.3 (95 % UI: 126.4, 142.2) per 100,000 to 105.7 (95 % UI: 98.8, 111.9) per
100,000 in 2010, which represents a 20 % decrease.
The number of disability adjusted life years (DALYs) due to cardiovascular
diseases increased from 240,667 (95 % UI: 227,084, 257,718) DALYs in 1990 compared with 295,036 (95 % UI: 273,061, 309,562) in 2010, which represents a 23 %
increase, while the rate of DALYs per 100,000 due to cardiovascular diseases
decreased by 6 % from 4540 (95 % UI: 4283, 4861) per 100,000 in 1990 to 4282
(95 % UI: 3963, 4493) per 100,000 in 2010.
Cancer
Global cancer deaths increased from 5.8 million (95 % UI: 5.4, 6.2) in 1990 to 8.0 million (95 % UI: 7.3, 8.4) in 2010, which represents a 38 % increase. Similar to other
cardiovascular diseases, age- and sex-adjusted rates of cancer deaths decreased from
140.8 (95 % UI: 131.0, 151.5) per 100,000 in 1990 to 121.4 (95 % UI: 111.6, 127.9)
per 100,000 in 2010, which represents a 14 % decrease [3]. Cancers of the trachea,
bronchus, and lungs were the leading cause of cancer deaths during both time periods.
The number of deaths increased from 1.0 million (95 % UI: 0.8, 1.3) cancers of the
trachea, bronchus, and lung in 1990 to 1.5 million (95 % UI: 1.1, 1.8), which represents
a 47 % increase. Age- and sex-adjusted death rates due to cancers of the trachea,
bronchus, and lung modestly decreased from 25.5 (95 % UI: 20.4. 32.4) per 100,000 to
23.4 (95 % UI: 17.3, 27.3) per 100,000 in 2010, which represents an 8 % decrease.
The number of disability adjusted life years (DALYs) due to cancer increased from
148,078 (95 % UI: 136,775, 158,256) DALYs in 1990 compared with 188,487 (95 %
UI: 174,452, 199,037) in 2010, which represents a 27 % increase, while the rate of
DALYs per 100,000 due to cancer decreased by 2 % from 2793 (95 % UI: 2580, 2985)
per 100,000 in 1990 to 2736 (95 % UI: 2532, 2889) per 100,000 in 2010.
Diabetes
Global diabetes deaths increased from 665,000 (95 % UI: 593,300, 757,500) in
1990 to 1.3 million (95 % UI: 1.1, 1.3) in 2010, which represents a 93 % increase.
Unlike cardiovascular diseases, cancer, and chronic lung disease, age- and
sex-adjusted rates of diabetes deaths increased from 16.3 (95 % UI: 14.5, 18.6)
per 100,000 in 1990 to 19.5 (95 % UI: 16.2, 20.5) per 100,000 in 2010, which
represents a 20 % increase.
The number of disability adjusted life years (DALYs) due to diabetes increased
from 85,084 (95 % UI: 73,638, 102,489) DALYs in 1990 compared with 122,437
(95 % UI: 107,437, 143,387) in 2010, which represents a 44 % increase, while the rate
of DALYs per 100,000 due to diabetes increased by 11 % from 1605 (95 % UI: 1389,
1933) per 100,000 in 1990 to 1777 (95 % UI: 1559, 2081) per 100,000 in 2010.
Tobacco
Smoking prevalence has decreased from 41 % (95 % UI: 40, 43) in 1980 to 31 %
(95 % UI: 30, 32) in 2012 for men >15 years and from 11 % (95 % UI: 10, 11) to
6 % (95 % UI: 6, 6) for women >15 years [9]. However, due to population growth
and aging as well as the inherent lag time between tobacco exposure and diseases
such as cancer, the number of deaths attributable to tobacco increased from 5.3
million (95 % UI: 4.8, 6.0) in 1990 to 6.3 million (95 % UI: 5.4, 7.0) in 2010 [10].
If recent trends continue, there will be an estimated 1 billion tobacco-related deaths
in the twenty-rst century, most of which will occur in low- and middle-income
countries and half of which will occur before age 70 years [11].
Unhealthy Diet
Global increases in body mass index from 1980 to 2010 (0.4 mg/kg2 per decade
(95 % UI: 0.2, 0.6) for men and 0.5 mg/kg2 per decade (95 % UI: 0.3, 0.7) for
women) [12] suggest that access to calories has increased. However, global trends
in diet quality are difcult to assess not only because of the inherent complexity in
comparing different dietary patterns across the world but also because of the limitations in instruments for dietary data collection. The Global Burden of Disease project evaluates the effects of 14 dietary variables (fruit intake, vegetable, whole grains,
nuts and seeds, milk, red meat, processed meat, sugar sweetened beverages, ber,
calcium, omega-3 containing seafood, polyunsaturated fats, trans fats, and sodium).
The investigators estimate the number of attributable deaths due to unhealthy diet
increased from 8.5 million (95 % UI: 7.9, 9.2) in 1990 to 12.5 million (95 % UI:
11.7, 13.3) in 2010, with the greatest proportion coming from diets low in fruits (4.9
million [95 % UI: 3.8, 5.9]), low in nuts/seeds (2.5 million [95 % UI: 1.6, 3.2]), and
low in vegetables (1.8 million [95 % UI: 1.2, 2.4]) [10].
Physical Inactivity
Major changes in migration, transportation, and mechanization over the past century
have undoubtedly led to declines in global physical activity [13]. However, like diet,
global physical activity estimates and time trends are difcult to obtain because of:
(1) limited number of global physical inactivity surveys; (2) limitations in survey
instruments that rely upon self-reporting of physical activity; and (3) historical reliance on leisure-time physical activity estimates, rather than inclusion of transport,
occupational, and domestic activity domains, which may overestimate physical
inactivity prevalence. These limitations notwithstanding, global physical inactivity
prevalence in 2010 has been estimated to be 28 and 34 % for men and women,
respectively [14]. In 2010, the Global Burden of Disease project estimated that the
number of attributable deaths due to physical inactivity was 3.2 million (95 %
UI: 2.7, 3.7) [10]. The Lancets Physical Activity Series Working Group produced
a higher estimate of deaths due to inactivity for 2008 (5.3 million, a 65 % higher
estimate), which reects the uncertainty in creating such estimates of attributable
disease burden [15].
Future Projections
Despite reductions in age-adjusted mortality from non-communicable, chronic
diseases (NCDs) overall, the burden of NCDs will continue to grow in absolute
terms because of the inexorable effects of population growth and aging. For example, if the 2010 death rates due to cardiovascular diseases, cancer, chronic lung
diseases, and diabetes remained unchanged until 2025, the annual numbers of
deaths would increase from 28.3 million to 38.8 million [16]. To galvanize global
action and momentum in reducing the burden of NCDs, member states of the World
Health Organization have adopted nine voluntary targets to reduce the burden of
NCDs and their risk factors (Box) [17]. The primary, equity-based target is to reduce
the risk of premature death, between the ages of 30 and 69 years, from NCDs by
25 % by 2025, or the so-called 25 25 target.
Kontis et al. estimated the effect of achieving six of the eight risk factor targets
(tobacco, alcohol, salt intake, obesity, raised blood pressure, raised glucose/diabetes)
on the 25 25 mortality target overall and on specic NCD subtypes, stratied by
sex and country, compared with business as usual trends [16]. These projections
suggest that, if these six risk factor targets were achieved, the risk of premature
10
deaths from NCDs would decrease by 22 % for men and 19 % for women between
2010 and 2025. These estimates compare favorably with projected decreases in the
risk of premature mortality from NCDs by 11 % for men and 10 % for women under
the business as usual scenario where recent declines in NCD mortality rates continue to 2025. Achieving these six risk factor targets would not only prevent or
postpone 16.1 million NCD-related deaths among individuals 3069 years old over
the 15 year period (20102025) but would also prevent or postpone an additional
21.4 million deaths among individuals 70 years and greater. The majority (70 %) of
these premature deaths prevented or postponed would be from cardiovascular
disease (11.4 million), followed by cancer (2.4 million), chronic lung diseases
(1.2 million) and diabetes (1.1 million). Because low- and middle-income countries
have a higher burden of NCD-related deaths and death rates compared with highincome countries, these countries would experience far greater progress toward the
25 25 mortality target if the risk factor targets were achieved.
Conclusions
Non-communicable chronic diseases (NCDs), including cardiovascular diseases,
cancer, chronic lung diseases, diabetes, and mental and behavioral disorders, are the
leading causes of death and disability worldwide. While global age-adjusted death
rates from NCDs have been falling over the past two decades, population growth
and aging have led to absolute and ongoing increases in NCD-related deaths and
disability adjusted life years (DALYs). Low- and middle-income countries are projected to bear even greater proportions of the global burden of NCDs in the coming
decades due, at least in part to their younger demographics, unless comprehensive,
sustainable, and intersectoral action is taken to prevent, detect, treat, and control
NCDs and their shared risk factors.
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14. Hallal PC, Andersen LB, Bull FC, Guthold R, Haskell W, Ekelund U, Lancet Physical Activity
Series Working Group. Global physical activity levels: surveillance progress, pitfalls, and
prospects. Lancet. 2012;380(9838):24757.
15. Lee IM, Shiroma EJ, Lobelo F, Puska P, Blair SN, Katzmarzyk PT, Lancet Physical Activity
Series Working Group. Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy. Lancet. 2012;380(9838):21929.
16. Kontis V, Mathers CD, Rehm J, Stevens GA, Shield KD, Bonita R, et al. Contribution of six
risk factors to achieving the 25 25 non-communicable disease mortality reduction target: a
modelling study. Lancet. 2014;384:42737.
17. World Health Organization. Global action plan for the prevention and control of noncommunicable diseases 20132020. World Health Organization; 2013.
13
14
actions are not implemented, by the year 2030, seven out of ten deaths will be due
to non-communicable diseases (NCDs), and CVD will account for the highest
percentage of these deaths [1, 3].
However, although the CVD mortality rates in developed countries have been
declining in recent decades, as previously mentioned, the rates in most developing
countries are still increasing. This is due, among other factors, to the increased economic power of developing countries. Rising incomes per capita have led to
improvement in the health and basic living conditions of these populations, resulting
in a signicant reduction in the incidence of and mortality from infectious and parasitic diseases, with a proportional increase in the number of deaths caused by NCDs.
In addition, the lifestyle adopted by urban populations in developing countries has
signicantly increased the prevalence of risk factors for cardiovascular diseases
such as obesity, physical inactivity, tobacco use, high blood pressure, excessive salt
intake, dyslipidemia, and diabetes [4, 5].
15
cities (Surveillance of Risk and Protective Factors for Chronic Diseases Telephone
SurveyVIGITEL), 15 % of adults 18 years and older are smokers, only 30 %
regularly consume fruits and vegetables, whereas 34 % reported consuming meat
with excess fat, and only 30 % practice physical activity regularly (including leisure
activities and commuting to work) [10, 11].
According to the 2012 European Guidelines on Cardiovascular Prevention, there
are eight reasons to promote cardiovascular prevention [12]:
1. Atherosclerotic CVD, especially coronary artery disease, is the leading cause of
premature death worldwide;
2. CVD affects men and women equally;
3. CVD mortality rates are declining in many European countries but remain high
in Eastern Europe;
4. More than half of the observed decrease in the CVD rate is related to changes in
risk factors, and 40 % is due to improved treatments;
5. Preventive efforts should be applied throughout life, from birth to old age;
6. Preventive approaches limited to high-risk individuals are less effective, and
education programs for the entire population are needed;
7. Despite gaps in knowledge, there is ample evidence to justify intensive efforts
related to public health and individual prevention;
8. There is still room for improvement in the control of risk factors, even in high-risk
individuals.
16
Risk factors
No Explication
40
54
40
60
Netherlands 78-85
46
44
10
43
50
Finland 72-92
24
76
35
60
35
55
10
38
52
10
40
55
47
44
23
53
24
36
55
0%
50%
100%
Fig. 1 Percent decrease in the number of deaths from coronary heart disease attributed to changes
in treatment and risk factors in different populations. (Adapted from Di Chiara and Vanuzzo [13])
The WHO has encouraged all countries to unite around this banner of cardiovascular disease prevention, proposing an alliance between the United Nations,
governments, civil society, and private sectors.
The goal of the WHO is to promote a collaborative effort to change the serious
epidemiological reality of CVD and the future prospects that have been projected
for the next 30 years [15, 16].
17
Targets from the Letter from Rio for the Prevention and Control of NCDs
25 % reduction in mortality rates from NCDs;
10 % reduction in the prevalence of physical inactivity among adults;
25 % reduction in the prevalence of hypertension (dened as a systolic
blood pressure 140 mmHg and a diastolic pressure 90 mmHg);
Reduction in the average intake of salt in the adult population to 5 g/day
(2000 mg sodium);
30 % reduction in the prevalence of tobacco use;
15 % reduction in the intake of saturated fatty acids to achieve the recommended level of <10 % of the daily fat requirements;
Reduction in the prevalence of obesity;
10 % reduction in excessive alcohol consumption;
20 % reduction in hypercholesterolemia;
50 % of eligible individuals should receive counseling and drug therapy to
prevent heart attacks and strokes;
Make available essential technologies and drugs, including generics, to 80 %
of the population suffering from NCDs in both the public and private sectors.
18
Conclusion
The recognition that CVD is responsible for 30 % of all deaths worldwide, together
with the alarming projections for the coming years, indicate that CVD should be
the target of actions against it that involve governments, trade associations, and
civil society.
The identication of the main factors responsible for the occurrence of CVD
and the signicant technological and scientic advancements in the diagnostic and
therapeutic arsenal against NCDs have created valuable tools for intervention in this
context. An analysis of the results of cardiovascular prevention programs implemented in some developed countries, using the triad of reduction of cardiovascular
risk factors, early diagnosis, and proper treatment, has shown signicant reductions
in CVD mortality and has indicated the paths to be followed in the future.
References
1. WHO Statistical Information Center. World Health Statistics 2009 En-WHS 2009.
2. Buttler D. Un targets top killers. Nature. 2011;477(7364):2601.
3. Beaglehole R. International trends in coronary heart disease mortality and incidence rates.
J Cariovasc Risk. 1999;6(2):638.
4. Beaglehole R, Bonita R. Global public health: a score-card. Lancet. 2008;372(9654):
198896.
5. World Health Organization, World Heart Federation, World Stroke Organization. Global atlas
on cardio-vascular disease prevention and control: policies, strategies, and interventions. 2011.
http://www.who.int/cardiovascular_dis-eases/publications/atlas_cvd/en/.
6. Dawber TR, Meadors GF, Moore Jr FE. Epidemiological approaches to heart disease: The
Framingham Study. Am J Public Health. 1951;41(3):27981.
7. Capewell S, Morrison CE, McMurray JJ. Contribution of modern cardiovascular treatment
and risk fac-tor changes to the decline in coronary heart disease mortality in Scotland between
1975 and 1994. Heart. 1999;81(4):3806.
8. Laatikainen T, Critchley J, Vartiainen E, Salomaa V, Ketonen M, Capewell S. Explaining the
decline in coronary heart disease mortality in Finland between 1982 and 1997. Am J Epidemiol.
2005;162(8):76473.
9. Thirty-ve-year trends in cardiovascular risk factors in Finland. Int J Epidemiol. 2010;
39(2):50418.
10. Vigitel Brasil 2012: vigilncia de fatores de risco e proteo para doenas crnicas por
inqurito telefni-co/Ministrio da Sade, Secretaria de Vigilncia em Sade, Departamento
de Vigilncia de Doenas e AgravosnoTransmissveis e Promoo de Sade. Braslia:
Ministrio da Sade, 2013.
11. Brasil. Ministrio da Sade. Secretaria de Vigilncia em Sade. Departamento de Anlise de
Situao de Sade. Plano de aes estratgicas para o enfrentamento das doenas crnicas no
transmissveis (DCNT) no Brasil 2011-2022/Ministrio da Sade. Secretaria de Vigilncia em
Sade.
12. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, et al. European Guidelines
on cardio-vascular disease prevention in clinical practice (version 2012). The Fifth Joint Task
Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease
Prevention in Clinical Practice (constituted by representatives of nine societies and by invited
experts). Eur Heart J. 2012;33(13):1635701.
19
13. Di Chiara A, Vanuzzo D. Does surveillance impact on cardiovascular prevention? Eur Heart
J. 2009;30:10279.
14. Ford ES, Ajani UA, Croft JB, Critchley JA, Labarthe DR, Kottke TE, et al. Explaining the
decrease in U.S. deaths from coronary disease, 19802000. Explaining the decrease in U.S.
deaths from coronary disease, 19802000. N Engl J Med. 2007;356(23):238898.
15. World Health Organization. Revised [third] WHO discussion paper on the development of a
comprehensive global monitoring framework, including indicators, and a set of voluntary
global targets for the prevention and control of NCDs. July 2012. http://www.who.int/nmh/
events/2012/ncd_discussion_paper/en/index.html.
16. World Health Organization. 65th World Health Assembly document A65/54: Second report of
Committee A. 25 May 2012. http://apps.who.int/gb/ebwha/pdf_les/WHA65/A65_54-en.pdf.
17. Andrade JP, Arnett DK, Pinto F, Pieiro D, Smith Jr SC, Mattos LAP, et al. Sociedade Brasileira
de Cardi-ologia Carta do Rio de Janeiro. Arq Bras Cardiol. 2013;100(1):35.
18. Simo AF, Prcoma DB, Andrade JP, Correa Filho H, Saraiva JFK, Oliveira GMM, et al.
Sociedade Brasile-ira de Cardiologia. I Diretriz Brasileira de Preveno Cardiovascular. Arq
Bras Cardiol 2013:101(6 Suppl 2):163.
21
22
A. Barekatain et al.
23
risk. A statistically signicant reduction of 2530 % was achieved in the composite risk score for cardiovascular disease as a result of signicant declines in
blood pressure, smoking, and cholesterol levels [9].
In the Stanford Five-City Project, a reduction in cholesterol level (about 2 %),
blood pressure (about 4 %), and smoking rate (13 %) was achieved in a 5-year,
low-cost, comprehensive educational and organizational programs by utilizing
about 26 h of exposure to multichannel and multifactor education. These risk
factor changes resulted in important decreases in composite total mortality risk
scores (15 %) and coronary heart disease risk scores (16 %) [10].
The North Karelia project offers a powerful lesson in successful populationbased interventions. This project was launched in 1972 to lower CVD rates by
improving the three cardinal risk factors for CHD: smoking, total cholesterol,
and blood pressure. Information was obtained about socioeconomic status, medical history, smoking, diet, alcohol consumption, physical activity, as well as
height, weight, skinfold thicknesses, blood pressure, and serum cholesterol.
Practical means were developed to modify risk factors by mass media, by training volunteers and community leaders, and through environmental changes such
as smoking restrictions, use of low-fat dairy and meat products. These interventions resulted in reduced rates of smoking, high total cholesterol and high blood
pressure. As a result, the CHD mortality rate among males aged 3564 years in
North Karelia decreased by 2.9 % per year between 1969 and 1978, signicantly
more than the national mortality rate (1.0 % per year) [11]. These experiences
suggest that population-based approaches to reduce risk factors could be effective
even in the absence of extensive medical treatments.
24
A. Barekatain et al.
Additional evidence supporting the need for primordial and primary prevention
beginning early in life comes from epidemiological studies indicating that major
risk factors for CVD in adulthood, including cigarette smoking, dyslipidemia, elevated blood pressure, physical inactivity, and obesity, are prevalent in childhood and
adolescence [15, 16], and are potentially modiable [17, 18]. Furthermore, noninvasive imaging studies demonstrated that adverse levels of major risk factors for CVD
measured in childhood and adolescence are associated with a signicant subclinical
atherosclerosis [19]. Risk factor exposures in 12- to 18-year-old adolescents predict
increased carotid intima-media thickness in adulthood independently of the risk factors for CVD present in adulthood [20]. Children with type 2 diabetes mellitus have
signicantly greater carotid intima-media thickness and stiffer carotid arteries than
their healthy counterparts [21]. Moreover, a combined data analysis from 4 cohorts
comprising 4380 patients showed that risk factors from 9 years of age were predictive
of carotid intima-media thickness in adulthood [22].
The efcacy and safety of modifying major CVD risk factors in early life with
therapeutic lifestyle change and pharmacologic interventions have also been demonstrated. Lowering dietary intake of total fat, saturated fat, and cholesterol in prepubertal boys and girls aged 810 years resulted in signicant reduction in low-density
lipoprotein cholesterol levels [23]. Other studies have shown that 2 years of pravastatin therapy induced a signicant regression of carotid atherosclerosis in children
with familial hypercholesterolemia, with no adverse effects on growth, sexual maturation, hormone levels, or liver or muscle tissue [24]. School-based prevention interventions, including nutrition and physical activity components, led to signicant decrease
in weight and blood pressures, particularly among girls [25]. Finally, favorable risk
factor levels in middle age are associated with a lower lifetime risk for CVD mortality,
increased survival, and improved quality of life. Framingham Heart Study participants
who were free of CVD at 50 years of age had very low lifetime risk for CVD and
markedly longer survival [26]. Collectively, these results should promote efforts
aimed at preventing development of risk factors in young individuals.
25
interventions that were less than three times a countrys growth national income
(GNI) per capita [27]. The strategies reviewed below are generally acceptable in all
developing regions, particularly since many are cost- saving interventions.
Cardiovascular disease burden can be lowered through both population-based as
well as individual-based interventions. When high-income countries brought CVD
under control, they used these preventive approaches in combination. Declines in CVD
mortality have run in parallel with decades of decreasing consumption of animal fat,
decreasing tobacco consumption, and growing community awareness about CVD
risk factors and heart health consciousness. In addition, medical and surgical treatments have improved in efcacy. These range from pharmaceuticals that lower
blood pressure and cholesterol to surgical interventions. Most estimates of the
effects of these interventions conclude that half of the declining CVD mortality is
due to community-based prevention and half to treatment [8, 28].
The focus of population-based primordial and primary prevention is life style
modication including tobacco cessation, physical activity, diet, and obesity. These
interventions have been found to be cost effective in all regions of the world [29].
Educational programs should be implemented to raise awareness of CVD in the
society and promote the important need for behavioral and life style modications
starting at early ages.
Smoking cessation is the most cost-effective intervention for prevention of cardiovascular disease [27]. There are more than one billion smokers worldwide, 80 % of
whom reside in developing countries. Current smoking increases the risk of acute
MI with an odds ratio (OR) of 2.95. The OR associated with former smoking falls
to 1.87 within 3 years of quitting [30]. Strategies should include interventions
to both quit smoking and prevent its initiation. Other public measures that are
non-price-related, such as restrictions on smoking in public places, public health
education, and advertising bans would also be highly cost-effective.
The centerpiece of a healthy lifestyle is a diet and physical activity pattern that
follows the evidence-based recommendations. The protective effects of regular
exercise and cardiorespiratory and general physical tness have been very well
documented. Similarly, numerous clinical trials have demonstrated the benets
of reduced sodium intake and the benets of healthy eating patterns such as the
Mediterranean-style diet [31].
Governmental policies on food production, processing, and marketing should be
focused on reducing salt and fat content of processed foods as well as nutrition and
cooking at schools. Urban planning policies such as city design that encourages
physical interaction with the environment should be implemented to promote physical activity. Educational programs including media projects should be set up to raise
the awareness of the society to the following subjects: risks of smoking, the causes
of high blood pressure and the benets of control strategies, the causes of hyperlipidaemia and dietary recommendations, the dangers of obesity and warnings about
diabetes, the importance of good nutrition and physical exercise in weight control.
As risk factors accumulate and become more prominent in the population, CVD
prevention must shift to be more individualized and medical. This entails delivering
26
A. Barekatain et al.
proven and affordable preventive care to those at high risk of fatal or catastrophic
events. As in high-income countries, an effective and affordable primary health care
system for targeted screening for the identication of individuals at very high risk of
a fatal or disabling cardiovascular event and the provision of cost-effective, evidencebased preventive care is essential for the prevention and control of CVD. Primary
health care services should be organized such that core interventions can be delivered
by non-physician health care workers, ideally working under the supervision of a
physician, to enable the most efcient use of scarce resources. Various risk prediction
tools, such as the Framingham risk prediction tool, have been developed to calculate
cardiovascular risk and tailor clinical management according to the level of risk. The
most appropriate screening tools for use in resource-poor settings should involve simple methods focused on medical history and physical measurements such as blood
pressure and body mass, without reliance on laboratory test results. Cost effectiveness
generally increases at higher risk thresholds for treatment.
Treatment regimens should be simple to administer and not require extensive
titration. In this regard, the concept of a CVD polypill for disease prevention is
attractive where combination of aspirin, a statin, and 1 or more blood pressurelowering drugs at low dose is cost-effective and well tolerated. This has been shown
in studies to be associated with a 20 % reduction in the blood cholesterol level, 28 %
reduction in difference in BP between 115 and current and 18 % reduction absolute
risk for CVD [32]. It is estimated that a 5060 % reduction in cardiovascular disease
would occur if all patients with a 10-year risk greater than 5 % were treated with
these regimens of four drugs, which are currently available and widely assessed in
clinical trials with event reductions. The incremental cost-effectiveness ratios (ICER)
remain at $3001300/QALY (quality adjusted life year) gained in all the regions
studied [29]. Other cost-effective strategies could include nicotine-replacement
therapy and low-dose, xed-combination blood pressure-lowering therapy for those
with moderate to severe hypertension. Use of these regimens would range between
$310 and 1220 per QALY gained across the developing regions, depending on the
risk level of those taking them for primary prevention [29].
Therefore, a concerted public health response must integrate population-based
prevention strategies and cost-effective clinical care, since the health systems of
developing countries can not afford the demands of technology-intensive treatments.
The population approach is more rewarding and sustainable in the medium and long
term, since even small reductions in each risk factor can add up to huge reductions in
the rate of cardiovascular events. And if healthy behavior is established as a desirable
norm in a society, it can have a multigenerational effect.
Conclusion
Cardiovascular disease remains the most common cause of death in all countries,
excluding sub-Saharan Africa, where it is the second. A high proportion of CVD
burden occurs earlier among working-age adults in developing countries and has a
27
huge social and economic impact in such countries. Therefore, prevention of premature
deaths due to CVD and reduction of related-health care costs should be the priority
of health policy makers. The risk factors for CVD are global and are becoming more
prevalent among children and adolescents. Prevention efforts started early in life may
have a lasting impact later or even from one generation to the next.
Reductions in CVD mortality in the United States and several other developed
countries are believed to be the result of both improvements in risk factorsprimarily
smoking, total cholesterol, and blood pressureand introduction of pharmacologic
treatments. Because the risk factors are the same, we can assume the same reductions in developing countries. The focus of population-based prevention should be
life style modication including tobacco cessation, physical activity, diet, and obesity. These interventions are cost effective in all regions of the world. Pharmacological
interventions offer further reductions in CVD mortality. Effective and inexpensive
treatments are available in developing countries but often underused despite the
proven benets. This problem is partly due to a belief that the treatments are too
expensive. Yet we have shown above that there are prevention regimens which are
cost-effective across the developing regions.
In sum, primordial and primary prevention of cardiovascular disease should be
the major goal of medicine. A multilevel approach that integrates policy actions,
health education, and efcient health care delivery systems should be the mission of
public health.
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1. Gaziano TA, Bitton A, et al. Growing epidemic of coronary heart disease in low- and middleincome countries. Curr Probl Cardiol. 2010;35(2):72115.
2. Gaziano TA. Reducing the growing burden of cardiovascular disease in the developing world.
Health Aff (Millwood). 2007;26(1):1324.
3. Kannel WB, Dawber TR, et al. Factors of risk in the development of coronary heart disease
six year follow-up experience. The Framingham Study. Ann Intern Med. 1961;55:3350.
4. American Heart Association. Heart Disease and Stroke Statistics2004 Update. http://www.
americanheart.org/downloadable/heart/1072969766940HSStats2004Update.pdf. Accessed 1
Dec 2004.
5. Yusuf S, Hawken S, et al. Effect of potentially modiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): casecontrol study. Lancet.
2004;364(9438):93752.
6. Joshi R, Jan S, Wu Y, et al. Global inequalities in access to cardiovascular health care: our
greatest challenge. J Am Coll Cardiol. 2008;52(23):181725.
7. Ford ES, Capewell S. Proportion of the decline in cardiovascular mortality disease due to
prevention versus treatment: public health versus clinical care. Annu Rev Public Health.
2011;32:522.
8. Ford ES, Ajani UA, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980
2000. N Engl J Med. 2007;356(23):238898.
9. Fortmann SP, Williams PT, et al. Effect of health education on dietary behavior: the Stanford
Three Community Study. Am J Clin Nutr. 1981;34(10):20308.
10. Fortmann SP, Taylor CB, et al. Effect of community health education on plasma cholesterol
levels and diet: the Stanford Five-City Project. Am J Epidemiol. 1993;137(10):103955.
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11. Puska P, Nissinen A, et al. The community-based strategy to prevent coronary heart disease:
conclusions from the ten years of the North Karelia project. Annu Rev Public Health.
1985;6:14793.
12. Barker DJ. Sir Richard Doll Lecture. Developmental origins of chronic disease. Public Health.
2012;126(3):1859.
13. Forse T, Eriksson JG, et al. Mothers weight in pregnancy and coronary heart disease in a
cohort of Finnish men: follow up study. BMJ. 1997;315:83740.
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Diabet Med. 1998;15:220e7.
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18. Foster GD, Linder B, et al. A school-based intervention for diabetes risk reduction. N Engl J
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19. Li S, Chen W, et al. Childhood cardiovascular risk factors and carotid vascular changes in
adulthood: the Bogalusa Heart Study. JAMA. 2003;290:22716.
20. McGill Jr HC, McMahan CA, et al. Effects of nonlipid risk factors on atherosclerosis in youth
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Introduction
Estimation of individual cardiovascular risk is essential to guide patient counseling
as well as for patients adherence to physicians recommendations. A particular difculty regarding patients adherence is that risk is, most of the time, conferred by
factors which by themselves do not cause symptoms. Further, risk modication
involves lifestyle changes or the use of medications. Neither are easily accepted
unless patients thoroughly understand the magnitude and long-term meaning of
risk stratication. Several attempts have been made to develop algorithms that
allow risk assessment. In this chapter we present a brief summary of such scores
focusing specically on practical issues.
Framingham Risk Score (FRS) [1] is a classic tool for CHD risk evaluation
also used to guide treatment. FRS classies patients into three categories over a
10 years period. High risk = >20 % + 2 or more risk factors (RF); Moderate/high
risk = between 10 and 20 % + 2 or more RF; Moderate risk = <10 % + 2 or more
RF. Low risk = 0 or 1 RF. RF include cigarette smoking, hypertension (blood pressure 140/90 mmHg or patients on antihypertensive medication), low high-density lipoprotein cholesterol (<40 mg/dL), family history of premature CHD (CHD
29
30
500
400
300
204
200
143
103
72
100
36
80
40
32
17
Overall
One
Two
None
Number of factors
Women
Three
Men
Fig. 1 Risk of CHD according to elevated blood pressure (BP), elevated cholesterol, and left
ventricular hypertrophy: Framingham cohort 6-year follow-up. Elevated BP = 160/95; elevated
cholesterol = 260 mg/dl (DAgostinho et al. [16] with permission)
in male rst-degree relative <55 years of age; CHD in female rst-degree relative
<65 years of age), and age (men 45 years; women 55 years). Figure 1 illustrates the cumulative nature of RF.
FRS has limitations since it does not include family history, activity level or
tness, obesity, the presence and magnitude of RF overtime. Moreover, low-risk
individuals were overestimated and high-risk underestimated by algorithms from
FRS over a xed time of 10 years. Ten years is indeed too short a period for a life
long disease as atherosclerosis.
Ridker et al. [2] developed the Reynolds Risk Score (RRS), especially for women
based on participants of the Womens Heart Study. To FRS they added novel
biomarkers: hs-CRP and premature familiar history (<60 years old). This score prediction reclassied 4050 % of women at intermediate risk based on the Adult Treatment
Panel III, into higher or lower-risk categories [2]. An 18 % improvement in risk prediction also was demonstrated in male population from Physicians Health Study II [3].
Despite these scores a recent review showed that for practicing clinicians risk
assessment by calculators is still inconsistent.
Clinical History
Detailed clinical history is essential. Information regarding diet, exercise, previous
cardiac events, smoking, marital status, stress, sleep apnea and general complaints
are decisive. In a multinational study [4] of 14,000 patients with suspected of CAD
subjected to coronary computed tomographic angiography, typical angina was
31
Physical Exam
Hypertension is one of the major modiable RF for CVD. In the Prospective Studies
Trialists Collaboration [10] an increment of 20 mmHg in SBP or 10 mmHg in DBP,
in middle-aged and elderly persons, increased by twofold the risk of CHD and
stroke mortality [10]. Children with prehypertension associated to overweight, obesity and positive family history had increased risk by about twofold 11]. In the
CARDIA study [12], FRS predicted hypertension risk in young individuals.
Adiposity measures and ethnicity were related in the prediction of hypertension risk
observed in the TOPS study [11]. Although African-Americans showed no inuence of adiposity in their hypertension risk, among Caucasian greater adiposity in
the neck and waist led to increased risk in 30 % to 56 %, respectively. Even in lean
or overweighted elderly, increased abdominal adiposity was strongly associated to
higher hypertension risk when compared with control without central obesity [13].
In the Strong Heart Study [14], in American Indians, the positive association
among age, obesity and ethnicity to hypertension development was conrmed. In that
study, microalbuminuria and macroalbuminuria elevated the risk to hypertension in
3.47 and 1.72 times, respectively; therefore albuminuria was considered a relevant
risk factor for hypertension.
32
Serum Biomarkers
Lipids-high LDL and triglycerides and low HDL are traditional RF [17]. We also
demonstrated that an elevated triglyderides/HDL ratio is associated with premature
CAD [17]. However, 1520 % of patients with acute cardiac events had no major
RFs. Hence, more than 20 new biomarkers have been proposed. Among those,
inflammatory markers such as high-sensitivity C-Reactive Protein (hsCRP), have
been especially considered in acute and chronic situations as well. The role of
hsCRP was emphasized in The JUPITER study [18] which included individuals
with low to normal LDL-C who were at increased CV risk as identied by elevated
hsCRP above 2 mg/L and who did not require statin treatment based on current
guidelines. In the group treated with Rosuvastatin, 20 mg/day, 44 % reduction in the
primary endpoint of major cardiovascular events and a 20 % in total mortality in the
statins group versus placebo were noted (p < 0.00001).
Yet, hsCRP has not been adopted uniformly in guidelines. That is due to the fact
that its power to predict absolute risk is low and it is a nonspecic marker, being
extremely high in other systemic infections or vessel injuries due to trauma.
Increments in several cytokines plasma concentrations, such as Interleukin-6 (IL-6)
have been correlated with plaque instabilization [19]. The TNF and CD40/ families,
are linked to immunemodulation and trombogenicity. Although their participation in
plaque instability is indisputable, lack of specicity makes them inappropriate for routine use in clinical practice. The same occurs with endothelial markers, the family of
ICAM (inter-cellular adhesion molecule) and VCAM (vascular cell adhesion molecule), E-selectin, PAI-I (plasminogen activator inhibitor) and others [20].
Results of the SIESTA study [21] suggest that the association of NT-proBNP and
brinogen could be a marker to predict acute events. Fibrinogen besides hsCRP,
higher plasma PAI-1 and serum aldosterone had also a strong correlation in MS
development [15].
33
Imaging Methods
Identication of incipient disease before clinical manifestations is a crucial step in
prevention. Since atherosclerosis has a long course before causing vessel obstruction,
identifying these early stages offers opportunity to halt progression. It is germane to
consider that RFs are dangerous primarily because they induce vascular damage, not
by themselves. The one exception is diabetes, which is a disease in its own.
34
Fig. 2 Pathways by which emotional stresses can lead to atherosclerosis development (da Luz
et al. [26] with permission)
Since risk assessment through RF is inaccurate the next step is the use of
noninvasive image methods. Despite access restriction and doubts in relation to
radiation and cancer, the benets can be justied by reclassication of low and
intermediate risk individuals and better individual therapeutic strategies. Moreover
an objective detection of disease makes acceptance of lifestyle behavior changes
and adherence to long-term treatment more appealing.
35
Fig. 3 Comparison of recommendations for statin therapy according to the NCEP and the
SHAPE. SHAPE incorporates CAC and therefore increases the number of individuals who should
receive statins (Berman et al., AHA 2007, with permission)
36
In the EISNER Trial [32], Rozanski et al. suggested that CAC scanning improved
RFs at 4 years prole due to greater reduction in SBP, LDL-C, waist circumference
and weight. Moreover, the degree of RF modication increased as CAC score
increased [30]. It is worth remembering that recommendations to repeat testing
are for 0 score, each 5 years and for any other score, between 3 and 5 years.
Stress Tests
EKG, echocardiogram and radioisotopes, under physical or pharmacological
stresses, are powerful tools to detect and quantify ischemia, myocardial viability or
brosis; all factors profoundly inuence outcomes and therapeutic decisions. There
are differences in sensitivity and accuracy among the tests; hence, their use should
be individualized according to local expertises and patient characteristics, taking
into special consideration the principles of the Bayes theorem. Both short and long
term prognosis can be predicted with considerable accuracy with these tests.
Global Risk
Framingham Risk Score [1] for CHD, which included coronary death, myocardial
infarction, coronary insufciency and angina is validated in US and with recalibrations were exported for different regions worldwide. However, to predict a global
risk for CVD, it was necessary to add the risk-estimate of cerebrovascular events,
namely ischemic stroke, hemorrhagic stroke, and transient ischemic attack, peripheral artery disease, and heart failure. A new algorithm (Framingham Website) based
in FRS produces an absolute risk to global CVD (i.e., idea of unity risk to the individual) and could estimate the risk of each component of CVD. The model included
37
Fig. 4 Suggested principal items to be considered in risk assessment. In a particular patient not all
items need to be fullled. For instance, non-invasive testing may not be necessary in a patient with
typical angina, multiple risk factors and advanced age. Straight angiography may be preferable
Conclusions
We can summarize the ndings above as follows: (1) Risk is incremental in an
exponential manner according to the number of RF; (2) Men and women have
distinct clinical proles; (3) Increased risk may be identied at early age (family
history, dyslipidemia); (4) Non-invasive detection of premature atherosclerosis
is an incentive to implement preventive measures in asymptomatic individuals;
(5) Global risk assessment is the desirable strategy; (6) Risk assessment must be
individualized.
38
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Framingham Heart Study. Circulation. 2008;117:74353.
2. Ridker PM, et al. Development and validation of improved algorithms for the assessment of
global cardiovascular risk in women: the Reynolds Risk Score. JAMA. 2007;297:6119.
3. Ridker PM, et al. C-reactive protein and parental history improve global cardiovascular risk
prediction: the Reynolds Risk Score for men. Circulation. 2008;118:224351.
4. Cheng VY, et al. Performance of the traditional age, sex, and angina typicality-based approach
for estimating pretest probability of angiographically signicant coronary artery disease in
patients undergoing coronary computed tomographic angiography. Results from the multinational coronary CT angiography evaluation for clinical outcomes: an International Multicenter
Registry (CONFIRM). Circulation. 2011;124:242332.
5. Rissanen AM, et al. Familial occurrence of coronary heart disease: effect of age at diagnosis.
Am J Cardiol. 1979;44:606.
6. Scheuner MT, et al. The general cardiovascular risk prole identies advanced coronary artery
calcium and is improved by family history. The Multi-Ethnic Study of Atherosclerosis. Circ
Cardiovasc Genet. 2010;3:97105.
7. Dekker LRC, et al. Familial sudden death is an important risk factor for primary ventricular
brillation: a casecontrol study in acute myocardial infarction patients. Circulation. 2006;
114:11405.
8. Imes CC, et al. Family history of cardiovascular disease, perceived cardiovascular disease risk,
and health-related behavior: a review of the literature. J Cardiovasc Nurs. 2014;29:10829.
9. Claassen L, et al. Being at risk for cardiovascular disease: perceptions and preventive behavior
in people with and without a known genetic predisposition. Psychol Health Med. 2012;
17:51121.
10. Turnbull F, et al. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed
overviews of randomized trials (Blood Pressure Lowering Treatment Trialists Collaboration).
Arch Intern Med. 2005;165:14109.
11. McAuley PA, et al. General and regional adiposity and hypertension risk in a multi-ethnic
community cohort of men and women: The Take off the Pressure Study (TOPS). Circulation.
2012;125:AP385.
12. Carson AP, et al. Evaluating hypertension risk prediction models in young adults: the Coronary
Artery Risk Development in Young Adults (CARDIA) study. Circulation. 2012;125, AMP049.
13. Mello RB, et al. Central obesity is a risk factor for hypertension independent of body mass
index in elderly individuals: results of a population-based study. Circulation. 2011;124,
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14. Wang W, et al. A longitudinal study of hypertension risk factors and their relation to cardiovascular disease. The Strong Heart Study. Hypertension. 2006;47:4039.
15. Ingelsson E, et al. Multimarker approach to evaluate the incidence of the metabolic syndrome
and longitudinal changes in metabolic risk factors. The Framingham Offspring Study.
Circulation. 2007;116:98492.
39
16. DAgostinho RB, et al. Cardiovascular disease risk assessment: insights from Framingham.
Glob Heart. 2013;8:1123.
17. Da Luz PL, et al. High ratio of triglycerides to HDL-cholesterol predicts extensive coronary
disease. Clinics. 2008;64:42732.
18. Ridker PM, et al. Rosuvastatin to prevent vascular events in patients with elevated C-reactive
protein JUPITER study group. N Engl J Med. 2008;359:2195207.
19. Gabay C, et al. Acute-phase proteins and other systemic responses to inammation. N Engl J
Med. 1999;340:44854.
20. Uydu HA, et al. Comparison of inammatory biomarkers for detection of coronary stenosis in
patients with stable coronary artery disease. Eur Rev Med Pharmacol Sci. 2013;17:1128.
21. Sauter C, et al. The assessment of vigilance: normative data on the SIESTA sustained attention
test. Sleep Med. 2013;14:5428.
22. Sheperd J, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;
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prediction of cardiovascular events after IMPROVE? J Am Coll Cardiol. 2012;16:15002.
30. Erbel R, et al. Coronary risk stratication, discrimination, and reclassication improvement
based on quantication of subclinical coronary atherosclerosis. The Heinz Nixdorf Recall
Study. J Am Coll Cardiol. 2010;56:1397406.
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of the Screening for Heart Attack Prevention and Education (SHAPE) task force report. Am J
Cardiol. 2006;98:2H15.
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downstream testing: The EISNER (Early Identication of Subclinical Atherosclerosis by
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57:162232.
41
42
A.C. Achutti
one can enjoy what was saved today. Education provides access to information and
enables the formation of a positive attitude, and the prevailing culture or dominant
collective behavior consolidate and also facilitate the adoption of healthy habits or
behavioral changes when undesirable deviations occur.
The goal of achieving a world free of tobacco and alcohol should be considered a
direction to follow and a slogan to promote, but it cannot be considered an achievable goal in the short term, as there are so many other evils throughout the world,
such as social inequalities, frustration, violence, and prot-related interests involving
a captive clientele (dependent).
Other abusive behaviors have factors in common with and should also be considered as additional risks for the phenomenon of dependence, including overeating to
the point of obesity, sexual obsession, abuse of other drugs, gambling, violence,
whether practiced or assisted, and disregard for the environment.
The distance from the goal or the difculties of the journey cannot be a disincentive to a professional approach to every patient treated.
As the eminent cardiologist and epidemiologist Geoffrey Rose said, physicians
are not responsible for the choices that society makes, but need to be aware of their
responsibility to denounce, and of their role as societys counselors and mentors.
The World Health Organization, academia, governments and scientic societies
have shown concern regarding this subject by producing extensive literature that
has accumulated over the course of half a century. The majority of this information
is available and accessible from several reliable sources, including the Internet, with
periodic updates [16]. Currently, there is little point discussing what is already
consolidated; it is more important to try to understand why the abuse is still frequent
and how to confront it.
Among the national bibliography, two topical references are recommended:
The Brazilian Cardiology Society Smoking Guidelines (Diretrizes da Sociedade
Brasileira de Cardiologia sobre Tabagismo) (now in press but will soon be available
through the SBC portal) and the chapters on smoking and problems concerning
alcohol intake in the book titled Ambulatory Medicine: evidence-based primary
care conduct (Medicina Ambulatorial: condutas de ateno primria baseadas em
evidncias). The authors of the latter have proposed to maintain updated references
available on the Internet. Among the international literature, reports from the World
Health Organization, World Heart Federation, American Heart Association, US
Centers for Disease Control and Prevention, and European Society of Cardiology
contain a great deal of information regarding the epidemiology, physiopathology
and treatment of these conditions, as previously discussed.
Cardiology societies joined the movement to control substances after some delay
[7] and today, no longer accept simply promoting the treatment of currently existing
injuries and their complications. The cardiologists professional prestige makes a
difference in terms of mobilizing politicians and governments to adopt appropriate
public health policies. In this sense, with respect to tobacco control, our country and
the SBC have been exemplary.
It is important to stress the ability of the physician to inuence their patients.
If cardiologists were to give the removal of preventable risk factors the same dedication
43
they give to the prescription of treatments for hypertension and dyslipidemia or to indicating invasive tests or cardiovascular surgery, the success rate would be even greater.
Expected Behavior of Health Professionals with Respect to Removable Risk
Factors
Not to drink in excess and not to smoke;
If smoking or using alcohol, not doing so in health care settings and taking into
account the responsibilities of a social model;
To ask for an anamnesis of current and past exposure to alcohol and active and
passive smoking and its intensity and duration, among other risk factors;
To record the responses on the medical record and give priority to high-risk
patients;
To determine possible complications related to these risk factors, taking advantage
of the opportunity to express professional concern regarding the consequences
inherent in abuse;
To recommend smoking and alcohol cessation as well as necessary measures to
prevent consequential damage via passive exposure of the individual and that of
bystanders;
To provide necessary support to the patient by monitoring the abandonment process using counseling strategies and techniques;
To keep themselves updated on existing therapeutic resources, prescribing these
therapies, or referring the patient to skilled professionals and services;
To cooperate with community activities and control campaigns.
With Regard to Both Risk Factors, Particular Attention Should Be Paid
to the Following High-Risk Groups
Children and the young, due to organic fragility and increased susceptibility to
injury and dependence;
Adolescents, due to the psychological characteristics of rebellion, experimentation irrespective of risk, and frequent anxiety in the discovery of new stages of
adulthood, leading them to pursue reward;
Pregnant women, due to the increased risk of damage to fetal development;
Women using birth control with a potential risk of thromboembolism;
Patients exposed to other risk factors;
Patients with heart disease or patients with other chronic diseases;
Patients belonging to socially marginalized groups;
Patients with other psychological problems or mental illness (both smoking and
alcoholism may be classied as mental disorders).
44
A.C. Achutti
older use alcohol at least once a year. This abuse is excessive in 28 % of cases,
harmful in 3 % of cases, and dependency occurs in 9 % of cases [8].
According to the WHO criteria, for men, an intake of over 21 units of 10 g
of alcohol per week is considered excessive. For women, this limit is reduced to
14 units.
A glass of wine on average is equivalent to one unit, spirits are twice that amount,
and beer (a 350 mL can) is approximately one and a half units.
It should also be noted that approximately 3.8 % of all deaths from all causes are
associated with alcohol use, as well as 4.5 % of the disability adjusted life years
(DALYS) [8].
Alcohol and tobacco abuse may be considered as indicators of ego fragility
and a chronic stress risk, which is also involved in the genesis of cardiovascular
diseases. It is possible, however, that together with biochemical mechanisms, the
moderate use of alcoholic beverages can explain the lower cardiovascular risk
observed in relation to abstinent individuals and those who drink to excess [911].
Brazil has one of the highest abusive alcohol consumption rates. The consequences can be easily observed when monitoring the news of accidents and trafc
fatalities. Young drivers under the inuence of alcohol are involved in the majority
of these deaths and in the demand for traumatology treatment. The depressant and
euphoric effects of alcohol reduce the awareness of immediate risk; therefore, driving under such conditions is equivalent to risking sudden death. Individuals who do
not take immediate risk into account do not have the sensitivity to prevent future
problems.
In addition to education and more restrictive legislation, control of advertising
and motorists conditions are essential for developing cultural awareness regarding
avoiding death or killing others due to external causes before we can move on to
other causal factors that promote cardiovascular diseases.
Cigarette consumption (the most frequent exposure method for burning tobacco)
is approximately 1200 units per year worldwide, per capita. It involves approximately 25 % of the adult population, half of whom are likely to die from problems
related to smoking and experience the loss of approximately 15 years of life. The
estimated worldwide mortality associated with smoking is six million and is just
over half a million by inhalation of passive smoke.
Brazil is a good example of the feasibility of smoking prevention. In the state of
Rio Grande do Sul, the countrys largest tobacco producer, the prevalence of smoking among men over 20 years old in the 1970s was higher than 60 %. Today, it has
dropped to less than half of that gure [12]. It takes time to have an effect on a
culture, but it is possible. The fact that our economic wealth was predicated on
something causing illness and death could have led to the guilt that gave rise to a
regional and then national awareness movement. Success was brought about initially via schoolchildren, with directed counter-propaganda, and then by a combination of organizations and activists and the law itself. The author of this article was
active at the time of these changes, both in the Department of Health and Environment
(Secretaria da Sade e do Meio Ambiente) and the Medical Association of Rio
Grande do Sul (Associao Mdica do Rio Grande do Sul). It was possible to wit-
45
ness the implementation of the rst Public Health Cardiovascular Disease Prevention
program in the country, and as a second step, it became evident that something had
to be done to control smoking as a major and preventable risk factor, despite going
against current economic state interests. One cannot fail to pay tribute to countryman Professor Mrio Rigatto (former president of the SBC) in this regard, who
recruited doctors sensitive to this subject throughout the country, as exemplied by
Professor Jos Rosemberg. Support from the WHO, PAHO, and the American
Cancer Society have been important to progress, and these initiatives have been able
to eliminate resistance and insensitivity, not only from the government but also from
scientic societies.
Astonishingly, people smoked during our conferences and the World Heart
Federation conferences and at the PAHO ofces and hospitals. A Smoke Free
Conference was declared, but the SBC General Assembly unanimously did not
adopt a declaratory motion to combat smoking until the year 2000.
To not focus solely on disease, death, and adverse outcomes, it is worth remembering the success achieved due to the joint effort of many people, typied by two
colleagues who have been fundamental to that success: Professor Antnio Pedro
Mirra of So Paulo, who has, from the beginning, advocated tobacco control within
the Brazilian Medical Association (Associao Mdica Brasileira), and Dra. Vera
Luiza da Costa e Silva, who, via the Ministry of Health, the National Cancer Institute
(Instituto Nacional do Cncer), and later, the WHO has been able to establish the
rst international treaty involving the production, processing, and trade of tobacco
products.
The nicotine in tobacco has an immediate stimulating and euphoric effect,
and alcohol has an opposite calming and depressing effect. It is likely that these
two characteristics, which to some extent are antagonistic, partially explain their
concomitant use in achieving a ne tuning of the mood.
Mass consumption and patronage have aroused many economic interests surrounding the production, processing, marketing, and commercialization of tobacco
products and alcoholic drinks.
The possibility of acquiring both alcohol and tobacco in a relatively free, culturally
accepted, and frequently glamorized manner is related to the extent of its use.
Governments have attempted to control use with tax increases in the commercialization of these products, which, however, has also made those governments dependent
on this new source of revenue.
Smokers inhale thousands of other substances when lighting a cigarette in addition to the nicotine that they crave, including carbon monoxide, which is mostly
responsible for damage to the endothelium. This is important in cardiovascular
disease. Bystander exposure to smoke (passive smoking) is also not negligible,
especially in indoor environments. Alcohol, in turn, also entails passive risk in the
form of trafc accidents and other types of violence.
Distortions resulting from misuse of the reward mechanism are frequent and not
only limited to the abuse of alcohol and nicotine. Reward can reinforce any behavior, and in general, this stimulus is accompanied by the pleasure of repetition or the
simple realization that the path was re-established (doing it again).
46
A.C. Achutti
47
they have been exposed. More details can be obtained by accessing the constantly
updated electronic addresses of the references.
A total of 4607 individuals aged 14 and older were interviewed in their homes in
the last phase of LENADs random probability sampling, which is representative of
the Brazilian population.
INPADs mission is to coordinate a set of actions of a preventive nature, including care, research, and community and public interventions, that will contribute to
the denition of policies concerning dependency control and the harmful use of
alcohol and other drugs in Brazil.
Regarding alcohol consumption, an increase was observed between 2006 and
2012, particularly in frequent drinkers (one or more times per week), from 45 to
54 %, especially among women (from 29 % in 2006 to 39 % in 2012). Two out of
10 drinkers do so in a harmful manner, as abusive or dependent drinkers.
Regarding smoking, the data indicate a reduction in prevalence of 20 % (from
19.3 to 15.6 %) between 2006 and 2012; the largest reduction was among adolescents (from 6.2 to 3.4 %). The study estimated the total number of smokers in the
country at 40 million, with 70 million passive smokers (taking into account an average of 4.5 people per smokers household).
The prevalence was reduced among men, but it is still higher than in women.
The southern region has the largest proportion of smokers, but there was a greater
decrease in prevalence in this region. Across the country, the average number of
cigarettes smoked per day by smokers increased from 12.9 to 14.1, likely due to the
effect of selection, with the overall decline in prevalence resulting from those who
smoke more and who have a greater degree of dependency remaining in the sample.
The number of former smokers is approximately 11.3 % of the population [20].
References
1. Achutti A, Lantieri CJ, Issa JS, Ismael SC, Alencar Filho AC. Diretriz da SBC Tabagismo.
No prelo. http://publicacoes.cardiol.br/consenso/.
2. Duncan BB, Schmidt MI, Giuliani ERJ, Duncan MS, Giugliani C. Medicina Ambulatorial:
condutas de ateno primria baseadas em evidncias. 4a edio. Captulo LX sobre tabagismo por Juliana DP dos Santos, Aloyzio Achutti e Paula Guths. Captulo LXI Problemas
relacionados ao consumo de lcool, por Mauro Soibelman, Thiago BM Rocha e Lisia von Die
men. Porto Alegre: Artmed, 2013.
3. Medicina Ambulatorial: http://www.grupoa.com.br/uploads/imagensExtra/legado/D/DUNCAN_
Bruce_B/Medicina_Ambulatorial_4Ed/Lib/hot/ref/05/Cap_60.pdf.
4. Medicina Ambulatorial: http://www.grupoa.com.br/uploads/imagensExtra/legado/D/DUNCAN_
Bruce_B/Medicina_Ambulatorial_4Ed/Lib/hot/ref/05/Cap_61.pdf.
5. WHO report on the global tobacco epidemic, 2013. http://www.who.int/tobacco/global_
report/2013/en/index.html.
6. WHO Global Status Report on Alcohol and Health 2011 http://www.who.int/substance_
abuse/publications/global_alcohol_report/en/index.html http://wwwwho.int/substance_abuse/
publications/global_alco hol_report/msbgsruproles.pdf.
7. Jabbour SK, Reddy S, Muna WFT, Achutti A. Cardio vascular disease and the global tobacco
epidemic: a wake-up call for cardiologists. Int J Cardiol. 2002;86(23):18592.
48
A.C. Achutti
Acronyms/Abbreviations
ACSM
AHA
BSC
CABG
CDC
CHD
CR
CVDs
DALYs
ESC
HF
LTPA
METs
MI
NCDs
NIH
PA
PCI
RC
USA
WHO
YLL
49
50
E. Rocha
Introduction
A sedentary behavior is one of the major risk factors for cardiovascular diseases
(CVDs). Regular physical activity (PA) and aerobic exercise training are related to a
reduced risk of fatal and non fatal cardiovascular events in healthy individuals, in high
risk individuals (subjects with hypertension, glucose intolerance/diabetes, dyslipidemia,
overweight/obesity), and cardiac patients. It is a very important non-pharmacological
tool for primary and secondary cardiovascular prevention [1]. Moreover, there is substantial evidence that physical inactivity is a major contributor to death and disability
from CVDs and other non-communicable diseases (NCDs) worldwide, identied by
the United Nations as threats to global health (diabetes, breast and colon cancer). This
modiable lifestyle has been identied as the fourth leading risk factor for global mortality, causing an estimated 3.2 million deaths globally, and the main cause for approximately 30 % of ischemic heart disease burden [2].
By the 1990s, health care agencies and organizations have issued position statements regarding benets and recommendations on PA for health (CDC, AHA, NIH,
Surgeon General, ACSM, WHO, ESC, BSC and other medical societies and national
healthcare authorities worldwide). Notwithstanding scientic knowledge outlining
the benets of exercise both for primary and secondary cardiovascular prevention,
the society and patients with known CVDs remain sedentary [3]. In view of the
prevalence and distribution, and health effects with cardiovascular and global
impact (mortality, YLLs and DALYs lost), physical inactivity should be addressed
as pandemic and a public health challenge [4]. Although the global ght against
CVDs has been very successful, due to the growing prevalence of metabolic disorders such as obesity and diabetes, poor exercise regimens, high fat and sugar diets,
alcohol and tobacco consumption, especially in the younger population, and the
ageing population, the incidence of atherosclerosis-related CVDs is expected to
increase in future. It means that CVDs should remain by far the leading cause of
death. It urges to take effective preventive interventions (healthful diet and PA) to
ght against the expected increase in CVDs, particularly coronary heart disease
(CHD) whose reduction was responsible for the largest increase in life expectancy
between 1970 and 2000 [5]. It has been estimated that elimination of physical
inactivity would increase the life expectancy of the worlds population by 0.68
(0.410.95) years [6].
Mechanisms
The evidence that a sedentary lifestyle leads to CHD, and particularly myocardial
infarction (MI) or sudden death, is based on observational studies in the general
population and in specic groups, on experimental studies that compare a sedentary
group with one doing more exercise. There is evidence that regular PA, together
with other risk reduction behaviors, can help prevent rst cardiac and stroke events,
51
reduces the risk of their recurrence and helps patients recover after MI, surgical
revascularization or coronary angioplasty (PCI). In relation to CHD, biological
mechanisms have been identied through which PA and exercise training may contribute to primary and secondary prevention: it maintains or increases myocardial
oxygen supply, decreases myocardial work and reduces cardiac work and oxygen
demand, increases myocardial function and electrical stability of myocardium by a
favorable modulation of autonomic balanceinduces ischemic pre-conditioning of
the myocardium, increasing their tolerance to more ischemic stress. The underlying
cardioprotective mechanisms involve changes in the coronary arteries, myocardial
heat shock proteins and cyclooxygenase-2 activity, endoplasmic reticulum stress
proteins, nitric oxide, sarcolemmal and/or mitochondrial adenosine triphosphate
(ATP)-sensitive potassium channels and myocardial antioxidant capacity, antioxidant enzymes, mitochondrial phenotype that protect against apoptotic stimuli [7].
At another level, PA has a positive effect on established risk factors for CVDs, leading
to improvements in blood pressure, glucose intolerance, diabetes, dyslipidemia, and
obesity. Specically, it helps to control body weight, prevents or delays the development of hypertension in normotensive subjects and reduces blood pressure in hypertensive patients, improves lipoprotein proleincreases HDL cholesterol levels,
improves carbohydrate metabolism, the bodys use of insulinlowering the risk of
developing type 2 diabetes mellitus, particularly in those at high risk of diabetes,
improves glycemic control and reduces type 2 diabetes medications and increases
exercise capacity [1, 8]. In short, antiatherogenic effects of PA and exercise training
are well documented by changes on the body fat mass, lipoprotein metabolism,
carbohydrate intolerance, regression of coronary lesions, vascular reactivity and
structure, and neurohormonal modulation [9].
52
E. Rocha
Worldwide, the relative risk (95 % CI) associated with physical inactivity,
activity level insufcient to meet WHO recommendations [2], adjusted for confounders, for incidence of CHD and diabetes is, respectively, 1.16 (1.041.30) and
1.20 (1.101.33) [6]. These numbers are consistent with ndings from INTERHEART
study, a casecontrol study conducted in 52 countries throughout Africa, Asia,
Australia, Europe, Middle East, and North and South America, in which the adjusted
OR for MI associated with physical inactivity was 1.16 (1.031.32) [11].
Numerous reviews or meta-analyses strengthened the evidence that PA has an
independent role in primary prevention of CHD, with a 2030 % lower risk of CHD
[10]. A meta-analysis of prospective cohort studies of occupational and LTPA and
CVDs (CHD and stroke), with follow-up 5 years, exploring the doseresponse
relationship, shows that high level of LTPA and moderate level of occupational PA
reduces the risk of incidental events of CHD and stroke among men and women by
2030 % and 1020 %, respectively [12]. On the other hand, the reduction in risk of
all-cause and cardiovascular mortality derived from systematic review is signicant,
3040 % [10] to 2030 % [1], with a stronger doseresponse gradient for tness
than for PA [13]. Fitness has direct doseresponse relations between intensity, frequency, duration and volume for CVDs and CHD. The weaker relation of PA than
cardiorespiratory tness with health benet may result from bias in the measurement method (objectively versus self-reports) and resultant misclassication. The
procedures to assessing PA in epidemiological research are critical both for understanding the relation between PA, or opposite physical inactivity, and measures of
health as for comparability of data around the world. Recent technological advances
(accelerometers and heart rate monitors) will increase in the future the accuracy of
the PA assessment.
The-Lancet-Series-Physical-Activity highlights global burden of physical inactivity
and suggests that its responsible for 5.8 % of the burden of CHD worldwide, ranging
from 3.2 % in Southeast Asia to 7.8 % in the Eastern Mediterranean. In addition, physical inactivity accounts for 11.9 % of the burden of CHD in the Cook Islands and Malta,
11.4 % in Swaziland and Saudi Arabia, 11.3 % in Argentina, 10.5 % in the UK, 6.7 %
in the US, and 5.6 % in Canada. Similarly, the burden of diabetes attributable to physical inactivity is 7.2 % worldwide, ranging from 3.9 % in Southeast Asia to 9.6 % in the
Eastern Mediterranean [6].
53
This association was stronger among women than men [14]. Some PA is better
than none. Other authors concluded that risk reductions routinely occur at levels of
150 min/week of at least moderate-intensity activity [2]. Specifying, the benets of
moderate-intensity PA or aerobic exercise training (common daily activities and
sport-related activities) in all-cause and cardiovascular mortality ranges from 2.5 to
5 h/week [10] equivalent to perform 11.5 h/week of vigorous-intensity PA/aerobic
exercise training. A moderate-intensity PA is an activity performed at 4059 % of
VO2 or at a rate of perceived exertion of 56 in the Borg CR 10 scale and a absolute
energy expenditure of 4.87.1 METs (1 MET = 3.5 ml/min/kg) in the young, 4.05.9
METs in the middle-aged, 3.24.7 METs in the old, and 2.02.9 METS in the very
old [15]. These results support European and American guidelines on physical
activity [1, 10].
54
E. Rocha
trials involving patients with heart failure (HF), diabetes, peripheral arterial disease
(PAD), pulmonary arterial hypertension, and congenital heart disease [18].
Even though the wealth of evidence supporting the scientic statements and
guidelines directed toward increasing referral and participation rates for CR, the
underutilization of CR is general worldwide. Recent surveys in USA reported referrals in the order of 20 %, averaging between 10 % and 30 % [19], and in Europe
fewer than half of eligible cardiovascular patients are advised to follow cardiac
prevention or rehabilitation programme [3, 20]. Beside, the enrollment rate varied
greatly between countries, e.g., in Portugal is less than 4 % [21]. So why isnt there
greater participation and referral for CR? Some of the reasons are identied (coverage and resources for outpatient CR services, lack of accessibility to formal
programs, etc.).
55
is expected that this intervention will benet 4000 municipalities by 2015 [24, 25].
Various studies in middle-income and high-income countries have shown that
school-based interventions reduce CVDs risk factors. Enhanced reporting of external validity elements will inform the translation of research into practice [26].
Concerning policy and environmental approaches, were effective: provision of
tness zone equipment (e.g., 12 parks in Los Angeles); urban environments friendly
to pedestrians (undertaken in the USA, Canada and outside North America); urban
environment improvements based in redesigning of streets and pavements, creation
of bike lanes and paths; travel interventions to increase active transport; communitywide policies to promote PA in conjunction with information (e.g., Ciclovias also
known as open streets initiatives, a program that started in Bogota and had many
replications in the Americas) [22].
56
E. Rocha
References
1. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, et al. European guidelines
on cardiovascular disease prevention in clinical practice: fth joint task force of European and
other societies on cardiovascular disease prevention in clinical practice. Eur Heart J. 2012;
33(13):1635701.
2. WHO. Global recommendations on physical activity for health. Geneva: World Health
Organization; 2010.
3. Kotseva K, Wood D, De Backer G, De Bacquer D, Pyorala K, Keil U. EUROASPIRE III: a
survey on the lifestyle, risk factors and use of cardioprotective drug therapies in coronary
patients from 22 European countries. Eur J Cardiovasc Prev Rehabil. 2009;16:12137.
4. Hallal PC, Andersen LB, Bull FC, Guthold R, Haskell W, Ekelund U, Lancet Physical Activity
Series Working Group. Global physical activity levels: surveillance progress, pitfalls, and
prospects. Lancet. 2012;380:24757.
5. Lenfant C. Clinical research to clinical practice-lost in translation? N Engl J Med. 2003;
349:86874.
57
6. Lee I-M, Shiroma EJ, Lobelo F, Puska P, Blair SN, Katzmarzyk PT, Lancet Physical Activity
Series Working Group. Effect of physical inactivity on major non-communicable diseases
worldwide: an analysis of burden of disease and life expectancy. Lancet. 2012;380:21929.
www.thelancet.com. Physical Activity. July 2012.
7. Kavazis AN. Exercise preconditioning of the myocardium. Sports Med. 2009;39:92335.
8. Marwick TH, Hordern MD, Miller T, Chyun DA, Bertoni AG, Blumenthal RS, et al., On
behalf of the American Heart Association Exercise, Cardiac Rehabilitation, and Prevention
Committee of the Council on Clinical Cardiology; Council on Cardiovascular Disease in the
Young; Council on Cardiovascular Nursing; Council on Nutrition, Physical Activity, and
Metabolism; Interdisciplinary Council on Quality of Care and Outcomes Research. Exercise
training for type 2 diabetes mellitus. Circulation 2009;119(25):324462.
9. Niebauer J, Cooke JP. Cardiovascular effects of exercise: role of endothelial shear stress. J Am
Coll Cardiol. 1996;28:165260.
10. US Department of Health and Human Services. Physical Activity Guidelines for Americans.
2008. http://www.health.gov/paguidelines/pdf/paguide.pdf.
11. Yusuf S, Hawken S, unpuu S, Dans T, Avezum A, Lanas F, et al. On behalf of the
INTERHEART Study Investigators. Effect of potentially modiable risk factors associated
with myocardial infarction in 52 countries (the INTERHEART study): casecontrol study.
Lancet. 2004;364(9438):93752.
12. Li J, Siegrist J. Int J Environ Res Public Health. 2012;9(2):391407.
13. Williams PT. Physical tness and activity as separate heart disease risk factors: a metaanalysis. Med Sci Sports Exerc. 2001;33:75461.
14. Sattelmair J, Pertman J, Ding EL, Kohl III HW, Haskell W, Lee I-M. Dose response between
physical activity and risk of coronary heart disease a meta-analysis. Circulation. 2011;
124:78995.
15. Kodama S, Saito K, Tanaka S, Maki M, Yachi Y, Asumi M, et al. Cardiorespiratory tness as
a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and
women: a meta-analysis. JAMA. 2009;301(19):202435.
16. Jolliffe JA, Rees K, Taylor RS, Thompson D, Oldridge N, Ebrahim S. Exercise-based rehabilitation for coronary heart disease. Cochrane Database Syst Rev. 2001;1:CD001800.
17. Heran BS, Chen JM, Ebrahim S, Moxham T, Oldridge N, Rees K, et al. Exercise-based cardiac
rehabilitation for coronary heart disease. Cochrane Database Syst Rev. 2011;7:CD001800.
18. Kwan G, Balady GJ. Cardiac rehabilitation-advancing the eld through emerging science.
Circulation. 2012;125(7):e36973.
19. Boyden T, Rubenre M, Franklin B. Will increasing referral to cardiac rehabilitation improve
participation? Prev Cardiol. 2010;13:198202.
20. Bjarnason-Wehrensa B, McGeeb H, Zwislerc A-D, Piepolid MF, Benzere W, Schmidf J-P,
et al. on behalf of the Cardiac Rehabilitation Section European Association of Cardiovascular
Prevention and Rehabilitation. Cardiac rehabilitation in Europe: results from the European
Cardiac Rehabilitation Inventory Survey. Eur J Cardiovasc Prev Rehabil. 2010;17:4108.
21. Abreu A, Bettencourt N, Fontes P. Overview of cardiac rehabilitation in Portugal 20072009.
Rev Port Cardiol. 2010;29:5458.
22. Heath GW, Parra DC, Sarmiento OL, Andersen LB, Owen N, Goenka S, Lancet Physical
Activity Series Working Group, et al. Evidence-based intervention in physical activity: lessons
from around the world. Lancet. 2012;380(9838):27281.
23. Kahn EB, Ramsey LT, Brownson RC, Heath GW, Howze EH, Powell KE, et al. The effectiveness of interventions to increase physical activity: a systematic review. Am J Prev Med. 2002;
22:73107.
24. Knuth AG, Simes EJ, Reis RS, et al. Atividade Fsica no Brasil: uma reviso de evidncias
em experincias selecionadas. In: Sade M, editor. Sade Brasil 2010: uma anlise da situao
de sade e de evidncias selecionadas de impacto de aes de vigilncia em sade. Brasilia:
Brazilian Ministry of Health; 2011.
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E. Rocha
25. Hoehner CM, Ribeiro IC, Parra DC, Reis RS, Azevedo MR, Hino AA, et al. Physical activity
interventions in Latin America: expanding and classifying the evidence. Am J Prev Med.
2013;44(3):e3140. doi:10.1016/j.amepre.2012.10.026.
26. Malta DC, Silva JB. Policies to promote physical activity in Brazil. Lancet. 2012;380:1956.
27. Dumith SC, Hallal PC, Reis RS, Kohl III HW. World prevalence of physical inactivity and its
association with human development index in 76 countries. Prev Med. 2011;53:248.
28. Blair SN. Physical inactivity: the biggest public health problem of the 21st century. Br J Sports
Med. 2009;43:12.
29. 66th World Health Assembly in May 2013. NCD Action Plan 20132020: Final Draft of the
Global NCD Action Plan 20132020.
30. Das P, Horton R. Rethinking our approach to physical activity. Lancet. 2012;380(9838):
18990.
Introduction
A healthy diet is the cornerstone of cardiovascular health, and individual behavior
and environmental level factors work together to inuence healthful dietary intake.
Across the world, correlations can be seen between cardiovascular health and
healthful food environments. Further, evidence from a large body of research studies shows that dietary intake is related to risk factors for cardiovascular disease and
stroke [1]. One framework for thinking about dietary intake is the socioecological
model which shows the dynamic inter-relations among various personal and environmental factors (Fig. 1) [2]. This framework for prevention highlights the complex
interplay amongst multiple levels of factors that inuence public health problems.
Individual level factors include genetics, sex, age, education, race, ethnicity, culture, socioeconomic status, health behavior, and occupation. Relationship factors
include family, peers, intimate partners, religious and social groups. Community
factors include neighborhood, schools, workplace, and geographical placement.
Societal factors include health care system, educational and economic policies,
politics, justice system, and the natural and built environment. All of these factors
must be considered in efforts to promote diets for optimal cardiovascular health.
Dietary intake across the world is inuenced by the level of modernization of the
society, and many populations are experiencing changes in diet that often do not
support the current recommendations for cardiovascular health. Currently, some
parts of the world struggle with the adverse impacts on cardiovascular health that
accompany modernization while other parts of the world are experiencing an epidemiologic transition (Table 1) [3]. To enhance success, public health efforts that are
59
60
Community
Societal
Relationship
Individual
Fig. 1 The socio-ecological model showing the complex interplay amongst multiple levels of
factors that inuence public health problems. Figure adapted from: Dahlberg LL, Krug EG.
Violence a global public health problem
Malnutrition and infectious diseases are the leading causes of mortality and
morbidity
Improved nutrition and public health leads to increase in non-communicable
diseases (NCDs)
Increased fat and caloric intake, widespread tobacco use, NCD deaths surpass
deaths from infections and malnutrition
CVD and cancer are the leading causes of morbidity and mortality; primary
and secondary prevention efforts lead to declines in age-adjusted CVD
Dietary Patterns
Dietary patterns can be dened as combinations of foods and nutrients that are typically eaten together. Dietary patterns are gaining popularity because of a growing
body of research on patterns, and increased recognition that we do not eat foods or
nutrients in isolation. Although dietary patterns vary across the world, there are
commonalities amongst them that are related to cardiovascular health. At the heart
of the current lifestyle recommendations from the American Heart Association/
61
Table 2 Lifestyle recommendations about blood pressure and LDL-cholesterol from the AHA/
ACC for individuals
Advise adults who would benefit from blood pressure lowering to:
1. Consume a dietary pattern that emphasizes intake of vegetables, fruits, and whole grains;
includes low-fat dairy products, poultry, sh, legumes, non-tropical vegetable oils and nuts;
and limits intake of sweets, sugar-sweetened beverages and red meats.
(a) Adapt this dietary pattern to appropriate calorie requirements, personal and cultural food
preferences, and nutrition therapy for other medical conditions (including diabetes
mellitus).
(b) Achieve this pattern by following plans such as the DASH dietary pattern, the USDA food
pattern, or the AHA diet.
2. Lower sodium intake.
3. Advise adults to consume no more than 2400 mg of sodium/day and that a further reduction
of sodium intake to 1500 mg/day can result in even greater reduction in BP. Even without
achieving these goals, reducing sodium intake by at least 1000 mg/day lowers BP.
4. Combine the DASH dietary pattern with lower sodium intake.
Advise adults who would benefit from LDL-cholesterol lowering to:
1. Consume a dietary pattern that emphasizes intake of vegetables, fruits, and whole grains;
includes low-fat dairy products, poultry, sh, legumes, non-tropical vegetable oils and nuts;
and limits intake of sweets, sugar-sweetened beverages and red meats.
(a) Adapt this dietary pattern to appropriate calorie requirements, personal and cultural food
preferences, and nutrition therapy for other medical conditions (including diabetes
mellitus).
(b) Achieve this pattern by following plans such as the DASH dietary pattern, the USDA food
pattern, or the AHA diet.
2. Aim for a dietary pattern that achieves 56 % of calories from saturated fat.
3. Reduce percent of calories from saturated fat.
4. Reduce percent of calories from trans fat.
62
Dietary Sodium
Evidence from around the world shows that excessive sodium intake is linked to the
epidemics of pre-hypertension, hypertension, cardiovascular disease and stroke.
In the United States, 97 % of the population consumes more than the recommended
daily sodium intake [12, 13]. Data from the National Health and Nutrition
Examination Surveys (NHANES) shows that adults 20 years and older had a median
daily sodium intake of 3371 mg excluding table salt (i.e., sodium chloride) [13].
Hypertension is the most prevalent modiable risk factor for CVD with approximately 34 % of the US adult population affected [14], and contributing to 62 % of
stroke and 49 % of coronary heart disease [15]. There is strong evidence indicating
63
64
results have been inconsistent. A review of the literature found that omega 3 fatty
acids may reduce death from vascular diseases, but not sudden death, stroke, or
arrhythmias [24].
Dietary fat is intimately linked to cholesterol, not only because many sources
high in fat also contain cholesterol but because saturated and trans fatty acids can
lead to accelerated atherosclerosis through dyslipidemia. A meta-analysis of 60
controlled trials found that low-density lipoprotein (LDL)-cholesterol levels increased when 1 % of energy from carbohydrates were replaced with saturated or trans
fat, but decreased when replaced with monounsaturated or polyunsaturated fats,
with the largest increase seen among trans fats and the largest decrease seen among
polyunsaturated fats [25]. Additionally, saturated, monounsaturated and polyunsaturated fats slightly raised high-density lipoprotein (HDL)-cholesterol levels while
trans fats did not.
Total cholesterol level is the product of LDL-cholesterol, very low-density lipoprotein (VLDL), and HDL-cholesterol. Clinical medicine has long focused on
LDL-cholesterol as the bad cholesterol and HDL as the good cholesterol, given
multiple studies indicating that higher LDL and lower HDL levels confer increased
risk of CVD [26]. The likelihood of developing an unbalanced lipid prole, is both
a product of diet and genetic background. Dietary cholesterol intake can be lowered
by reducing intake of cholesterol-rich foods, and saturated [27, 28] and trans fats;
however there is limited and insufcient evidence to determine whether lowering
dietary cholesterol reduces LDL-C.
To improve cardiovascular health, and reduce the risk of CVD and death due to
CVD, current recommendations include eliminating trans-fatty acids completely,
reducing and substituting saturated fat with monounsaturated or polyunsaturated
fatty acid, eating cholesterol in moderation, and not using carbohydrates as a saturated fat substitute [4]. Individuals who would benet from lowering their LDLcholesterol are further advised to eat a healthful pattern and limit saturated fat and
trans fat intake [4].
65
according to their glycemic index (GI). According to this system, foods that cause a
greater spike in prandial glucose are assigned a higher glycemic index. Associations
have been documented between diets comprised of high GI foods and type 2 diabetes mellitus, HDL-cholesterol, high triglyceride levels, and coronary heart disease
[30, 31]. Furthermore, whole grains (grains which have not been milled and contain
the entire grain, e.g., whole-wheat our, brown rice and oatmeal) are classied as
low glycemic foods, and increased consumption has been linked to reduced risk of
weight gain [32], coronary heart disease [33] and type 2 diabetes [34].
Over the years, simple sugar sweeteners (e.g., high-fructose corn syrup, cane
sugar, beet sugar), often referred to as added sugar, have played a role in excess
carbohydrate overconsumption. Although their consumption appears to be on the
decline in the United States, they still contribute approximately 77 g of sugar and
15 % of total energy intake per day [35]. Excess consumption of added sugar, particularly in the form of sugar-sweetened beverages, has been implicated as a major
contributor to overweight and obesity [36], type 2 diabetes [37] dyslipidemia [38],
and cardiovascular disease [39].
References
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lifestyle recommendations revision 2006: a scientic statement from the American Heart
Association Nutrition Committee. Circulation. 2006;114:8296.
2. Krug E, Dahlberg LL, Mercy JA, Zwi AB, Lozano R, editors. World report on violence and
health. Geneva: World Health Organization; 2002. p. 156.
3. Gaziano TA. Reducing the growing burden of cardiovascular disease in the developing world.
Health Aff. 2007;26(1):1324.
4. Eckel RH, Jakicic JM, Ard JD, Hubbard VS, de Jesus JM, Lee I, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College
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5. Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among US adults, 19992010. JAMA. 2012;307(5):4917.
6. Poirier P, Giles TD, Bray GA, et al. Obesity and cardiovascular disease: pathophysiology,
evaluation, and effect of weight loss an update of the 1997 American Heart Association
Scientic Statement on obesity and heart disease from the Obesity Committee of the Council
on Nutrition, Physical Activity, and Metabolism. Circulation. 2006;113(6):898918.
7. Stein DJ. Benecial health effects of modest weight loss. Int J Obes Relat Metab Disord.
1992;16(6):397415.
8. Spiegelman BM, Flier JS. Obesity and the regulation of energy balance. Cell. 2001;104(4):
53143.
9. Ledikwe JH, Blanck HM, Khan LK, et al. Dietary energy density is associated with energy
intake and weight status in US adults. Am J Clin Nutr. 2006;83(6):13628.
10. Young LR, Nestle M. The contribution of expanding portion sizes to the US obesity epidemic.
Am J Public Health. 2002;92(2):2469.
11. Rolls BJ, Roe LS, Meengs JS. The effect of large portion sizes on energy intake is sustained
for 11 days. Obesity. 2007;15(6):153543.
12. Lloyd-Jones DM, Hong YL, Labarthe D, et al. Dening and setting national goals for cardiovascular health promotion and disease reduction the American Heart Associations strategic
impact goal through 2020 and beyond. Circulation. 2010;121(4):586613.
66
13. Cogswell ME, Zhang Z, Carriquiry AL, et al. Sodium and potassium intakes among US adults:
NHANES 20032008. Am J Clin Nutr. 2012;96(3):64757.
14. World Health Organization. Reducing risks, promoting healthy life. World Health Organization,
2002. http://www.who.int/whr/2002/en/. Accessed 6 Nov 2013.
15. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics 2012 update: a
report from the American Heart Association. Circulation. 2012;125(1):e2220.
16. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary
sodium and the dietary approaches to stop hypertension (DASH) diet. N Engl J Med.
2001;344(1):310.
17. He F, MacGregor GA. Effect of modest salt reduction on blood pressure: a meta-analysis of
randomized trials. Implications for public health. J Hum Hypertens. 2002;16(11):76170.
18. Bibbins-Domingo K, Chertow GM, Coxson PG, et al. Projected effect of dietary salt reductions on future cardiovascular disease. N Engl J Med. 2010;362(7):5909.
19. Mattes RD, Donnelly D. Relative contributions of dietary sodium sources. J Am Coll Nutr.
1991;10(4):38393.
20. Appel LJ, Anderson CA. Compelling evidence for public health action to reduce salt intake.
N Engl J Med. 2010;362:6502.
21. Appel LJ, Frohlich ED, Hall JE, et al. The importance of population-wide sodium reduction as
a means to prevent cardiovascular disease and stroke: a call to action from the American Heart
Association. Circulation. 2011;123(10):113843.
22. Anderson CAM. Beyond the clinic: importance of community involvement in sodium reduction efforts. J Public Health Manag Pract. 2014;20:S68.
23. Hu FB, Stampfer MJ, Manson JE, et al. Dietary fat in-take and the risk of coronary heart disease in women. N Engl J Med. 1997;337(21):14919.
24. Kotwal S, Jun M, Sullivan D, Perkovic V, Neal B. Omega 3 fatty acids and cardiovascular
outcomes: systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2012;
5:80818.
25. Mensink RP, Zock PL, Kester ADM, Katan MB. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins:
a meta-analysis of 60 controlled trials. Am J Clin Nutr. 2003;77(5):114655.
26. Wilson PWF, DAgostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction
of coronary heart disease using risk factor categories. Circulation. 1998;97(18):183747.
27. Mozaffarian D, Micha R, Wallace S. Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized
controlled trials. PLoS Med. 2010;7(3), e1000252.
28. Jakobsen MU, OReilly EJ, Heitmann BL, et al. Major types of dietary fat and risk of coronary
heart disease: a pooled analysis of 11 cohort studies. Am J Clin Nutr. 2009;89(5):142532.
29. Crapo PA, Reaven G, Olefsky J. Postprandial plasma-glucose and plasma-insulin responses to
different complex carbohydrates. Diabetes. 1977;26(12):117883.
30. Barclay AW, Petocz P, McMillan-Price J, et al. Glycemic index, glycemic load, and chronic
disease risk a meta-analysis of observational studies. Am J Clin Nutr. 2008;87(3):62737.
31. Abbasi F, McLaughlin T, Lamendola C, et al. High carbohydrate diets, triglyceride-rich lipoproteins, and coronary heart disease risk. Am J Cardiol. 2000;85(1):458.
32. Mozaffarian D, Hao T, Rimm EB, Willett WC, Hu FB. Changes in diet and lifestyle and longterm weight gain in women and men. N Engl J Med. 2011;364(25):2392404.
33. Liu SM, Stampfer MJ, Hu FB, et al. Whole-grain consumption and risk of coronary heart
disease: results from the Nurses Health Study. Am J Clin Nutr. 1999;70(3):4129.
34. Meyer KA, Kushi LH, Jacobs DR, Slavin J, Sellers TA, Folsom AR. Carbohydrates, dietary
ber, and incident type 2 diabetes in older women. Am J Clin Nutr. 2000;71(4):92130.
35. Welsh JA, Sharma AJ, Grellinger L, Vos MB. Consumption of added sugars is decreasing in
the United States. Am J Clin Nutr. 2011;94(3):72634.
67
36. Vartanian LR, Schwartz MB, Brownell KD. Effects of soft drink consumption on nutrition and
health: a systematic review and meta-analysis. Am J Public Health. 2007;97(4):66775.
37. Schulze MB, Manson JE, Ludwig DS, et al. Sugar-sweetened beverages, weight gain,
and incidence of type 2 diabetes in young and middle-aged women. JAMA. 2004;292(8):
92734.
38. Welsh JA, Sharma A, Abramson JL, Vaccarino V, Gillespie C, Vos MB. Caloric sweetener
consumption and dyslipidemia among US adults. JAMA. 2010;303(15):14907.
39. Fung TT, Malik V, Rexrode KM, Manson JE, Willett WC, Hu FB. Sweetened beverage
consumption and risk of coronary heart disease in women. Am J Clin Nutr. 2009;89(4):
103742.
Dyslipidemia has been proven to be one of the most important risk factors for
atherosclerotic vascular disease. It has been shown that raised serum total cholesterol causes an estimated 4.4 million deaths every year worldwide [1]. According to
the World Health Report published in 2002, it was estimated that around 8 % of all
disease burden in developed countries was caused by raised blood cholesterol and
that over 60 % of CHD and around 40 % of ischaemic stroke in developed countries
was due to elevated total blood cholesterol levels [2]. In that report, the highest rates
of raised cholesterol levels were seen in the high income countries of Northern and
Western Europe at that time. There have been major changes in the epidemiology of
risk factors since then. A systematic analysis of health examination surveys and
epidemiological studies with 321 country-years and 3.0 million participants was
performed in 2010 looking at global trends in cholesterol levels since 1980.
According to this more recent report, age-standardised mean total cholesterol
worldwide was 4.64 mmol/L for men and 4.76 mmol/L for women. Globally, mean
total cholesterol changed little between 1980 and 2008, falling by less than
0.1 mmol/L per decade in men and women. Despite converging trends, serum total
cholesterol in 2008 was highest in the high income region consisting of Australasia,
North America, and western Europe [3]. This recent report conrms that hypercholesterolemia is still an important risk factor we need to combat if we want to decrease
the epidemic of cardiovascular disease.
We know today that plasma lipids are transported in macromolecular complexes
referred to as lipoproteins so that the hydrophobic lipid constituents become soluble. Lipoproteins vary in size, density, lipid and apoprotein content. High-density
lipoprotein, VLDL, IDL, LDL, and Lp(a) are secreted primarily by the liver, while
chylomicrons carry dietary lipid. Two-thirds of the cholesterol in the plasma is
transported by LDL fraction of lipoproteins. Although the earlier clinical trials
L. Tokgozoglu, MD, FACC, FESC (*)
Hacettepe University, Ankara, Turkey
e-mail: lalet@hacettepe.edu.tr
Springer International Publishing Switzerland 2015
J.P. Andrade et al. (eds.), Prevention of Cardiovascular Diseases,
DOI 10.1007/978-3-319-22357-5_8
69
70
L. Tokgozoglu
71
the rst time that lowering cholesterol in high-risk patients could increase survival [9].
To determine the effect of lowering cholesterol in primary prevention, several studies were conducted. The Air Force/Texas Coronary Atherosclerosis Prevention
Study (AFCAPS/TexCAPS) showed that a 5-year period, treatment with lovastatin
reduced the risk for a rst acute major coronary event by 37 % in primary prevention [10]. Another landmark study was the The Heart Protection Study (HPS) which
was a large study with over 20,000 subjects in the UK showed benet with 40 mg/day
of simvastatin regardless of baseline LDL-C level in high risk patients. The relative
risk reduction in major vascular events was 24 % in this study [11]. Further evidence of benet with statin therapy was provided by the Cholesterol Treatment
Trialists (CTT) meta-analysis which reported the results for more than 90,000 subjects treated with statins in primary and secondary prevention trials showing that for
every 1 mmol/L (39 mg/dL) reduction in LDL-C, there was a 21 % relative reduction in risk for major vascular events. An update of the CTT meta-analysis included
trials of intensive statin therapy showing a 22 % reduction in major vascular events
per 1 mmol/L reduction in LDL-C suggesting that there is no lower threshold of
benet for LDL-C reduction [12, 13].
In light of all this evidence, lowering LDL cholesterol levels became one of the
most important goals in Preventive Cardiology both for primary and secondary
prevention. The importance of knowing the lipid prole was also recognised both
by physicians and the general public.
Management of Dyslipidemia
All the current guidelines on the management of dyslipidemia recommend that
assessment of total cardiovascular risk is important to plan the therapy of the patient.
Dyslipidemia is only one of the risk factors therefore all the other risk factors need
72
L. Tokgozoglu
to be assessed and targeted. Higher risk patients need more aggressive therapies
therefore calculation of the patients risk of having a cardiovascular event is important.
Treatment targets of dyslipidaemia are primarily based on results from clinical trials.
In nearly all lipid-lowering trials the LDL-C level has been used as an indicator of
response to therapy. Therefore, LDL-C remains the primary target of therapy in
most strategies of dyslipidaemia management. The overall guidelines on CVD
prevention in clinical practice strongly recommend modulating the intensity of the
preventive intervention according to the level of the total CV risk. Therefore the
targets should be less demanding when the total CV risk decreases from very high
to high or moderate. The most frequently used risk prediction systems are the
SCORE and Framingham risk calculation systems [15, 16]. The SCORE system
estimates the 10 year risk of a rst fatal atherosclerotic event (heart attack, stroke,
aneurysm of the aorta or other). Most other systems estimate coronary heart disease
risk only. The ESC/EAS Guidelines recommend the use of SCORE system.
Risk can be calculated based upon new SCORE charts in which, in addition to total
cholesterol, systolic blood pressure, age, sex and smoking, and HDL-C is taken into
account (www.heartscore.org).
The ESC/EAS Dyslipidemia guidelines have dened the following levels of total
CV risk:
1. Very high risk:
Documented CVD by invasive or non-invasive testing, previous myocardial
infarction (MI), ACS, coronary revascularization (percutaneous coronary
intervention, coronary artery bypass graft and other arterial revascularization
procedures, ischaemic stroke, PAD).
Patients with type 2 diabetes, patients with type 1 diabetes with target organ
damage (such as microalbuminuria). Patients with moderate to severe CKD
[glomerular ltration rate (GFR) <60 mL/min/1.73 m2)].
A calculated 10-year risk SCORE 10 %.
2. High risk:
Markedly elevated single risk factors such as familial dyslipidaemias and
severe hypertension.
A calculated SCORE 5 % and <10 % for 10-year risk of fatal CVD.
3. Moderate risk:
Subjects are considered to be at moderate risk when their SCORE is 1 % and
<5 % at 10 years. Many middle-aged subjects belong to this risk category. This
risk is further modulated by a family history of premature CAD, abdominal obesity, physical activity pattern, HDL-C, TG, hs-CRP, Lp(a), brinogen, homocysteine, apo B, and social class.
4. Low risk:
The low risk category applies to individuals with SCORE <1 %. After determining the risk level and LDL cholesterol levels of the patient, intervention
strategies on lifestyle and pharmacotherapy are decided according to the LDL
cholesterol goal for each category. The main target of treatment is LDL cho-
73
Table 1 Intervention strategies recommended according to risk and LDL level of the patient
LDL-C levels
Total CV
risk
(SCORE)
%
<1
70 to
<100 mg/dL
<70 mg/dL
1.8
<1.8 mmol/L to < 2.5 mmol/L
No lipid
No lipid
intervention intervention
Class/level
1 to <5
I/C
Lifestyle
intervention
Class/level I/C
>5 to <10, Lifestyle
or high risk intervention,
consider
druga
Class/level
10 or
very high
risk
IIa/A
Lifestyle
intervention,
consider
druga
Class/level
IIa/A
100 to
<155 mg/dL
2.5 to
<4.0 mmol/L
Lifestyle
intervention
155 to
<190 mg/dL
4.0 to
<4.9 mmol/L
Lifestyle
intervention
>190 mg/dL
>4.9 mmol/L
Lifestyle
intervention,
consider drug
if uncontrolled
I/C
I/C
I/C
IIa/A
Lifestyle
Lifestyle
Lifestyle
Lifestyle
intervention
intervention,
intervention,
intervention,
consider drug consider drug consider drug
if uncontrolled if uncontrolled if uncontrolled
I/C
IIa/A
IIa/A
I/A
Lifestyle
Lifestyle
Lifestyle
Lifestyle
intervention,
intervention
intervention
intervention
consider druga
and immediate and immediate and immediate
drug
drug
drug
intervention
intervention
intervention
IIa/A
IIa/A
I/A
I/A
Lifestyle
Lifestyle
Lifestyle
Lifestyle
intervention and intervention
intervention
intervention
immediate drug and immediate and immediate and immediate
intervention
drug
drug
drug
intervention
intervention
intervention
IIa/A
I/A
I/A
I/A
74
L. Tokgozoglu
Table 2 Percentage reduction of LDL-C required to achieve goals as a function of starting value
Starting
LDL-C
mmol/L
>6.2
6.26.2
4.45.2
3.94.4
3.43.9
2.93.4
2.32.9
1.82.3
<2.5 mmol/L
(~100 mg/dL)
>60
5060
4050
3540
2535
1025
<10
<3 mmol/L
(~115 mg/dL)
>55
4055
3045
2530
1025
<10
To make it easier for the physician, guidelines have a table to calculate the
percentage reduction of LDL-C required to achieve goals as a function of starting
value (Table 2). According to this table, treatment decisions can be made. Before
starting any treatment, it is important to exclude secondary caused such as
nephrotic syndrome, hypothyroidism, excessive alcohol consumption, pregnancy,
corticosteroid excess, anorexia, and use of immunosuppressive agents.
75
Table 3 Dietary recommendations to lower total and LDL cholesterol according to ESC/EAS
Guideline for the management of dyslipidemia
Dietary recommendations to lower TC and LDL-C
To be used with
To be preferred
moderation
Cereals
Whole grains
Rened bread, rice and
pasta, biscuits, com
akes
Vegetables
Raw and cooked
vegetables
Legumes
All (including soy
and soy protein)
Fruit
Fresh and frozen
Dried fruit, jelly, jam
fruit
canned fruit, sorbets,
popsicles
Sweets and
Non-caloric
Sucrose, honey,
sweeteners
sweeteners
fructose, glucose,
chocolate, candies
Meat and sh Lean and oil sh,
Lean cuts of beef, lamb,
poultry without
pork or veal, seafood,
skin
shellsh
Dairy food
Skimmed milk and Low fat milk, low fat
and eggs
yogurt, egg white
cheese and other milk
products
Cooking fat
Vinegar, ketchup,
Vegetable oils, soft
and dressings mustard, fat-free
margarines, salad
dressings
dressing, mayonnaise
Nuts/seeds
Cooking
procedures
Grilling, boiling,
steaming
All
Stir-frying, roasting
To be chosen occasionally in
limited amounts
Pastries, mufns, pies,
croissants
Vegetables prepared in butter
or cream
76
L. Tokgozoglu
recommended for this purpose. A combination of statins with brates may also be
considered while monitoring for myopathy but the combination with gembrozil
should be avoided [18]. It is also important to note that statin-brate combination
has not been proven to decrease mortality in all patients. If the patient is intolerant
to statins, a cholesterol absorption inhibitor, alone or in combination with bile acid
sequestrants may also be considered. In general, statins have been remarkably safe.
The 2005 CTT meta-analysis showed that LDL-C reduction with statins was not
associated with increased risk for cancer, and that the 5-year excess risk for rhabdomyolysis, the primary serious adverse reaction with statins, was extremely low and
non-signicant. Myopathy and rhabdomyolysis were seen in patients who were
immunosuppressed or on immunosuppressant drugs, as well as in patients taking
both a statin and gembrozil. Changes in liver enzymes can occur, particularly at
higher doses of statins, but are almost always reversible. Recently, a slight increase
in development of diabetes in patients taking statins has been reported [19]. A metaanalysis of statin trials found a 9 % greater risk for incident diabetes equivalent to 1
extra case of diabetes per 255 patients treated with statins for 4 years [20]. The CTT
collaborators meta-analysis found that cardiovascular risk reduction with statins
was equivalent in patients both with and without diabetes, so that after 5 years of
statin therapy, 42 major vascular events would be prevented per 1000 diabetic
patients treated with a statin [21]. These should be kept in mind in starting a statin
and follow up of patients in primary prevention but should not deter from using
statin if indicated by guidelines.
Female Patients
Treatment with statins is recommended for female patients with established CVD
in the same way as for males. As for primary prevention, statin treatment is recommended in high risk women. Lipid lowering drugs should not be given during
pregnancy or breast feeding.
77
Diabetic Patients
In people with type 1 diabetes with microalbuminuria or other target organ damage,
LDL-C lowering therapy with statins is recommended irrespective of their basal
LDL-C. In patients with type 2 diabetes and CVD or CKD and in those without
CVD who are over age of 40 years with one or more other CVD risk factor the recommended goal for LDL-C is <1.8 mmol/L (<~70 mg/dL) and the secondary goal
for non-HDL-C is, <2.6 mmol/L (<100 mg/dL) or for apo B <80 mg/dL. LDL-C
<2.5 mmol/L (<~100 mg/dL) is the primary target for all other people with type 2
diabetes and the secondary targets for non-HDL-C are <3.3 mmol/L (<100 mg/dL)
or for apo B <100 mg/dL.
Other Dyslipidemias
Patients with insulin resistant states such as diabetics, metabolic syndrome patients
and obese patients tend to have a state of atherogenic dyslipidemia characterised by
elevated triglyceride rich proteins, low HDL and small dense LDL particles. Statins
are effective in lowering LDL and non-HDL in these patients. An important question
is whether we can lower cardiovascular risk by targeting other non-LDL lipoproteins
in these patients to decrease residual risk. Clinical trials conducted with brates have
yielded disappointing results in terms of mortality reduction in general [22, 23].
A meta-analysis looking at the effects of brates in clinical trials showed a 10 %
decrease in cardiovascular events and microalbuminuria but no decrease in mortality
[24]. The ACCORD study evaluated the combination of brate and statin compared
to statin alone and found no signicant benet in the combination group in general
[23]. However, subgroups of these patients with high triglycerides and low HDL in
the ACCORD study did benet from addition of brates to statins. In a meta-analysis
of brate trials, the subgroup of patients with high triglycerides and low HDL had a
35 % reduction in cardiovascular events [25]. For today, LDL lowering with statin
based therapies are the standard of care for patients with high cardiometabolic risk,
but event rates are still high. There is no conclusive evidence about use of brates for
cardiovascular protection to decrease remaining risk. However, since adding brates
to statin is relatively safe, in the high risk diabetic subgroup with high TG and low
HDL, brates may be considered [26].
78
L. Tokgozoglu
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Peto R, Collins R, Simes R, Cholesterol Treatment Trialists (CTT) Collaborators. Efcacy
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Kjekshus J, Pedersen TR, Cook TJ, Gotto AM, Cleareld MB, Downs JR, Nakamura H,
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81
82
E. Shlyakhto
83
Primary health care facilities should be able to screen for hypertension, map
diagnosed cases, set up a community-based follow-up system, treat hypertension
and undertake relevant emergency management.
According to the hypertension guidelines primary examination should include
routine tests which are being performed in any hypertensive patient, additional tests
which are done for special indications revealed during physical examination or after
the results of routine test are obtained, and extended evaluation usually done by
specialists (Table 1).
The next step needed for appropriate treatment selection is risk stratication,
which is based not only on the level of blood pressure, but also on the presence of
other risk factors (e.g. family history, smoking, etc.), target organ damage and coexistence of cardiovascular or renal diseases.
84
E. Shlyakhto
salt restriction,
moderation of alcohol consumption,
high consumption of vegetables and fruits and low-fat and other types of diet,
weight reduction and maintenance and
regular physical exercise.
Smoking cessation, which is mandatory in order to improve CV risk, and
because cigarette smoking has an acute pressor effect that may raise daytime
ambulatory BP.
Obviously all team members should participate in patients education, and the
role of nurses, nutrition specialists and psychologists can not be overestimated.
A number of randomized clinical trials have demonstrated the signicant improvement
of blood pressure control with nurse- of pharmacist-led care [3, 4]. The results of
such studies demonstrated a reduction in blood pressure to a maximum of
13/8 mmHg [5]. The Cochrane review authors conclude that an organized system
of registration, recall and regular review allied to a vigorous stepped care approach
to antihypertensive drug treatment appears the most likely way to improve the control of high BP [6]. They also have conrmed that nurse or pharmacist led care was
promising, with the majority of randomized clinical trials being associated with
improved blood pressure control and reduction in mean systolic and diastolic blood
pressure [7].
An increased amount of investigations needed for hypertensive patient, including
those aimed at detection of asymptomatic target organ damage (see Table 1),
together with the shortage of time for adult primary care rise a serious dilemma.
One of the possible solutions lies in delegating less complex activities from
85
physicians to other members of the primary care team so that the whole team, not
solely the physician, becomes responsible for the health of patients [8]. Margolius
et al. [9] have performed a qualitative research approach to determine clinicians
opinions on the Treat-to-Target study, an intervention to improve blood pressure
control. They concluded that clinicians appreciate the presence of nonclinicians on
the primary care team. In the coming era of primary care clinician shortage, clinicians can be supportive of nonprofessional team members assisting with the care of
patients with hypertension. Telemedicine, dened as the use of telecommunications
to provide medical information and service, or remote monitoring in patients homes
has been offered as a plausible solution of improving ambulatory medical care.
Concerning the primary healthcare system it means the integration of medical,
information and communication technologies in order to provide appropriate medial
consultation to the patient basing on the information received from the patients
home. From another hand, telemedicine can be helpful in getting advice from a
remote specialized medical center to primary care professionals in complicated situations. Besides delivering care to hypertensive patients telemedicine has a critical
role in educating patients, in improving their adherence to both non-pharmacological and medical therapy. In some countries and communities the role of telemedicine is especially important because of its capability to solve the problem of large
distances and access to medical assistance. The remote counseling helps avoiding
unnecessary transportation and loss of time in the physicians ofces and out-patient
department.
Today the interest to out-of-ofce blood pressure monitoring is a subject
of extreme practical and scientic interest among cardiologists. According to the
Position Paper of the European Society of Hypertension on Ambulatory Blood
Pressure monitoring (2013), ambulatory blood pressure control has a lot of advantages over ofce blood pressure:
1. It gives a larger number of readings than ofce blood pressure measurement
2. Provides a prole of blood pressure behavior in the patients usual daily
environment;
3. Allows identication of white-coat and masked hypertension phenomena;
4. Demonstrates nocturnal hypertension;
5. Assesses blood pressure variability over the 24-hours period;
6. Assesses the 24-hours efcacy of antihypertensive medications;
7. Is a stronger predictor of cardiovascular morbidity and mortality than ofce
measurement.
According to ESH/ESC guidelines on the management of arterial hypertension
there are following indications for out-of-ofce blood pressure measurement:
A. Indications for home and ambulatory blood pressure monitoring:
86
E. Shlyakhto
87
Drug
ACE inhibitor, calcium antagonist, ARB
Calcium antagonist, ACE inhibitor
ACE inhibitor, ARB
ACE inhibitor, ARB
Any agent effectively lowering BP
BB, ACE inhibitor, ARB
BB, calcium antagonist
Diuretic, BB, ACE inhibitor, ARB,
mineralocorticoid receptor antagonists
BB
Consider ARB, ACE inhibitor, BB or
mineralocorticoid receptor antagonist
BB, non-dihydropyridine calcium antagonist
ACE inhibitor, ARB
ACE inhibitor, calcium antagonist
Diuretic, calcium antagonist
ACE inhibitor, ARB, calcium antagonist
ACE inhibitor, ARB
Methyldopa, BB, calcium antagonist
Diuretic, calcium antagonist
Of course such mode of system rises a lot of concerns about the adequacy and
accuracy of patients blood pressure readings, correct use of devices, availability
and competence with information technologies particularly in elderly patients. That
kind of problems should be solved with well-established system of patients
education.
Modern International guidelines state that the choice of antihypertensive medication should be based on (1) risk level and (2) on the presence of specic clinical
conditions and on possible side-effects. It reconrm that diuretics, beta-blockers, calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors and angiotensin
receptor blockers are all suitable for the initiation and maintenance of antihypertensive treatment, either as monotherapy or in some combinations (Table 2).
Today the physicians are faced a serious problem of treatment resistance and
wide prevalence of concomitant risk factors (e.g. obesity and/or diabetes mellitus).
Modern guidelines more and more tend to recommend early start of combination
therapy. When rapid blood pressure lowering is essential (e.g., in patients with high
and very high cardiovascular risk) pharmacological treatment should be started
with the combination of two drugs (Fig. 1) which, inter alia, signicantly improves
88
E. Shlyakhto
Thiazide diurecics
Beta-blockers
Angiotensin-receptor
blockers
Others
Antihypertensives
Calcium
antagoniscs
ACE inhibitors
89
The task of translating evidence into practice is not easy, it requires investigating
real-world settings to identify the contextual variables that will inuence the implementation process. Nevertheless, today it seem impossible to improve the quality of
care for hypertensive patients without signicant changes in the primary healthcare
system [19].
References
1. European Society of Hypertension Position Paper on Ambulatory Blood Pressure Monitoring.
J Hypertens. 2013;31:173168.
2. Rutten FH, Grobbe DE, Hoes AW. Differences between general practitioners and cardiologists
in diagnosis and management of heart failure: a survey in every-day practice. Eur J Heart Fail.
2003;5:33744.
3. De Castro MS, Fuchs FD, Santos MC, et al. Pharmaceutical care program for patients with
uncontrolled hypertension. Report of a double-blind clinical trial with ambulatory blood pressure monitoring. Am J Hypertens. 2006;19(5):52833.
4. Tobe SW, Pylypchuk G, Wentworth J, et al. Effect of nurse-directed hypertension treatment
among First Nations people with existing hypertension and diabetes mellitus: the Diabetes
Risk Evaluation and Microalbuminuria (DREAM 3) randomized controlled trial. CMAJ.
2006;174(9):126771.
5. Glynn LG, Murphy AW, Smith SM, Schroeder K, Fahey T. Self-monitoring and other nonpharmacological interventions to improve the management of hypertension in primary care: a
systematic review. Br J Gen Pract. 2010. doi:10.3399/bjgp10X544113.
6. Fahey T, Schroeder K, Ebrahim S. Interventions used to improve control of blood pressure in
patients with hypertension. Cochrane Database Syst Rev. 2006;4, CD005182.
7. Carter BL, Bosworth HB, Green BB. The hypertension team: the role of the pharmacist, nurse
and teamwork in hypertension therapy. J Clin Hypertens (Greenwich). 2012;14:5165.
8. Margolius D, Bodenheimer T. Transforming primary care: from past practice to the practice of
the future. Health Aff. 2010;29:77984.
9. Margolius D, Wong J, Goldman ML, Rouse-Iniguez J, Bodenheimer T. Delegating responsibility from clinicians to nonprofessional personnel: the example of hypertension control. J Am
Board Fam Med. 2012;25:20915.
10. Green BB, Cook AJ, Ralston JD. Effectiveness of home blood pressure monitoring, web
communication, and pharmacist care on hypertension control: a randomized controlled trial.
JAMA. 2008;299:285767.
11. Green BB, Ralston JB, Fishman PA, et al. Electronic Communications and Home Blood
Pressure Monitoring (e-BP) study: design, delivery, and evaluation framework. Contemp Clin
Trials. 2008;29(3):37695.
12. Bobrie G, Postel-Vinay N, Delonca J, Corvol P. Self-measurement and self-titration in hypertension. Am J Hypertens. 2007;20:131420.
13. Walsh JM, McDonald KM, Shojania KG, et al. Quality improvement strategies for hypertension management: a systematic review. Med Care. 2006;44:64657.
14. Carter BL, Rogers M, Daly J, Zheng S, James PA. The potency of team-based care interventions for hypertension: a meta-analysis. Arch Intern Med. 2009;169:174855.
15. Robins LS, Jackson JE, Green DD, Korngiebel D, Force RW, Baldwin L-M. Barriers and
facilitators to evidence-based blood pressure control in community practice. J Am Board Fam
Med. 2013;26:53957.
16. Anchala R, Pinto MP, Shrou A, Chowdhury R, Sanderson J, Johnson L, Blanco P, Prabhakaran
D, Franco OH. The role of decision support system (DSS) in prevention of cardiovascular
disease: a systematic review and meta-analysis. PLoS One. 2012;7(10), e47064.
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E. Shlyakhto
17. Carrington MJ, Jennings GL, Stewart S. Pressure points in primary care: blood pressure and
management of hypertension in 532 050 patients from 2005 to 2010. J Hypertens. 2013;31:
126575.
18. Frthauer J, Flamm M, Snnichsen A. Patient and physician related factors of adherence to
evidence based guidelines in diabetes mellitus type 2, cardiovascular disease and prevention:
a cross sectional study. BMC Fam Pract. 2013;14:47.
19. The Task Force for the management of arterial hypertension of the European Society of
Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertension.
2013;31:12811357.
91
92
System, for example, showed that adults with diabetes met goals for preventive
practices such as diabetes education, vaccinations, and annual dental examinations
only 5060 % of the time [6]. Further, only 14.3 % of adult diabetics met all of
the recommended targets for glycated hemoglobin (HbA1c), blood pressure (BP),
low density lipoprotein (LDL) cholesterol, and achieved non-smoking status.
Moreover, in specific populations such as younger adults; older patients; those with
complicated co-morbidities; those with mental illness; racial and ethnic minorities;
and patients with language barriers, financial, or social hardships, the gap between
actual and desired outcomes is even greater [712].
93
team-based approach to care has emerged [14, 18]. Unfortunately, many individuals
living with diabetes do not experience this model of care. This was demonstrated by
the Diabetes Attitudes, Wishes, and Needs (DAWN) Study, an international survey
of randomly selected generalist and specialist physicians and nurses, and patients
with diabetes. The DAWN study revealed that the majority of patients did not
receive diabetes care with a multi-disciplinary team of providers, including a PCP
or diabetes specialist, diabetes nurse, dietitian, eye doctor, foot doctor, and behavioral specialist [19].
In addition to the DAWN Study based on patient surveys, additional research
published over the last decade and a half has helped to paint a fuller picture of the
current status of chronic disease management and diabetes care. This research has
revealed that practitioners were not following established clinical guidelines, were
not coordinating care with each other, and were not actively following patients to
ensure optimal outcomes. At the same time, this research revealed that patients were
not adequately trained to manage their own illnesses [20]. To address these deficiencies among practitioners and patients, one of the most prominent models of care has
been the Chronic Care Model (CCM), which has been extensively applied to diabetes care. The CCM system shifts care from the traditional model of health-care to
one that is proactive in managing chronic diseases. The CCM is built upon the
principle that optimal chronic disease management necessitates a health-care system composed of six connected components. It includes leadership that encourages
a culture of quality improvement and provides the resources needed to change delivery system design. Delivery systems should be planned to provide coordinated care,
structured to prevent rather than react to disease complications. The next component
is decision support, which equips providers with evidence-based guidelines that
should be considered along with patient preferences to guide care decisions. The
CCM also incorporates clinical information systems to organize patient and population data (i.e., registries) and provides reminders to patients and physicians to enable
proactive care. The next component empowers patients to play the leading role
in the management of their disease by providing education and enabling selfmanagement support. Finally, policies and community resources to improve patient
access and care should be in place [20]. Collaboratively, these six components are
designed to improve population health in a way that makes it easier and more
efficient to address individual patients needs. In 2013, a systematic review of
16 studies, in which the CCM was applied in primary care settings providing diabetes care, showed that the CCM was effective in improving diabetes care and clinical
outcomes [21]. The authors and others acknowledge that further work is needed to
determine how well the CCM is helping patients and providers manage their diabetes and how the CCM can be more easily integrated into smaller or less motivated
practices with fewer resources [22]. Nevertheless, in promoting strategies to
improve diabetes care, the American Diabetes Association has endorsed the CCM
and noted that, care should be aligned with components of the CCM to ensure
productive interactions between a prepared proactive practice team and an informed
activated patient [7].
94
A key component of the CCM is the electronic health (EHR) or medical record,
which not only enables providers to efficiently navigate through individual patient
records, but also readily allows for population-based management. Use of EHR has
been shown, across a broad range of practices, to lead to improved outcomes. In a
study of 27,207 diabetic adults seen in 46 practices, EHR practices had a 35.1 %
increase in process measures of checking HbA1c, testing for urinary micro-albumin,
prescribing angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker
medications, performing screening eye examinations, and providing a pneumococcal vaccination. Albeit slightly lower, improvement in intermediate outcomes
HbA1c, BP, LDL, body-mass index, and nonsmoking statuswas also 15.2 %
higher in EHR practices [23]. Nevertheless, even with federal incentives and
meaningful use guidelines to promote implementation of EHR, more research on
how to use EHR in an efficient manner is needed [24].
The patient-centered medical home (PCMH) has emerged as another model for
chronic disease management and prevention in primary care and been described as
a vehicle to adopt the Chronic Care Model. [25] The PCMH is built on the
principle that management of chronic care should include the following basic elements: (1) coordination and integration of care to guide the patient through the
health system; (2) a focus on quality and safety which incorporates up-to-date
guidelines, is applied consistently, and is incorporated into patient registries so that
performance can be tracked; (3) whole person orientation which focuses on primary, secondary, and tertiary prevention; (4) a personal physician who is a first
contact for the patient, is aware of individual psychosocial and cultural components
that may influence a patients health, and, among members of the health-care team,
who serves as the lead coordinator of the patients care, (5) enhanced access with
flexible scheduling and easy access to members of the team, and (6) a system where
quality improvement and care coordination is appropriately reimbursed. Practices
that are recognized as a PCMH receive a per member per month fee in addition to
regular reimbursement through fee-for-service.
PCMH interventions have been studied a great deal and more pilots are underway. In a recent study, 8 PCMH pilots, from geographically diverse settings, were
reviewed and noted to report outcomes data. All have led to variable improvement of
intermediate outcomes including improved HbA1c, BP, and LDL control, and several have shown reduced emergency room and inpatient admissions, cost savings,
and improved patient satisfaction [25]. Of note, all of these programs included a
structured role for care coordination, in most cases, through a case manager. In a
meta-analysis of quality improvement strategies and glycemic control, case management and team changes, which add additional health-care providers to the patients
care team, or expand the role of an existing nurse or pharmacist, were identified as
the two most effective strategies in improving patient outcomes [26].
There have been a few large prospective studies designed to evaluate the
effectiveness of similar multi-component system change models. The Translating
Research Into Action For Diabetes (TRIAD) Study was a multi-center study which
gathered a cohort of 180,000 demographically and geographically diverse diabetic
individuals from 10 different health plansincluding for-profit, not-for-profit,
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96
lipid control, and patient satisfaction [31, 32]. Group visits may also facilitate
improved care coordination and efficiency if multiple providers are able to see the
patient and address different needs including medication issues, self-management
support, lifestyle and behavioral counseling, and ophthalmologic and foot evaluations in the same visit. One major impediment to restructuring care around teambased visits has been payment. Traditional payment models have not addressed
the time spent to coordinate care among members of the chronic care team.
Provisions of the Affordable Care Act, including increased Medicare reimbursement for primary care services, grants for development of patient-centered medical homes and coordinated care, and improving access to health insurance
coverage, which can improve self-reported health and lead to future reductions in
health care use and spending, are a first step towards improving outcomes from a
systems perspective [33, 34].
Conclusion
Despite all of these struggles, using an evidence-based approach, and through the
unique relationship built from continuity of care with patients, PCPs can empower
and assist their patients in improving diabetes prevention and reducing cardiometabolic risk. Approximately 7.0 million Americans have diabetes that has not been
diagnosed [1]. PCPs play a critical role in secondary prevention and should be
familiar with evidence-based screening guidelines in order to proactively diagnose
and treat diabetes. Similarly, there is now evidence, from multiple prospective trials, demonstrating sustainable interventions that are effective at preventing or
delaying diabetes [35]. The Diabetes Prevention Program (DPP), for example,
showed that a dietary intervention with a low-calorie low-fat diet leading to a 7 %
weight loss, and moderate intensity physical activity for 150 min/week lead to a
58 % reduction in type 2 diabetes risk over a mean of 2.8 years. The DPP also
showed that metformin use resulted in a 31 % risk reduction compared with placebo. The Diabetes Prevention Program Outcomes Study (DPPOS) followed these
patients for 10 years from initial randomization and also demonstrated that these
changes were sustainable [35]. Recently, the Look AHEAD (Action for Health in
Diabetes) research group published their findings that overweight/obese adults
with type 2 diabetes randomized to intensive lifestyle counseling achieved and sustained weight loss significantly more, over 8 years, than compared to patients
assigned to the usual care of diabetes support and education [36]. Taken together,
these findings further support the need to design diabetes care systems in a way that
enables such preventive programs.
Primary care providers can champion initiatives to improve diabetes care by
helping to create and engaging in the type of system that has been described.
Individual providers can build a framework for diabetes care by familiarizing themselves with the established, up-to-date, evidence base and guidelines such as the
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8. TRIAD Study Group. Health systems, patient factors, and quality of care for diabetes. A synthesis of findings from the TRIAD Study. Diabetes Care. 2010;33:94047.
9. Huang ES, Laiteerapong N, Liu JY, et al. Rates of complications and mortality in older patients
with diabetes mellitus. The Diabetes and Aging Study. JAMA Intern Med. 2014;174:2518.
10. Frayne SM, Halanych JH, Miller DR, et al. Disparities in diabetes care. Impact of mental
illness. Arch Intern Med. 2005;165:26318.
11. Peek ME, Cargill A, Huang ES. Diabetes health disparities: a systematic review of health care
interventions. Med Care Res Rev. 2007;64 Suppl 5:S10156.
12. Nam S, Chesla C, Stotts NA, Kroon L, Janson SL. Barriers to diabetes management: patient
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13. Peterson KA, Radosevich DM, OConnor PJ, et al. Improving diabetes care in practice.
Findings from the TRANSLATE trial. Diabetes Care. 2008;31:223843.
14. Rothman AA, Wagner EH. Chronic illness management: what is the role of primary care? Ann
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Background
In recent decades a shift in the epidemiology of cardiovascular diseases (CVD)
from high to middle and low income countries has been observed. CVD mortality is
declining in the high income regions but it still remains a major cause of premature
death and presently >80 % of all CVD mortality occurs in the remaining part of the
world. As atherosclerotic disease is a chronic disorder developing early in life and
progressing over decades before symptoms occur factors that influence its onset
should be sought as early as in childhood.
The change in pediatric epidemiology is impressive: soon one may observe
globally more children to be overweight or adipose than children suffering from
with underweight and malnutrition. With increasing socioeconomic affluence the
access to high caloric food such as sweetened drinks and fast food may contribute
to childhood obesity. TV, video and other computer games increase the risk of a
sedentary lifestyle with significant lack of physical activity. The option of mobile
telephone communication on most hours of the day and night might interfere with
healthy sleeping habits and thereby add to a lifestyle that may be harmful for the
health of the growing child and may lead to the early onset of atherosclerosis.
Cardiovascular risk factors can be detected in childhood and may predict the risk
of CVD later in life [1, 2]. Autopsy studies have shown the influence of CVD
risk factors on the development of the early atherosclerotic lesion, the lipid loaded
subendothelial plaque, which can be observed in as early as in childhood [3]. Crosssectional studies have demonstrated an increasing trend in carotid artery intimamedia thickness (IMT) related to a number of risk factors in asymptomatic healthy
young adults [4, 5]. Data from the Bogalusa Heart Study indicated that low-density
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Obesity
Prevention of childhood obesity should be a global public health priority due to
the significant impact of obesity on acute and chronic diseases, general health,
development and quality of life. The importance of childhood obesity for CVD
development later in life has been convincingly demonstrated in a Danish study
where height and weight data collected from 276,835 Danish individuals when they
were children were related to data on CVD when they were adults. Here it was
shown that the risk for any CVD event was positively and linearly associated with
body mass index (BMI) for boys aged 713 years and girls aged 1013 years, with
a greater risk as age increased for both boys and girls [10].
Obesity as early as at the age of 5 years may lead to an increased prevalence of
both type 1 and 2 diabetes mellitus at the age of 21 which was reported from a
group of 2639 Australian young adult participants of the Mater-University study of
103
pregnancy. The odds ratio for diabetes if there was overweight at 5 years amounted
to 2.60 [11]. In addition, teenagers and young adults who are already obese or have
type 2 diabetes have an increased carotid artery intima-media thickness and arterial
stiffness [12]. Participants in this US study were more likely than the lean individuals to have other cardiovascular risk factors. Their risk factors correlated with both
carotid IMT and stiffness but group was reported to be an independent predictor
of common carotid artery IMT and for the beta stiffness index. Additional effects of
type 2 diabetes and obesity appear to influence changes in the carotid structure and
function beyond traditional risk factors.
Several direct and indirect methods of assessing overweight in children and adolescents have been proposed but body mass index and waist circumference can be
recommended as the best measures for estimating adverse levels of blood lipids and
blood. Mller and co-workers found that among children and adolescents with an
elevated obesity index 2030 % also had elevated levels in blood pressure and blood
lipids. Their data did not support the statement that direct measures of fat mass or
waist circumference exceed the value of BMI [13].
Are interventions aimed to improve diet or physical activity effective at preventing obesity in children? An updated analysis of a Cochrane Review included
55 childhood obesity prevention studiesan additional 36 from the previous
Cochrane reviewall with a duration of 12 weeks or more [14]. In this review
strong evidence was found to support beneficial effects of child obesity prevention
programs on BMI, particularly for programmes targeted to children aged 612 years.
The review included 55 childhood obesity studiesan additional 36 from the previous reviewall with a focus on prevention and a duration of 12 weeks or more. The
team conducted a meta-analysis using available BMI or standardized BMI (zBMI)
score data and subgroup analyses were performed by age group (05, 612, and
1318 years). The interventions were generally effective at reducing adiposity; the
overall mean reduction in adiposity (measured as BMI or zBMI) was 0.15 kg/m2,
with the largest reduction occurring among children aged 612 years. Thus there
is nowadays sufficient scientific support for conducting prevention targeted programmes for childhood obesity.
Over the years the public awareness of nutrition high in saturated fat has resulted
in an unfortunate increased use of high caloric carbohydrates. Many children and
adolescents consume significant amounts of sweetened soft drinks. These are generally both cheap and everywhere accessible. The deleterious effects of a chronic caloric
overload have become a major public health hazard. Welsh and co-workers found that
adolescents who consume high amounts of added sugars have blood lipid levels that
place them at a clearly increased risk for future CVD: increased dyslipidemia was
observed among adolescents who had a high intake of added sugars, regardless of
body size, as well as increased levels of insulin resistance among those who were
overweight or obese. Therefore minimizing the consumption of added sugars in the
young population is an important task both for parents as for society as a whole [15].
It is known that the maturing of the human brain takes mainly place in the first
two decades of life. Could unhealthy nutritional habits influence this process, especially as diet supplies the nutrients needed for the development of brain tissues in
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early life? A study from Australia investigated the impact of diet on the intelligence
quotient (IQ) by assessing data from 7097 children from the Avon Longitudinal
Study of Parents and Children. They examined dietary patterns for the children
using parental questionnaires completed at 6, 15, and 24 months of age and when
the children were aged 8 years, the Wechsler Intelligence Scale for Children was
used to measure IQ. A small but significantly higher IQ at 8 years was found when
a healthy diet had been provided during the first 2 years of life [16].
Physical Inactivity
With the growing access to electronic communication devices, smart phones etc,
there is a tendency among children to become less active. Instead, children should
be encouraged to increase their participation in physical activity, rather than reducing their time spent sedentary, to improve their cardiovascular health. Ekelund et al.
pooled data from 14 studies involving more than 20,000 children (aged 418 years)
and found that higher time spent on moderate to vigorous activity spent by children
and adolescents was associated with better cardiometabolic risk factors regardless
of the amount of sedentary time. They recommend to increase daily activity at this
intensity level by participating in activities such as brisk walking, jogging, cycling,
playing soccer, and other team sports [17].
Even maintaining a high level of fitness plays an important role as children and
adolescents with higher levels of cardiorespiratory fitness (CRF) have reduced clustering of cardiometabolic risk factors. After assessing CRF and physical activity
levels in 100 children and adolescents (aged 1014 years) using a maximal cycle
ergometer test and accelerometry, Bauley et al. used a clustered risk score. They
found in comparing between fit and unfit participants, according to previously proposed health-related thresholds, that the fit group had a significantly lower mean
clustered risk score than those in the unfit group (0.74 vs 2.22, respectively) [18].
Keeping up physical activity and fitness may reduce the risk of type 2 diabetes
mellitus as children grow into adulthood. A prospective Australian cohort study followed 647 adults who had participated in the Australian Schools Health and Fitness
Survey in 1985 when they were aged 915 years and followed up in 20042006.
The study showed that the decline in fitness and in physical activity which often can
be seen in many teenagers is a stronger predictor of adult obesity and insulin resistance than low levels of fitness in childhood. Thus, efforts aimed at maintaining high
childhood physical activity levels into adulthood may have a potential to reduce the
burden of obesity and type 2 diabetes in adults [19].
Not all video and computer games seem to be hazardous, as has been considered
previously. A research team from New Zealand randomized 322 overweight and
obese children aged 1014 years, who were current users of sedentary video games,
to receive either an active video game upgrade or to have no change. After 24 weeks
the active video game intervention had a small but significant effect on BMI and
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Hypertension
Hypertension in childhood has been considered a rare condition but data from the
Healthcare Cost and Utilization Project Kids Inpatient Database (USA) may have
changed this common belief: it has now been observed that hypertension-related
hospitalizations in the age group 218 years almost doubled between 1997 and
2006 from 12,661 to 24,602 cases annually. As a child with high blood pressure is
at increased risk for maintaining high blood pressure (BP) in adulthood this will
result in increased CVD later in life. Therefore there is a need to invest in early
detection, prevention, and treatment of elevated blood pressure in children [22].
What does predict the development of high BP in childhood? This question has
been addressed in the largest reported contemporary cohort of healthy, prepubertal
children. It appeared that the strongest anthropometric association with BP at 10 years
was weight gain after infancy. Even effects of the babys size at birth and of early postnatal growth were noticed but their magnitude was substantially smaller than weight
gain in a later phase. Greater reductions in BP at population level may be expected
from strategies that reduce the development of adiposity from infancy onwards than
merely emphasizing the nutrition and weight of mothers and infants [23].
Current salt intake remains high in children. This is likely to predispose to
develop hypertension. A recent meta-analysis showed that even modest reductions
in salt intake could lessen age-related BP increases, which will result in major
reductions in CVD. Feng et al. carried out a meta-analysis of ten trials, including
966 children and adolescents, aged 816 years, in which the effects of reducing salt
intake were investigated. The study showed that salt intake was reduced by 42 %,
with significant reductions in both systolic (by on average 1.2 mmHg) and diastolic
(1.3 mmHg) BP. In a separate, analysis of three trials, including 551 infants, a 54 %
reduction in salt intake was associated with a significant 2.5 mmHg reduction in
systolic BP. This first meta-analysis of salt reduction in children shows that a modest reduction in salt intake will lead to immediate falls in BP and, if continued, may
probably attenuate a subsequent rise in BP with age [24]. Experts now recommend
that children should consume <2300 mg of sodium per day.
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Smoking
Smoking rates have fallen in several countries over the past years, however smoking
among adolescents remain a substantial public health problem, especially among
teenage girls. The so-called passive smoking contributes to an increased CVD
risk. In a cross sectional surveys of nationally representative samples of secondary
school children carried out between 1988 and 1998, in England, showed that exposure to passive smoking among children had approximately halved since the late
1980s. This reduction was partly explained by the fall in the percentage of parents
who smoke and may also likely reflect reductions of smoking in public places [25].
Parental smoking can raise the blood pressure (BP) levels of healthy children
under the age of 5 years, according to findings among Swiss children. Here, smoking
was reported by 28.5 % of fathers, 20.7 % of mothers, and 11.9 % of parent sets (both
parents). This led to a slightly higher BP among children exposed to parental smoking than those with no parental smoking exposure, with mean systolic and diastolic
BP levels of 100 versus 101 mmHg and 62 versus 62.5 mmHg, respectively [26].
New studies have clarified the vascular and metabolic consequences of smoking in
young age. In a study on 2273 subjects 1219 years of age from the National Health
and Nutrition Examination Survey III (NHANES III, 19881994) the relation between the prevalence of the metabolic syndrome and exposure to smoking has been
investigated, showing a doseresponse, cotinine-confirmed relationship between
tobacco smoke and metabolic syndrome among adolescents with a threefold increase
for passive smoking and a up to fivefold increase among active smokers [27].
Kallio and co-workers investigated the effect of exposure to tobacco smoke on
the arterial wall in healthy 13-year-old adolescents from the atherosclerosis prevention trial STRIP. They showed an independent association with exposure and
preclinical atherosclerosis as seen in the effect of smoking on maximum carotid
and aortic intima-media thickness and brachial artery flow-mediated dilation [28].
Clearly the rationale for a complete tobacco smoke free environment for the young
generation is increasingly convincing!
Hyperlipidemia
The main lipid disorder in childhood and adolescence is familial hypercholesterolaemia (FH), a common genetic disorder affecting approximately 30 children per
100,000 persons. The disorder leads to a marked elevation in LDL-C levels that
predisposes to premature CVD in adult life. The majority of children and adolescents with FH remain undiagnosed, as the clinical symptoms develop after decades.
Once a family member with FH has been diagnosed screening is the recommended
approach that allows the diagnosis of FH to be made in the young, before significant
atherosclerosis develops. With the availability of effective lipid lowering drugs,
these children should be referred to a paediatrician for specialist management and
follow-up, thus improving the prognosis for these children [29].
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Summary
Prevention of CVD in childhood and adolescence remains a challenge that calls for
high priority among many stakeholders: politicians, health care providers, schools,
parents, sport clubs etc. The targets for preventive programmes are creating a
tobacco-free environment, combating the childhood obesity pandemic and promoting regular physical activity on most days of the week. Promising policies and strategies can be a school curriculum that includes healthy eating, physical activity and
body image. Improvements in nutritional quality of the food supply in schools, environments and cultural practices that support children eating healthier foods and
being active throughout each day are needed. Parent support and home activities
that encourage children to be more active, eat more nutritious foods and spend less
time in screen based activities are invaluable for an effective CVD prevention [14].
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Introduction
Cardiovascular diseases (CVD) are responsible for 30 % of the annual worldwide
mortality. There is a trend toward decreased mortality rates in developed countries
but increased rates in countries with lower socioeconomic levels, particularly the
socialist and emerging third world countries. India, China, and Latin America have
the worst predictions of growth of cardiovascular mortality [1]. In 2010, Brazil
accounted for one third of all deaths and nearly 30 % of all deaths in the age group
of 2059 years, which affected the economically active adult population [2].
All developed and developing countries have experienced large reductions in
mortality rates over the past century, and the pattern of epidemiological transition
in these countries suggests that the main causes of mortality have changed from
transmissible diseasesespecially those prevalent among children and the young
109
110
Social Determinants
Since the establishment of the World Health Organization in 1948, health has been
defined as a state of complete physical, mental, and social development and not
merely the absence of disease [4].
In the first International Conference for the Promotion of Health conducted on
November 21, 1986 in Ottawa, a letter of intent known as the Ottawa Charter was
drafted with the aim to promote improvement of the health of the worlds population. This letter stressed that the improvement of health conditions would require
the allocation of core resources to health, including those for the promotion of
peace, shelter, education, food, income, stable ecosystems, sustainable resources,
social justice, and equity [4].
Subsequently, a Commission of Social Determinants of Health was established
by the WHO in 2005 to address the social factors responsible for inequalities in
health. The main objective was to draw the attention of governments and society to
the development of better social conditions for health, especially for those populations living in vulnerable conditions [4].
These actions are focused on the key risk factors that can significantly decrease
the incidence of atherosclerotic diseases and other non-communicable diseases. The
target risk factors were tobacco use, high blood pressure, increased cholesterol levels,
and diabetes mellitus, whose incidence has increased significantly in recent years
because of populational aging and the increased prevalence of obesity [6]. Other
contributing factors include low socioeconomic status, physical inactivity, poor diet,
obesity, insulin resistance, and family history of early coronary disease [7].
111
Other diseases, including Chagas disease and rheumatic heart disease, are closely
associated with the socioeconomic level of the country and with the uncontrolled
urbanization of major urban centers, leading to poverty, malnutrition, improper
housing, and overcrowding, among other problems [8, 9].
Social and economic determinants not only affect the occurrence and distribution
of traditional risk factors but also directly influence the biological mechanisms
closely associated with cardiovascular pathogenesis (e.g., low birth weight and the
chronic impairment of neuroinflammatory processes). Due to the limited knowledge of the relationship between social sciences and neuropsychology and how
these determinants interact in the regionalization of biological vulnerability to
diseases, the advancements in this field have been limited [10].
One of the most important determinants that should be addressed for the
prevention of cardiovascular diseases is social inequality, considering the internal
socioeconomic differences in certain countries. The socioeconomic status (SES)
has four main characteristics, which were described by Link and Phelan [11]: influence of multiple diseases, influence of SES on disease outcomes through multiple
risk factors, access to resources (or loss of resources) that can prevent risks and
disease outcomes, and the association between the fundamental cause of healthrelated problems and health conditions, which, over time, may be replaced by
predisposing factors (lifestyle, behavior, and strategies aimed to minimize social
inequalities).
The migration of knowledge from individual-based determinants of disease to
determinants based on socioeconomic indicators, particularly low socioeconomic
status, poverty, and loss of benefits from social interaction, was achieved by understanding how these determinants affect prevalence, morbidity, and disease outcomes, particularly mortality, because this understanding is essential for resource
allocation for disease prevention, treatment, and longevity in multiple population
groups [12].
Phelan et al. observed that the incorporation of new knowledge of the risk factors
that affect multiple non-communicable diseases, including the effect of smoking on
cardiovascular and neoplastic diseases, and the incorporation of new technologies,
including antiretroviral therapy and surgical procedures for the treatment of ischemic heart disease, produced the most benefits for the reduction of mortality and
morbidity among the population groups with higher socioeconomic status [13].
A systematic review of 20 studies published between 1998 and 2010 on social
inequalities in health and disease prevention in Germany showed a significant association between morbidity, mortality, horizontal inequalities (age, gender, marital
status, and nationality), and vertical inequalities (occupation, education, and
income) [14]. The INTERHEART study analyzed the association between risk factors and myocardial infarction in men and women and indicated that psychosocial
factors, together with diabetes, dyslipidemia, smoking, obesity, and high blood
pressure, were the major causes of myocardial infarction [15].
A review on social determinants in India confirmed the association between low
socioeconomic status and increased morbidity and mortality from cardiovascular
diseases and diabetes. It also highlighted that 52 % of deaths from CVD occurred
112
among individuals younger than 70 years and that the population groups with lower
educational levels living in urban communities were the most vulnerable. The
authors emphasize the importance of changing the paradigm from the biological
model to the populational model together with intervention, in addition to improvements in the health sector, with joint planning by the education, agriculture, economy, trade, urbanization, and transportation sectors [16].
In a study conducted in 73 districts of Porto Alegre, Brazil, Bassanesi et al.
showed that more than 50 % of the cases of mortality from CVD in the age group
below 65 years can be attributed to poverty; therefore, investments in socioeconomic development of the population are necessary [17]. Strong correlations were
found between decreased infant mortality, increased gross domestic product (GDP)
per capita, and increased levels of education, with reductions in mortality from
cardiovascular diseases in adults since 1980 in the state of Rio de Janeiro [3].
A document published by the WHO indicates that social injustice is the main
determinant of the inequalities that affect cardiovascular disease outcomes. This
document emphasizes that the primary approach should be based on the implementation of key actions, including balanced investment between prevention and cure
with a focus on vulnerable population groups, intersectoral collaborations led by the
public sector, and increased awareness of cardiovascular risk factors and their social
determinants. The document concludes that further studies are needed to elucidate
the mechanisms by which social determinants contribute to the social stratification
of cardiovascular diseases [18].
Urbanization
Most researchers use the urbanrural dichotomy, considered an inadequate division,
for the assessment of urbanicity. There is also variation of the factors involved in this
problem. To address this issue, Dahly and Adair constructed an urbanicity scale using
different methods to validate the performance against the urbanrural dichotomy and
evaluated the best relationship between urbanization and health. These determinants
included population size, demographic density, communication (presence of telephone service, e-mail, newspapers, internet, cable TV, and mobile phones), transportation (density of paved roads and availability of public transport), presence of
educational establishments and institutions (including secondary schools, universities,
and vocational schools), and healthcare services (hospitals, medical clinics, maternal
health clinics, family planning clinics, and community healthcare centers) as well as
the presence of markets, pharmacies, retail stores, supermarkets, and gas stations.
Each of these seven items was assigned a score between 0 and 10, for a maximum of
70 points. This scale allowed better understanding of the differences between urban
and rural areas [19].
The comparison studies that evaluate urban and rural areas have important limitations because of the concept of rurality. The concepts found in the literature are
diverse and do not allow more accurate analyses, and regional and cultural differ-
113
ences greatly influence these interpretations. In Brazil, with its large territorial
dimension, rural areas suffer from a lack of care resources. Despite this problem, it
is important to highlight the predisposition of genetic factors and lifestyle habits
present in rural areas, which may be inserted in the family environment. Giroldo
et al. evaluated adolescents living in a city with one of the lowest human development index (HDI) scores in the state of Paran and showed that children of parents
with coronary risk factors had the highest incidence of hypertension, obesity, and
dyslipidemia compared to adolescents of healthy parents [20].
The association between urbanization and the risk of CVD is determined by
lifestyle changes, particularly smoking, sedentary lifestyle, air pollution, poor
diet, and excessive use of alcohol and illicit drugs [21]. A systematic literature
review conducted by Holmboe-Ottesen and Wandel demonstrated that inadequate
carbohydrate-rich diets showed a strong association with obesity, diabetes, and cardiovascular risk among individuals who migrated from southern Africa to Europe [22].
India has experienced an increase in the number of cases of CVD in both urban
and rural areas. Coronary artery disease (CAD) cases have increased more than
fourfold in the last 40 years, and in rural areas, where over 700 million people live,
the incidence has doubled in the last 30 years and has even surpassed the incidence
of infectious diseases [23].
Globalization
The world population is rapidly increasing, with an estimated 9.3 billion people by
2050 [24]. To better understand globalization, one must understand the determinants
of populational health involving the institutional, economic, sociocultural, and environmental sectors. In the institutional sector, the most important factors include the
government structure, legislation, environmental policies, and regulatory systems.
In the economic sector, the occupational structure and tributary and marketing systems should be considered. In the sociocultural sector, the role of religion, customs
system, populational aspects (size and geographic distribution), and social infrastructure (social organization, knowledge development, social security, insurance
system, mobility, and communication) are important. In the environmental sector,
the ecosystem and climate should be considered [25].
Rapid globalization has generated trends that are influencing human health patterns. The many changes observed on global, socioeconomic, sociodemographic,
and environmental scales, particularly climate changes, are involved in the increased
prevalence of obesity, regional changes in food production, emergence of infectious
diseases, increased use of tobacco, and persistence of health inequalities [26].
The determinants of populational health that affect the planet have a cumulative
effect with regard to the emission of pollutants and climate change and may lead to
the decreased availability of drinking water, changes in soil properties, and food
shortages. Because of this population growth, other factors can affect the globaliza-
114
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possibly the aggregate of multiple small effects. The relatively small phenotypic
variation (compared to monogenic traits) of intermediate CVD traits (such as hypertension) disposes individuals toward disease development. For these reasons, genetics (the study of the function of individual genes) and genomics (the study of the
function of the entire genome, i.e., genes, non-protein-coding stretches of DNA,
genegene interactions, etc.) play a potentially important part in our evolving understanding of CVDs, including risk prediction, discovery and functional explorations
of susceptibility loci, and ultimately identification of new therapeutic targets.
This chapter will review the current state of CVD genetics and genomics research,
with some attention given to monogenic disease but a more detailed discussion of
the flourishing arena of complex CVD genomics. Given the number of studies and
the rapidly evolving research front in this discipline, we cannot hope to be
comprehensive. This survey, however, should supply interested readers with the
fundamental terms and methods of genetic and genomics, the areas of CV health
and disease that have been most robustly explored, and the existing and potential
clinical implications of this work.
119
FH [8]; interestingly, other mutations in this gene can lower LDL-C and be cardioprotective [9]. The study of the functional effects of PCSK9 mutations have lead, in
part, to the development of a number of therapeutic agents that inhibit PCSK9 to
reduce LDL-C [10]. Population studies estimate that 553 % of individuals with clinical ADH phenotypes do not have mutations in any of the known ADH genes [11].
This diagnostic gap suggests other forms of ADH remain to be discovered.
Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy
without dilation or any obvious systemic causes (e.g., aortic stenosis, hypertension).
In individuals with HCM, the normal alignment of myocytes is disrupted and electrical functions of the heart can be impeded. HCM is the most common cause of sudden
death in young athletes, and it is an important contributor to heart failure and stroke
[12]. The 0.2 % prevalence of HCM in the general population is considered high for a
monogenic disease [13]. Some 1400 mutations in 20 genes have been identified in
HCM [14], the majority of which are in sarcomere- and myofilament-related genes.
About 70 % of HCM patients have mutations in either the -myosin heavy chain gene
(MYH7) or the myosin-binding protein C gene (MYBPC3) [12]. Although HCM traditionally falls within the realm of monogenic disorders, genetic dissection of this
disease has complicated the simple-complex disease dichotomy: a number of modifier genetic variants have been identified (e.g., END1 [15]) that add to or interact with
the implicated Mendelian variants. Given that HCM can go undiagnosed until after
the occurrence of a severe clinical event, it would seem an obvious candidate for
genetic testing. However, given that the number of potentially pathogenic mutations
(nearly all families with HCM in their pedigree have a different mutation) and that
pathogenic mutations can be identified in 50 % of clinically affected individuals, it
is likely that HCM-causing mutations would go unrecognized in a significant number
of those tested. Thus, HCM illustrates the challenges of translating even detailed
genetic knowledge of a monogenic disorder into fruitful clinical tools.
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data from over 200,000 individuals of European and South Asian ancestry to identify and replicate more than 30 novel loci for CAD susceptibility [19]. About a
quarter of the variants with validated CAD associations in these studies were also
significantly associated with lipid traits (e.g., LDL-C and triglycerides (TG), data
from the Global Lipids Genetics Consortium) and about 10 % were also significantly associated with blood pressure (data from the International Consortium of
Blood Pressure), reinforcing the causal link between these risk factors and CAD
risk [19]. Although findings from these studies suggest that many CAD-associated
loci are important for both sexes and across racial and groups, data for blacks and
other non-Caucasian groups is limited. Studies of CAD illustrate a number of critical themes that, as will become apparent, have emerged in studies of other complex
diseases and phenotypes. First, genetic associations were generally stronger for hard
endpoints (e.g., MI, angiographically-diagnosed CAD) rather than intermediate
phenotypes like lipids [20]. Although endpoint phenotypes may not be the best
choice for all complex diseases, studies of CAD underscore the importance of judicious phenotype selection and measurement in genetic studies. Second, the effect
sizes of genetic variation in CAD studies were often modest (i.e., with odds ratios
typically <1.2). It appears the common variants interrogated by GWAS assays
explain only a small proportion of CAD heritability.
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Hypertension
Blood pressure (BP) is a quantitative trait with 3060 % heritability in humans [28].
As in the realm of lipid genetics, the study of the complex traits of BP and essential
hypertension has often been influenced by earlier work on more severe monogenic
forms of hypertension and hypotension. This earlier research identified functional
mutations influencing mineralocorticoid activity, renal sodium reabsorption, and
the renin-angiotensin-aldosterone system, which subsequently cause physiological
imbalances presenting as abnormal BP. As with lipids, however, these rare syndromes account for only a small fraction of the population burden of hypertension,
and studies of the genes associated with these Mendelian forms suggest that they
contribute little to population hypertension risk [29]. Given the complexity of BP
homeostasis, it is likely that genes influencing the central nervous system, endocrine system, vasculature, and blood also play a role in the phenotype. Early studies
of common variants on BP-related traits were plagued by low statistical power, and
heterogeneous ascertainment, comorbidities, treatment, and phenotype definitions
(e.g., office BP, ambulatory BP, hypertension defined with different cutpoints, etc.)
that made comparison, replication, and meta-analysis difficult. More recently, GWAS
with sufficient statistical power and comparable phenotypes have found significant
associations between common variants and BP-related traits. Two large GWAS consortia joined forces to form the International Consortium for Blood Pressure to perform a mega-meta-analysis on a discovery-phase sample of >79,000 individuals
of European decent with follow up replication in >200,000 individuals from diverse
ancestral populations [30]. Twenty-nine loci were associated with SBP, DBP, and
hypertension. However, these statistically significant associations illustrate dramatically a conundrum that has been called the problem of missing heritability: the
29 BP loci discovered in the mega-meta-analysis account for less than 1 % of
the trait variance, leaving unexplained the remaining 2959 % of variation
123
attributable to genetic factors. This is a phenomenon that has been widely reported
in studies of common genetic variation (i.e., GWAS) of most presumed polygenic
traits.
The majority of successful BP and hypertension genetic association studies have
been conducted in cohorts of European origin. GWAS in non-European populations
have also been conducted; however, fewer significantly-associated loci have been
discovered, probably because of much smaller sample sizes [31]. Many of the genes
identified in studies of BP-related traits in non-European populations point to an
important role of natriuretic factors and their precursors (e.g., NPPA, NPPB,
GUCY1A3, etc,) and novel renal genes (e.g., PLCE1, SLC4A7) [32].
Cardiovascular Pharmacogenetics
The field of pharmacogenetics concerns itself with interactions between drug therapies
and genetic variants that result in interindividual variation in response to a drug.
This variability of response is of interest with respect to both safety and efficacy.
Because the variant-drug interactions that result in adverse reactions typically have
large effect sizes, pharmacogenetic GWAS of drug safety can often be conducted with
considerably smaller samples than the complex disease phenotypes discussed above.
These variants are more likely to be rare, and because the drugs have only recently
been used in large populations, natural selection hasnt yet had an impact on them.
Pharmacogenetic biomarkers have been identified for adverse reactions to a number
of cardiovascular drugs. To date, pharmacogenetic research on the antithrombotic
drugs clopidogrel and warfarin has had the greatest translational impact. Clopidogrel
is a prodrug that requires enzymatic activation by cytochrome P450 2C19 (encoded
by CYP2C19) [33]. A number of loss-of-function variants in CYP2C19 can lead to
reduced production of the drugs active form with a consequent reduction in its antiplatelet effects. Up to 70 % of individuals with Asian ancestry and approximately
2530 % of those with European and African ancestry carry at least one CYP2C19
allele that is non-functional [33]. In 2010, relying on internal and published literature,
the US Food and Drug Administration (FDA) issued a black box warning on the
clopidogrel product label informing clinicians of potentially reduced efficacy of the
drug as function of CYP2C19 genotype. The label does not mandate genetic testing,
but it does outline risks associated with particular variants. Subsequent research on
clopidogrel pharmacogenetics called into question the value of genotype-guided
dosing: one meta-analysis found associations between clopidogrel CYP2C19 lossof-function alleles and responsiveness to the drug but found no significant association
between genotype and cardiovascular events [34]. A recent update of therapeutic recommendations issued by the Clinical Pharmacogenetics Implementation Consortium
acknowledged that there was an absence of randomized clinical trial evidence that
CYP2C19 genotyping improves outcomes. However, this group also acknowledged
that genotype-guided therapy was an option for clinicians. In general, this group
recommended that standard clopidogrel dosing be used for those with extensive or
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125
disease and associated risk factors. In some cases, the findings of genetics researchers have been translated into improved clinical care. It should be evident from the
above discussion, however, that the promises of personalized medicine have yet to be
fully realized. In many cases, the aggregate contributions of the genetic associations
reported to date explain only small fraction of the trait variability; this has made
translation to clinical utility difficult. But every obstacle encountered in the journey
from bench to bedside represents a net gain in our more general understanding of
disease genetics: the common disease/common variant hypothesis has been problematized; our understanding of the relative importance of coding and non-coding
regions of DNA has been refined; our consideration of epigenetics, mitochondrial
DNA, and other factors that lie outside the classic genetic paradigm has blossomed;
the care with which disease phenotypes are defined and measured has increased, the
importance of gene-environment interactions has been underscored; and the necessity of careful coordination among studies has become apparent. We are poised on
the cusp of the next methodological revolution in the field: soon our gaze will extend
beyond the mere millions of variants typed with genotyping arrays and limited
sequencing to billions of nucleotides as whole-genome sequencing becomes economically feasible in large study populations. This deluge of data will no doubt present both logistical and statistical challenges, but it will also offer unprecedented
opportunities for the study of cardiovascular disease.
The American Heart Association recently issued a list of recommendations to
be put into practice now to foster discovery and optimize patient care [32]. These
included:
Basic research: Foster continued research that characterizes genetic associations
with CVD, with attention paid to ancestry/race, gene-environment (including
drug) interactions, and functional follow up studies.
Translational research: Foster research that accelerates the translation of genetic
discoveries to prevention and treatment of CVD.
Implementation research: Foster research that anticipates clinical genetic screening, including research that establishes effective screening triggers, sets appropriate
genetic laboratory oversight, and assesses the potential cost effectiveness of genetic
screening programs.
Education: Train clinicians to understand genetic testing and its use; train
researchers in genetics, computational biology, and statistical genetics.
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Introduction
CVD ranks number one in all-cause mortality in women around the world annually
[1]. According to the World Health Organization (WHO) 2008 data, one-third of
women died from heart attacks due to ischemic heart disease (IHD) and strokes
globally. Although men and women share similar health challenges, the presentation of CVD in women deserves additional attention. Emerging studies have shown
that women do not present or respond the same way as men do. Unfortunately,
though public awareness of CVD in men has increased over the years, women
remain understudied and under-promoted. The presentation of CVD in women
warrants further study due to its growing incidence and prevalence in the aging
female population around the world.
129
130
Risk Factors
There are numerous non-modifiable risk factors of CVD, such as age, race, and
genetic factors. However, 90 % of CVD in women is attributable to modifiable risk
factors, which stratifies women into three risk categories: at high risk, denoting a
10-year predicted risk for CVD >20 % based on documented CVD, diabetes mellitus, or end-stage or chronic kidney disease; at risk based one or more CVD risk
factors, metabolic syndrome, or poor exercise tolerance on treadmill testing or
evidence of subclinical atherosclerotic disease; and at optimal risk, denoting the
absence of CVD risk factors or a healthy lifestyle in the setting of a Framingham
risk score <10 % [2]. Modifiable CVD risk factors include dyslipidemia, hypertension, smoking, diabetes, obesity, physical inactivity, stress, diet, alcohol consumption,
pregnancy-related complications, and most recently autoimmune disorders, such as
systemic lupus erythematosus and rheumatoid arthritis [2, 3].
Hypertension
Hypertension is a well-established risk factor that contributes to CVD in both men
and women, and numerous studies have demonstrated that treatment of hypertension leads to improved CVD outcomes. In a prospective study among 13,740 Dutch
women, those with SBP >185 were 3 times more likely to develop CVD compared
to women with SBP <135 [4]. In the Womens Health Initiative (WHI) study, 17 %
of women were noted to have isolated elevated systolic BP, of which treatment in
the elderly showed a profound reduction in the risk of hemorrhagic stroke within the
first year and ischemic stroke in the second year of treatment of hypertension [5].
The JNC 8 (Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure) recommends the goal BP <150/90 for elderly
patients age 60 years or older without diabetes mellitus or chronic kidney disease
(CKD) and goal BP <140/90 in younger patients without major co-morbidities or in
elderly patients who have diabetes mellitus or CKD [6].
Dyslipidemia
Dyslipidemia also remains a known high-risk contributor to IHD in both men and
women. Even though a high LDL predisposes both males and females to high incidence of CVD, a follow-up study from the Lipid Research Clinic showed that low
HDL is actually the most significant predictor of death in IHD in women [7]. In addition, the Atherosclerosis Risk in Communities (ARIC) study showed that elevated
triglyceride levels greater than 400 mg/dL increases the risk of CVD specifically
in older women, but not in men [8]. However, current guidelines by the National
Cholesterol Education Program (NCEP) do not include hypertriglyceridemia as a
131
primary risk factor for CVD. Surprisingly, the ARIC study did not reveal significant
findings with dyslipidemia and its association with incidence of ischemic stroke,
though it did show a decreased risk of an event in women with high HDL [9]. Recent
guidelines released from the ACC/AHA recommend moderate to high intensity
statin for patients with clinical atherosclerotic cardiovascular disease (ASCVD),
with LDL-C >190 mg/dL. or with diabetes mellitus (aged 4075 years) and 10-year
ASCVD risk score of >7.5 %, based on pooled cohort equations [10].
Diabetes
Diabetes is the strongest risk factor for CVD in women. CVD mortality in diabetic
women is 35 times higher than their non-diabetic peers compared to 23 times in
diabetic men when compared to non-diabetic peers [11]. In addition, diabetic women
are more likely to develop CVD and subsequent heart failure than diabetic men.
Unfortunately, a significant 43 % relative reduction in CVD mortality in diabetic
males has not been the same for diabetic females in the last 30 years [12]. Diabetic
females are treated less aggressively in terms of achieving goal HgbA1c and are at
increased risk for hypertension, low HDL, and elevated triglycerides than diabetic
males [13]. Women with gestational diabetes are at increased risk of developing
diabetes later in life and warrant routine screening.
Smoking
In addition, the NHS also noted that an increasing daily number of cigarettes is associated with an increased risk of CVD, in which 15 cigarettes daily were associated
with a two- to threefold increase, while 20 cigarettes daily with a sixfold increase [18].
132
Similarly, smoking is associated with a twofold increase with ischemic stroke and 7.2
times increase in risk when used with oral contraceptives [19]. Surprisingly, CVD
mortality is decreased by 24 % within 2 years of tobacco cessation and essentially the
same as non-smokers after 1014 years.
Autoimmune Diseases
In the Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease
in Women2011 Update, autoimmune collagen-vascular disorders, such as systemic lupus erythematosus and rheumatoid arthritis, were added as risk factors for
CVD risk in women [2]. In addition to accelerated atherosclerosis due to underlying
inflammation and possibly due to chronic steroid use, women with systemic autoimmune disorders are also at risk of electrical disturbances including sinus tachycardia, transient atrial fibrillation, complete heart block, and ventricular arrhythmias
[24]. Fibromuscular dysplasia, antiphospholipid antibodies syndrome, Takayasu
arteritis, and SICRET (Small Infarcts of the Cochlear, Retinal, and Encephalic
Tissues) syndrome all contribute to stroke risk in younger women.
Pregnancy-Related Complications
Pregnancy-related complications are associated with increased risk of CVD.
Peripartum cardiomyopathy, though rare in Western society (occurring 1 in 2500 to
4000 live births) is much more common in developing countries (1 in 1000 live
births in South Africa and 1 in 300 in Haiti). It usually occurs within 3 months of
delivery and only half of those patients recover normal heart function. Though pregnancy is not associated with an increased risk of stroke, etiologies include eclampsia
(24 % pregnant women with cerebral infarction and 14 % with intracerebral hemorrhage), choriocarcinoma, peripartum cardiomyopathy, and amniotic fluid embolism.
133
Menopause
The incidence of CVD in postmenopausal women is comparable to age-matched
men. Estrogen deficiency is associated with worsening of CVD risk factors, including a shift to adverse lipid profile, coagulability, and increased arterial stiffness [28].
However, exogenous supplementation with hormone therapy in post-menopausal
women has not been shown to be beneficial. The Womens Health Initiative (WHI),
a 15-year study sponsored by the National Institute of Health (NIH), revealed that
the use of combined hormone replacement therapy (HRT)conjugated equine
estrogens, 0.625 mg/day, and medroxyprogesterone acetate, 2.5 mg/dayin menopausal women increased the incidence of MI by 29 % and CVD by 22 % in comparison those who did not receive hormones [29]. Similarly, the use of combined
HRT was associated with a hazard ratio of 1.44 for ischemic stroke and 0.82 for
hemorrhagic stroke. It also increased the risk of dementia and mild cognitive impairment. Results of the more recently conducted randomized controlled trial in healthy
women with no established CVD showed that hormone therapy may be safe if
started early in menopause for treatment of symptoms.
Presentation
Men and women can present with both typical and atypical symptoms of IHD. While
men present with typical severe radiating sub-sternal chest pressure associated with
nausea, many women experience more atypical symptoms such as mild chest pain,
134
fatigue, nausea, shortness of breath, upper back pain, feelings of anxiety, or loss of
appetite. Interestingly, in a recall study of 515 women, 47 % of women who experienced a myocardial infarction did not experience any episodes of chest pain prior to
the ischemic event [30]. Unfortunately, a national survey conducted on 1000 women
revealed that although more than two-thirds of women were aware of the classic
signs of a heart attack (chest pain or tightness with radiation to arm or jaw associated with shortness of breath), only 10 % knew of the symptoms more likely to
affect women (light-headedness, nausea, and fatigue). It should also be noted that
women with persistent chest pain and non-specific chest pain are also at higher risk
of MI [31, 32].
A condition that can mimic the presentation of MI is Takotsubo cardiomyopathy
(ie., Broken Heart Syndrome or stress cardiomyopathy). Patients often present with
chest symptoms with troponin leak and a spectrum of EKG changes. However, there
is an absence of obstructive CAD on angiography and is primarily characterized by
apical wall ballooning, although wall motion abnormalities at base and midventricular have also been described. It is often associated with a high emotional
stress, catecholamine-excess state. In majority of cases, the left ventricular dysfunction is transient and resolves over 3 to 6 months [33].
Gender differences are present in cerebrovascular disease (Table 1). Women tend
to have more pre-stroke comorbidities than men do, since they typically present
with an older age at onset (an average of 4 years) and are more likely to have hypertension and atrial fibrillation. In the WHI, 18.7 % of all strokes were hemorrhagic;
the ARIC Study found that the 30-day age and race-adjusted case-fatality in women
was increased in hemorrhagic stroke by 4.7 times when compared to ischemic
stroke. In addition, several studies have found that women have a higher incidence
of cardioembolic stroke than men have, likely due to increased prevalence of atrial
fibrillation in older women. Stroke is characterized by the sudden onset of symptoms such as unilateral numbness or weakness, confusion, trouble seeing in one or
both eyes, loss of balance or coordination, or severe headache with no known cause.
Diagnostic Testing
Exercise Treadmill Testing (ETT)
An ETT is usually recommended as the first test for IHD to assessment. The current
ACC/AHA guidelines recommend ETT for evaluation of chest symptoms in patients
at risk for CAD (Class IIb) and vasospastic angina (Class IIa). However, it can be of
a lower utility in women because of its lower specificity and sensitivity in detecting
obstructive coronary artery disease (CAD) in women compared to men. This may
be due to lower prevalence of obstructive CAD in women, increased frequency of
non-specific ST changes in baseline EKGs compared to men (32 % versus 23 %,
respectively), and inability to achieve maximal functional capacity secondary to
increased prevalence of obesity and osteoarthritis in women [34].
135
Women
More
More
More
More
Greater
Men
More
More
More
More
More
More
More
More
More
Greater
Greater
More
Non-Invasive Imaging
Stress-induced changes in non-invasive cardiac imaging are better markers in
assessing for IHD in women. In a study with more than a 1000 women with suspected obstructive CAD, stress echocardiography had a high sensitivity (8189 %)
and high specificity (86 %) in patients with multi-vessel CAD in its ability of
predict IHD [35]. In addition, a stress echo can be conducted in various ways, such
as a treadmill, bicycle, and pharmacologically. Exercise stress testing is encouraged
as it can also assess the patients functional capacity and exercise tolerance. The
WOMEN (What is the Optimal Method for Ischemia Evaluation in Women?) trial,
in which 824 symptomatic women with suspected obstructive CAD were randomized to ETT or exercise myocardial perfusion imaging (MPI), found at 2 years that
there was no significant difference in major cardiac events predicted by either
modality [36].
Myocardial gated single-photon emission computed tomography (SPECT) is
recommended for both men and women with CVD risk factors, and allows for
visualization of global or regional perfusion defects. The accuracy of the MPI is
comparable between women and men, and is advantageous in patients who have
poor exercise tolerance. However, limitations in the MPI include high rate of
false positives in global perfusion defects, patients with small hearts, and breast
tissue artifact.
136
Cardiac computed tomography (CT) and magnetic resonance imaging (MRI) are
newer imaging modalities that assess cardiac ischemia different from coronary
angiography. Cardiac MRI can assess for subendocardial ischemia, one of the initial
manifestations of cardiac ischemia, and can explain the etiology of chest pain in the
setting of non-obstructive CAD. Coronary computed tomography angiography
(CCTA) assesses coronary atherosclerosis, and is often used in the place of invasive
coronary angiography. In a large, multicenter prospective international cohort study,
the CONFIRM trial demonstrated that CCTA improves the ability to predict mortality
and non-fatal MI in symptomatic patients with suspected obstructive CAD [37].
Multiple studies have shown that CCTA can detect significant stenosis in smaller
coronary arteries and side branches with 8694 % sensitivity and 9397 % specificity, such that it can rule out the presence of hemodynamically significant CAD [38].
However, while the CCTA is an excellent tool to detect anatomic CAD severity, it is
unable to assess whether a lesion causes ischemia [31, 32]. To help with risk stratification in primary prevention, very low dose radiation testing with electron beam
CT (EBCT) can assess the amount of calcium in coronary arteries, in which a
calcium score between 100 and 400 is associated with increased obstructive CAD.
137
Stroke Diagnostics
On arrival to the hospital with stroke symptoms, women have longer door-to-scan
times than men. A European study revealed that after age-adjustment, women are
less likely than men are to receive imaging of brain, carotid ultrasound, or echocardiograms [43].
Treatment
Medical Therapy
Women are less likely to be medically optimized after MI or stroke compared to
men. Aspirin use is associated with a reduction in future events in women with a
history of CVD, such as unstable angina and acute MI, and stroke. It is recommended for primary prevention for MI in women after age 65 and for stroke prevention after age 50 [44]. However, women are less likely to be discharged on
dual antiplatelet therapy, ACE-inhibitor, or statins after an acute event, such as a
stroke of MI.
Many CVD medications found to be life-saving have not been adequately tested
in women likely due to the under-representation of women in most trials. Betablockers have been found to reduce the risk of subsequent MI by 25 % in both
women and men (though not statistically significant in women, likely due to the
small sample size) [45]. Similarly, the Heart Outcomes Prevention trial demonstrated a reduction in death, MI, and stroke equally in women and men with vascular
disease or diabetes with the ACE inhibitor or ARB therapy. If an ACE-inhibitor is
used in a woman of child-bearing age, a discussion regarding its teratogenic effects
is warranted.
HMG-CoA reductase inhibitors (or statins) are commonly prescribed for dyslipidemia though their pleotropic effects have been found to extend beyond lowering
the cholesterol. Statins have been observed to improve endothelial dysfunction and
myocardial perfusion, in which treatment for 612 weeks of fluvastatin was shown
to significantly improve myocardial perfusion in ischemic segments [46]. In addition, long-term therapy with statin in the CARE trial lowered hs-CRP levels in postinfarction patients though the effects have not been shown to correlate with LDL-C
levels [34]. The Heart Protection Trial Study (HPS) demonstrated that statins led to
a prominent reduction in all-cause mortality in women and a 24 % reduction in
vascular events [4].
138
Stroke Interventions
Interestingly, in a study by Patrick et al. of patients hospitalized for ischemic stroke,
women underwent fewer cerebral angiography (7.2 %) and carotid endarterectomy
(5.7 %) than did men (11.8 % and 10.6 %, respectively), but the differences were not
significant after the increased prevalence of carotid disease in men were adjusted
[49]. Both men and women benefit equally from carotid endarterectomy. In addition, most studies show that women were less likely to receive alteplase than men.
An analysis of a Michigan registry study of ischemic stroke patients revealed that
the adjusted odds ratio for alteplase treatment in women was 0.56 (95 % CI 0.40.9)
compared to men [50].
139
Conclusion
In the setting of the growing prevalence of cardiovascular disease in women globally, gender differences in the presentation, evaluation and treatment of CVD are
notable and warrant more extensive studies. Women are often overlooked in diagnostic studies and interventions when presenting with symptoms compared to men.
Promoting public awareness and education of the CVD in women are crucial for
prevention and timely treatment.
Acknowledgement This work was supported by contracts from the National Heart, Lung
and Blood Institutes, nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164,
K23HL105787, grants U0164829, U01 HL649141, U01 HL649241, T32HL69751, R01-HL090957,
1R03AG032631 from the National Institute on Aging, GCRC grant MO1-RR00425 from the
National Center for Research Resources and grants from the Gustavus and Louis Pfeiffer Research
Foundation, Danville, NJ, The Womens Guild of Cedars-Sinai Medical Center, Los Angeles, CA,
The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA, and QMED, Inc.,
Laurence Harbor, NJ, the Edythe L. Broad Womens Heart Research Fellowship, Cedars-Sinai
Medical Center, Los Angeles, California, the Barbra Streisand Womens Cardiovascular Research
and Education Program, Cedars-Sinai Medical Center, Los Angeles, The Society for Womens
Health Research (SWHR), Washington, D.C., and the Linda Joy Pollin Womens Heart Health
Program, Los Angeles, C.A.
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and its surgical and medical management, 19741979. The Coronary Artery Surgery study.
Circulation. 1982;66:III1623.
Patrick SJ, Concato J, Viscoli C, Chyatte D, Brass LM. Sex differences in the management of
patients hospitalized with ischemic cerebrovascular disease. Stroke. 1995;26:57780.
Gargano JW, Reeves MJ. Sex differences in stroke recovery and stroke-specific quality of life:
results from a statewide stroke registry. Stroke. 2007;38:25418.
Acute Rheumatic fever (ARF) and its chronic sequel, rheumatic heart disease
(RHD) result from an autoimmune disease that starts with an infection caused by
Streptococcus pyogenes (Group A streptococciGAS) and remain the most common cause of preventable childhood heart disease worldwide. It follows a nontreated throat infection in susceptible children and teenagers (3- to 19-years old); and
strongly relates to socioeconomic and environmental determinants, such as overcrowding, poor standard of living, poor access to medical care and inadequate
expertise of health-care teams [1, 2].
Epidemiology
Despite being considered today as virtually eliminated [3] after a documented
decrease in the incidence of ARF in developed countries during the past 6 decades,
RHD remains a medical and public health problem, especially in low and middleincome countries and in indigenous populations, where it causes disability and
143
144
premature death in children and young adults in their most productive years [1].
As stated recently, RHD does not get the same attention as cancer as a chronic noncommunicable disease (NCD) because it is a disease of the bottom billion of the
poorest people in the worldone of the most neglected of the neglected diseases [2].
In 2005, the World Health Organization (WHO) estimated a prevalence of at least
15.6 million cases of RHD worldwide, with 282,000 new cases (ARF) and 233,000
deaths related to RHD each year. The burden of stroke due to RHD in less developed countries was also considered: 144,000360,000 new strokes each year [4].
However, these are conservative assumptions, and future incoming-data will show
these figures to be dramatically underestimated [5].
In Brazil, estimates based on WHO epidemiological model and data from the last
Census in 2010, appointed to around 30,000 new cases of ARF each year, of which
around 12,800 can develop RHD [1, 6]. Brazilian official figures have shown a significant reduction in the number of hospitalizations due to ARF and RHD in the last
10 years, however, in 2012, 2713 ARF and 4268 RHD hospital admissions were still
reported [7], since, similar to other countries, Brazil has not yet implemented a
national register system and a RHD control program. Underreporting of cases and
difficulties in access to hospital admission, especially for adolescents and young
adults, are very common.
In a recent linkage study with 53,210 Brazilian in-hospital children and adolescents admitted for heart failure (HF) from 2001 to 2007 the survival analysis for the
ARF/RHD patients showed only 61 %, 55 % and 36 % survival rate at 1, 2 and
7 years, respectively, with a hazard ratio observed for RHD patients death of 15.5.
These poor results were strongly related to social conditions measured by human
development index (HDI) of the patients residence [8].
Another Brazilian study with 100 RHD low-income patients in Sao Paulo analyzing the entire course of the disease concluded that costs of ARF/RHD amounted to
approximately 1.3 % of the annual family income in this population. Direct and
indirect costs, such as school failure rate of 22 %, 23 % parents work absenteeism,
about 5 % lost jobs, and the intangible costs associated with RHD, resulting from
premature disability and death, and loss of intellectual opportunities, with its adverse
effects on the socioeconomic family and society development. The estimated annual
cost of RF for society in Brazil was estimated in 2001 as US$ 51,144,347.00 [9].
More recently, advocacy groups, including the World Heart Federation (WHF),
have put greater efforts into rectifying this neglect disease [2]. In April 2013, the
WHF issued a statement of commitment to the strategic objective of a 25 % reduction in premature deaths from ARF and RHD among individuals aged <25 years by
the year 2025. To achieve the objective of controlling RHD and eliminating ARF,
five strategic targets have been identified: (1) Comprehensive register-based control
programs; (2) Global access to Benzathine penicillin G; (3) Identification and development of public figures as RHD champions; (4) Expansion of RHD training
hubs; and (5) Support for vaccine development [10].
A recent editorial about RHD discussed that the challenge regarding RHD does
not relate to knowledge of the disease, but to the implementation of measures to
control the disease globally [5], which depends on the political will of the governments and inclusion of ARF in public health policies. It requires advocacy, awareness, commitment, coordination, and resources [5].
145
Pathogenesis
The pathogenesis of ARF/RHD is complex and both environmental and genetic
factors contribute to its etiology, but still remains incompletely understood [11].
Streptococcus, in the appropriate condition, triggers the pathogenic sequence that
starts with pharyngitis, leading, in a small percentage of cases (1 to 5 % of susceptible
children), to ARF which, in about 60 % of the cases, will develop life-threatening
valve lesions characteristic of RHD [2].
Several genes associated with RHD have been described, related to both the
innate and adaptive immune responses. The susceptibility of developing ARF/RHD
is associated with some alleles of HLA (human leukocytes antigens) class II genes
(DRB1, DQB and DQA), as well as with TNF- gene which are all located on
human chromosome 6. HLA alleles are involved in antigen recognition by T lymphocytes through the T cell receptor (TCR). TNF- gene encodes the inflammatory
TNF alpha protein, which is involved in the inflammatory process mediating hearttissue lesions in RHD. Several other associations have been established through
single nucleotide polymorphisms (SNPs) for genes code for other proteins also
involved with the immune response (innate and adaptive pathways) [11].
Molecular mimicry between streptococcal antigens and human proteins is central to RHD pathogenesis, and mainly cardiac myosin epitopes and vimentin seem
to be the major target antigens. Autoreactive T cells (CD4+) migrate from the
peripheral blood to the heart and proliferate in the valves in response to stimulation
with specific cytokines. High TNF alpha, interferon gamma, and low IL4 are found
in the rheumatic valve. IL-4+ cells are found in the myocardium; however, these
cells are very scarce in the valve lesions of RHD patients. IL-4 is a Th2-type cytokine and plays a regulatory role in the inflammatory response mediated by Th1
cytokines. These findings indicate that the Th1/Th2 cytokine balance has a role in
healing myocarditis, while the low numbers of IL-4-producing cells in the valves
probably induce progressive and permanent valve damage [11].
Diagnosis
The diagnosis of ARF is essentially clinical and laboratory exams are not pathognomonic of the disease, only contributing to confirm the inflammatory process and the
streptococcal infection. Clinical diagnosis of carditis is usually made by the auscultation of a pathological mitral regurgitation (MR) murmur. Jones criteria [12] created in 1944, are characterized in major and minor, and represent the gold standard
for the diagnosis of the first attack. They are an epidemiological and not clinical tool
for the initial attack and have been revised, modified and updated by the American
Heart Association [13, 14] and by the WHO [1] (Tables 1 and 2).
For the initial attack, the presence of two major manifestations or of one major
and two minor manifestations supported by the evidence of a preceding GAS
infection indicates high probability of ARF. For the diagnosis of recurrences in a
146
Table 1 Modified Jones
criteria for the diagnosis of
rheumatic fever (1992)
Minor criteria
Fever
Arthralgia
Elevation of inflammatory markers
(ESR, CRP)
Prolonged PR interval in the ECG
Criteria
2 major criteria or 1 major and 2 minor +
evidence of previous streptococcus
infection
2 major criteria or 1 major and 2 minor +
evidence of previous streptococcus
infection
2 major criteria + evidence of previous
streptococcus infection
No other major criteria or evidence of
previous streptococcus infection is
required
No additional criteria for the diagnosis
of RHD is necessary
patient with established RHD, just two minor criteria plus evidence of preceding
GAS infection is sufficient. The presence of chorea, insidious carditis and chronic
valve lesions are exception and do not require any other criteria to be considered as
having rheumatic fever [1].
Subclinical carditis (SCC) is also a major concern, since 16.827 % may have it.
In endemic areas, strict adherence to the revised Jones criteria can result in underdiagnosis of ARF [15]. Failure to diagnose these patients can lead to severe adverse
consequences since prophylaxis will not be started [16, 17]. In Australia, diagnosis
rates increased significantly when monoarthritis and SCC were included as major
criteria and low-grade fever (37.5) as a minor criterion [17].
The disease usually presents with an acute febrile onset, with variable combinations of arthritis, carditis, chorea and skin manifestations. Published criteria are
useful for epidemiological purposes, but clinical judgment should prevail, especially in areas of the world where RHD is still common.
147
Evidence of previous GAS infection is demonstrated by increased or rising antistreptolisin O titer or other antibodies or a positive throat swab for GAS. Inflammatory
markers, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
are usually elevated. Though unspecific, they can add in monitoring the inflammatory process and its remission.
Carditis
It is the most serious manifestation of the disease, and the only one that leaves
sequelae. Clinically, it is present in 4070 % of the cases, however the percentage is
much higher when the diagnosis is made by echocardiography [18, 19]. Although
there is a pancarditis (endocardial, myocardial and pericardial involvement), valve
lesions are the ones responsible for the clinical presentation and prognosis.
Myocarditis can be diagnosed by histology, but it does not cause HF and systolic
function is usually preserved at the initial presentation. Pericardium involvement is
not common, does not happen in isolation and does not lead to constriction, but the
presence of a pericardial effusion may help confirm the diagnosis [20].
The most common valve lesion is MR and its pan-systolic murmur does not
indicate permanent lesion. Aortic regurgitation (AR) is less common and stenotic
lesions do not happen in the early stage of the disease. Tricuspid regurgitation may
occur in acute carditis secondary to pulmonary hypertension.
The severity of carditis can vary from SCC to a fulminant form. In SCC, cardiovascular exam, X Ray and ECG are normal (except for a prolonged PR). Doppler
echocardiogram is essential for its diagnosis, as it can detect pathological mild MR
and/or AR [21]. Mild carditis is present when there is tachycardia disproportional to
the degree of fever, diminished S1 and MR systolic murmur. Chest X Ray and ECG
are normal (except for a prolonged PR), but Doppler echocardiogram shows mild or
moderate regurgitations and a normal-sized left ventricle (LV). In the moderate
148
Chorea
Sydenhams chorea may occur in association with other manifestations, but it may
also be the sole expression. It is a neurological disorder characterized by rapid and
involuntary movements, which are more common during stress and cease during
sleep. Its incidence varies from 5 to 36 % and it occurs predominantly in female
children and adolescents [20].
Eritema Marginatum
It is a rare skin manifestation (415 % of the patients), generally occurring at the
beginning of the disease. It is usually associated with carditis, but not with its severity, being characterized by a non-itchy pink-red lesion, which predominantly affects
the trunk and spares the face. It may disappear within hours and it is difficult to
detect in dark-skin patients [20].
Subcutaneous Nodules
They are firm and painless, varying greatly in size, and representing a rare manifestation (25 %) of the disease. The overlying skin is not inflamed and they are usually located over bones surfaces or tendons and best detected by palpation and not
inspection. Their presence is strongly associated with severe carditis [20].
Minor Manifestations
They are unspecific and only when associated with major criteria and evidence of
previous GAS infection help to establish the diagnosis. Fever and tachycardia out of
proportion to the fever are usually present. Fever is usually of low grade when there
is carditis without arthritis, and absent in isolated chorea [20].
149
After recovery from the initial episode, 72 % of patients will develop valve heart
diseases [18]. Recurrence of the disease can lead to progression of valve lesions
with all its consequences, as HF, atrial fibrillation, stroke, infective endocarditis and
pregnancy-related complications. With progression of the disease, cardiac surgery
becomes mandatory and, if not performed, premature death from RHD and its complications is frequent, with some countries presenting the unacceptable mean age of
death <25 years [22, 23]. Otherwise, patients under regular secondary prophylaxis
may present recovery on the severity of valve lesions.
ECG
ECG is unspecific, since it can be normal in the presence of carditis. A prolonged PR
interval (minor sign) can be present in the absence of carditis. Sinus tachycardia, ST-T
abnormalities, low QRS and T amplitude in the frontal leads can be present [20].
Echocardiogram
Although echocardiogram has been shown to be much more sensitive in the diagnosis
of rheumatic lesions, screening by echocardiography is not always feasible, especially in low-income countries, where the disease is usually more prevalent. Besides,
physiological regurgitations in normal individual can be interpreted as secondary to
RHD. To avoid this misclassification, regurgitation should be considered abnormal
only in the presence of morphological valve abnormalities [21] (Table 3).
Since secondary prevention can avoid adverse outcomes, early echocardiographicbased diagnosis of valve lesions by active surveillance strategies has been shown in
several countries to be of major importance [2427].
MR is the most frequent lesion in ARF, being present in up to 94 % of the cases.
Valve thickening and focal nodules in the distal portion of the leaflets are frequent
and disappear in the follow-up [28]. AR is not a frequent lesion in ARF, but in males
it can occasionally be an isolated lesion. Stenosis is a late finding. LV dilation may
be present and both cardiomegaly and valve regurgitation can disappear. Systolic
function is usually preserved and HF, when present, is considered nowadays to
occur due to valve lesion and not to myocardium involvement.
In patients with chronic RHD, recurrence is always associated with carditis,
which can be expressed as pericarditis, new or worsening of a pre-existing valve
regurgitation, increase in cardiac silhouette and HF. Size and function of cardiac
chambers, left valve abnormalities (stenosis and regurgitation), tricuspid lesion
(much less frequent) and associated pulmonary hypertension can all be adequately
detected by echocardiography in RHD.
Features in the AV
Irregular or focal thickening
Coaptation defect
Restricted leaflet motion
Prolapse
150
M. de Melo Barbosa et al.
151
Treatment
General Measures
Treatment aims to suppress the acute inflammatory process, minimizing clinical
repercussions on the heart, joints and central nervous system, in addition to eradicating GAS infection and promoting relief of main symptoms [20, 29].
Absolute bed rest is no longer recommended, except in the presence of carditis,
when bed rest, at least during the symptomatic stage, is recommended. Return to
normal activities should be gradual depending on the improvement of symptoms
and normalization or marked reduction of inflammatory activity tests.
In cases of high temperature, paracetamol is recommended as a first option, and
dipyrone as a second. Anti-inflammatory drugs, including acid acetylsalicylic, are
not indicated before the diagnosis of ARF is confirmed [20].
Therapeutic Modalities
Acute carditis has generally been treated with steroids even though they have
no effect on the progression of RHD. Nevertheless, in the setting of severe, potentially life-threatening HF, steroid administration is largely employed [20, 2931].
Treatment of cardiac manifestations follows established guidelines, including management of HF and severe valve regurgitation. Digitalis can be used but with special
attention because of the risk of development of heart block. Cardiac surgery should
be avoided whenever possible during ARF, being indicated only in the presence of
severe valve regurgitation with HF refractory to drug therapy [20, 29, 31].
Treatment for chorea is indicated only in severe forms, when uncoordinated
movements interfere with usual activity of the patients. Drugs used to control chorea symptoms are haloperidol, valproic acid, and carbamazepine. Small series have
studied corticosteroids, along with plasmapheresis and intravenous immunoglobulin,
to assess their influence on the severity and time course of symptoms, but there is
not enough evidence for the indication of these therapies [20, 29].
152
Varies by drug
300 mg PO
500 mg PO day 1
250 mg PO days 25
250 mg PO
Dose
<20 kg: 600,000 U IM
20 kg: 1,200,000 U IM
500 mg PO
500 mg PO
100 mg/kg/day PO
Clarithromycin
Penicillin V
Amoxicillin
Ampicilin
Penicillin allergic
Narrow-spectrum cephalosporins
Clindamycin*
Azithromycin
Antibiotic
Benzathine penicillin G
Twice
daily
Varies by drug
Twice daily
Daily
2 or 3 times daily
Thrice daily
Thrice daily
Frequency
1 time
10
days
10 days
10 days
5 days
10 days
10 days
10 days
Duration
Acutely only
154
Secondary Prevention
Prevention of recurrent episodes of GAS pharyngitis is the most effective method to
prevent the development of severe RHD [20, 29]. Recurrences of ARF are most
common in patients who have had carditis during their initial episode. A recurrent
attack can be associated with worsening of the severity of RHD that developed after
a first attack, or less frequently with the new onset of RHD in individuals who did
not develop cardiac manifestations during the first attack.
For these reasons, prevention of recurrent ARF requires continuous antimicrobial
prophylaxis. The preferred method of prophylaxis is with Benzathine penicillin G,
1.2 million units intramuscularly every 3 weeks (Table 5) [20, 30].
Successful oral prophylaxis depends primarily on patient adherence to prescribed
regimens. The recommended oral agent is V penicillin. The dosage for children and
adults is 250 mg twice daily (Table 5). There are no published data about the use of
other penicillins, macrolides, azalides, or cephalosporins for the secondary prevention of rheumatic fever. If the patient is allergic to penicillin, sulfadiazine is recommended. Although sulfonamides are not effective in the eradication of GAS, they
prevent infection. For the patient who is allergic to both penicillin and sulfadiazine,
an oral macrolide (erythromycin or clarithromycin) [20, 29].
Recurrences are uncommon after 5 years following the first episode and in
patients over 25 years of age. Prophylaxis is usually discontinued after these times,
except in groups with a high risk of streptococcal infection, such as parents or teachers of young children, nurses, military recruits, etc.
Secondary prevention of RF depends on whether carditis has occurred (Table 6).
If there is no evidence of carditis, preventive therapy can be stopped at age 21.
If carditis has occurred but there is no residual valve disease, it can be stopped at
10 years after the first episode. If carditis has occurred with residual valve involvement,
it should be continued for 10 years after the last episode or until the age of 40 years,
if the patient is in a situation in which re-exposure would be expected [29]. Lifelong
prophylaxis should be considered in high-risk patients according to the severity of
valve heart disease and exposure to group A streptococcus, in a situation in which
penicillin G
Penicillin V
Penicillin allergic
Sulfadiazine
Penicillin and sulfadiazine allergic
Erythromycin
Dose
<20 kg: 600,000 U IM
20 kg: 1,200,000 U IM
250 mg PO
Twice
1g
Daily
PO
250 mg
PO
Frequency
Every 3 weeks
Twice
daily
daily
155
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Introduction
In 1909, the Brazilian physician Carlos Chagas reported to the scientific community
the discovery of a new pathogenic agent, Trypanosoma cruzi (T. cruzi) and the previously unknown illness it caused [1]. Far from being rare, it was soon noted that the
new disease affected millions of people across nearly the entire Latin American
subcontinent. The recovery of T. cruzi genetic material from South American
159
160
Etiopathogenesis of CHD
The pathogenetic mechanisms that underlie the development of the chronic stage of
CHD have not yet been fully elucidated.
Fundamentally, CHD is an inflammatory form of dilated cardiomyopathy often
accompanied by low-intensity, although effectively relentless myocardial damage,
resulting in reactive and reparative fibrosis and progressive ventricular dysfunction [4].
Among various other particular pathophysiological characteristics germane to
CHD, several investigators have independently observed destruction of the neurons
of the cardiac intramural ganglia, particularly those of the parasympathetic subtype,
with consequent dysregulation of autonomic circulatory control. The cardiac dysautonomia observed in patients with CHD results in abolition of the overall vagal
inhibition of the sinoatrial node and also deprives such patients of the mechanism of
rapid adjustment of the heart rate to transient variations of the systemic arterial pressure and venous return. Based on those changes in the intrinsic cardiac nervous
system, characterized by the (non-exclusive) predominance of parasympathetic
denervation, the so-called neurogenic theory of CHD postulated that autonomic
imbalance accounted for a true heart disease induced by excessive adrenergic stimulation [5]. However, this theory could not be validated due to the lack of correlation
between the degree of parasympathetic denervation and the extent of myocardial
injury, among other factors [4]. Nevertheless, the hypothesis that cardiac dysautonomia may contribute to the occurrence of malignant arrhythmias and sudden death
as well as to the development of disorders of coronary microcirculation regulation,
remains attractive [4].
161
162
below, together with the all-important issue regarding the prevention of CHD development in patients with chronic T. cruzi infection.
To summarize, several crucial aspects of the etiopathogenesis of CHD have not
yet been definitively elucidated [15]. Whereas the available pathogenetic hypotheses and theories are reasonable to some extent, they lack firm support in conclusive
studies. Thus, in the course of one century of research, some negligence in the
approach to CHD pathogenesis appears to have been unavoidable. Such relative
negligence appears obvious, for example, in the fact that over one decade, some
studies and investigators insisted repeatedly in asserting certain aspects of the
pathophysiology of CHD instead of seeking to investigate more objectively and
persistently the consequences of those disorders to elucidate the prognostic meaning of the abnormalities that were already exhaustively demonstrated [16].
Prevention of CHD
Vector-borne transmission remains the main route of human infection with T. cruzi
and is usually associated with the vectors blood meals. Indeed, the hematophagous
insects defecate while sucking the hosts blood, and thus the parasites enter the
bloodstream through the skin disruption caused by the sting, or even through intact
mucous membranes close to the sting site. The insects also played a role, albeit
passive, in recently reported outbreaks of infection via the intake of contaminated
food, that is, during the preparation of food (usually during the grinding of sugarcane, aa palm, etc.) [17, 18]. As a result of the interventions that led to the eradication of the main vectors in Latin America, the oral route of transmission became the
most common route in several countries, including Brazil. The second most frequent route of transmission of infection with T. cruzi is via blood transfusions, the
prevalence of which is most likely underestimated due to poor reporting within the
medical sector [19]. This is the most pertinent route of transmission of infection in
countries where Chagas disease is not endemic, due to the lack of efficacious serologic control and the increasing number of infected immigrants from Latin America,
particularly in Europe and the United States.
The incidence of vertical mother-to-child transmission of infection through the
transplacental route is estimated to vary from 1 % in Brazil to 7 % in some areas of
Bolivia and Paraguay, depending on factors such as parasite strain, the mothers
immune status and the diagnostic technique used to detect infection [20]. Transmission
is less often due to transplantation of organs donated by infected individuals or to
laboratory accidents. Most of the cases of transmission via transplanted organs occur
in countries where Chagas disease is not endemic and are due to the lack of efficacious and validated serologic techniques, lack of familiarity with the manifestations
of acute disease and the presence of Latin American donors, many of whom have
dual citizenship, which may make the identification of high-risk donors difficult.
Among the parasitic diseases, only malaria and schistosomiasis are more significant from an epidemiological point of view than Chagas disease [21]. Chagas
disease was historically confined to rural areas with very low levels of social develop-
Strategies
Responsible entities
Intervention
aims
163
Primary prevention
Secondary prevention
Individuals
at risk
Early/asymptomatic
stage of disease
Tertiary prevention
Established
disease
Vector control
Prevention of
of transmission
via blood transfusions
Prevention of
transmission
via organ transplantation
Care in
laboratory
handling ofT. cruzi
Screening
Detection of infected
individuals
Early intervention
Antiparasitic
treatment
Periodic health exams
Antiparasitic disease
(selected cases)
Pharmacological and
non-pharmacological
interventions
Symptomatic treatment
Management of
complications
Permanent care
Public health
Primary care
Other
Primary care
Public health
Specialized services
Hospital units
Prevent transmission
of Chagas disease
Avoid progression of
the indeterminate form
to the clinical forms
of disease
Chagas disease
absent
Indeterminate
form
and mortality of
disease
manifestations
Cardiac and
digestive forms
Disease progression
ment in nearly all of the continental Latin American countries. That scenario changed
quite recently, as the epidemiological significance of Chagas disease in those countries was greatly reduced [22]. In global terms, 810 million people are currently
estimated to be infected [23, 24] versus 1618 million in the 1990s [25]. In parallel,
as a function of migration circuits involving infected individuals from endemic countries, Chagas disease became a public health problem in the United States and other
countries, such as Spain, Belgium, France, England, Japan and Australia [26]. Such
epidemiological transitions in non-endemic countries accentuated the concern
regarding the possible transmission of infection via blood transfusions, solid organ
donation and the transplacental route. Additionally, the search for diagnostic and
clinical treatment methods for infected individuals was intensified in those countries,
which also targeted the prevention of transmission to other people [27].
The methods available to reduce the medical and social impact of Chagas disease
are based on three levels of prevention, primary, secondary and tertiary, and are
discussed next [28] (Fig. 1).
Primary prevention seeks to avoid the occurrence of new infections, i.e., to eliminate the risk of infection of exposed individuals and to interrupt the chain of
transmission. Those goals are mainly achieved by means of strategies focusing on
the control of both vector- and non-vector-borne transmission. However, in the case
of the vertical route, it should be borne in mind that there is no procedure available
to reliably impede mother-to-child transmission.
Secondary prevention consists of the screening and detection of individuals
infected with T. cruzi in the early stages of disease. This strategy is essential in acute
cases. In chronic cases, and more particularly those with the indeterminate form of
164
165
era of combat against the disease began between 1945 and 1955, when residual
insecticides were used to combat the vectors and pathologic, serologic and clinical
studies became systematized [34]. Beginning in the 1960s, national programs of
vector control were launched; serologic screening for T. cruzi in blood banks became
mandatory in the 1980s, parallel to the measures established for the control of the
emerging HIV pandemic [19, 34].
Control of Vectors
Vector control is essential under conditions of domiciliary and peridomiciliary
infestation, by means of continuous and regular application of residual insecticides
also followed, in principle, by continuous and sustained epidemiological surveillance. Synthetic pyrethroids derived from chrysanthemic acid (deltamethrin,
lambda-cyhalothrin, cyfluthrin, etc.) are currently the most effective insecticides. In
cases of resistance to those agents, which seldom occurs, organochlorine or carbamate compounds may be alternatively used [34].
The perception that population-based educational campaigns and active
participation of the community in strategies for vector control are an essential part
of epidemiological surveillance is universally accepted. Improvement of housing
conditions is also quite effective; however, except for rare exceptions (such as the
2001 experience in Venezuela), this has never been properly prioritized in national
programs [35].
It should be noted that eradication, namely, complete interruption of Chagas disease transmission, is practically an unattainable epidemiological target. Even in
places where that goal could be partially achieved, such as the extinction of transmission by Triatoma infestans in countries such as Uruguay, Chile and Brazil,
entomological surveillance must be maintained for many years. The proposal that
infection with T. cruzi evolved from a primitive type of zoonosis to a true and highly
spread anthropozoonosis is currently very clear. Moreover, the parasite is currently
disseminated across many sylvatic areas, in which its ecotopes are being increasingly altered by human activity (e.g., indiscriminate deforestation) such as in the
Amazon region, where the incidence of autochthonous cases is increasing [36].
Evidence also exists for the presence of several secondary vectors, namely, triatomine insects potentially susceptible to domiciliation, as well as that of vector
resistance to the most commonly used insecticides.
166
highly accurate serologic tests based on two different techniques (e.g., indirect immunofluorescence and ELISA) should be employed for the screening of blood donors.
However, starting in 2002, the World Health Organization (WHO) recommends
performing only one test (ELISA) to detect blood donors infected with T. cruzi [20].
Likely due to technical inadequacies in the performance of the serologic tests, this
recommendation led to a significant reduction in the sensitivity of detecting infected
blood and organ donors, the consequences of which are only beginning to be understood. For example, acute Chagas infection was detected in one individual without
Chagas disease who received the transplanted liver of an allegedly non-infected donor
in Brazil, which is an endemic country [37]. The challenge is heightened by the fact
that a large fraction of the donors and recipients are transfused with large amounts of
blood components on the occasion of the event leading to death or in the perioperative
period of heart transplantation, respectively. Under such circumstances, high-sensitivity serologic control of hemodiluted sera, with sufficient specificity so as not to reject
viable organs should be mandatory. The need to improve the methods for serologic
detection of T. cruzi infection in endemic and non-endemic areas is reinforced by the
recent description of a series of patients with chest pain and segmental wall-motion
abnormalities of the left ventricle (such as apical aneurysm) highly suggestive of
CHD, but who had negative results by the immunofluorescence serologic test [38].
167
The same principles apply when both donor and recipient are seropositive; as a
rule, specific treatment is recommended for the donor before transplant surgery
[28]. Relative to heart transplantation, which is not allowed when the donor is seropositive, relative to other organs, prior specific consent is required.
Finally, the situation of a seropositive potential donor and a seronegative recipient (in the case of living donors) is a particular cause of concern because
transplantation is a priority that cannot be bypassed. In such cases, it is recommended to administer antitrypanosomal treatment to the donor for at least 10 days
(60 days ideally) to reduce or eliminate the parasitemia as well as to the recipient
along with treatment for 10 days after surgery to minimize the odds of parasite invasion and multiplication in his/her body. If the recipient becomes seropositive,
standard trypanosomicidal treatment for 6090 days is recommended [28].
168
Oral Transmission
Being unpredictable, primary prevention of transmission by the oral route is unfeasible; only progressive improvement of the populations educational and hygienic
levels will allow the control of this mechanism of Chagas disease transmission.
Because the parasitic load is usually high, and because the mucosa of the digestive
tract is highly permeable to T. cruzi, the mortality in the acute stage of infection may
be quite high. Healthcare professionals should develop a high degree of diagnostic
suspicion, as atypical cases with gastrointestinal bleeding and myopericarditis with
large pericardial effusions are often described, to achieve effective parasitological
confirmation and to begin etiological treatment immediately. Similarly, epidemiological surveillance should be established later on, also including the people in
contact with patients infected with T. cruzi per the oral route [40].
169
Acute stage
Other
exposure
routes
Chronic stage
No infection
4050%
Human
Infected
triatomine insects
exposed to
T. cruzi
Acute
asymptomatic
infection
Acute
Chagas
disease
Time interval
1-2 weeks
Parasitemia
Diagnosis
Etiological treatment
% cure
Indeterminate
chronic form
Determinate
chronic forms
cardiac
digestive
mixed
Remission
Death
4-12 weeks
high
detection of parasites
mandatory
50-80
20-30 years
Lifelong
recommended
optional
to be
established
Fig. 2 Progression of Chagas disease: clinical, diagnostic and therapeutic aspects [28]
Etiological Treatment
Although specific treatment is the cornerstone of the secondary prevention of Chagas
disease, only two compounds admittedly active against T. cruzi are available for
clinical use, that is, benznidazole and nifurtimox. Both were developed 40 years ago,
170
and thus, the lack of further investigation of additional drugs bears witness to the
neglect of Chagas disease by the medical and scientific community and society at
large, in this case represented by governmental agencies and the industrial sector.
Both available drugs have trypanosomicidal activity against the amastigote and
more intensively against the circulating trypomastigote forms [43]. Those agents
were tested for the treatment of patients in the acute stage of infection, inducing
clinical remission and parasitological and serological negative conversion (delayed)
in up to 80 % of the cases [44]. Based on such evidence and in the absence of more
definitive studies, there is essentially universal agreement that etiological treatment should be indicated in all patients diagnosed with acute Chagas disease,
independent of the route of transmission [41]. That indication is also unanimously
accepted relative to episodes of reactivation in patients in the chronic stage of disease, who usually exhibit natural or iatrogenic immunosuppression.
However, the most propitious scenario of secondary prevention is not represented by the patients diagnosed in the acute stage of disease but by the much larger
number of patients with the indeterminate form of chronic disease. That crucial
epidemiological fact notwithstanding, the indication for trypanosomicidal treatment
in patients in the chronic stage of Chagas disease [45] has been repeatedly discredited and called into question, to the point that consensus is nonexistent in this regard,
although it is an essential component of secondary prevention [41]. This position,
which is not justified under the current knowledge, is largely due to an erroneous
concept, according to which the main pathogenetic mechanism in Chagas disease is
autoimmunity, in disregard of the fact that this was challenged long ago [46]. Further
arguments for that unfounded position derive from the personal experience of some
physicians with the more advanced stages of diseasewhen, indeed, trypanosomicidal treatment has little to contributewho refuse to acknowledge the evidence
that, although not definitive, reasonably supports the fundamental notion that
Chagas disease is, in essence, an infectious disease, the etiological agent of which
remains in the human body, where it is the direct cause of a low-intensity although
practically incessant inflammatory state in some tissues, such as the myocardium.
Multiple and an increasing number of studies indicate that parasite persistence is
the essential mechanism that accounts for the establishment of inflammatory tissue
lesions either directly or mediated by the immune system. Such lesions damage the
contractile myocardium and the specialized system generating and conducting cardiac electrical activity, causing cell necrosis and intensive reactive and reparative
fibrosis [4, 47]. Thus, it is natural to speculate that antitrypanosomal treatment in the
non-advanced chronic stage of CHD may favorably modify the natural history of
the disease [48]. The underlying hypothesis is that elimination, or at least reduction,
of the parasitic load may attenuate and/or delay the progression of myocarditis in
the chronic stage of CHD. That basic notion reflects the theory that autoimmune
aggression (disregarding the presence of parasites in the tissues) is not the decisive
mechanism in the pathogenesis of CHD [49].
Although still a controversial subject, etiological treatment should be administered, as a rule, to most patients with the indeterminate and the cardiac and digestive
forms of disease in the non-advanced stages [48, 49]. In some South American
171
countries, this indication became official public health policy. This recommendation
is also considered fundamental in the United States, based on studies, seminars and
a systematic literature review conducted by investigators at the Centers for Disease
Control and Prevention (CDC) and Latin American collaborators [50]. This position
is supported by a systematic review with meta-analysis of the few randomized studies performed with asymptomatic infected patientspresumably most of them with
the indeterminate form of disease. The results indicated that etiological treatment
(particularly with benznidazole) is beneficial in as much as it improves the hostparasite relationship, resulting in negative conversion of the xenodiagnosis and the
reduction of circulating anti-T. cruzi antibodies, as demonstrated by the serologic
tests [51, 52]. The two most conclusive studies included in that meta-analysis were
performed in children; the results demonstrated seroconversion and cure of infection in approximately 60 % of the participants after follow-up of 34 years [53, 54].
Children characteristically tolerate trypanosomicidal treatment better than adults.
Relative to infected individuals with clinical and laboratory abnormalities demonstrating established CHD, many investigators consider that specific treatment
should still be offered, except in cases of highly advanced myocardial injury. That
position is based on several lines of evidence that taken together tip the balance in
favor of this strategy:
evidence resulting from experimental models of infection with T. cruzi collected
by different groups of investigators, according to which etiological treatment
attenuates the progression of heart disease, although complete eradication of the
parasite was not attained (the parasitic load was merely reduced) [5557];
the side effects of either available trypanosomicidal agent occur less frequently
and are better tolerated than was previously believed; moreover, such undesirable effectsgastrointestinal and skin reactions, polyneuropathy, leukopenia
might be considered as tolerable and reversible, thus contrasting with the
beneficial potential of short-term treatment (23 months) [5859];
the results of several observational studies that assessed the effect of etiological
treatment in patients with heart disease and applied clinically relevant outcome
measures point to a true positive effect, with favorable modification of the natural history of the disease [6064];
a meta-analysis that included three randomized and six observational studies
concluded that the patients treated with benznidazole exhibited significant risk
reduction of presenting clinical events over time compared to the patients not
subjected to etiological treatment (odds ratio: 0.29; 95 % confidence interval:
0.160.53) [65].
To summarize, based on the actions and individual positions of many investigators [58, 66, 67], and on official statements by agencies responsible for developing
health policies, an emergent current convergence favors the position that etiological
treatment should be made available to most infected patients in the chronic stage of
Chagas disease [25, 40, 50, 68]. This perspective is based on the concept that as a
function of the currently available knowledge and while still awaiting the conclusive
evidence of the BENEFIT randomized study [69], the risk of incurring an alpha error
172
Asymptomatic
Unspecific
electrocardiographic
abnormalities : incomplete
RBBB,
LAFB , mild bradycardia,
st
1 degree AVB , discrete ST -T
abnormalities
Chest x-ray: normal
2D echo: normal
24-h Holter: absence of
complex VAs
173
STAGE II
STAGE III
Asymptomatic or
mild symptoms
monomorphic VEs,
primary T-wave
abnormalities,
nd
rd
2 and 3 degree AVB
Chest x-ray: normal
2D echo: contractility
segmental
abnormalities, apical
aneurysm
24-h Holter: complex VAs
ECG*: Q waves,
polymorphic VEs,
considerable bradycardia,
low QRS
voltage
Chest x-ray: mild
cardiomegaly
2D echo: mild-to-moderate
global LV dysfunction
24-h Holter: complex VAs
STAGE IV
Causes of death
*in addition to the electrocardiographic abnormalities characteristic of the previous stages
2D echo= two-dimensional Doppler echocardiogram; VAs= ventricular arrhythmias; AVB= atrioventricular block;
RBBB= right bundle branch block; LAFB = left anterior fascicular block; ECG= conventional electrocardiogram;
VEs= ventricular extrasystoles; CHF= congestive heart failure; LV= left ventricle.
Fig. 3 Stages and causes of death in Chagas heart disease (CHD) [28]
174
The heart chambers undergo progressive global dilatation, the functional class
becomes gradually worse, and in the more advanced stages, significant biventricular
systolic dysfunction develops, which is followed by heart failure in which the signs
and symptoms of congestion are sometimes clearly predominant over the pulmonary signs and symptoms. Perfusion defects might be detected in patients with chest
pain, being initially ischemic with progression to irreversible abnormalities, which
denote the presence of fibrotic areas [78].
Although ventricular arrhythmias often manifest in the early stages of disease,
they become typically exacerbated parallel to the progression of the heart affliction,
being somewhat associated with the aggravation of the ventricular dysfunction.
Complex and multiform ventricular ectopic rhythms are a common finding, appearing in pairs or as episodes of non-sustained ventricular tachycardia, being most
evident on Holter monitoring. Another characteristic manifestation of CHD is sustained ventricular tachycardia, which might cause presyncope and syncope and
progress into ventricular fibrillation with sudden death [79]. This form of arrhythmia usually originates in reentrant micro- or macro-circuits due to the presence of
fibrosis in the lateral inferoposterior area of the left ventricle and might be
reproduced in the laboratory in most patients who manifest it on electrophysiology
studies with programmed ventricular stimulation [80].
Similarly, systemic and pulmonary thromboembolic events may occur, which are
often found only at necropsy [81]. Such events account for approximately 10 % of
CHD deaths. Stroke is the most frequent complication, with Chagas disease being
an acknowledged independent risk factor for cerebral embolism in areas where disease is endemic [82].
It should be emphasized that the prognosis of heart failure due to CHD is poorer
compared to other causes of this condition [83]. Congestive heart failure, which is a
typical occurrence in stage four, causes 25 % of the deaths by CHD. Nevertheless, sudden death is the most conspicuous threat posed by CHD, as it accounts for more than
60 % of the mortality associated with this condition. As a rule, sudden death occurs in
the course of some physical exertion, sometimes in patients previously asymptomatic,
but more often in stages two and three (Fig. 3). More than 90 % of deaths are due to
ventricular fibrillation, with the remainder of sudden deaths occurring during the state
of asystole, sometimes preceded by complete atrioventricular block.
Tertiary prevention of CHD, namely, death, may now be based on the application
of a risk score that was developed and validated, also externally, in a multivariate
analysis study conducted with 424 non-selected patients who were followed up for
approximately 8 years on average. Among other advantages, Rassis score includes
just six variables that proved to behave as independent predictors of mortality in
CHD and are assessed by means of simple clinical methods, such as 24-hour Holter
monitoring, exercise testing, two-dimensional transthoracic echocardiogram, chest
radiographs and conventional ECG. Those variables, which are weighted to compound the final score, are as follows: male gender, low QRS voltage, NYHA functional class III or IV, cardiomegaly, left ventricular dysfunction on echocardiogram
and non-sustained ventricular tachycardia on Holter monitoring. Based on that
175
score, 60 % of the patients are classified as at low risk of death, 20 % as high risk
and 20 % as intermediate risk [884].
176
the need for treatment with angiotensin-converting enzyme inhibitors or betablockers to eventually prevent the development of heart failure.
Other peculiarities of the pathogenesis and pathophysiology of CHD pose additional challenges to the treatment of heart failure to impede or delay the progression
of ventricular dysfunction and its inherent mortality. Thus, it is often necessary to
administer higher doses of diuretics, either loop or thiazide, to manage the signs and
symptoms of systemic and pulmonary congestion. Beta-blockers tend to be less
well tolerated, particularly when used concomitantly with digoxin and amiodarone,
as a function of the aggravation of the heart electrical generation and conduction
disorders, and with full doses of angiotensin-enzyme converting inhibitors, due to
the greater tendency to arterial hypotension. Although the extrapolation of the
highly significant results obtained in the treatment of heart failure by other causes is
attractive, neither the efficacy nor the effectiveness of beta-adrenergic blockers to
modify the natural history of heart failure due to CHD have been demonstrated; the
results of the single randomized study specifically performed for that purpose have
not yet been communicated [85].
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are
liberally used; however, without confirmation of their efficacy. In turn, spironolactone, an aldosterone inhibitor, is used based on the results of a study that demonstrated reduction of mortality among patients with heart failure by several causes,
including a few dozen cases with CHD [86]. Although subgroup analysis according
to cause was not performed, one further rationale underlying the empirical use of
spironolactone is based on the assumption that because aldosterone blockers inhibit
fibrosis formation, they may play a relevant role in CHD, especially, in this cause of
heart failure that induces most fibrosis.
Cardiac resynchronization therapy was empirically used in small observational,
case series studies; however, the results do not appear promising for patients with
CHD because in this condition, prolonged QRS occurs more often compared to
right bundle branch block.
Heart transplantation represents the last alternative for many patients in very
advanced stages of heart failure. The results obtained in a series of patients with CHD
thusly treated are particularly encouraging in comparison with other etiologies due to
several reasons, and notwithstanding the previous misgivings regarding the induction
of immunosuppression in individuals with a chronic infectious disease [41].
177
caused by sinus node dysfunction and atrioventricular block and less often by atrial
fibrillation with a slow ventricular response. The standard treatment consists of permanent pacemaker implantation, which is empirically based on the results of case
series reported in the literature. Ventricular tachyarrhythmias are treated with amiodarone or an automatic implantable cardioverter defibrillator (AICD).
Electrophysiological mapping followed by radiofrequency catheter ablation has
been described as sporadically used in patients with refractory malignant arrhythmias such as arrhythmic storm and incessant ventricular tachycardia; however, there
is no sound evidence confirming its efficacy [80, 87, 88].
The empirical use of amiodarone is recommended as first-choice therapy in
patients with non-sustained tachycardia or even the sustained variety without serious hemodynamic repercussions (as a rule, while the global systolic function of the
left ventricle is still preserved). In the absence of evidence from randomized studies,
the indication of amiodarone is supported by the results of observational studies that
suggest that it might increase the survival of patients with CHD at high risk of death
by arrhythmia [79, 89, 90].
Adequate evidence for AICD implantation is also lacking; it is recommended
also empirically for patients with sustained ventricular tachycardia and serious
hemodynamic repercussions, as well as for cases of recovery from sudden death
[89]. The discrepancy among the results of a few observational series of patients
with implanted AICDs demonstrates that the singular pathophysiology of CHD
poses an additional challenge to the treatment of these potentially fatal arrhythmias.
Additionally, it points to the need for rigorous scientific studies instead of the mere
extrapolation of evidence gathered from patients with arrhythmias due to other
causes [91]. The concomitant use of amiodarone is mandatory in many cases with
implanted AICDs to minimize the number of appropriate electric shocks and their
deleterious consequences for myocardial contractility. One randomized study comparing treatment with AICD or amiodarone for patients with CHD at moderate and
high risk of death according to Rassis score and with non-sustained ventricular
tachycardia by Holter monitoring is currently in progress [92].
178
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183
184
Table 1 Risk of myocardial infraction associated with risk factorsINTERHEART study [6]
Risk factor
Apo-B/ApoA-1
Smoking
Diabetes
Hypertension
Abdominal obesity
Psychosocial stress
Daily intake of vegetables and fruits
Physical activity
Alcohol consumption
All combined
OR (CI 99 %)
3.25 (2.813.76)
2.87 (2.583.19)
2.37 (2.072.71)
1.91 (1.742.10)
1.62 (1.45180)
2.67 (2.213.22)
0.7 (0.620.79)
0.86 (0.760.97)
0.91 (0.821.02)
129.2 (90.2185.0)
185
Table 2 PAR values associated wit risk factors for strokeINTERSTROKE study [7]
Risk factor
Hypertension
Smoking
Abdominal obesity
Diet (risk score)
Physical activity
Diabetes
Alcohol consumption
Psychosocial stress
Depression
Cardiac causes
Apo B/Apo-A1
With a proposal similar to INTERHEART, the INTERSTROKE study is underway and aims at assessing risk factors and their weight in the incidence of ischemic
and hemorrhagic stroke. This international casecontrol study will also evaluate
patients from all continents and ethnic groups. The patients are selected at the time
of their first stroke and are compared with controls. The INTERSTROKE study [7]
has already evaluated 3000 affected patients and 3000 controls, and its preliminary
results (Phase 1) showed a risk factor profile similar to that reported for myocardial
infarction in the INTERHEART study. Hypertension was the most important risk
factor for both stroke subtypes, with a more prominent effect on hemorrhagic stroke.
When associated with active smoking, abdominal obesity, diet, and sedentary
behavior, the PAR reached 80 % of the overall risk of stroke. The analysis of these
five risk factors together with the effects of diabetes, alcohol consumption, psychosocial factors, cardiac causes, and the Apo-B/Apo A1 ratio yielded a list of 10 risk
factors, which accounted for 90.3 % of the PAR. Diets with greater consumption of
fish and fruits (components of the Mediterranean diet) and physical activity were
protective factors. The interaction between alcohol consumption and risk of stroke
in INTERSTROKE was complex, suggesting a J-curve relationship for ischemic
stroke and a gradual increase of the risk for hemorrhagic stroke as alcohol consumption increased. The risk factors with significant associations with stroke and their
respective PAR values are shown in Table 2.
186
Lifestyle Changes
Lifestyle changes consist primarily of the control of tobacco and obesity, regular
physical activity, and proper diet and have a significant impact on the primary prevention of CVD in a cost-effective manner. The Quality Adjusted Life Years (QALY)
indicator is an important tool for the quantification of the impact of a disease or
intervention because it combines quantity and quality of life in a single score.
Eriksson et al. [9] showed that a lifestyle intervention program based on physical
activity and dietary guidance had a cost ranging from USD 1668 to USD 4813 per
QALY, a value compatible with a cost-effective measure. A prospective cohort study
with 43,685 men and 71,243 women [10] demonstrated that a low-risk lifestyle
involving an adequate diet, body mass index (BMI) < 25 kg/m2, no smoking, regular
physical activity, and moderate alcohol consumption can reduce the risk of stroke,
especially ischemic. In the U.S., between 1985 and 2003, there was a linear and
independent relationship between total expenditure on government programs for
tobacco control and the decrease in smoking prevalence [11].
Pharmacological Treatment
The effective treatment of diabetes can decrease the number of macrovascular outcomes, according to a meta-analysis that combined the results of the ACCORD,
ADVANCE, UKPDS, and VADT studies [12]. A total of 27,049 patients were evaluated, and the results indicated that the risk of myocardial infarction decreased by
15 % (hazard ratio [HR] 0.85, 95 % confidence interval [CI] 0.760.94) in the intensive glycemic control group. With regard to the role of statins in the primary prevention of cardiovascular disease, a recent meta-analysis of the Cholesterol Treatment
Trialists (CTT) collaboration [13] involving 27 clinical trials demonstrated that the
use of these drugs could reduce disease outcomes in patients with low estimated risk
of adverse events (<10 % in five years). This study reported decreases in the number
of major coronary events, stroke, need for revascularization, and major vascular
events regardless of the presence of previously diagnosed vascular disease. The use
of statins as recommended by current guidelines would cost USD 42,000 per QALY,
considering the cost of USD 2.11 per tablet (this value is above the market), which
is also a cost-effective strategy [8]. The emerging concept of the polypill can also
have important future implications in public health policies. A mathematical analysis of the TIPS study, which evaluated the control of blood pressure, lipid level,
heart rate, and antiplatelet effect of aspirin in patients with no history of cardiovascular disease (CVD) with at least one risk factor, reported that the use of polypills
could potentially decrease the rate of CVD by 62 % and of stroke by 48 % [14].
Subsequently, Bautista et al. [15] reported that the strategy of the TIPS study is costeffective in Latin American countries, even among those countries with lower per
capita incomes.
187
Life-course approach;
Empowerment of individuals and communities;
Evidence-based strategies;
Universal healthcare coverage;
Management of real, perceived or potential conflicts of interest;
Protection of human rights;
Equity-based approach;
National action and international cooperation and solidarity; and
Multisectoral actions.
With regard to financial matters, according to estimates, the cost of action would
be considerably outweighed by the cost of inaction. The total costs of implementing
the measures proposed in relation to the current spending on health are approximately
188
10% relative
0% Increases in
reduction
10% relative
30% Relative
reduction in
sodium/salt intake
30% reduction in
25% reduction in
hypertension
the prevalence
rates of diabetes
and obesity
tobacco use
2025
Fig. 1 Adapted from the 65th World Health Assembly (WHO) [18]
Tobacco Control
The goal for tobacco control is a 30 % relative reduction in the prevalence of tobacco
use among individuals aged 15 years or older. For this purpose, it is important to:
Protect tobacco control policies from commercial interests of the tobacco
industry;
Ensure that all indoor environments and other public places are completely
smoke-free.
Develop mass media campaigns to alert the population about the dangers of
tobacco use;
189
190
Fig. 2 Steps suggested by The Lancet BCD Action Group for the implementation of the target
proposed by the WHO [19]
191
Responses
Construction of new units
Reform of the medical curriculum
Reassessment of salary structures and career plans
Restructuring of Health Ministries
Decentralization of administrations with representation
from various sectors
Development of accreditation and regulation systems
192
Digoxin
Amiodarone
Lipid-lowering
Simvastatin
Antidiabetic
Gliclazide
Metformin
NPH insulin
Regular Insulin
Anti-smoking therapies
Nicotine replacement therapy
(Gum or transdermal)
Amiloride
Rational selection
Ensure quality
Monitor availability
Rational use
with the pharmaceutical industry and the monitoring of the results of interventions
are other important strategies.
Based on the above considerations, it is clear that the knowledge necessary to
establish priorities and to initiate actions for CVD prevention is available. Political
will and the involvement of healthcare professionals and civil society is essential to
achieve the targets proposed by the WHO and to decrease the major impacts of noncommunicable diseases worldwide.
193
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General Considerations
The role of cardiovascular diseases as the main cause of death in the socioeconomically developed world has long been recognized [1].
There is mounting epidemiological evidence indicating the increasing role of
these diseases as causes of mortality in developing countries, as well as in those
with a lower development index and reduced financial resources [2].
Determinants of that phenomenon have been correlated with progressive urbanization, the consequent epidemiological transition resulting from exposure to risk
factors in the industrialized world, physical inactivity, and psychosocial stress [3].
In addition, there is reduced government funding for enabling the implementation of health policies aimed at achieving the best control of the disease with effective prevention, diagnosis, and treatment measures.
195
196
G.S. Feitosa
Such conditions coincide with the improved control of infectious and parasitic
diseases, improved access to healthcare, and increased adult survival rates.
However, a whole new population group has been exposed to the conditions of
an increasingly industrialized world. The inevitable consequences of that fact
include increased daily intake of salt and saturated animal fats, higher dietary content of trans fats, increased tobacco use, and significant physical inactivity.
Consequently, the incidence of hypertension, obesity, and diabetes mellitus has
worsened.
Hypertension has shown increasing prevalence, and its future numbers are projected to be even more striking, particularly in less developed regions (Fig. 1).
These conditions have contributed to the progressive manifestation of atherosclerosis at an epidemic scale across the contemporary world. Most notably, the
disease has reached, in absolute terms, less developed and more numerous populations [8] without easy access to education on the subject or even access to modern
resources that mitigate the problem in more developed countries.
It is estimated that approximately nine million people died from cardiovascular
diseases in developing countries and that five million died in developed countries in
1990, and the estimates for 2020 are six and 19 million people, respectively.
This prediction undoubtedly reiterates the widespread epidemic threat of cardiovascular disease in the contemporary world, especially in developing countries.
Although the entire transition process occurred in the early twentieth century,
much time had elapsed until one could recognize the impact caused by noncommunicable diseases in the underdeveloped or developing world, particularly
cardiovascular diseases, as subsequently noted.
The World Health Organization began to warn about the problem in the midtwentieth century.
The overview of socioeconomic disparities between areas affected by hunger
and poverty and affluent regions, per se, has already hindered the establishment of
uniform measures. The emergence of AIDS/HIV has worsened the situation.
197
Men
50
37.4
Hypertension Prevalence %
40
37.2
35.3
40.7
39.1
30
Women
34.8
22
20.6 20.9
20
23.7
22.6
26.9 28.3
19.7
17
14.5
10
0
2025
50
45.9
41.6 42.5
44.5
39.1
40
30
40.2
24
22.9 23.6
27
27.7 27
27
18.8
20
28.2
17.1
10
fric
a
s
-Sa
har
Sub
trie
sa
nd
un
Oth
er
Co
an
A
Isla
nd
ina
Ch
ast
in t
nt
sce
Cre
rica
me
in A
he
and
Mi
Car
dd
ibb
le E
ean
ia
Ind
st E
Old
Soc
iali
Lat
Est
abl
ish
ed
Ma
rke
tE
con
con
om
i
om
i
es
es
198
G.S. Feitosa
Considering these diseases and using the mortality rate per 100,000 inhabitants
as the only indicator, a value of more than 200 is obtained. The mortality rate of
developing countries ranges from 200 to 300/100,000, while almost all underdeveloped countries remain above 300/100,000 in habitants for both men and women
(Figs. 2 and 3).
The other relevant epidemiological indices, including disability-adjusted life
years (DALY), among others, are equally impressive (Fig. 4).
Some cardiovascular diseases, including Chagas disease in South America and
rheumatic fever in Africa and some regions of the Americas, among other less common types, including endomyocardial fibrosis, occur in some underdeveloped or
developing regions.
Chagas disease, caused by the protozoan Trypanosoma cruzi, and transmitted by
the insect Triatoma infestans(commonly known as the barber bug), among other
insects, is a disease autochthonous to South America that affects approximately
1618 million people, including 5 million in Brazil (Table 2).
A quarter of the people affected with Chagas disease present or will present with
severe forms of myocardiopathy.
Successful campaigns against the transmission agent have prevented the appearance of new cases, and some of the regions affected have been recognized as
disease-free by the WHO.
Cardiovascular diseases and diabetes, age-standardized mortality rates per 100.000 inhabitants,Women,
2008
Fig. 2 Mortality of women from cardiovascular diseases worldwide. Modified from the WHO
[11]. Source: World Health Organization. Map: Public Health Information and Geographic
Information Systems (GIS) World Health Organization. WHO 2011.
The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the WHO concerning the legal status of any country,
territory, city or area or of its authorities or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full
agreement
199
Cardiovascular diseases and diabetes, age-standardized mortality rates per 100.000 inhabitants,
Men, 2008
Fig. 3 Mortality in men from cardiovascular diseases worldwide. Modified from the WHO [11].
Source: World Health Organization. Map: Public Health Information and Geographic Information
Systems (GIS) World Health Organization. WHO 2011.
The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the WHO concerning the legal status of any country,
territory, city or area or of its authorities or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full
agreement
120
Sensory disorders
100
Neuropsychiatric disorders
80
60
Cancer
40
Cardiovascular diseases
20
0
Men Women
High
income
Men Women
Men Women
Medium-high
income
Medium-low
income
Men Women
Low
income
Fig. 4 Disability-adjusted life years (DALY). Modified from the WHO 2004
200
G.S. Feitosa
Population (millions)
2005
32.6
9.2
186.4
16.3
45.6
13.2
0.7
6.2
28.0
0.4
3.5
26.6
201
Table 4 Risk attributable to hygiene and dietary factors in the world population by region [14]
Region
Western Europe
Central and Eastern
Europe
Middle East
Africa
North Asia
China
South and East Asia
Australia/New Zealand
South America
North America
Global
% alcohol
18.9
12.9
All risk
factors
67.8
49.6
44.8
38.0
37.5
35.8
36.2
44.7
38.5
26.3
35.7
4.4
27.3
5.3
5.3
27.9
18.5
3.1
25.3
6.7
45.5
63.2
55.2
62.4
69.9
65.8
56.9
59.8
54.6
8.1
3.8
18.4
17.8
11.2
10.7
6.7
19.8
13.7
4.0
11.1
24.3
21.1
31.4
23.8
27.2
25.3
12.2
202
G.S. Feitosa
HTN
%
22.0
24.5
DM %
14.9
9.1
Obesity
63.6
28.0
Psychosocial
stress %
38.9
4.9
Lipids
%
44.6
35.0
9 risk
factors
94.0
72.5
9.7
29.9
19.4
22.1
38.4
22.8
32.8
18.9
17.9
15.5
17.1
12.1
10.0
21.0
7.2
12.8
7.9
9.9
26.7
58.3
37.0
5.5
58.0
61.6
45.4
59.6
20.1
41.6
40.0
15.9
35.6
26.7
28.9
35.6
51.4
32.5
70.5
74.1
58.7
43.8
67.7
43.4
47.6
50.5
49.2
95.0
97.4
89.4
89.9
93.7
89.5
89.4
98.7
90.4
Table 6 Expenditure on health and life expectancy statistics of some countries selected2009
[16, 17]
Countries
Argentina
Brazil
Canada
USA
France
Japan
UK
Total expenditure
on Health per
capita (USD)
1322
837
3900
7285
3709
2696
2992
% of government
expenditure on
health
50.8
41.6
70.0
45.5
79.0
81.3
81.8
% of expenditure on
health (GDPgross
domestic product)
10.0
8.4
10.1
15.7
11.0
8.0
8.4
Life
expectancy at
birth
76.6
72.0
81.2
78.1
80.9
82.1
79.0
< 2.17
2.17-3.7
3.7-5.2
5.2-6.7
> 6.7
203
Human development
index
< 0.682
0.682-0.705
0.705-0.746
0.746-0.776
0.776-0.844
204
G.S. Feitosa
Conclusions
Along with the developed world diseases, including ischemic heart disease and
cerebrovascular diseases, developing and low-income countries face a challenging
reality of diseases that have already been eradicated in first world countries, namely,
rheumatic heart disease, and other diseases typical in those countries, including
Chagas disease in South America and beriberi, which is still recorded in some
African countries.
The burden of cardiovascular diseases not only results in reduced life expectancy
but also entails a significant reduction in the productive work force in those regions
because most people affected by those conditions are fit to work.
Thus, the challenge for those regions is enormous and relies on the civic spirit,
humanism, integrity, commitment, and political will of governments and society in
general toward promoting changes in education, leading to the improved use of
human resources and to disciplined, selfless, and honest actions to assist those at
risk of developing infectious and deficiency diseases, non-communicable diseases,
and especially cardiovascular diseases.
References
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1990 and 2010: a systematic analysis for the global burden of disease study 2010. Lancet.
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2. Kim SA, Johnston SC. Global variation in the relative burden of stroke and ischemic heart
disease. Circulation. 2011;124:31423.
3. Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization.
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243840.
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Organization; April 2011.
205
12. Institute of Medicine. Promoting cardiovascular health in the developing world: a critical
challenge to achieve global health. Washington: National Academies Press; 2010.
13. Feitosa GS. Cardiology in South America. J Am Coll Cardiol. 2007;50:6436.
14. Yusuf S, et al. INTERHEART Study Investigators. Effect of potentially modifiable risk factors
associated with myocardial infarction in 52 countries (the INTERHEART study): case-control
study. Lancet. 2004;364:93752.
15. ODonnell MJ, et al. INTERSTROKE investigators. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study.
Lancet. 2010;376:11223.
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in Feb 2014.
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18. Polanczyk CA, Ribeiro JP. Coronary artery disease in Brazil: contemporary management and
future perspectives. Heart. 2009;95:8706.
19. Ramos Jr AN, Maul CD. The various meanings of Brazils certification as free of Chagas disease. Cad Sade Pblica. 2001;17:140312.
Cardiovascular disease (CVD) is the leading cause of death worldwide, despite the
growing evidence for the efficacy of primary prevention. The EURIKA study of
2010 was the first to attempt a large scale comparative assessment of primary CVD
prevention among individuals with varying degrees of CVD risk across Europe,
after the EuroAspire I, II and III trials had previously delved into secondary prevention. On both accounts, the results highlighted a generally poor control of the risk
factors [1, 2]. CVD is strongly connected to unhealthy life style, tobacco smoking,
inappropriate diet, physical inactivity and psychosocial stress. The World Health
Organization (WHO) has stated that over three quarters of CVD mortality could be
prevented with adequate changes in lifestyle. Prevention of CVD should ideally
start in utero and last until the end of life. It is defined as a coordinated set of actions,
at both public and individual levels, aimed at eradicating, eliminating or minimizing
the impact of CVDs and their related disability [3]. Comprehensive lifestyle interventions, in addition to medical therapy when indicated, are effective strategies that
can significantly impact individual and global heart disease prevention. Despite this,
the fact that there are still uncontrolled risk factors, lifestyle counseling is often not
well implemented and that there is substantial variation between countries, indicates
there is room for improvement [1].
Every child born in the new millennium has the right to live until the age of at least 65 without
suffering from avoidable cardiovascular disease (St Valentines Declaration, 14 February 2000)
D. Gaita, MD, FESC (*)
University of Medicine and Pharmacy Victor Babes, Timisoara, Romania
e-mail: dgaita@cardiologie.ro
L. Sperling, MD, FACC, FACP, FAHA
Emory University School of Medicine, Atlanta, GA, USA
e-mail: lsperli@emory.edu
Springer International Publishing Switzerland 2015
J.P. Andrade et al. (eds.), Prevention of Cardiovascular Diseases,
DOI 10.1007/978-3-319-22357-5_19
207
208
Lifestyle Changes
Tobacco Smoking
Smoking is one of the most preventable causes of mortality and morbidity in
developed countries. The adverse effects of smoking are numerous, including lung
cancer, cerebrovascular disease and chronic pulmonary obstructive disease. A report
in 2000 estimated that worldwide, nearly five million premature deaths occur every
year due to tobacco smoking [4]. Moreover, there is overwhelming evidence that
there is an increase in mortality and morbidity due to passive smoking (second-hand
smoking). Thus, we can no longer consider smoking a matter of personal preference, but a health threat to everybody exposed to cigarette smoke [5].
Epidemiological evidence has confirmed without doubt that active smoking is a
risk factor for cardiovascular disease and the leading cause of preventable death.
The risk for coronary heart disease increases twofold among smokers when compared with non-smokers, two-thirds of sudden cardiac deaths due to acute coronary
thrombosis occur in cigarette smokers and smoking is associated with an 50 %
increase in the risk of stroke [6].
Non-smokers live 8.66 (men) and 7.59 (women) years longer than smokers and
more years free of cardiovascular disease: 6.22 years for males and 4.93 for females.
But non-smokers spend more years with cardiovascular disease over the life course:
2.43 years for males and 2.66 years for females [6]. The Framingham Heart Study
analyzed the cardiovascular life course of their cohort by smoking status. Their
results showed that smoking both shortens the duration of life free of cardiovascular
disease and the duration of life with cardiovascular disease [7].
A study carried out among the cadets from the General Military Academy in
Zaragoza regarding tobacco smoking, physical exercise and lipid profile showed
that smoking 10 or more cigarettes per day decreases HDL cholesterol levels and
significantly increases triglycerides levels, total cholesterol/HDL cholesterol ratio,
leucocytes, haematocrit and haemoglobin values [8].
However, clinical data gathered in the Atherosclerosis Risk in Communities
(ARIC) studies have shown that both active and passive smoking were associated
with accelerated atherosclerosis progression as assessed by the increase in the
carotid artery intimalmedial thickness [6]. Evidence shows that passive smoking
increases the risk for coronary heart disease, but also that a non-smoker living with
a smoking spouse has an estimated 30 % higher risk of CVD, while exposure in the
work place is associated with a similar increase in risk [3]. In the US more than
50,000 deaths annually from ischemic heart disease are linked to second hand
smoking [6]. Relatively low doses of toxins inhaled by passive smokers are sufficient to elicit endothelial dysfunction, platelet activation, oxidative stress and
inflammatory reactions involved in the pathogenesis of atherosclerosis. But most
importantly, passive smoking seems to be capable of precipitating atherothrombosis
and may also have a negative impact on patients who suffer acute coronary syndromes [6].
209
Legal bans and increased taxation appear to be the most effective measures for
decreasing overall smoking, in addition to passive tobacco exposure [5]. The first
known public smoking ban was issued in 1590 by Pope Urban VII who threatened
to excommunicate anyone who took tobacco in the porchway of or inside a church,
whether it be by chewing it, smoking it with a pipe, or sniffing it in powdered form
through the nose. Quitting smoking must be encouraged in all smokers, especially
since there is no age limit to the benefits of smoking cessation [3]. Moreover, smoking reduction cannot be generally recommended as an alternative to quitting smoking since it has not been shown to enhance the probability of future smoking
cessation [3]. On the other hand the benefits of quitting smoking are amply reported:
a systematic review and meta-analysis of 20 cohort studies of smoking cessation
after myocardial infarction have demonstrated a mortality reduction of 36 % compared with continued smokers [9].
Advising individuals regarding tobacco cessation can be approached through
behavioural interventions involving limited clinical interaction (a brief advice to
stop smoking delivered in <20 min by a healthcare worker during a single consultation), individual counseling (one or more face-to-face encounters of 15 min or more
between a smoker and a trained smoking cessation counsellor not involved in routine
clinical care), group counseling (two or more behavioural therapy meetings in which
at least two smokers were present) and telephone counseling (the provision of telephone calls to aid in smoking cessation). All four of these interventions have similar
efficacy, which importantly increases when used in combination with pharmacological interventions as part of a comprehensive smoking cessation strategy [10].
Smoking, either active or passive, has been unequivocally proved as a major
cardiovascular risk factor capable of decreasing life expectancy and thus must not
be approached leniently or considered a matter of personal preference, but actively
combated through any means available.
Nutrition
The role of nutrition in preventing CVDs has long been investigated and there is
strong evidence that shows that diet may influence atherogenesis directly or through
effects on traditional risk factors such as lipid levels, blood pressure or glucose
levels.
Saturated fatty acids (SFAs) are a dietary factor with a strong impact on LDL-C
levels (0.020.04 mmol/L or 0.81.6 mg/dL of LDL-C increase for every additional
1 % energy coming from saturated fat) [11]. Partially hydrogenated fatty acids of
industrial origin represent the major source of trans fatty acids in the diet.
Quantitatively, dietary trans fatty acids have a similar raising effect on LDL-C to
that of SFAs [12].
If 1 % of the dietary energy derived from SFAs is replaced by monounsaturated
fatty acids (MUFAs), LDL-C decreases by 0.041 mmol/L (1.6 mg/dL); if replaced
by n-6 polyunsaturated fatty acids (PUFAs) the decrease would be 0.051 mmol/L
210
(2.0 mg/dL); and if replaced by carbohydrate it would be 0.032 mmol/L (1.2 mg/
dL). PUFAs of the n-3 series have no direct hypocholesterolaemic effect; however,
frequent fish consumption is associated with a reduced CV risk that is mostly independent of any effect on plasma lipids. When consumed in pharmacological doses
(>2 g/day) the effect of n-3 PUFAs on LDL-C levels is either neutral or a slight
increase with a concomitant decrease of triglycerides (TG) [12]. Dietary carbohydrate presents no effect on LDL-C; therefore, carbohydrate-rich foods represent one
of the possible options to replace saturated fat in the diet. Dietary fibre (particularly
of the soluble type), which is present in legumes, fruit, vegetables, and wholemeal
cereals, has a direct hypocholesterolaemic effect [12].
Studies have shown that every 1.0 mmol/L reduction in LDL-C is associated
with a corresponding 22 % reduction in CVD mortality and morbidity [12].
Another effect of diet is that an alimentation that includes high monounsaturated
fats also improves insulin sensitivity compared to a high saturated fat diet. This goes
along with a decrease in TG levels, especially in the post-prandial period. On the
other hand alcohol intake can have a major negative impact on TG levels [12].
Daily ingestion of phytosterols found in vegetable oils (2 g/day), which is more
common in the Mediterranean countries compared to the rest of Europe, can lower
total cholesterol and LDL-C by 710 %, with little or no effect on HDL-C and TG
levels when consumed with the main meal [12].
Available evidence is notable for a TC- and LDL-C-lowering effect of watersoluble fibre from oat bran, -glucan, and psyllium at a daily dose of 515 g/day
soluble fibre [12].
There is strong evidence of an association between high sodium intake (>5 g/
day) and CVD. However, some diets may be high in sodium content but also high in
other cardioprotective factors (e.g. salted fish and vegetables), while other diets may
be high in sodium content and low in cardioprotective factors (e.g. fast foods, some
processed foods) [13]. Epidemiological studies have also reported that increased
potassium intake is associated with a reduced risk of CVD, most notably for stroke,
but also that the association between sodium intake and CVD may be mitigated by
increased potassium intake. The ONTARGET/TRANSCEND study observed that
the lowest rate of CV events occurred in the group with moderate sodium intake and
high potassium intake [13].
A healthy diet contributing to cardiovascular disease prevention should be varied
and rich in fruits and vegetables of different types to obtain a sufficient amount and
variety of antioxidants. At least two or three portions of fish per week are recommended to the general population for the prevention of CVD, together with regular
consumption of other food sources of n-3 PUFAs (nuts, soy, and flaxseed oil); for
secondary prevention of CVD, the recommended amount of n-3 unsaturated fat
should be 1 g/day, which is not easy to derive exclusively from natural food sources,
and use of n-3 nutriceuticals and/or pharmacological supplements may be considered. Salt intake should be limited to <5 g/day, not only by reducing the amount of
salt used for food seasoning but also by reducing the consumption of foods preserved by the addition of salt [12].
211
The European Heart Network proposes a series of targets for a healthy nutrition
based on the current dietary and physical activity patterns in Europe, including what
might be aimed for in the next 510 years. Thus, total fat should constitute less than
30 % of the dietary energy, while saturated fat should represent less than 10 % and
trans fats less than 1 %. On the other hand the intake of PUFAs and MUFAs should
increase to 611 % respectively 813 % of dietary energy. The consumption of fruit
and vegetables should include 400 g/day, while added sugars should not constitute
more than 10 % of energy and sugar sweetened drinks should be avoided as much
as possible. The total intake of carbohydrates should represent more than 55 % of
the dietary energy [14].
A recent study conducted in Germany discovered that consumption of 6 g of
chocolate per day was associated with a 39 % lower risk of the combined outcome
of myocardial infarction and stroke. Chocolate consumption appears to lower CVD
risk, in part through reducing blood pressure, improving endothelial and platelet
function, as well as reducing the markers of inflammation. The flavanols in cocoa
are thought to be responsible for these effects [15].
A healthy diet is comprised of nutrientdense foods rather than energydense
foods and plays a crucial role in decreasing cardiovascular risk.
Physical Activity
The first scientific evidence concerning the beneficial effects of physical exercise
was published by Morris in 1953, after he examined the incidence of coronary
artery disease (CAD) in London bus driver teams. He observed that the incidence of
CAD was less in the middle-age conductors than in the sedentary drivers of the
same age [16]. Decades later, after the publication of many more supportive studies,
physical activity became part of the guidelines for CVD prevention (class I recommendation), recommending at least 30 min of moderate intensity aerobic activity, 7
days per week with a minimum of 5 days per week [17]. Physical activity promotes
health through many metabolic and other pathways which affect cardiovascular risk
factors. It improves the plasma lipid profile, reduces body weight, lowers blood
pressure, reduces platelet aggregation, increases fibrinolytic activity, improves cardiac function, improves cardio-respiratory fitness and lowers the resting heart rate.
Furthermore, exercise training seems to improve endothelium-dependent vasodilatation and to increase urinary sodium excretion and insulin sensitivity. Long-term
exercise may be associated with a decrease of atherogenic activity of blood mononuclear cells and with lower C-reactive protein levels [18]. Recently, Katzmarzyk
et al. reported that reducing excessive sitting to <3 h/day and excessive television
viewing to <2 h/day would result in gains in life expectancy of 2.0 and 1.4 years,
respectively [19]. Moreover, Nocon et al. published a systematic review and meta
analysis of 33 cohort studies consisting of 883,372 participants, which revealed that
physical activity was associated with 35 % risk reduction for CVD mortality and
33 % risk reduction for all-cause mortality [20]. More recently, Wen et al. [21] and
212
Sattelmair et al. [22] have reported that that even 15 min of daily exercise
(about half of the minimal level of guideline recommendation) is associated with a
significant reduction of all-cause mortality or CAD risk. This finding may support
the guidelines assertion that some physical activity is better than none. However,
one of the existing problems is patient compliance. The 2009 HF-ACTION trial
documented that during the initial period of supervised training sessions only 84 %
of the patients were compliant decreasing even to 62 % at 1 year, and to 40 % at 3
years during individual home-based exercises [23]. Suboptimal adherence is unfortunately common, particularly in home based exercise programs, where supervision
is less intensive and compliance much lower. There are many reasons why patients
elude exercise; in older patients sickness and pain are the dominant reasons given
for non-adherence, whereas younger patients usually blame economic factors and
lack of time. Most patients entering secondary prevention programs are beyond the
age of 50 years; they have often not participated in regular physical exercise for
decades since leaving school, thus long-term adherence can be challenging [16].
In order to improve physical activity on a large scale several recommendations
need to be implemented: community wide campaigns, point-of-decision prompts to
encourage using stairs, school-based physical education, social support interventions in community settings, individual adaptations promoting health behaviour
change and creation of enhanced access to places for physical activity combined
with informal outreach activities [24].
A study conducted in Finland several years ago concerning physical activity
showed that moderate levels of leisure time physical activity and occupational physical activity are associated with a reduced CVD and all-cause mortality among both
men and women. This protective effect was observed regardless of body mass index,
age, education, smoking, total cholesterol, systolic blood pressure and other forms
of physical activity [25].
Daily exercise under any given form should become the gold standard for the
entire population, the health benefits derived from it outweighing all other reservations, and it should commence as early as possible and continue throughout life.
213
214
Preventive Strategies
The North Karelia project on cardiovascular prevention was initiated out of the need
of the Finnish people to reduce the high mortality caused by cardiovascular diseases
and through the course of 40 years it decreased dramatically, by 80 %, through the
combined intervention of environmental changes, reorganization of health services,
training of professionals as well as use of the media [35, 36]. This comes to show
that cardiovascular prevention is a matter of team work, aiming at all the risk factors
and working together with specialist across multiple fields.
Simon Capewells analysed the US CHD deaths prevented or postponed by treatments and risk factor changes between 1980 and 2000 using the Impact mortality
model. The results showed that while obesity and diabetes mellitus increased more
than expected, improving risk factors such as smoking, diet, physical activity and
blood pressure as well as primary and secondary prevention treatments had a high
negative impact on CVD mortality [37].
During the 65th World Health Assembly in May 2012, all WHO Member States
endorsed a historic target to reduce premature deaths from non-communicable diseases (which include cardiovascular diseases) by 25 % by 2025. This should be
achieved by reducing the consumption of tobacco, salt, alcohol and transfats as
well as reducing the prevalence of physical inactivity, blood pressure and obesity
and ensuring the availability of essential medicines for persons living and coping
with NCDs.
To be efficient, CVD prevention has to start earlyso, for a young adult steps
into life, there are three numbers which he must keep in mind related to the reduced
risk: 100/120/0. That means maximum 100 mg/dL for glycaemia, 100 mg/dL for
LDL cholesterol and 120 mmHg for systolic blood pressure. Of course, 0 for the
consumption of tobacco. This is the essence of primary prevention and these four
elements are the cornerstones of CVD risk but the healthy DNA has inside the
solution and the promise of a healthy life for many years to come (Fig. 1).
215
Acknowledgements We would like to give thanks to Svetlana Mosteoru, MD, for the outstanding
help in the process of writing this chapter.
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Introduction
Over the past century, life expectancy has increased by approximately 10 years.
Although this is a remarkable achievement, cardiovascular diseases (CVDs)
remain the biggest cause of deaths worldwide. More than 17 million people died
from CVDs in 2008 alone! More than 3 million of these deaths occurred before the
age of 60 and could have been prevented [1]. The situation is further alarming
because over the last decade mortality rates have declined in many high-income
countries and astronomically increased in low-middle income countries, leading to
growing inequalities in the occurrence and outcome of CVDs between countries
and population [1].
In reality, when successful, cardiology has converted an acute disease into a
chronic one and even this result, although of paramount importance, is a mixed
blessing. There is a distinct downside to this success, mainly the dramatic inversion
of the population pyramid that is projected to take place in the not too distant future,
at least in the western part of the world. The consequences of this evolution, together
with the drop in the birth rate of western societies will have major effects in terms
of demographic changes.
The aging of the post-baby boom population means that there will not be enough
young people to ensure the sustainability of the funding of healthcare and pension
benefits for the elderly. This will have important socioeconomic consequences,
which we are already starting to have to come to grips with in the western world.
Furthermore, lifestyle, too, is undergoing sweeping changes. Major social
milestones are being crossed increasingly later in life, such as getting married,
starting a family and assuming greater work responsibilities. It is no longer posR. Ferrari (*) L. Marcantoni G. Guardigli
Department of Cardiology and LTTA Centre, University Hospital of Ferrara and Maria
Cecilia Hospital, GVM Care & Research, E.S. Health Science Foundation, Cotignola, Italy
e-mail: roberto.ferrai@unife.it
Springer International Publishing Switzerland 2015
J.P. Andrade et al. (eds.), Prevention of Cardiovascular Diseases,
DOI 10.1007/978-3-319-22357-5_20
219
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R. Ferrari et al.
sible to experience somebodys death at home and when this happens we are
unprepared to cope with it.
Nevertheless, lets not be too pessimistic. We should praise where praise is due.
Much to our pride, cardiologists take most of the credit for the extended life
expectancy, as we contributed to at least 7 of the 8 years in the observed increase
in life expectancy, while much less success has resulted from progress in other
specialities [2].
Prevention vs Treatment
The reduction in cardiovascular (CV) mortality is mainly due to the reduction of
atherosclerosis progression and to efficacious treatment of its clinical manifestation,
i.e. acute myocardial infarction (MI) and heart failure (HF). Unfortunately, the ultimate cause of atherosclerosis is still a mystery. Therefore, all the attention of the
cardiological community is devoted to the treatment of its sequel or to a reduction
of the modifiable risk factors such as smoking, sedentariness, nutritional imbalance,
blood pressure elevation, impaired glucose tolerance and diabetes, dyslipidaemia,
overweight and abdominal adiposity and markers of chronic inflammation.
Treatments play an important role in any strategy aimed to reduce the burden of
CVDs. The potential contribution of pharmacological treatments such as aspirin,
-blockers, statins, and angiotensin converting enzyme inhibitors is enormous,
particularly if delivered at low cost to avoid the progressive bankruptcy of national
health services. Interestingly, the more recent drugs, such as renin inhibitors and
angiotensin receptor blockers do not provide any further benefit, although they are
highly promoted to cardiologists. Equally, the most costly therapeutic interventions, although highly advocated by cardiologists contribute relatively little to the
reduction in CVDs. This is probably because these interventions in any case are
applied too late or to too few of the people at risk and are too expensive. In the US,
revascularization procedures explain only 5 % of the observed fall in CVD mortality. Even doubling the number of revascularisation procedures will make little difference. It is estimated that we can attribute between 45 and 75 % of the CVD
mortality decline to prevention and changing risk factors and the remaining
5525 % to treatment in general [3]. This is encouraging as changes in lifestyle
and diet are doubly more effective than other high-profile and expensive strategies.
It follows that the future lies in reducing risk factors in primary and secondary
prevention settings and selected intervention for high-risk patients. The various
models suggest that to decrease the global occurrence of a disease, even small
changes in population risk factors are crucial, particularly in primary prevention.
Therefore, we need to prioritise our strategy to change the disease burden of the
entire population and not only of the people at high risk or of the patients already
affected by the disease.
221
Fig. 1
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R. Ferrari et al.
223
to go by bike, or to exercise any other type of recreational activity. The city wall, or
the so-called mura, has become a sort of meeting place for the citizens of Ferrara,
where they go not only to exercise but also to meet their friends. Therefore, in
Ferrara, at least, a small degree of exercise is a must!
Furthermore, from an economic point of view, Ferrara is completely dominated
by the agriculture industry and Ferrara is famous all over Italy for its vegetable
(mainly asparagus) and fruit production (pears in particular). Therefore, it is not
difficult to obtain the recommended five portions of fruits and vegetables a day in
Ferrara. Being situated close to the flood plain of the river Po, the biggest river in
Italy, Ferrara is also famous for its fish industry and particularly for the so-called
bluefish which is very tasty, inexpensive and extremely rich in omega 3 which has
been proven, once again by two Italian studiesthe GISSI trialsto be effective in
preventing myocardial infarction and also in reducing the progression of heart failure [8, 9]. Thanks to all of these characteristics Ferrara has the basis for being a city
of prevention.
Several initiatives have been put into action to this end, some are still ongoing,
and others are in the pipeline. This is indeed a joint effort of the entire city, of its
municipality, university, Mayor, hospital local province, supermarkets, banks and
private industries, etc.
What have we achieved so far?
First of all, we launched an initiative called Ferrara-Arte e Prevenzione. Ferrara
is also known for its art exhibitions shown in marvelous historic palaces, such as the
Palazzo dei Diamanti built in 1503 and the Castello Estense built in 1385. The castle
has also become the official national site of the well-known Hermitage museum in
St Petersburg. The province kindly provided the Chair of Cardiology of the
University of Ferrara a room in the castle where doctors performed free-of-charge
calculations of the risk chart of the 4208 visitors in a period of 2 months. The project
was carried out in conjunction with the Istituto Superiore di Sanita, the Italian
Health Ministry and the region Emilia Romagna.
Two types of risk charts were used. One, which is the official chart from the Italian
Ministry of Health and of the ISS, the same one used for the project Cuore [10], and
one modified by the University of Ferrara which, in addition to the usual risk factors,
also takes into consideration the heart rate, the abdominal circumference, the body
weight and provides ideas of the degree of education and anamnestical data.
The data obtained, reported in Figs. 2, 3, 4 and 5 are astonishing. In a rather
highly educated population interested in visiting a rather sophisticated art exhibition
and motivated to have the risk chart determined 17 % were smokers, 25 % sedentary, 45 % overweight, 10 % hypertensive and 61 % had high cholesterol levels.
Heart rate was above 70 b/m in 56 % of them.
The same project and the same risk charts will be used in different types of populationfor example, in housewives doing the grocery shopping at the supermarket,
metal-mechanic industry workers and the employees of the hospital of Ferrara. The
idea is to compare the level of risk of all different population classes and to see
whether education, socioeconomic background, awareness and knowledge affect
the outcome. It will be interesting to see the data of the hospital employees!
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R. Ferrari et al.
Fig. 2
Fig. 3
Fig. 4
Another initiative is the establishment of the Centre of Prevention where all the
residents in Ferrara as well as the patients discharged from the cardiology department of the University Hospital Ferrara can go, have their risk chart calculated and
find dedicated personnel able to provide proper recommendations and tools in terms
of lifestyle and prevention. The centre is equipped with a kitchen to run professional
225
Fig. 5
courses on how to shop for food and ways to prepare healthy recipes and to give a
proper introduction to exercise (Fig. 4).
In this way, we hope to encourage the population of Ferrara to decrease the consumption of saturated fats and equally importantly to increase the consumption of
polyunsaturated fats, fish, fruit and vegetables and, of course, to reduce smoking.
Counselling for this is also provided at the centre. In addition, proper and guided
introductions to daily exercise are provided.
One of the major problems encountered in the establishment of the centre was to
find ad hoc personnel to run it. Unfortunately, he cardiologists working at the Chair
of Cardiology as well as other doctors in general medicine did not show a real interest
towards to the centre and would not have had the necessary time to dedicate to this
project. Therefore, the University of Ferrara has launched a Master aimed at education specific non-medical personnel to obtain a degree in Prevention Professional.
The master has a duration of 6 months and its official title is: Master in Health
Prevention: focus on cardiovascular risk and will be available on-line from 2014 [11].
Acknowledgments This work was supported by a grant from Fondazione Anna Maria Sechi per
il Cuore (FASC), Italy. The funders had no role in the study design, data collection and analysis,
decision to publish or the preparation of the manuscript.
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for incident CVD or whether other types of interventions reduce CVD risk in
patients with PTSD. Such research is sorely needed.
Fortunately, multiple trials have demonstrated that the potential mechanisms of
PTSDs association with CVD can be improved with behavioral and pharmacologic
therapies [16]. For example, inflammation can be decreased with exercise interventions [30] and/or statin therapy, leading to improved cardiac risk [31]. Specifically
in PTSD patients, integration of tobacco cessation counseling in mental health care
significantly improves smoking rates [32], and both prazosin and cognitive behavioral therapy have demonstrated efficacy for sleep disturbances [33]. As research
continues to identify which of these mechanisms are most important for CVD risk
reduction, future trials of pharmacologic and behavioral treatments for PTSD should
incorporate those mechanisms and CVD events as secondary outcomes.
231
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et al. [42] found that 12 % of 213 participants screened positive for ACS-induced
PTSD at 12 months post-ACS, and that 12.8 % of 179 of those participants screened
positive for ACS-induced PTSD at 36 months. However, while PTSD symptoms
were relatively stable, there were participants who screened positive at 12 months
who did not at 36 months, and vice versa, as 63 % of the variance in 36 month PTSD
symptoms were explained by 12 month PTSD symptoms. Ginzburg and Ein-Dor
[44] published the longest follow-up of ACS patients with measurement of ACSinduced PTSD, with multiple measurements of PTSD symptoms over multiple
years. They found that participants generally were able to be categorized into a large
resilient group who experience some psychological distress in the first 7 months
after the ACS but recover, and a much smaller group of about 6 % of participants
who still had significant ACS-induced PTSD symptoms 8 years later.
Mechanisms
Many of the mechanisms that have been proposed to explain the association between
ACS-induced PTSD and adverse outcomes are the same as those proposed to
explain the association of PTSD to incident CVD. However, whereas the average
length of follow-up for studies that have shown an association of PTSD to incident
CVD is almost 10 years, ACS-induced PTSD seems to increase risk for recurrent
ACS and mortality within a few months or years. As such, either the mechanisms
that are thought to exert long-term cumulative effects on the cardiovascular system
work more quickly in post-ACS patients, or the more short-acting mechanisms are
the most likely candidates for mediators of the ACS-induced PTSD to ACS recurrence/mortality association.
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Conclusions
Research conducted in the past decade has now accumulated such that we can confidently conclude that an association exists between PTSD and incident CVD, and
likely exists between PTSD and recurrent CVD, and that the association is independent of other known risk factors. However, we are not able to point to a single
mechanism that can explain that association. That inability likely exists for two
reasons: the studies that could pinpoint that mechanism have not been conducted,
and the association is carried by multiple mediators whose relative effects are modified by individual patient factors. Future research should focus on (1) methods for
decreasing PTSD, particularly where medical settings can be modified to decrease
PTSD due to ACS, stroke, and other life-threatening illnesses, (2) identifying modifiable mechanisms of the association of PTSD and CVD, particularly non-traditional
risk factors, and (3) determining whether PTSD treatment can offset CVD risk.
Acknowledgements This work was supported by grants HL088117 and HL117832, and in part
by Columbia Universitys CTSA grant No. UL1RR024156, from the National Institutes of Health,
Bethesda, Maryland, United States.
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Introduction
Noncommunicable diseases (NCDs) are the leading causes of death globally, killing
more people each year than all other causes combined. Of the 57 million deaths that
occurred globally in 2008, 36 millionalmost two thirdswere due to NCDs,
comprising mainly cardiovascular diseases (CVDs), cancers, diabetes and chronic
lung diseases. About one fourth of global NCD-related deaths take place before the
age of 60 and the combined burden of these diseases is rising fastest among lowerincome countries, populations and communities, where they impose large, avoidable costs in human, social and economic terms. NCDs are caused, to a large extent,
by four behavioural risk factors that are pervasive aspects of economic transition,
rapid urbanization and 21st-century lifestyles: tobacco use, unhealthy diet, insufficient physical activity and the harmful use of alcohol. Together these behavioural
risk factors are strongly associated to other major cardiovascular (CV) risk factors
including hypertension, diabetes, obesity and metabolic syndrome [1].
Interventions to prevent NCDs on a population-wide basis are not only achievable but also cost effective. The income level of a country or population is not a
barrier to success. Low-cost solutions can work anywhere to reduce the major risk
factors for NCDs.
Currently, the main focus of health care for NCDs in many low- and middleincome countries is hospital-centred acute care. NCD patients present at hospitals
when CVD, cancer, diabetes and chronic respiratory disease have reached the point
of acute events or long-term complications. This is a very expensive approach that
will not contribute to a significant reduction of the NCD burden. It also denies
people the health benefits of taking care of their conditions at an early stage.
P. Giannuzzi, MD (*)
Department of Cardiology, Salvatore Maugeri Foundation IRCCS,
Scientific Institute for Clinical Care and Research of Veruno, Verona, Italy
e-mail: pantaleo.gianuzzi@fsm.it
Springer International Publishing Switzerland 2015
J.P. Andrade et al. (eds.), Prevention of Cardiovascular Diseases,
DOI 10.1007/978-3-319-22357-5_22
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238
P. Giannuzzi
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240
P. Giannuzzi
241
242
P. Giannuzzi
Conclusions
All coronary patients should be advised and have the opportunity to access a comprehensive cardiovascular prevention and rehabilitation programme, addressing all
aspects of lifestylesmoking cessation, healthy eating and being physically
activetogether with more effective management of blood pressure, lipids and glucose. To achieve the clinical benefits of a multidisciplinary and multifactorial prevention programme we need to integrate professional lifestyle interventions with
effective risk factor management, and evidence based drug therapies, appropriately
adapted to the medical, cultural, and economic setting of a country. The challenge
is to engage and motivate cardiologists, physicians and health professionals to routinely practice high quality preventive cardiology and a health care system which
invests in prevention.
References
1. Global status report on noncommunicable disease 2010. Geneva: World Health Organization;
2011.
2. Global strategy for the prevention and control of noncommunicable diseases. Geneva: World
Health Organization; 2000.
243
244
20.
21.
22.
23.
P. Giannuzzi
pies in coronary patients from twenty two European countries. Eur J Cardiovasc Prev Rehabil.
2009;16:12137.
Hammill BG, Curtis LH, Schulman KA, Whellan DJ. Relationship between cardiac rehabilitation and long-term risks of death and myocardial infarction among elderly Medicare beneficiaries. Circulation. 2010;121:6370.
Goel K, Lennon RJ, Tilbury RT, Squires RW, Thomas RJ. Impact of cardiac rehabilitation on
mortality and cardiovascular events after percutaneous coronary intervention in the community. Circulation. 2011;123:234452.
Wood DA, Kotseva K, Connolly S, et al., on behalf of the EUROACTION Study Group.
EUROACTION: A European Society of Cardiology demonstration project in preventive
cardiology. A paired cluster randomised controlled trial of a multi-disciplinary family based
preventive cardiology programme for coronary patients and asymptomatic high risk individuals. Lancet. 2008;371:19992012.
Giannuzzi P, Temporelli PL, Marchioli R, et al. Global secondary prevention strategies to limit
event recurrence after myocardial infarction: results of the GOSPEL study, a multicenter, randomized controlled trial from the Italian Cardiac Rehabilitation Network. Arch Intern Med.
2008;168:2194204.
According to the World Health Organization (WHO), 36 million (63 %) of the 57 million deaths that occurred in 2008 resulted from chronic non-communicable diseases
(NCD), with particularly notable contributions from cardiovascular diseases (CVD),
diabetes, cancer and chronic respiratory diseases. Nearly 80 % of these deaths from
chronic diseases (29 million) occurred in middle- and low-income countries (developing countries), and 26 % of these deaths were regarded as premature [1].
NCD are the most common cause of death in most American countries. In 2007,
CVD accounted for 30 % of deaths from all causes in the Americas, including
662,011 deaths from ischemic heart disease (299,415 women and 362,596 men) and
336,809 deaths from cerebrovascular disease (183,689 women and 153,120 men).
The situation is particularly complex in Latin America, where 40 % of deaths
occurred during individuals most productive life stages [2].
In Brazil, similarly to other countries, NCD are the leading health problem,
accounting for 72 % of deaths from all causes, with CVD (31.3 %), cancer (16.3 %),
diabetes (5.2 %) and chronic respiratory disease (5.8 %) as the most notable
NCD. These NCD affect individuals from all socioeconomic strata, with the greatest effects on vulnerable groups, including the elderly and individuals with little
education and low incomes [3]. Approximately 300,000 Brazilians die each year
from CVD, which include heart attack, stroke, cardiac and renal failure and sudden
death; this death total corresponds to 820 deaths per day, 30 deaths per hour or one
death every two minutes [3, 4].
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246
C.A. Machado
The NCD-related situation involves high socioeconomic costs for countries, particularly low- and middle-income nations. Approximately 80 % of cases of CVD
and type 2 diabetes and approximately one-third of cancer cases could be prevented
if common risk factors, including tobacco smoking, physical inactivity, inadequate
diet and alcohol abuse, could be eliminated [5].
Several determinants hinder the control of CVD, the primary contributor to
NCD. The main determinants are a lack of awareness of the importance of CVD,
which leads to a dearth of funding and resources for the prevention and control of
these diseases; challenges associated with prioritizing government and donor
resources targeting CVD; the impairment of healthcare services in low- and middleincome countries with respect to supporting the prevention, diagnosis and treatment
of CVD; difficulties in relationships between governments and the private sector,
which are complicated by conflicts between share holder interests and public health
goals; uncertainty regarding the applicability and effectiveness of programs and
services in the context of local implementation; and the fragmentation of global
measures for preventing CVD [6].
There is a clear gap between the current knowledge published in the literature
regarding the primary and secondary prevention of NCD and the implementation of
planned actions in clinical practice. It is necessary to understand the complex relationship between healthcare policies and changes in individual behavior, which are
affected by environmental factors and appropriate access to the healthcare system.
Recently, the WHO published a document titled The World Health Report 2013
that drew attention to the need for more creative research to expand the universal
coverage provided by healthcare systems and reduce effectiveness gaps in the practical implementation of proposed measures. This report described a 5 % increase in
investment in health-related research during the 2000s in low- and middle-income
countries. The report also focused on the social mobilization that had occurred in
these countries, emphasizing the fact that many publications were derived from
emerging countries, including China, Brazil and India, and represented the result of
collaborations among universities, governments, international organizations and the
private sector. However, the report also noted the need to establish national and global
networks to coordinate research, collaboration and information exchange among
countries, with a focus on social inclusion as a means of modifying societies [7].
The policies developed for preventing CNCD should be directed toward lifestyle
changes and should particularly target the four common modifiable risk factors of
tobacco smoking, physical inactivity, inadequate diet and alcohol abuse. These factors are affected by economic growth, globalization and unplanned urbanization.
Thus, success in implementing those policies will only be achieved with involvement from multiple public and private sectors that encompasses social mobilization.
Beyond investments in health alone, joint planning of the education, agriculture,
economy, trade, urbanization and transport sectors, among others, is necessary [8].
Conversely, there exists a unique window of opportunity to control the metabolic
factors responsible for CNCD, such as obesity, hypertension and dyslipidemia.
Social mobilization and integrated actions involving various entities in organized
247
civil society, including scientific societies, patient associations and the government,
are essential to impacting these indicators.
The Brazilian Society of Cardiology (Sociedade Brasileira de Cardiologia
SBC) has an important tradition of promoting these social mobilization actions
through the National Program for the Prevention of Cardiovascular Diseases
(Programa Nacional de Preveno das Doenas Cardiovasculares). These actions
include national campaigns corresponding to theme days for warning about
traditional risk factors, such as the 12 8 campaign and a campaign to raise awareness of the need to reduce salt in food; comprehensive programs for treating congenital heart diseases and training physicians to focus on CVD; and initiatives to
train the general populace and healthcare professionals in appropriate responses to
cardiovascular emergencies.
Strategic actions to combat CVD are based on an alliance among the SBC, the
government, civil society, schools and the family unit. Several actors have been
enlisted for these actions, including primary education students, who were mobilized through the SBC program SBC Vai a Escola [SBC goes to school]. In addition,
a government decree created a healthy eating program in schools, and teachers and
students received training as health-promoting agents. The Brazilian population was
mobilized through walks and other actions. Moreover, teaching materials and field
work were used to clarify the importance of diagnosing and treating CVD to this
population. Furthermore, a samba school used its samba plot to spread a message
indicating the need to reduce salt intake, and families were mobilized through a
partnership with the Pastoral Healthcare (Pastoral da Sade) religious organization.
Recently, 200 leaders of National Pastoral Healthcare of the National Conference
of Brazilian Bishops (Pastoral Nacional da Sade da Conferncia Nacional dos
Bispos do Brasil -PNS-CNBB) were recently trained. In turn, these leaders will
train 100,000 PNS-CNBB agents operating in the 15,000 parishes of the Brazilian
Catholic Church. This action resulted from the Campaign for Preventing and
Fighting Against Hypertension (Campanha de Preveno e Combate Hipertenso)
initiative titled Treating High Blood Pressure is an act of faith in life (Tratar a
Presso Alta ato de f na vida), which was implemented throughout Brazil in
2008 and 2009.
Actions conducted in partnership with governments must also be emphasized. In
2000, the Brazilian Societies of Cardiology, Nephrology, Hypertension and Diabetes
and the National Associations of Hypertensive and Diabetic Patients proposed the
creation of a National Program for Hypertension and Diabetes Education to the
Brazilian Ministry of Health. This proposal was accepted, leading to the process of
implementing the plan for the reorganization of Arterial Hypertension (AH) and
Diabetes Mellitus (DM) Care, which sought to increase the prevention, diagnosis
and treatment of AH, DM and other risk factors for CVD by reorganizing the approximately 44,000 units of the Primary Healthcare Services Network/Public Healthcare
System (Rede Bsica dos Servios de Sade/Sistema nico de SadeSUS) to provide these units with problem-solving capacities and improve quality of care.
The aforementioned action sought to improve the quality of life of the Brazilian
population by reducing numbers of hospitalizations, emergency room visits and
248
C.A. Machado
spending relating to the treatment of complications; early retirements; and cardiovascular mortality. Several strategies have been implemented, including the training
of multipliers to update primary health services professionals in the SUS and campaigns to detect and treat AH and DM; these campaigns encouraged the promotion
of healthy habits and the registration and linking of patients to Primary Healthcare
Units (Unidades Bsicas de SadeUBS)
Approximately 14,000 healthcare professionals were trained as multipliers, with
two professionals reached per UBS. Approximately 23 million capillary blood glucose tests were performed in 73 % of the target population examined by the SUS;
borderline and definitive cases of DM were detected in 12.8 and 3.6 % of the test
results, respectively. The blood pressures of approximately 12.5 million individuals
were measured, and 36 % of these individuals had blood pressures higher than
140/90 mmHg. A policy and specific budget for AH and DM drugs were created; as
a result, these drugs and necessary supplies to perform capillary blood glucose tests,
including syringes, needles and strips, became available through the UBS system. A
national registry of diabetic and/or hypertensive patients (HiperDia) was created,
allowing federal, state and municipal managers to plan for the resources required to
care for this population.
To monitor and evaluate this project, several entities were created, including the
National Coordination, which is responsible for managing actions associated with
project implementation; the National Committee, which includes representatives
from the Ministry of Health, the Brazilian Societies of Cardiology, Nephrology,
Hypertension and Diabetes, the National Federations of Hypertensive and Diabetic
Patients, the National Council of Health Secretaries (Conselho Nacional de
Secretrios de SadeCONASS) and the National Council of Municipal Health
Secretariats (Conselho Nacional de Secretarias Municipais de SadeCONASEMS);
and state committees. These entities provided advice and monitored the Plan for the
Reorganization of AH and DM Care at the national and state levels.
In Brazil, this plan induced changes in the healthcare provided to hypertensive
and diabetic patients by basic health services in sampled municipalities [9], and
participation in the program therefore became mandatory for all Brazilian municipalities. In 2008, a report from the Ministry of Health indicated that the mortality
rate from CVD had decreased by 20 % during the prior 20 years; this decrease was
attributed to greater control of tobacco smoking, hypertension, diabetes and dyslipidemia, among other factors [10].
Interdisciplinarity, inter-sector involvement and social participation in the formation of work teams are key to the successful achievement of the WHO-proposed
objective of reducing mortality from NCD by 25 % in 2015. The high-level committees formed by professional societies, the public and private sectors, and the populace will contribute to the sustainability of planning actions that pervade local
policies, thereby creating a critical mass that will contribute to short- and long-term
changes and supporting the transition from a biomedical approach to an approach
based on social determinants of health [11].
249
References
1. Global status report on noncommunicable diseases 2010. World Health Organization; 2011.
2. Prioridades para la salud cardiovascular en las Amricas. Organizao Panamericana de la
Salud, Washington; 2011.
3. Plano de Aes Estratgicas para o Enfrentamento das Doenas Crnicas No Transmissveis
no Brasil 20112022. Ministrio da Sade Secretaria de Vigilncia Sade.
4. Andrade JP, Arnett DK, Pinto F, Pieiro D, Smith Jr SC, Mattos LAP, et al. Brazilian Society
of cardiology letter from Rio de Janeiro III Brazil prevent/I Latin American prevent.
Arq Bras Cardiol. 2013;100(1):35.
5. World Health Organization. Action plan for the global strategy for the prevention and control
of noncommunicable diseases. The World Health Report from 2008. World Health
Organization; 2008.
6. Fuster V, Kelly BB, Vedanthan R. Promoting global cardiovascular health. Moving forward.
Circulation. 2011;123:16718.
7. Research for Universal Health Coverage. The World Health Report 2013. World Health
Organization; 2011.
8. Mendis S. The policy agenda for prevention and control of non-communicable diseases. Br
Med Bull. 2010;96:2343.
9. Avaliao do Plano de Reorganizao da Ateno Hipertenso Arterial e ao Diabetes Mellitus
no Brasil/Ministrio da Sade, Organizao. Pan-Americana da Sade Braslia: Ministrio
da Sade; 2004.
10. Sade Brasil 2008: 20 anos de Sistema nico de Sade (SUS) no Brasil/Ministrio da Sade,
Secretaria de Vigilncia em Sade, Departamento de Anlise de Situao em Sade. Braslia:
Ministrio da Sade; 2009.
11. Social Determinants of Health Discussion Paper 9. Integration of social determinants of health
and equity into health strategies, programmes and activities: health equity training process in
Spain. World Health Organization; 2013.
In recent decades cardiovascular disease (CVD) rates have dropped in some parts of
the developed world; however, the incidence of CVD has increased in other regions,
especially those characterized by low- and middle-incomes [1, 2]. A cursory summary of global trends for one important CVD risk factor, elevated blood pressure
(BP), is illustrative:
High BP (systolic BP (SBP) 140 or diastolic BP (DBP) 90 mmHg) is currently the leading cause of global disease burden [3].
In 2008, 1 billion individuals worldwide had uncontrolled BP [4].
From 1980 to 2008, mean systolic blood pressure (SBP) declined by 7.3 mmHg in
high-income countries, but increased by 3.3 mmHg in low-income countries [4].
Worldwide, SBP is highest in low-income and middle-income countries [4].
Fewer than half of those who have uncontrolled hypertension are aware of their
BP status. Of those receiving drug treatment, only one-third have BP controlled
to target levels [5].
Given this global picture of BP and its control (and that of other CV risk factors,
such as blood cholesterol levels [6]), trends in CVD event rates are unsurprising.
For example, for adults age 3575 years living in China (classified in 2011 as an
upper-middle income country; however, according to the World Bank as of 2014,
nearly 100 million people in China still lived below the national poverty level [7]),
D.K. Arnett, M.S.P.H., Ph.D. (*)
Department of Epidemiology, School of Public Health, University of Alabama
School of Medicine, Birmingham, AL, USA
American Heart Association, Dallas, TX, USA
e-mail: arnett@uab.edu
S.A. Claas, M.S.
Department of Epidemiology, School of Public Health, University of Alabama
at Birmingham, Birmingham, AL, USA
e-mail: sclass@uab.edu
Springer International Publishing Switzerland 2015
J.P. Andrade et al. (eds.), Prevention of Cardiovascular Diseases,
DOI 10.1007/978-3-319-22357-5_24
251
252
the rate of coronary events plus strokes increased from 2.3 to 4.4 % annually in the
period from 1984 to 1999 [8]. In the low-income countries of Africa, projections
suggest that, by 2030, CVD will be the leading cause of deathcontributing 13.4 %
of total mortality (compared to 13.2 % for HIV/AIDS) [9]. Globally, coronary heart
disease is projected to rank as the fifth highest cause of disability-adjusted life-years
lost in low-income countries by 2030 [9]. The 20032009 Prospective Urban Rural
Epidemiological (PURE) study, which recruited 153,996 adults from 628 urban and
rural communities in high-, upper-middle-, lower-middle-, or low-income countries, found that an overwhelming majority of individuals in the upper-middle-,
lower-middle-, or low-income nations suffering from acute coronary syndrome or
stroke receive no treatment [10].
In sum, these CVD risk factor, event, and treatment trends point to a future for
low- and middle-income countries that commentators have described as dismal
and a population emergency that will cost tens of millions of preventable deaths
in the coming decades [11]. Overshadowing these trends are a number systemic and
economic truths: prevention and treatment strategies capable of reducing population
level CVD risk factors and event rates exist; however, existing approaches are economically unviable and unsustainable for those populations and nations most in
need [11]. Upon publication of the findings of the Global Burden of Metabolic Risk
Factors of Chronic Diseases Collaborating Group, which included some of the
trends noted above, editors of The Lancet stated with conviction that Failure to
make population-based cardiovascular health a greater priority, particularly in lowincome and middle-income countries, is unconscionable. This chapter discusses a
possible paradigm with which solutions to this global crisis may be understood and
ultimately addressed.
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254
the founding of the BMVSS in 1975, more than 400,000 individuals in some 26
nations have been fitted with a Jaipur foot [16].
There are other frugal medical device success stories. The General Electric (GE)
corporation markets a US $3000 (cf. the high-income market device at US $12,000)
baby warmer called the Lullaby in 62 countries [14]. A collaboration between
biomedical engineers at Rice University, the University of Malawi, Texas Childrens
Hospital, and the 3rd Stone Design company resulted in the development of a bubble continuous positive airway pressure (bCPAP, a neonatal respiratory-assist
device) machine that costs US $160 to build (cf. the high-income market device sold
at about US $6000) [14]. A device invented by Argentinian car mechanic Jorge
Odn demonstrates that frugal innovations are not merely less expensive versions of
the tools used in high-income nations. The Odn device is a fetal extraction tool that
can, in many cases, replace forceps or vacuum extractors during vaginal delivery.
The Odn device (currently undergoing trials) consists of an insertion tool, a disposable plastic sheath, and a hand air pump. The lubricated plastic sheath is inserted
into the birth canal and is wrapped around the babys head; the air pump is used to
gently inflate an inner compartment of the sheath, which grips the babys head. The
sheath can then be pulled to extract the infant. Although the Odn devices relatively
low cost qualifies it as a frugal innovation, the fact that it can be used safely by nonexperts in a non-clinical setting greatly increases the devices potential impact in
low-income areas where complicated births must be handled without the services of
a trained physician and a modern delivery suite [17].
In general, frugally innovative medical and healthcare devices must have the following characteristics: [14]
Devices must be safe and effective in the hands of the available healthcare workforce (e.g., technicians with minimal training).
Devices must be appropriate for the local infrastructure (e.g., hand- or solarpowered in areas lacking a reliable power supply).
Devices must be appropriate for the local environment (e.g., able to withstand
extremes of heat and cold, exposure to dust and moisture).
Devices must be designed for intensive and prolonged use and have a sustainable
cost-of-ownership over the lifetime of the device (i.e., durability may be as or
more important than initial cost).
Devices must not require constant inputs of high-cost or difficult to procure disposable components (e.g., custom tubes, fittings, batteries, etc.).
255
with an earlier onset in India than in the West. Founded by Dr. Govindappa
Venkataswamy in 1976 to address this need, the Aravind Eye organization has
grown from a single 11-bed hospital to a network of hospitals and care centers
throughout India with nearly 3000 beds. Avarinds success is due in large part to
Dr. Venkataswamys obsession with efficiency: Venkataswamy even spent time at
McDonalds Hamburger University in Illinois studying the time and motion principles and quality control standards the fast food empire employs in its franchises. In
Aravind Eye Hospital surgical suites, doctors stand between two operating tables.
While one patient is undergoing surgery, the next is being prepared on the adjacent
table. After finishing one procedure, the surgeons need do little more than turn to
begin work on the next patient. In 1992, faced with rising costs from suppliers,
Aravind established Aurolab, an in-network manufacturer of intraocular lenses.
Aurolab can supply the lenses at about US $2 per unit (cf. often more than US
$600 in high-income markets). Since its foundation, Aravind doctors have treated
>32 million patients and performed >4 million surgeries and currently performs
60 % as many eye surgeries annually as the UKs National Health System.
Complication rate after surgery is half that reported in Britain, and the surgeries can
be performed at about one one-thousandth of the cost. Most remarkably, the Aravind
Eye Hospitals are self-sustaining: paying customers who may opt for higher-end
services (such as private, air conditioned rooms) subsidize those who are able to pay
little to nothing [18, 19].
To date, perhaps the clearest articulation of the status of and need for frugal innovation in cardiovascular healthcare was offered by Professor Stephen MacMahon of The George Institute for
Global Health in the Lewis A. Conner Memorial Lecture at the 2012 American Heart Associations
Scientific Sessions. A video of Professor MacMahons lecture and information about The George
Institutes pioneering work can be found at http://www.georgeinstitute.org. The authors of this
chapter are indebted to Professor MacMahons research and advocacy in this area.
256
a modest budget and an even more modest timeline for product development. In less
than two years, the MAC 400 ECG was released. This laptop-sized device made use
of inexpensive off-the-shelf microprocessors; simplified signal-processing algorithms; and a small, durable paper strip printer adapted from those used in ticket
kiosks in dusty bus terminals. The MAC 400 was sold for US $1500 (cf. its semiportable predecessor that cost US $10,000) and was a success for GE Healthcare.
Since the introduction of the MAC 400, GE has continued to develop and market a
line of low-cost ECGs. As processing power has increased and the cost of other
components has decreased, the price tag of the newer devices has dropped to about
one-third of the original MAC 400, allowing clinicians to provide ECG services at
US $0.20 per test [20].
Providing adequate healthcare in low-income nations is sometimes made difficult by a paucity of practicing physicians. In India, for example, most primary
healthcare is delivered by nonphysician health workers (NPHWs). To date, Indian
public health efforts administered by NPHWs have focused primarily on maternal
and child health programs and have had considerable success. Researchers sought
to determine whether the work of NPHWs could successfully be extended to cardiovascular care. The Rural Andhra Pradesh Cardiovascular Prevention Study
(RAPCAPS) was conducted in 44 villages in India from 20062008. In one arm of
the study, the villages were randomized to either a clinical intervention treatment
group or a control group. The primary objective of treatment was to boost the identification of individuals at high risk for CV events (i.e., those with a self-reported
history of stroke, heart attack, or angina) who might be candidates for drug therapy.
Treatment consisted of use of an opportunistic clinical screening tool (a simple,
hard-copy algorithm) by NPHWs. For those individuals assessed to be high-risk, the
algorithm was used to determine appropriate treatment decisions. After assessment
by NPHWs, patients consulted with physicians and the physicians recorded their
treatment decisions. About 18 months after initiation of the opportunistic clinical
screening, every household in every treatment and control village was surveyed to
identify high-risk individuals and question them whether they had been assessed
for risk of heart disease/stroke/angina by a health-care provider in the past 12
months? The percentage of high-risk individuals identified in the household survey
who reported having been screened for CVD was 12 % higher in the treatment villages compared to the control villages (63.4 % vs. 51.4 %, P = 0.026). Additionally,
comparisons of NPHW assessments vs. physician assessments revealed that only
3 % of the individuals classified as high risk by NPHWs would have been classified
as low risk by physicians. Drug treatment decisions made by the NPHWs using the
algorithm were the same as those made by the physicians in 88.5 % of cases of
suspected stroke and 87.2 % of cases of suspected heart attack or angina. These
findings suggest the services of NPHWs could potentially be used to improve CV
care in rural India. The authors acknowledge that NPHWs would doubtless make
more diagnostic and management decision errors than trained doctors, but the
adverse impact of such errors would be minimal: high-risk individuals misclassified
257
as low-risk might not receive appropriate treatment, but it is likely they would have
gone untreated without an NPHW CV program anyway, given current treatment
rates; low-risk individuals misclassified as high-risk would be unlikely to suffer
serious adverse events given the excellent overall safety of the various CV drug
therapies available [21].
Another Indian effort, spearheaded in 2000 by Dr. Devi Shetty, aims to be the
heart surgery equivalent of the Aravind Eye Hospitals. Dr. Shettys initial 1000-bed
hospital, located near the electronics manufacturing district of Bengaluru,
specializes in cardiovascular care and surgery. Adopting a philosophy of high efficiency, high patient throughput, and a tiered fee structure similar to Aravind, by
2010 the Narayana Institute of Cardiac Sciences (as it is now known) was performing about 600 heart surgeries a week. The high number of patients treated in the
hospitals operating rooms allows surgeons to specialize and gain a high level of
efficiency and expertise in a particular procedure. Open heart surgery costs an average of US $2000 (cf. US $20,000100,000 in the US) and success rates match the
best seen in the US. The success of the cardiac hospital has lead to explosive growth:
Narayana Health now operates 23 multispecialty hospitals in 14 cities [22, 23].
258
Conclusion
In his Lewis A. Conner Memorial Lecture at the 2012 American Heart Associations
Scientific Sessions, Stephen MacMahon spoke bluntly to his audience of CV
researchers, clinicians, and public health practitioners: the tremendous advances in
CV science, public health/disease prevention, diagnosis, surgery, and medicine that
higher-income nations have enjoyed for the past decades represent only the opening
maneuvers in a much larger campaign against a looming global CVD epidemic. We
may one day look back and see the development of risk scores, echocardiographic
imaging, and our well furnished pharmacopeia as trivial achievements when compared to the task of spreading these advances to a global population. Frugal innovation provides a conceptual way forward. Recently initiated academic programs,
such as the Frugal Innovation Lab sponsored by the School of Engineering at Santa
Clara University; [25] publications, such as The Journal of Frugal Innovation by
Springer; conferences, such as the International Conference on Frugal Innovation
planned for February, 2015 in Singapore; [26] and research funding opportunities,
such as the Indo-US Collaborative Program on Affordable Medical Devices sponsored by the US National Institutes of Health [27] all attest to a growing recognition
of the unmet needs and untapped potential of those at the bottom of the pyramid.
From the population perspective, the bottom of the pyramid represents not only a
market for procedures and devices to treat existing disease, but also a public health
target for three levels of disease prevention: secondary prevention among those at
highest risk (i.e., those who have suffered an event), primary prevention (i.e., prevention among those with risk factors), and primordial prevention (i.e., the prevention of the development of risk factors). While the systems needed to attack primary
and secondary prevention may progress most expeditiously through frugal and
innovative therapeutic systems (e.g., medications for blood pressure, cholesterol,
and diabetes management), primordial prevention presents a unique challenge: the
need not only to change the beliefs and attitudes within populations about cardiovascular health, but also to devise frugal and innovative disease prevention solutions where healthy options become the default options for entire populations. If
successful, such frugal innovations will disrupt the predicted dismal risk factor,
event, and treatment trends and reverse a population emergency that will cost tens
of millions of preventable deaths [11] in the coming decades.
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S. Explaining the decrease in U.S. deaths from coronary disease, 19802000. N Engl J Med.
2007;356:238898.
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260
11.
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13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
Introduction
Atrial fibrillation (AF) is a supraventricular arrhythmia, usually tachycardic, where
in irregular atrial activation occurs, almost always leading to the loss of 2025 % of
cardiac output. These values may be higher in cases of hypertrophic myocardium
resulting from hypertension or hypertrophic cardiomyopathy [1].
AF mostly occurs in late-onset cardiomyopathies, pericarditis, mitral valve disease, bradycardiatachycardia syndrome (where it may present with low ventricular
rate) and acute myocardial infarction [2]. AF is almost always concomitant with
severe myocardial damage in patients with the latter condition and causes onset or
worsening of heart failure in all of these conditions. In this chapter we will exclu-
261
262
sively focus on its relevance as a primary arrhythmia in the genesis and onset of
thromboembolic events. We will not discuss the advantages and disadvantages of
rhythm control or reversal of AF, paroxysmal or persistent AF, or AF triggered by
extracardiac problems.
263
3.00%
2.50%
2.00%
AF
1.50%
AFRVR
1.00%
Atrial flutter
0.50%
0.00%
AF
2009
2010
2011
Mean
2.51%
2.25%
1.89%
2.22%
AFRVR
0.93%
0.79%
0.94%
0.89%
Atrial flutter
0.14%
0.12%
0.12%
0.13%
Fig. 1 Atrial fibrillation and atrial flutter data from the tele-ECG system. AFRVR atrial fibrillation
with rapid ventricular response (DeMoraes et al. [7])
264
Table 1 Risk of stroke in atrial fibrillation
Study
Atrial fibrillation
investigators
Patient population
Five randomized studies
N = 1593, 106 strokes in an average
follow-up period of 1.4 years
Age
Female
Diabetes
265
area and female gender also score 1 point. That new score is more sensitive in the
low-risk range and apparently enables us to better separate who effectively lacks
risk factors and is not required to use anticoagulants from who has low risk but
requires medications.
It is extremely important to accurately assess the risk of bleeding when intending
to indicate the use of oral anticoagulants. That condition is particularly difficult in
AF because many known risk factors for the occurrence of thromboembolic events
are also risk factors for bleeding, including heart failure, advanced age, hypertension, prior stroke and concomitant use of antiplatelet drugs. The HAS-BLED [24]
risk score was developed using scores from 0 to 9, and a score >3 indicates a high
risk of bleeding (Table 2). That score serves as a counterpoint to the clinical decision of whether to use anticoagulants in a patient with AF and reminds us of the
limitations we face in decision-making processes because a patient at high risk for
stroke most likely will also be a patient at high-risk for bleeding. In those cases, the
careful use of drugs at lower doses, or a slightly lower international normalized ratio
(INR) in the case of warfarin, is most likely the most indicated.
Table 2 Breakdown of the CHA2DS2-VASc score and annual rate of stroke according to the
number of points scored in that scale
Abbreviation
C
H
A2
D
S2
V
A
Sc
Parameter
CHF -congestive heart
failure
Hypertension
Age> 75 years
Diabetes
Prior stroke or TIA
Vascular disease
Age between 65 and 74
years
Female gender
Value
1
Points in CHA2DS2
VASc score
0
Annual rate of
stroke* (%)
0
1
2
1
2
1
1
1
2
3
4
5
6
1.3
2.2
3.2
4.0
6.7
9.8
7
8
9
9.6
6.7
15.2
266
267
Therefore, many strokes that could be prevented are not, even though the drug has
an extremely low cost. Thus, similar to other undeveloped countries, Brazil has a
lower rate of permanently adequate INR (meaning improper medication, nonstandardized laboratories or external interference with the drug), which, added to
the logistical difficulties of the Brazilian healthcare system, hinders even more the
proper maintenance of the treatment. The information to be collected from the AF
Registry of the Brazilian Society of Cardiology will be extremely important to
better assess that scenario and confirm or refute the results found in So Paulo in
the AF sample analyzed through tele-ECG.
Clopidogrel
The ACTIVE-W [30] study compared warfar into aspirin and clopidogrel in 6706
patients with AF and at least one additional risk for vascular events. The study was
discontinued early by the Data and Safety Monitoring Board (DSMB) due to warfarins superiority (primary objective consisting of stroke, non-Central Nervous
System (CNS) systemic embolism, AMI or vascular deathannual risk of 3.90 %
in the warfarin group and 5.60 % in the aspirin + clopidogrel group). In turn, the
ACTIVE-A [31] study tested aspirin + clopidogrel compared to aspirin alone in
patients deemed unsuited to receive warfarin, with AF and another risk factor for
vascular events. The combination resulted in an 11 % decrease in the primary objective when compared to aspirin alone, although bleeding increased from above 1.3 %
per year to 2.0 % per year. Briefly, three years of treatment with aspirin + clopidogrel would prevent 28 strokes compared to the use of aspirin alone, although they
would cause 20 severe bleeding events, including three fatal. The indication of the
combined use of aspirin + clopidogrel instead of aspirin alone in patients who cannot take warfarin is still questionable, was not approved by the Federal Drug
Administration (FDA) and became much farther from approval upon the release of
new anti-Xa agents and direct thrombin inhibitors.
The development of new antithrombotic agents that would provide new therapeutic options involves a number of prerequisites to achieve an optimal drug: as or
more effective than warfarin, with a larger therapeutic window, with a low number
of adverse effects; lack of need for routine monitoring of anticoagulation, absence
268
or low level of food or drug interactions, oral fixed dose, rapid onset and termination
of drug action, and, finally, low cost.
Although not all of those prerequisites may be achieved, some new drugs meet
several of them, and with those qualifications, they are already or will soon be available in the international and Brazilian market. We will briefly describe below the
main new products currently used for the prevention of stroke in AF.
Dabigatran
Dabigatran is a direct thrombin inhibitor, which proved effective in the RELY study
[32] when compared to warfarin. The study evaluated 18,113 patients with nonvalvular AF and tested two doses of dabigatran: 110 mg twice daily did not perform
worse than warfarin regarding stroke and systemic embolism prevention (0.91 relative risk, RR [95 % confidence interval, CI 0.531.11]; p < 0.001 for non-inferiority),
albeit showing a lower number of major bleeding events (dabigatran, 2.71 % per
year; and warfarin, 3.36 % per yearp = 0.003). The results with a dose of 150 mg
twice daily were superior compared to warfarin regarding stroke and systemic
embolism (0.66 RR [95 % CI 0.530.82]; p < 0.001 for dabigatran superiority),
albeit with results similar to warfarin regarding major bleeding events. Due to concerns about bleeding, the FDA approved a dose of 75 mg twice daily for patients
with creatinine clearance ranging from 15 to 30 ml/min, and the drug should not be
used in patients with clearance <15 ml/min or patients undergoing dialysis [33].
Thus, the lower dose could be more indicated in cases of increased risk of bleeding,
and the higher dose could be chosen in cases of reduced risk of bleeding, considering that the higher dose was superior to warfarin in decreasing thromboembolic
events while it performed similarly regarding the risk of severe bleeding. The realworld clinical practice will reveal whether those parameters of the RELY study are
maintained and whether the drugs effect in the elderly is well tolerated.
Rivaroxaban
Rivaroxaban is an oral inhibitor of factor Xa that ultimately inhibits thrombin formation through tissue factor pathways and the intrinsic pathway. Rivaroxaban was
evaluated in the ROCKET-AF study (focused on cases with the highest-risk
CHADS2) and was compared to warfarin in 14,264 patients with non-valvular AF at
a dose of 20 mg once daily (15 mg/day in chronic renal patients with clearance from
30 to 49 ml/min, excluding from the study patients with clearance <30) for noninferiority assessment, and the number of strokes or systemic embolism was the
primary objective [34]. In the intention-to-treat (ITT) analysis, 2.1 % events per
year occurred with rivaroxaban and 2.4 % per year with warfarin (hazard ratio, HR
0.88 [95 % CI 0.741.03]; p < 0.001 for non-inferiority),and the total rates of major
269
or minor bleeding events were 14.9 % for rivaroxaban and 14.5 % for warfarin (HR
1.03; p = 0.44). However, a relative reduction of 33 % in intracranial bleeding and of
50 % in fatal bleeding occurred when compared to warfarin. Rivaroxaban is a valid
alternative to treat AF, especially in high-risk cases for bleeding and, like the other
new agents, requires no treatment monitoring through blood testing.
Apixaban
Apixaban is another oral inhibitor of factor Xa used twice daily, excreted biliarily
(two-thirds) and renally (one-third), similarly to rivaroxaban. Apixaban was evaluated in the ARISTOTLE study [35] in 18,201 patients and compared to warfarin.
The study showed a rate of stroke and systemic embolism of 1.27 % per year in the
apixaban group and of 1.60 % in the warfarin group (HR 0.79 [95 % CI 0.660.95];
p < 0.0001 for non-inferiority and 0.011 for superiority). A relative decrease of 49 %
in hemorrhagic stroke (0.51 HR [95 % CI 0.350.75]), 31 % in severe bleeding
(0.69 HR [95 % CI 0.600.80]) and 11 % in overall mortality rate (0.89 HR [IC
95 % 0.800.99]) were observed. This drug will likely have a very successful release
into the market thanks to its excellent results in the ARISTOTLE study. It needs to
be used twice daily and may apparently be used safely inpatients with renal dysfunction, although the data supporting that hypothesis were derived from a substudy
of the main study with a small number of patients. There is no antidote for apixaban,
and it is unclear whether an antidote will be necessary because of the short half-life
of this drug. Preliminary studies are ongoing to assess the effect of a universal antidote against any factor Xa inhibitor.
Edoxaban
Edoxaban is an oral anti-Xa agent with renal and gastrointestinal excretion evaluated
in comparison to warfarin in the ENGA-GE-AF TIMI 48 study [36], which randomized 21,105 patients with non-valvular AF for less than one year and with a CHADS2
score higher than 2. The study had an average follow-up of 2.8 years. Dose correction
was performed for chronic renal failure patients (from 60 to 30 mg), and the primary
objective was the number of strokes and systemic embolism events. The drug at doses
of 30 and 60 mg were not inferior to warfarin regarding the primary objective or
regarding safety, leading to a 46 and 53 % reduction in hemorrhagic stroke at doses
of 60 and 30 mg, respectively, and reducing severe bleeding by 20 % at the highest
dose and by 53 % at the lowest dose. A slight increase in ischemic stroke occurred
with the lowest dose, although the mortality rate from cardiovascular causes decreased
with the dose of 60 mg (4.43 % 3.85 %, 0.87 HR and 95 % CI 0.780.96).
The RELY, ROCKET AF, ARISTOTLE and ENGAGE AF studies overall showed
similar non-inferiority and safety results. Although the positive points have been
270
emphasized above, some important aspects may be limiting for new agents: medications
that need to be used twice daily, which decreases compliance with treatment; use in
patients with severe kidney disease; lack of specific antidotes in the event of severe
bleeding; and, although it may be minimized with a shorter half-life, how those agents
behave pre- and post-electrical cardioversion or post-ablation in electrophysiological
studies. The use of prothrombin complex may be useful to reverse the anticoagulation of
Xa inhibitors in emergency situations. The main characteristics of warfarin, the main
three new anticoagulant drugs approved for use in Brazil, and the comparisons of specific effects of those agents with warfarin are shown in Table 3.
These differences and contrasts occur in Brazil regarding not only drug use but
also interventions: [37] in FA, only 1000 ablations per year are being performed in
50 centers in the country, with a 70 % success rate; these are good results but affect
only a few patients.
Recent Guidelines
Recent guidelines from the American College of Cardiology/American Heart
Association (ACC/AHA)-2011, European Society of Cardiology (ESC) and
American College of Clinical Pharmacology (ACCP), the latter from 2012 [3840],
generally reinforce the notion that thrombin inhibitors and anti-Xa agents should be
used as an alternative to warfarin and as a class I indication when there is a risk
score above 1, without specific indication of which score. Risk factors, cost, tolerability, patient preference and drug and food interactions should be considered in
the choice of drug. The Guideline from the Brazilian Society of Cardiology on
Antiplatelet and Anticoagulant drugs in Cardiology from 2013, currently available
online [41],recommends CHA2DS2-VASc as the risk score.
The above guidelines generally agree that AF without risk factors for stroke
should be treated with aspirin (81325 mg/day) as class I, with a strong tendency for
questioning the use of aspirin alone. Patients with moderate-risk factors (age older
than 75 years or hypertension or heart failure or ejection fractionEF <35 % or
diabetes) should be treated with aspirin or warfarin (2.03.0 INR), with the ACCP
Guideline expressing a preference for warfarin rather than aspirin. Cases of AF and
high-risk factors for stroke (stroke or prior TIA, non-SNC embolism, mitral stenosis, valve prosthesis) should be anticoagulated with warfarin (2.03.0 INR).
The indication of dabigatranin the Brazilian Guideline for Anticoagulant Drugs
(Diretriz Brasileira de Anticoagulantes) [41] is classified as IA, and rivaroxaban is
classified as IB. We transcribe below the considerations made for both drugs using
the original tables (Tables 4 and 5) included in that guideline; Apixaban is now
available in Brazil but it was not at the time the last Guidelines was written and
therefore does not have a Brazilian guidelines indication. Its indication by Brazilian
doctors has followed the American and European guidelines as by Table 4 .
There is no indication of anticoagulation in AF alone in patients younger than 60
years who lack risk factors.
271
Table 3 Main characteristics of warfarin, dabigatran, rivaroxaban and apixaban and changes
found in the number of ischemic and bleeding events of the new agents compared to warfarin
Year of FDA
approval
Mechanism of
action
Oral
bioavailability of
drugs
Main excretion
pathway of drugs
Need to control
anticoagulation
Time until peak
effect
Half-life
Dose usually
recommended
Use in patients
with severe
chronic renal
failure or
undergoing
dialysis
Interactions with
other drugs
Warfarin
1954
Dabigatran
2010
Rivaroxaban
2011
Apixaban
2012
Inhibition of
factors II, VII,
IX, X
100 %
Selective
inhibition
factor IIa
37 %
Selective
inhibition factor
Xa
80 %
Selective
inhibition factor
Xa
66 %
100 % biliary
20 % biliary
80 % renal
No
65 % biliary
35 % renal
No
56 % fecal
25 % renal
No
1h
2.54 h
13 h
1217 h
713 h
815 h
110150 mg
2/day
> Risk of
bleeding
with
1530 ml/
min creat cl,
use then
75 mg 2/
day with no
info on
patients
undergoing
dialysis
Rifampicin,
quinidine,
amiodarone
20 mg 1/day
5 mg 2/day
2.5 mg 2/day
under moderate
dysfunction and
with < bleeding
than warfarin.
Without info on
severe renal
failure/dialysis
CYP3 A 4/5,
ketoconazole,
Macrolide
antibiotics,
clarithromycin
CYP3 A 4/5
ketoconazole,
Macrolide
antibiotics,
clarithromycin
Yes, by INR
Full
anticoagulant
effect within
7296 h
2060 h, mean
40 h
25 mg 1/day,
INR-adjusted
Yes, in both
conditions;
without dose
correction,
although those
patients have >
risk for stroke,
regardless of
drug
Increase the
effect: CYP
450, antiinflammatory
drugs, serotonin
reuptake.
Decrease the
effect:
rifampicin,
ritonavir,
bosentan,
barbiturates
(continued)
272
Table 3 (continued)
Non-inferiority
for stroke and
systemic
embolism
Reduction of
ischemic stroke
Warfarin
Warfarin as
reference
Dabigatran
Yes for 110
and 150 mg
2/day
Rivaroxaban
Yes for 20 mg 1/
day
Apixaban
Yes for 5 mg 2/
day
Warfarin as
reference
Yes, dose
150 mg VO
2.
Yes for both
doses
No
No
Yes
Yes
No
Yes
Yes
No
No
Yes
Reduction of
hemorrhagic
stroke
Reduction of
major bleeding
Warfarin as
reference
Increase of
bleeding/GI
Warfarin as
reference
Reduction of
mortality rate
Warfarin as
reference
Warfarin as
reference
Yes, dose
110 mg VO
2.
Yes, dose
150 mg VO
2.
No
273
IIa
III
Indications
Dabigatranis recommended as an alternative to warfarin for
patients with non-valvular AF for whom oral
anticoagulation is indicated.
The preferential dose of dabigatran should be 150 mg 2/
day, especially for patients at higher risk for stroke and/
orthromboembolic events, provided they have low risk of
bleeding.
That drug may be indicated as an alternative to the vitamin
K antagonist anticoagulant drug inpatients with difficulty in
maintaining an adequate INR, difficulty of blood collection
for routine laboratorial tests, or by patient choice.
Dabigatranis indicated for patients with non-valvular AF
and CHA2DS2-VASc risk score = 1, under the same
conditions as above.
The preferential dose of dabigatran should be 110 mg 2/day
for patients at higher risk of bleeding (older than or 75
years, creatinine clearance ranging from 30 to 50 ml/min,
history of gastrointestinal or intracranial bleeding,
concomitant use of ASA, clopidogrel, amiodarone, chronic
or abusive use of NSAI, BMI < 18 kg/m2).
At least three weeks of uninterrupted use of dabigatran
(preferentially 150 mg 2/day) is recommended for stable
patients with persistent AF who will be subjected to
electrical or chemical cardioversion, without requiring
monitoring tests. TEE is optional. During four weeks of
cardioversion, the use of dabigatran should be maintained,
and its continuity should be decided based on the
CHA2DS2-VASc risk score.
Dabigatran was not adequately tested and should not be
used inpatients with valve prostheses, hemodynamically
severe valve disease or during pregnancy.
Dabigatranis not indicated for prevention of stroke or
systemic thromboembolism in patients with AF and
CHA2DS2-VASc risk score = 0.
Evidence
level
A
AF Atrial fibrillation, ASA acetylsalicylic acid (aspirin), NSAI nonsteroidal anti-inflammatory, TEE
transesophageal echocardiogram, BMI body mass index, INR international normalized ratio
Reproduced from reference [41] (originally Table 4 of the chapter on Anticoagulation in AF of the
Brazilian Guidelines on Platelet aggregation inhibitors and anticoagulant drugs in Cardiology
(Diretrizes Brasileiras de Antiagregantes Plaquetrios e Anticoagulantes em Cardiologia, 2013)
274
IIa
III
Indications
Rivaroxabanis recommended as an alternative to warfarin
for patients with non-valvular AF for whom oral
anticoagulation is indicated.
The preferential dose of rivaroxaban should be 20 mg 1/
day, provided patients have low risk of bleeding.
That drug may be indicated as an alternative to the vitamin
Kantagonist anticoagulant inpatients with difficulty in
maintaining an adequate INR, difficulty in blood collection
for routine laboratorial tests, or by patient choice.
Rivaroxaban is indicated for patients with non-valvular AF
and CHA2DS2-VASc risk score = 1, under the same
conditions as above.
The preferential dose of rivaroxaban for patients with
creatinine clearance ranging from 3049 ml/min should be
15 mg 1/day.
Rivaroxaban was not adequately tested and should not be
used in patients with valve prostheses, hemodynamically
severe valve disease or during pregnancy.
Rivaroxaban is not indicated for prevention of stroke or
systemic thromboembolism in patients with AF and
CHA2DS2-VASc risk score = 0
Evidence
level
B
B
C
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39. De Caterina R, Husted S, Wallentin L, Andreotti F, Arnesen H, Bachmann F, et al. New oral
anticoagulants in atrial fibrillation and acute coronary syndromes: ESC Working Group on
Thrombosis-Task Force on anticoagulants in heart disease position paper. J Am Coll Cardiol.
2012;59(16):141325.
40. You JJ, Singer DE, Howard PA, Lane DA, Eckman MH, Fang MC, et al. American College of
Chest Physicians. Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and
prevention of thrombosis. 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e531S75.
41. Diretrizes Brasileiras de Antiagregantes Plaquetrios e Anticoagulantes em Cardiologia. Arq
Bras Cardiol 2013;101(3 Suppl):193.
Cardiovascular diseases are the leading cause of death worldwide and atherosclerotic disease is the largest contributor to all non-communicable diseases (NCDs)
which include all cancers, diabetes mellitus and chronic lung diseases. In 2008 of
the 57 million deaths globally, 36 millionalmost two thirdswere due to NCDs
and the mortality burden of these diseases is growing rapidly in middle and low
income countries [1]. Many of these deaths are premature and about one quarter of
these NCD deaths worldwide occur in those below the age of 60 years.
Cardiovascular diseases and other NCDs can be prevented. A modern lifestyle
characterized by tobacco use, unhealthy diets and sedentary behaviour, together
with harmful use of alcohol, is the primary determinant of all these diseases which
have aetiologies in common. The combination of unhealthy eating and physical
inactivity lead to overweight and obesity, together with central obesity, elevated
blood pressure, dyslipidaemia and diabetes mellitus. Therefore the potential to prevent CVDs and other NCDs is massive through (1) primordial prevention in whole
populations; (2) identification through screening of the adult population for those at
high multifactorial risk of developing CVD and related diseases followed by primary preventive care; and (3) secondary prevention and rehabilitation for those who
survive their initial presentation with symptomatic atherosclerotic CVD. Feasible
and cost-effective interventions to reduce the burden and impact of NCDs exist, and
sustained action to prevent risk factors and improve health care could avert millions
of preventable premature deaths [25].
At a United Nations High-level meeting of the General Assembly in New York
on 19th and 20th September 2011 the prevention and control of non-communicable diseases worldwide was addressed for the first time. Heads of State and
Government addressed non-communicable diseases with a particular focus on
D.A. Wood (*)
Garfield Weston Professor of Cardiovascular Medicine, International Centre for Circulatory
Health, National Heart and Lung Institute, Imperial College London, London, UK
e-mail: d.wood2@ic.ac.uk
Springer International Publishing Switzerland 2015
J.P. Andrade et al. (eds.), Prevention of Cardiovascular Diseases,
DOI 10.1007/978-3-319-22357-5_26
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developmental and other challenges and social and economic impacts, particularly
for developing countries [6].
The General Assembly:
1. Acknowledged that the global burden and threat of non-communicable diseases
constitutes one of the major challenges for development in the twenty-first century, which undermines social and economic development throughout the world
and threatens the achievement of internationally agreed development goals;
2. Recognized that non-communicable diseases are a threat to the economies of
many Member States and may lead to increasing inequalities between countries
and populations;
3. Recognized the primary role and responsibility of Governments in responding to
the challenge of non-communicable diseases and the essential need for the
efforts and engagement of all sectors of society to generate effective responses
for the [?] prevention and control of non-communicable diseases; Recognize
also the important role of the international community and;
4. International cooperation in assisting Member States, particularly developing
countries, in complementing national efforts to generate an effective response to
non-communicable diseases;
5. Reaffirmed the right of everyone to the enjoyment of the highest attainable standard of physical and mental health;
6. Recognized the urgent need for greater measures at the global, regional and
national levels to prevent and control non-communicable diseases in order to
contribute to the full realization of the right of everyone to the highest attainable
standard of physical and mental health.
This High-level meeting called upon the World Health Organisation (WHO)
before the end of 2012, to:
(1) develop a comprehensive global monitoring framework, including a set of indicators, capable of application across regional and country settings, including
through multi-sectoral process, to monitor trends and to assess progress made
in the implementation of national strategies and plans on NCDs;
(2) prepare recommendations for a set of voluntary global targets for the prevention
and control of NCDs.
The UN meeting also urged Member States to consider the development of
national targets and indicators, based on national situations, building on guidance
provided by WHO.
In May 2012 the Ministers of Health at the World Health Assembly proposed a
global target to reduce premature mortality from non-communicable diseases. The
target was a 25 % relative reduction in overall mortality from cardiovascular
diseases, cancer, diabetes, or chronic respiratory diseases by 2025now widely
quoted as the 25 by 25 agenda (Table 1). This was the first of nine voluntary
targets embracing mortality and morbidity, risk factors and national systems
response, all of which were subsequently adopted by 119 member states at a meeting on 5th to 7th November 2012 [7].
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Table 1 (continued)
Risk factors
Diabetes and obesityb
Target: Halt the rise in diabetes and
obesity.
Indicators
The targets have a political dimension to all of them and there were important
omissions. Diet is a major determinant of cardiovascular disease and fatty acid compositionsaturated, monounsaturated and polyunsaturatedwas not addressed.
Nor were trans fatty acids which are widely used by the food industry in processed
foods such as margarines. A substantial reduction in saturated fat consumption, and
the elimination of trans fatty acids in all food production, could have a major impact
on reducing the incidence of cardiovascular disease. Substitution of saturated fats in
part with polyunsaturated fatty acids, both n-6 fatty acids which mainly come from
plant foods and n-3 fatty acids coming mainly from fish oils, will further reduce
cardiovascular disease. The current recommendations of professional bodies are to
reduce saturated fat to <10 % of total energy intake and to substitute polyunsaturated fatty acids. Trans fatty acids should be eliminated from the human diet.
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The omission of fats from the lifestyle targets was political because it will impact
directly on the business of major food manufacturers but this does not preclude
national action. Several countries have already banned the use of trans fatty acids in
all manufactured foods although this product continues to be widely used around
the world. Other important aspects of the diet were also omitted from the targets.
Sugars in the form of simple carbohydrates, widely used in sweetened soft drinks
and other foods are a major source of calories in the diet and regular consumption is
associated with the development of obesity and type 2 diabetes. Sweetened soft
drinks have no nutritional value and therefore have no part in a healthy diet which
should encompass a wide variety of wholegrain products, fresh fruit and vegetables.
The combination of unhealthy eating and physical inactivity is driving the epidemic
of obesity and, as a consequence, type 2 diabetes. To halt the rise in obesity and
diabetes is not sufficient as a target because in some western populations a majority
of the adult population are already overweight. To halt a further rise is important but
this adverse trend needs to be reversed. This requires action at a population level on
adopting healthy eating and becoming more physically active at the same time. To
achieve the recommendation that all adults should spend 2.55.0 h a week on physical activity, or aerobic exercise training of at least moderate intensity, or 12.5 h per
week on vigorous intense exercise, requires radical changes in the built environment
in order to facilitate such activity in everyday life. Lifestyle also impacts directly on
blood pressure, lipids and glucose and although there is a target for blood pressure,
and one for diabetes, there is no target for cholesterol. Low density lipoprotein cholesterol (LDL-C) is a major risk factor for CVD, just like blood pressure and glucose, and high density lipoprotein cholesterol (HDL-C) is protective. The
concentrations of both LDL-C and HDL-C are influenced by lifestyle, both diet and
physical activity, and a target for LDL-C would also have been appropriate.
At the 66th World Health Assembly in May 2013 the WHO Global Action Plan
for the Prevention and Control of Non-communicable Diseases 20132020 was
endorsed [7] (Table 2). The vision is a world free of the avoidable burden of noncommunicable diseases.
The goal is To reduce the preventable and avoidable burden of morbidity,
mortality and disability due to noncommunicable diseases by means of multisectoral collaboration and cooperation at national, regional and global
levels, so that populations reach the highest attainable standards of health
and productivity at every age and those diseases are no longer a barrier to
well-being or socioeconomic development.
The plan contains the following overarching principles and approaches:
Human rights approach recognizes that enjoyment of the highest attainable
standard of health is one of the fundamental rights of every human being as enshrined
in the Universal Declaration of Human Rights.
Equity based approach recognizes the unequal burden of noncommunicable
diseases is influenced by the social determinants of health and that action on these
determinants is essential to reduce the overall burden of noncommunicable diseases
and create inclusive, equitable, economically productive and healthy societies.
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Table 2 WHO global action plan for prevention and control of noncommunicable diseases
Global action plan for the prevention and control of noncommunicable diseases 20132020
Overview
Vision: A world free of the avoidable burden of noncommunicable diseases.
Goal: To reduce the preventable and avoidable burden of morbidity, mortality and disability due
to noncommunicable diseases by means of multisectoral collaboration and cooperation at
national, regional and global levels, so that populations reach the highest attainable standards of
health and productivity at every age and those diseases are no longer a barrier to well-being or
socioeconomic development.
Overarching
Life-course approach
Human rights approach
principles:
Empowerment of people and
Equity-based approach
communities
National action and
Evidence-based strategies
international cooperation and
Universal health coverage
solidarity
Management of real, perceived
Multisectoral action
or potential conflicts of interest
Objectives
1. To raise the priority accorded to the prevention and control of noncommunicable diseases
in global, regional and national agendas and internationally agreed development goals,
through strengthened international cooperation and advocacy.
2. To strengthen national capacity, leadership, governance, multisectoral action and
partnerships to accelerate country response for the prevention and control of
noncommunicable diseases.
3. To reduce modifiable risk factors for noncommunicable diseases and underlying social
determinants through creation of health-promoting environments.
4. To strengthen and orient health systems to address the prevention and control of
noncommunicable diseases and the underlying social determinants through people-centred
primary health care and universal health coverage.
5. To promote and support national capacity for high-quality research and development for
the prevention and control of noncommunicable diseases.
6. To monitor the trends and determinants of noncommunicable diseases and evaluate
progress in their prevention and control.
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Empowerment of people and communities recognizes the need for people and
communities to be empowered in activities for prevention and control of noncommunicable diseases including advocacy, policy, planning, legislation, service provision, education and training, monitoring, research and evaluation.
Evidence-based strategies recognizes that all strategies and practices for prevention and control of noncommunicable diseases should be based on scientific
evidence and/or best practice, cost effectiveness, affordability and public health
principles taking cultural considerations into account.
Universal health coverage recognizes that all people should have access to
nationally determined sets of the needed promotive, preventive, curative and rehabilitative and palliative basic health services and essential, safe, affordable, effective
and quality medicines and diagnostics.
Management of real, perceived or potential conflicts of interest recognizes
that public health policies for the prevention and control of noncommunicable diseases must be protected from undue influence by any form of vested interest.
There are six objectives (Table 2):
Objective 1. To raise the priority accorded to the prevention and control of noncommunicable diseases in global, regional and national agendas and internationally agreed development goals, through strengthened international cooperation and
advocacy.
Advocacy and international cooperation are vital for resource mobilization,
capacity strengthening and advancing the political commitment to reducing premature mortality from noncommunicable diseases. The desired outcomes of this objective are strengthened international cooperation, stronger advocacy, enhanced
resources, improved capacity and creation of enabling environments to attain the
nine voluntary targets.
Objective 2. To strengthen national capacity, leadership, governance, multisectoral action and partnerships to accelerate country response for the prevention and
control of noncommunicable diseases.
As the ultimate guardians of a populations health, governments have the lead
responsibility for ensuring that appropriate institutional, legal, financial and service
arrangements are provided for the prevention and control of noncommunicable diseases. The desired outcomes of this objective are strengthened leadership, increased
resources, improved capacity and creation of enabling environments for forging a
collaborative multisectoral response at a national level in order to attain the nine
voluntary global targets.
Objective 3. To reduce modifiable risk factors for noncommunicable diseases
and underlying social determinants through creation of health promoting
environments.
Governments are the key stakeholders in the development of a national policy
framework for promoting health and reducing risk factors through multisectoral
action using incentives and disincentives, regulatory and fiscal measures, laws and
other policy options, and health education with a special focus on maternal health,
children, adolescents and youth, including prevention of childhood obesity. Although
deaths from noncommunicable diseases mainly occur in adulthood, exposure to risk
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factors begins in childhood and builds up throughout life which underlines the
importance of legislative and regulatory measures to prevent tobacco use, physical
inactivity, unhealthy diet, obesity and harmful use of alcohol.
Objective 4. To strengthen and orient health systems to address the prevention
and control of noncommunicable diseases and the underlying social determinants
through people-centred primary health care and universal health coverage.
For comprehensive care of noncommunicable diseases all people require access
to a nationally determined set of promotive, preventive, curative, rehabilitative and
palliative basic health services. A strengthened health system addressing noncommunicable diseases should aim to improve health promotion, prevention, early
detection, treatment and sustained management of people with or at risk of noncommunicable diseases in order to prevent complications, reduce the need for hospitalizations and costly high-technology interventions and premature deaths.
Objective 5. To promote and support national capacity for high-quality research
and development for the prevention and control of noncommunicable diseases.
Although effective interventions exist for the prevention and control of noncommunicable diseases their implementation is inadequate and comparative, applied and
operational research is required to scale up and maximize the impact of existing interventions. WHOs prioritized research agenda for the prevention and control of noncommunicable diseases provides guidance on future investment in noncommunicable
disease research. The agenda prioritizes (1) research for placing noncommunicable
diseases in the global development agenda and for monitoring; (2) research to understand and influence the multisectoral, macroeconomic and social determinants of
noncommunicable diseases and risk factors; (3) translation and health systems
research for global application of proven cost effective strategies; (4) research to
enable expensive but effective interventions to become accessible and be appropriately used in resource-constrained settings.
Objective 6. To monitor the trends and determinants of noncommunicable
diseases and evaluate progress in their prevention and control.
Monitoring will provide internationally comparable assessments of the trends in
noncommunicable diseases over time, help to benchmark the situation in individual
countries against others in the same region or development category, provide the foundation for advocacy, policy development and coordinated action and help to reinforce
political commitment. Strengthening the capacity of countries to collect, analyse and
communicate data for surveillance and global and national monitoring will require
financial and technical support taking account of innovations and new technologies to
increase effectiveness in data collection and improve data quality and coverage.
The political imprimatur of Heads of State for prevention of NCDs has given the
cardiovascular disease prevention agenda a colossal boost around the world because
atherosclerotic diseases dominates causes of death. To achieve the 25 by 25 ambition prevention of premature heart attacks and strokes will be essential starting with
secondary prevention, because they have already declared themselves to be at high
risk, having survived an acute cardiovascular event, and there is strong scientific evidence that risk can be substantially reduced through the combination of lifestyle, risk
factor and therapeutic management. The next priority is all those at high risk of developing cardiovascular disease, identified by screening the adult population without a
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history of vascular disease and estimating their total cardiovascular risk, and then
targeting those at highest multifactorial risk. All patients diagnosed with diabetes
mellitus are also included in this high risk group because they are usually at high
multifactorial risk as well [8]. And finally those whose lifestyles through exposure to
tobacco, unhealthy food habits and sedentary behavior puts them on a lifetime trajectory towards obesity, central obesity and ultimately diabetes and cardiovascular disease are the ultimate challenge requiring fiscal and legal instruments to modify the
behaviour of whole populations towards healthier living, productivity and longevity.
In response to this political call for action the European Association for
Cardiovascular Prevention and Rehabilitation (EACPR), formed a Reach Out Task
Force to bring together all those like minded organisations around the world focused
on prevention and rehabilitation in clinical practice. www.escardio.org/communities/eacpr/congresses/pages/global-forum-on-cvd-prevention.aspx.
The mission is to work together as an alliance towards the 25 by 25 agenda by
addressing secondary prevention and rehabilitation and then primary prevention.
The first meeting was convened on the occasion of EuroPRevent in Rome in April
2013 and a list of professional organisations represented at this and subsequent
meetings is given in Table 3.
Coming together in Rome for this first Global Forum had a special historical meaning: it was here where the Forum Romanum was the central public meeting place for
all Romans to exchange ideas and debate their future. In the tradition of this Forum
the elected representatives of societies and organisations with a professional role in
cardiovascular prevention and rehabilitation, were invited from all around the world
for this first Global Forum on Cardiovascular Disease Prevention in Clinical Practice.
The global goal to reduce premature mortality from non-communicable diseasesmost notably cardiovascular diseasesby 25 % by the year 2025 calls for
global cooperation. We need to learn from each other on how best to help our
patientsthose with established cardiovascular disease and those at high risk of
developing cardiovascular diseaseto achieve longer and healthier lives. We need
to create guidelines and standards, drawn from best scientific evidence, for cardiovascular prevention and rehabilitation which are appropriate to the needs of each
country. We need to promote education and training in cardiovascular prevention
and rehabilitation among physicians, nurses and allied professions in order to translate the clinical guidelines into clinical reality. We need to strengthen health services
provision for cardiovascular prevention and rehabilitation, and promote effective
and cost effective service delivery tailored to the needs of each population. We need
to research the burden of lifestyle and related risk factors in our populations, and
how these are changing over time, and what outcomes our patients are achieving in
relation to the standards set in our guidelines. We need to build leadership in cardiovascular prevention and rehabilitation, and promote the organisation of professional
societies in those countries where there are none, to deliver our common agenda to
reduce the burden of cardiovascular disease.
We believe that a Global Alliance on Cardiovascular Prevention in Clinical
Practice could achieve all of this by working together towards the ambitious target
of 25 by 25. Our European Association for Cardiovascular Prevention and
Rehabilitation is reaching out to you as equal partners to build together this global
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alliance for the benefit of all our patients. The principle of a Global Alliance for
CVD Prevention in Clinical Practice was unanimously agreed and a list of potential
roles discussed is given below:
Providing an international forum to share the wealth of experiences of regional
and national organisations in advocating for, delivering and evaluating cardiovascular prevention and rehabilitation programmes for secondary and primary
prevention in different health care settings and economies around the world.
Creating an inventory of all regional and national organisations focussed on prevention and rehabilitation in clinical practice, and a library of professional and
patient resources, to be shared on a common electronic platform and freely
accessible to all health professionals.
Leading the development of international guidelines on CVD prevention for
clinical practice tailored to the needs and resources of high, middle and low
income countries.
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Creating advocacy tools for health professionals to influence politicians and policy makers to invest in preventive care services in hospital, primary care and the
community.
Sharing, developing and adapting clinical protocols for secondary and primary
prevention services.
Developing regional and national CVD risk estimation models for primary prevention of cardiovascular disease.
Certification of programmes of excellence in preventive and rehabilitative care.
Focus on children, young people and families as incubators of the epidemic of
cardiovascular and other non-communicable diseases.
Promoting the availability and use of essential medicines and technologies in all
countries to reduce the risk of cardiovascular disease.
Engaging the wider professional communitydoctors, nurses, dieticians, physiotherapists, physical activity specialists, occupational therapists, psychologists,
pharmacists and othersin the prevention and rehabilitation agenda.
Building partnerships with international and national sports and leisure service
industries to engage in preventive and rehabilitative care.
Setting up education and training programmes in cardiovascular prevention and
rehabilitation for physicians, nurses and allied professionals in both secondary
and primary care.
Influencing the curricular content for postgraduate and undergraduate medical
education, and the education of other health professionals, to include CVD prevention at a population and individual level.
Engaging patients as ambassadors for prevention and rehabilitation services.
Undertaking international surveys of the delivery of preventive and rehabilitative
care, in both secondary and primary prevention, using standardised methodology
in different health care settings to provide comparisons between countries.
Develop professional leadership in prevention and rehabilitation through the creation of specialist societies, or sub-speciality sections of national societies, in
cardiovascular prevention and rehabilitation.
Bring forward new leadership in CVD prevention among young physicians,
nurses and allied health professionals.
Collaborate with pharmaceutical, device and imaging companies as responsible
partners in research and development in cardiovascular medicine and in delivering evidence based care to all patients.
Utilise health economic modelling in different health economies around the
world to make the case for investing in CVD prevention.
Create a media forum and media training of health professionals for dissemination of key messages on CVD prevention to politicians, policy makers and other
key stakeholders responsible for the CVD prevention agenda at a regional and
national level.
A follow-up Global Forum was convened on August 31st 2013 on the occasion
of the ESC Congress in Amsterdam and the World Heart Federation proposed that
the Global Alliance be formally incorporated into the structures of WHF in order to
align the efforts of all actors engaged in this global agenda to maximize our impact.
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The WHF brings together the continental and national leadership of cardiac societies and heart foundations to urge greater action from policy makers, healthcare
professionals, patient organisations and individuals to work together to reduce the
burden of heart disease and stroke and ensure people all over the world can have
better and longer lives.
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ER, Driscoll T, Duber H, Ebel B, Erwin PJ, Espindola P, Ezzati M, Feigin V, Flaxman AD,
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N, Karthikeyan G, Kassebaum N, Keren A, Khoo J-P, Knowlton LM, Kobusingye O, Koranteng
A, Krishnamurthi R, Lipnick M, Lipshultz SE, et al. Global and regional mortality from 235
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2. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, Albus C, Benlian P,
Boysen G, Cifkova R, Deaton C, Ebrahim S, Fisher M, Germano G, Hobbs R, Hoes A,
Karadeniz S, Mezzani A, Prescott E, Ryden L, Scherer M, Syvanne M, Scholte Op Reimer WJ,
Vrints C, Wood D, Zamorano JL, Zannad F. European Guidelines on cardiovascular disease
prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European
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Practice (constituted by representatives of nine societies and by invited experts). Developed
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3. WHO. WHO report on the global tobacco epidemic 2013. Enforcing bans on tobacco advertising, promotion and sponsorship. ISBN 978 92 4 150587 1 (NLM classification: WM 290)
ISBN 978 92 4 069160 5 (PDF) ISBN 978 92 4 069161 2 (ePub), Luxembourg. 2013. http://
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4. WHO/FAO. Diet, nutrition and the prevention of chronic diseases. Geneva; 2003.
5. WHO. Global Recommendations on Physical Activity and Health. ISBN 978 92 4 159 997 9
(NLM classification: QT 255), Switzerland. 2010. http://whqlibdoc.who.int/publications/
2010/9789241599979_eng.pdf?ua=1.
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8. WHO. Prevention of Cardiovascular Disease. Pocket Guidelines for Assessment and Management
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Introduction
Advances in science and research rarely happen in big leaps, but rather as continuous developments of long-term trends. In order to predict the future of research in
cardiovascular disease prevention and to identify the priority areas for research that
really need to be addressed in the years to come we therefore have to take a step
back and look at the major trajectories that have ruled epidemiological and clinical
research in prevention in the last decades.
Several specific peculiarities of cardiovascular disease prevention, however,
make this area very difficult and complex to predict and its future development:
From the methodological point of view research in cardiovascular disease prevention ranges from epidemiological observational studies to clinical intervention studies, animal experiments on pathophysiological mechanisms, and studies
on prevention strategies at population level.
With regard to the content of prevention interventions preventive cardiology covers a wide array of risk factors from hypertension to smoking, from hyperlipidaemia to diabetes. These areas are so big that researchers e.g. in hypertension and
diabetes have their own professional societies to coordinate their scientific
efforts. Prevention societies are not in a position to claim ownership to these
areas.
Finally, it is not easy to define cardiovascular disease prevention. Its advantage
(an interdisciplinary approach to preventing the development and the consequences of cardiovascular diseases) is also its disadvantage, because it lacks the
organocentric intuitive approach of traditional medical disciplines such as
S. Gielen, MD (*)
University Hospital, Martin-Luther-University of Halle/Wittenberg,
Ernst-Grube-Str. 40, 06120 Halle, Germany
e-mail: stephan.gielen@uk-halle.de
Springer International Publishing Switzerland 2015
J.P. Andrade et al. (eds.), Prevention of Cardiovascular Diseases,
DOI 10.1007/978-3-319-22357-5_27
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1,000
Deaths in Thousands
Genetic Studies
800
Studies on Implementation
600
Studies on Mechanisms
Studies on Risk Factor Interventions
400
200
1925
1950
1975
2000
2025
2050
Fig. 1 Time-course of cardiovascular mortality in the United States [2] with an overlay of important prevention research phases from the 1940s until today
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cardiovascular disease [4]. Due to the difficult post-war situation in Europe the first
prevalence studies in Europe did not appear before the 1960s [5]. The era of the
large-scale risk factor studies saw a further landmark publication in 2004, when the
results of the global INTERHEART study were published [6]. Risk factor studies
evolved into two different directions during the last two decades: On the one hand,
risk factor prevalence studies were pooled across Europe to develop a simple and
valid risk prediction model (the SCORE model) [7]. On the other hand, researchers
moved away from traditional environmental risk factors and used high-throughput
genetic testing to identify genes variants such as 9p21 associated with increased
cardiovascular risk [8].
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Fig. 2 Projections for cardiovascular disease prevalence in high, middle, and low income countries from 2004 to 2030. Please note this significant increase projected for low and medium income
countries. Disease prevalence is likely to decrease in the developed world. Cited after Beaglehole
and Bonita [19]
clinical studies showed that exercise led to improved endothelial function through
repetitive increases in laminar are shear stress at the vascular vessel wall [13, 14].
Studies like these are important in two regards: (1) They replace a statistical
association between increased exercise activity and reduce cardiovascular mortality
by a causal mechanism. Better understanding of this mechanism, in turn, helps to
optimise the treatment intervention in order to achieve greater gains in cardiovascular health. (2) Identifying specific mechanisms related to reduce cardiovascular
events can ideally lead to targets for future pharmaceutical interventions.
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295
or dying from a heart attack. However, relative risk and odds ratio are no terms
that patients understand in relation to their individual life. Additionally, the reiteration of long lists of dos and donts can lead to frustration on the side of the
patient. While we do have plenty of data which information to give to the patient
we clearly lack good clinical research in how to best motivate patients to implement lifestyle changes in their daily life and to continue long beyond the rehabilitation intervention. Motivational research is a key area to reformulate the
prevention message in a way that reaches its target audience and sends a positive
sign of support to the patient, who may be in a vulnerable psychological situation
after a first cardiovascular event.
2. Cost-effectiveness:
Expenses in health care are limited. Although generally prevention interventions
are more cost-effective then sophisticated tertiary care in the setting of acute
events not all prevention interventions are equally cost-effective. Health economy research is needed to determine which treatment thresholds provide the best
costs-effectiveness ratio e.g. for pharmaceutical treatment of hyperlipidaemia or
hypertension.
3. Infrastructure:
At the moment there are wide variations regarding the infrastructure for prevention interventions both at population level end at patient level for high risk individuals. In some countries, for example, patients after an acute myocardial
infarction are hospitalised for up to 3 weeks for postacute in-hospital rehabilitation programs. In other countries, the same patients are discharged from acute
care only 3 or 4 days after the event and I then followed through outpatient secondary prevention programs. We lack well-designed prospective randomised
studies comparing different infrastructures for prevention administration in
regard to their clinical effectiveness and their ability to reduce recurrent events.
The same extends to the question which experts and team members are required
to establish effective prevention programs. Do we always need academic physicians or it can well-educated nurses be equally effective?
Even greater are at the differences in the administration of primary prevention: Some countries establish nurse-led prevention programs in central
offices while others send out teams of preventionists into the homes of the
people.
4. Quality Control:
Prevention programs are only successful if followed long-term. However, only a
very small minority of programs actually performs this type of long-term monitoring of programme compliance. Telemonitoring today provides new means of
following patients over long time in reminding them to continue their efforts in
living a healthy lifestyle. Research is needed to establish effectiveness of
telenursing and telemedicine to improve prevention programme adherence in
both primary and secondary prevention.
296
S. Gielen
Epidemiological Research
Today, we have a very comprehensive knowledge about the risk factors and their
relation to the prevalence of cardiovascular disease. In most Western countries risk
factor prevalence is monitored through multinational cohort studies such as
MONICA or it the Score Project of the European Society of Cardiology. Nonetheless,
in underdeveloped areas of the world epidemiological data on risk factor prevalence
and its change over time is not available. This makes it very difficult to assess longterm changes in risk factor behaviour and to verify if primordial or primary prevention programs actually have an effect on population risk factor prevalence. To
develop a true global picture of risk factor prevalence huge efforts are needed to
coordinate and standardise epidemiological monitoring of changes in risk factor
prevalence and cardiovascular morbidity and mortality in many countries of the
evolving economies and the developing world.
297
Conclusion
To achieve our common goal of reducing global mortality from non-communicable
diseases (especially cardiovascular diseases) by 25 % until 2025 research CVD prevention needs to shift significantly towards implementation-oriented research that
aims at finding practical, cost-effective, sustainable ways to optimise primary and
secondary prevention especially in countries with increasing CVD prevalence. In
the past research was focused on improving individual patient outcomes. Evidence
is accumulating, however, that we need to have the same level of evidence for
population-based interventions through restructuring of healthcare infrastructure
and health care-related legislation.
These priority areas, however, are most likely not the priorities of research communities in the developed countries. Co-ordinated political action is therefore
needed to develop a framework of research support programs that foster the type of
research that is needed to tackle the global epidemic of cardiovascular disease.
298
S. Gielen
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Superior doctors prevent the disease; mediocre doctors treat the disease before evident;
inferior doctors treat the full blown diseaseHuang Dee: Nai Ching 2,600 BC
It is better to healthy than ill or dead. That is the beginning and the end of the only real
argument for preventive medicine. It is sufficient.Geoffrey Rose: The Strategy of
Preventive Medicine, Oxford University Press 1992
Introduction
Suppose that, starting next week, you are Minister for Health. And suppose that, for
the sake of argument, you are not bound by too many political constraints, and that
you have adequate access to data and advice from your medical advisors. You might
consider the following:
1. Population demographicsthe size of population, age and gender distributions,
education, social deprivation and so forth.
2. The major causes of death and disability.
3. Are effective treatments available?
4. Are the causes known? If so, is prevention possible?
5. Resources available and how to allocate themhow to balance need with political and media demands.
301
302
303
Within about two hours of a coronary artery occlusion due to plaque rupture, one
half of deaths will have occurred and survivors, if not in time for percutaneous intervention (PCI) or thrombolysis, are likely to have sustained irreversible myocardial
damage [5]. The implications of these observations are that treatments such as PCI,
while impressive for those fortunate enough to be in time to benefit from them, will
of course be inapplicable for those who suffer sudden or early death, and palliative
for many others due to the advanced nature of the underlying disease and the likelihood of irreversible myocardial damage.
304
NOMANCLATURE AND
MAIN HISTOLOGY
SEQUENCES IN PROGRESSION
OF ATHEROSCLEROSIS
EARLIEST
ONSET
MAIN GROWTH
CLINICAL
MECHANISM COLLERLATION
Initial lesion
histologically normal
macrophage Infiltration
Isolated foam cells
Fatty streak
from
first
decade
clinically
silent
ENDOTHEHELIAL DYSFUNCTION
Intermediate lesion
Atheroma
from
third
decade
Fibroatheroma
Complicated lesion
surface defect
hermatoma-hemorrhage
thrombosis
from
fourth
decade
increased
smooth
muscle
and
collagen
increase
clinically
silent
or overt
thrombosis
and/or
hematoma
Originating in the work of Doll and Hill [6] relating to smoking and lung cancer,
a list of criteria has been developed to allow a judgment as to whether an association
between a putative factor and CVD is sufficiently likely to be one of cause and
effect to justify public health action:
1.
2.
3.
4.
5.
6.
7.
8.
Based on a century of grinding research, the following conclusions may be reasonable with regards to risk factors and CVD:
Clearly causal: High saturated fat die, blood cholesterol level, tobacco smoking,
hypertension.
305
Excess alcohol
consumption
Physical inactivity
Biochemical or physiological
characteristics (modifiable)
Elevated plasma cholesterol (LDL
cholesterol)
Low plasma HDL cholesterol
Personal characteristics
(non-modifiable)
Age
Sex
306
Risk %
2
5
8
21
if the lady as no other risk factors and the man has untreated hypertension and is a
smoker. It follows a single factor approach to risk may lead to under- or overtreatment. It is a problem that most trials of risk factor treatment look only at single
factors and not at combined effectsindeed current trials do not tell which person
or persons in Table 2 should receive a statin.
307
A preventive measure that brings large benefits to the community offers little to each participating individual (The prevention paradox, p. 12).
Conclusions
The case for the prevention of CVD has a cohesive logic and evidence base that has
been built up over many decades. It is sufficient to justify intensive public health
action. But a logical evidence base may not be sufficient because prevention requires
long-term planning that is not always politically attractive.
The primary determinants of disease are mainly economic and social, and therefore its
remedies must also be economic and social. Medicine and politics cannot and should not be
kept apart. [16]
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308
9.
10.
11.
12.
13.
14.
15.
16.
17.