Risk Factors and Cardiovascular

Disease
08/23/13
1:00 p.m.
Financial Disclosures:
None
Cardiovascular Risk
-Objectives

Identify the scale of the problem
Define risk factors, absolute and relative risk
Identify the major risk factors
Be able to perform a risk assessment
Identify the basics principles of prevention
Be aware of future challenges

Key Words
Atherosclerotic plaque
Absolute risk, relative risk, odds ratio
Primary prevention, secondary prevention
Framingham Heart study, NHANES
Endothelial dysfunction
Diabetes, metabolic syndrome
ATP III lipid classification
HMG CoA reductase inhibitors (statins)

Magnitude of the BurdenCauses of Death in
the United States
0
100
200
300
400
500
600
700
800
900
1,000
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1
9
9
6

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CVD Cancer Accidents HIV/AIDS
959.2
544.7
93.8
32.7
American Heart Association. 1999 Heart and Stroke Statistical Update. 1998.
The Leading Cause of Death in
US Women
9.9
33.1
31.9
43.8
45.1
48.9
60.6
96.4
375
0 50 100 150 200 250 300 350 400
Deaths (1,000)
Ovarian cancer
Diabetes
Accidents
Breast cancer
Pneumonia/Influenza
COPD*
Lung cancer
Cerebrovascular disease
Heart disease
*COPD=chronic obstructive pulmonary disease.
Adapted from Anderson RN et al. Monthly Vital Statistics Report.
Vol 45(suppl 2):June 12, 1997.
Economic Direct and Indirect Cost of
CVD in the United States
Hospital/nursing home
Physicians/other professionals
Drugs
Home health/
other medical durables
Lost productivity/
morbidity
Lost productivity/
mortality
American Heart Association. Heart and Stroke Statistical Update.
2009 estimated
Total direct and
indirect costs:
$475 billion
Pathobiology




TM
1999 Professional Postgraduate Services

The Matrix Skeleton of Unstable

Coronary Artery Plaque
Davies MJ. Circulation. 1996;94:2013-2020.
Fissures in
the fibrous
cap
Terminology
What is a risk factor?


Factor whose presence is associated with an
increased likelihood that disease will develop

Risk factor vs Risk marker
Absolute Risk

Probability of developing disease over a finite
period

10 year risk of a coronary event in a 50 year old
man with total cholesterol of 250 is 6% or 0.6%
annually

Relative Risk
Relative risk or odds ratio is the ratio of
absolute risk in comparison to a person with
standard risk

Relative risk in a 50year old man with
cholesterol of 250 of a coronary event compared
with a cholesterol of 200 is 50% greater or an
odds ratio of 1.5
Absolute risk is still relatively low at 0.6%and
0.4% annually
Attributable Risk

Attributable risk is the additional probability an
individual with a risk factor will have an event
over time compared with standard risk

The attributable risk of the 50mg extra
cholesterol is 0.2% annually or 2% over 10
years
Prevention



Primary

Secondary


How do we learn about risk
factors?
Epidemiological studies

Framingham Heart Study

MRFIT Trial

Interheart
Emerging Risk Factors
Lipoprotein (a)
Homocysteine
Pro-thrombotic factors (fibrinogen)
Pro-inflammatory factors (C-reactive protein)
Impaired fasting glucose (insulin resistance)
Hypertriglyceridemia
Chronic infection
Dental hygiene
How do we assess risk?
Risk Assessment
Count major risk factors
For patients with multiple (2+) risk factors
Perform 10-year risk assessment

For patients with 01 risk factor
10 year risk assessment not required
Most patients have 10-year risk <10%


Risk assessment - Major Risk Factors
Cigarette smoking
Hypertension (BP 140/90 mmHg or on
antihypertensive medication)
Low HDL cholesterol (<40 mg/dL)

Family history of premature CHD
CHD in male first degree relative <55 years
CHD in female first degree relative <65 years
Age (men 45 years; women 55 years)

HDL cholesterol 60 mg/dL counts as a negative risk factor; its
presence removes one risk factor from the total count.
Risk Assessment

Multiple tools available such as
Framingham risk calculator. No risk
assessment tool is ideal.
Smoking
Single most important preventable cause of
death in USA
142,000 cardiovascular deaths per annum
30% of CHD deaths attributable to smoking
6X risk of MI in women 3X risk in men
Increasing in certain subgroups

Global mortality ~ 10 million by 2030
Smoking
Smoke more = more risk
Low tar/nicotine no benefit to risk
Decreases HDL
Endothelial dysfunction
Platelet adhesiveness
ETS (second hand smoke)
Pack year = one pack a day for a year
Smoking Cessation
Lowers risk immediately (50% @ 1 year)

Nicotine supplements, counselling

80% of smokers start by age 18
Smoking

Male smoker dies 13.2 years prematurely


Female smoker dies 14.5 years prematurely


Hypertension
Hypertension

>70 million Americans

31 % unaware 26 % inadequately controlled

African Americans increased risk
Prevalence of High Blood Pressure in
Americans by Age and Sex
NHANES: 1999-2002
Source: CDC/NCHS and NHLBI.
11.1
21.3
34.1
5.8
55.5
74.0
46.6
60.9
69.2
18.1
34.0
83.4
0
10
20
30
40
50
60
70
80
90
20-34 35-44 45-54 55-64 65-74 75+
Ages
P
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P
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Men Women
0
20
40
60
80
100
120
140
160
180
Kannel WB et al. Am Heart J 1991;121:1268-1273.
Blood Pressure and CVD: Blood Pressure and CVD: Framingham Heart Framingham Heart
Study Study
A
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C
V

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1
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0
0
0
Systolic BP (mmHg)
105 135 165 195
0
20
40
60
80
100
120
140
160
180
Systolic BP (mmHg)
105 135 165 195
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0
24
50
38
77
59
119
90
174
15
31
23
48
36
74
56
113
No Glucose
Intolerance
Glucose
Intolerance
No Glucose
Intolerance
Glucose
Intolerance
MEN MEN WOMEN WOMEN
Hypertension
Continuum of risk
Multiple recordings (white coat hypertension)
Target blood pressure JNC Vll
Patient compliance
Physician compliance


Benefits of Lowering BP
Average Percent Reduction
Stroke 3540%

Myocardial infarction 2025%

Heart failure 50%

Lifestyle Modification
Modification Approximate SBP reduction
(range)
Weight reduction 520 mmHg/10 kg weight loss
Adopt DASH diet 814 mmHg
Dietary sodium
reduction
28 mmHg
Physical activity 49 mmHg
Moderation of alcohol
consumption
24 mmHg
Diabetes
Diabetes

Diabetes is a CHD risk equivalent

CHD Risk Equivalents
Other clinical forms of atherosclerotic disease
(peripheral arterial disease, abdominal aortic
aneurysm, and symptomatic carotid artery
disease)

Diabetes

Multiple risk factors that confer a 10-year risk
for CHD >20%
.

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Kannel WB, McGee DL. JAMA 1979;241:2035-2038.
Framingham Study: DM and CHD
Framingham Study: DM and CHD
Mortality
Mortality
20-Year Follow-up
20-Year Follow-up
17 17
8 8
17 17
4 4
Men Men Women Women
DM DM
Non-DM Non-DM
Metabolic Syndrome

Synonyms
Insulin resistance syndrome
(Metabolic) Syndrome X
Dysmetabolic syndrome
Multiple metabolic syndrome
Metabolic Syndrome

General Features of the Metabolic Syndrome
Abdominal obesity
Atherogenic dyslipidemia
Elevated triglycerides
Small LDL particles
Low HDL cholesterol
Raised blood pressure
Insulin resistance ( glucose intolerance)
Prothrombotic state
Proinflammatory state


Diabetes + Hypertension
=
VERY HIGH RISK

Target BP < 130/80

Cholesterol
TM
1999 Professional Postgraduate Services

0
5
10
15
20
25
30
(2.60) (3.25) (3.90) (4.50) (5.15) (5.80) (6.45) (7.10) (7.75) (8.40) (9.05)
Cholesterol and CHD: Seven Countries Study
TC mg/dL (mmol/L)
CHD
mortality
rates
(%)
Verschuren WMM et al. JAMA. 1995;274:131-136.
100 125 150 175 200 225 250 275 300 325 350
Northern Europe
United States
Southern Europe, Inland
Southern Europe, Mediterranean
Siberia
Japan
Clinical Trials-Cholesterol
TM
1999 Professional Postgraduate Services

4S Group. Lancet. 1994;344:1383-1389.

*P<0.00001.

95% CI: -27 to -54.

P=0.003.
4S: Effect of LDL-C Lowering on Coronary Events
in Secondary Prevention Trial in Men and Women
-25
-35
8
-42

-30

-34
-45
-40
-35
-30
-25
-20
-15
-10
-5
0
5
10
Subjects: 4,444
(81% men, 19% women)
Age range: 35-70 yr
Mean baseline TC: 261 mg/dL
Mean baseline LDL-C: 188 mg/dL
Duration: 5 yr
Intervention: Simvastatin
20-40 mg/day
TC LDL-C
HDL-C
Nonfatal
MI/CHD
death
CHD
death
All-cause
mortality
%+
*
TM
1999 Professional Postgraduate Services

-20
-26
5
-33
-22
-31*
-35
-30
-25
-20
-15
-10
-5
0
5
10
Shepherd J et al. N Engl J Med. 1995;333:1301-1307.
* P<0.0005.

P=0.042.

P=0.051.
Subjects: 6,595 men
Age range: 45-64 yr
Mean baseline TC: 272 mg/dL
Mean baseline LDL-C: 192 mg/dL
Duration: 5 yr
Intervention: Pravastatin
40 mg/day

TC LDL-C
HDL-C
Nonfatal
MI/CHD
death
CHD
death
All-cause
mortality
WOSCOPS: Effects of Lipid Lowering on Coronary
Events in Primary Prevention Trial in Men

%+
TM
1999 Professional Postgraduate Services

Statin Trials: Therapy Reduces

Major Coronary Events in Women
n = number of women enrolled.
* 4S = primarily CHD death and nonfatal MI;
CARE = coronary death, nonfatal MI, angioplasty, or bypass surgery;
AFCAPS/TexCAPS = fatal/nonfatal MI, unstable angina, or sudden cardiac death.
Miettinen TA et al. Circulation. 1997;96:4211-4218.
Lewis SJ et al. J Am Coll Cardiol. 1998;32:140-146.
Downs JR et al. JAMA. 1998;279:1615-1622.
4S (n=827) CARE (n=576) AFCAPS/TexCAPS (n=997)
2 Prevention 1 Prevention
-50
-45
-40
-35
-30
-25
-20
-15
-10
-5
0
5
10
Major coronary events*
-34
-46 -46
%
P=0.012
P=0.001
TM
1999 Professional Postgraduate Services

4S: Reductions in Coronary Events in Older

Adults With Hypercholesterolemia
7.1
-43
-34 -34
-25.1
-34.2
6.9
-42
-28
-33
-35.9
-25.8
-13.6
-16.4
-45
-40
-35
-30
-25
-20
-15
-10
-5
0
5
10
65 yr
<65 yr
Data from Miettinen TA et al. Circulation. 1997;96:4211-4218.
TC LDL-C TG
CHD
mortality
All-cause
mortality
Nonfatal
MI
%
HDL-C
Guideline Levels
ATP III Lipid Classification

Total Cholesterol (mg/dL)
<200 Desirable
200239 Borderline
240 High
ATP III Lipid and
Lipoprotein Classification
LDL Cholesterol (mg/dL)
<100 Optimal
100129 Near optimal
130159 Borderline high
160189 High
190 Very high
ATP III Lipid Classification

HDL Cholesterol (mg/dL)
<40 Low
60 High (negative risk factor)
Triglycerides
Classification of Serum Triglycerides
Normal <150 mg/dL
Borderline high 150199 mg/dL
High 200499 mg/dL
Very high 500 mg/dL
Risk Category
CHD and CHD risk
equivalents

Multiple (2+) risk factors

Zero to one risk factor


*Optional lower target in
high risk patients

LDL Goal (mg/dL)
<100*

<130

<160
Three Categories of Risk that Modify
LDL-Cholesterol Goals
Consider Secondary Causes
Causes of Secondary Dyslipidemia
Diabetes
Hypothyroidism
Obstructive liver disease
Chronic renal failure
Drugs that raise LDL cholesterol and lower
HDL cholesterol (progestins, anabolic
steroids, and corticosteroids)
Lifestyle Modification
TM
1999 Professional Postgraduate Services

Dietary Therapy for

Elevated Blood Cholesterol
*Calories from alcohol not included.
Expert Panel on Detection, Evaluation, and Treatment of
High Blood Cholesterol in Adults. JAMA. 1993;269:3015-3023.
10% of total calories
Nutrient* Recommended intake
Step I Diet Step II Diet
Total fat <30% of total calories

Saturated fatty acids 8-10% of

total calories
<7% of
total calories

Polyunsaturated
fatty acids

Monounsaturated
fatty acids
15% of total calories
Carbohydrates
55% of total calories
Protein ~15% of total calories
Cholesterol <300 mg/day <200 mg/day
Total calories To achieve and maintain
desirable weight
TM
1999 Professional Postgraduate Services

Lyon Diet Heart Study: Cumulative Survival

Without Cardiac Death and Nonfatal MI
de Lorgeril M et al. Circulation. 1999;99:779-785.
1 2 3 4 5
70
80
90
100
Year
Experimental
Control
%
without
event
P=0.0001
-8
-7
-6
-5
-4
-3
-2
-1
0
Metabolic Response to 10-lb Weight Loss:
Framingham Data
Higgins M et al. Acta Med Scand Suppl 1988;723:23-36.
Cholesterol
Small
changes
can add up
to
significant
changes in
long-term
risk
Syst BP Glucose
mg/dl mm Hg mg/dl
Men
Women
Drug Therapy
HMG CoA Reductase
Inhibitors (Statins)
Demonstrated Therapeutic Benefits
Reduce major coronary events
Reduce CHD mortality
Reduce coronary procedures (PTCA/CABG)
Reduce stroke
Reduce total mortality

Appears to be additional benefit beyond
cholesterol lowering Pleiotropic effects of
statins
Its more than just high
cholesterol
Total Cholesterol Distribution:
CHD vs Non-CHD Population
Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9.
1996 Reprinted with permission from Elsevier Science.
35% of CHD
Occurs in People
with TC<200
mg/dL
150
200
Total Cholesterol (mg/dL)
250 300
No CHD
CHD
Framingham Heart Study26-Year Follow-up
Multiple Risk Factors: Additive Risk
The total severity of multiple low-level risk factors often
exceeds that of a single severely elevated risk factor.
8%
Grundy SM et al. J Am Coll Cardiol 1999;34:1348-1359.
BP 165/95 mm Hg BP 165/95 mm Hg
Age 56 years
BP 165/95 mm Hg
Age 56 years
LDL-C 155 mg/dL
BP 165/95 mm Hg
Age 56 years
LDL-C 155 mg/dL
Smoker
13%
19%
27%
0
5
10
15
20
25
30
What About the Cost ?
Cost-Effectiveness
Therapeutic lifestyle changes (TLC)
Most cost-effective therapy

Drug therapy
Dominant factor affecting costs
Declining price of drugs: increases cost
effectiveness
How are we doing?
Deaths From Diseases of the Heart*
United States: 19002003*

Note: Total CVD data are not available for much of the period
covered by this chart.

Source: CDC/NCHS. *Preliminary.
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Trends in Cardiovascular Risk Factors in
the U.S. Population Aged 20-74
NHES: 1960-62, NHANES:1971-75 to 1999-2000
Source: J AMA 2005. 293: 1868-74.
30.8
33.6
1.8
39.2
28.2
3.4
33.1
3.5
26.3
36.0
27.2
19.0
14.8
29.3
4.6
17.0
14.9
26.4
5.0
0
5
10
15
20
25
30
35
40
45
High Total Cholesterol High Blood Pressure Smoking Diagnosed Diabetes
P
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1960-62 1971-75 1976-80 1988-94 1999-2000
1980-2000
RISK FACTOR Change in Risk Factor %
Smoking Prevalence 32
Systolic BP 4
Total Cholesterol 6.1
Physical inactivity 7.8
BMI 10
Diabetes prevalence 44.2
Ford ES et al NEJM 2007;356:2388-98
Change in Risk Factors 1980-2000
Smoking
Diabetes
prevalence
-40
-30
-20
-10
0
10
20
30
40
50
Smoking
Systolic BP
Total Cholesterol
Physical Inactivity
BMI
Diabetes prevalence
1980-2000
47% of the reduction
attributed to treatments

44% due to modification
of risk factors

BMI and Diabetes
increased
0
100
200
300
400
500
600
Men Women
1980
2000
Ford E S, et al NEJM 2007; 356:2388-98
Events/100,000
INTERHEART- 9 modifiable risk factors
predict 90% of acute MI
52 countries first MI
Apo B/ ApoA
Smoking
Diabetes
Hypertension
Abdominal Obesity
Psychosocial


Vegetable and fruits
Daily
Exercise
Alcohol Intake
Yusuf S, et al Lancet 2004;364:937-952
Alcohol


Moderate consumption appears to
lower risk of CHD events
Mental Stress
Difficult to measure

Incidence CV events appears higher in Type A
personality and depression
CRP


Copyright 2009 American Heart Association
Ridker, P. M Circ Cardiovasc Qual Outcomes 2009;2:279-285
Cumulative incidence of cardiovascular events in the JUPITER trial, according to study
group
Newer Tests for Risk Assessment
Noninvasive imaging of early
atherosclerosis
Carotid ultrasoundIMT
Ultrafast CTcalcium score
Magnetic resonance imaging
Noninvasive assessment of endothelial
function
Brachial forearm flow reserve



European SC Guidelines
No smoking
Healthy diet Renal function *
Physical activity
BMI < 25
SBP <140mmHg
Cholesterol <190
LDL <115
Glucose <110
Future Challenges

Patient compliance
Physician compliance

Improved understanding of risk factors
Improved ability to modify risk factors
Gene therapy
Predictive Preemptive Personalized

Take Home

Big Problem
We are part of the problem
Systemic Disease
Continuum of risk, Multiple risk factors

Diabetes + Hypertension = BAD