Review of Literature 9

HRV
The last two decades have witnessed the recognition of a significant
relationship between the autonomic nervous system and cardiovascular mortality,
including sudden cardiac death (Lown B and Verrier RL 19!"# $%perimental
evidence for an association between a propensity for lethal arrhythmias and signs of
either increased sympathetic or reduced vagal activity has encouraged the
development of &uantitative mar'ers of autonomic activity (Tas' (orce 199!"#
)eart rate variability ()RV" represents one of the most promising such
mar'er# The apparently easy derivation of this measure has populari*ed its use# +s
many commercial devices now provide automated measurement of )RV, the
cardiologist has been provided with a seemingly simple tool for both research and
clinical studies (,reifus L- et al 199."#
The clinical relevance of heart rate variability was first appreciated in 19!/s
when )on and Lee noted that fetal distress was preceded by alterations in interbeat
interval before any appreciable change occurred in the heart rate itself# 0n the 1912,
$wing et al used short3term )RV measurements as a mar'er of diabetic autonomic
neuropathy# 0n 191, 4olf 55 et al showed that patients with reduced )RV after a
myocardial infarction had an increased mortality and this was confirmed by studies
showing that )RV is an accurate predictor of mortality post myocardial infarction
(50" (Bigger 6T et al 1997"#
The importance of )RV became apparent in the late 191/s when it was
confirmed that )RV was a strong and independent predictor of mortality following
an acute myocardial infarction (8leiger R$ et al 1919 5ali' 5 et al 19199 Bigger
6T et al 1997"# -ayers and others focused attention on the e%istence of physiological
rhythms imbedded in the beat3to3beat heart rate signal (-ayers B5 19.9 :ena* 6 et
al 19!19 )irsch 6+ and Bishop B 1911"#
4ith the availability of new, digital, high fre&uency, 7;3hour multi3channel
electrocardiographic recorders, )RV has the potential to provide additional valuable
insight into physiological and pathological conditions and to enhance ris'
stratification#
Review of Literature 10
HRV analysis
8obayashi and 5usha (1917"9 -aul et al (1911"9 <amamoto and )ughson
(1991" defined three methods for )RV analysis3 time domain, fre&uency domain and
non3 linear method#
Time Domain Methods
The variations in heart rate may be evaluated by a number of methods, time
domain measures are the simplest to perform# +charya =R et al (7//!" postulated
that analysis of )RV using time domain methods is simple but it has a limitation of
discriminating the sympathetic and parasympathetic contributions of )RV#
Time domain measures are based on the inter3beat interval (0B0", i#e# the
distance in milliseconds (ms" between normal heart beats, usually measured as R3R
intervals in an electrocardiogram ($>?"#
Tas' (orce of the $uropean -ociety of >ardiology and the @orth +merican
-ociety of :acing and $lectrophysiology (199!" described the most commonly used
and simplest variable is to calculate the standard deviation of all normal to normal
RR intervals (-,@@"# 0t reflects all the cyclic components responsible for variability
in the period of recording# Ather parameters of time domain variables are -,+@@,
which is standard deviation of the averages of RR intervals in all 2 min segments of
the entire recording, R5--, which is the s&uare root of the mean of the sum of the
s&uares of differences between adBacent RR intervals, -,-, that is the standard
deviation of differences between adBacent RR intervals, @@2/ the number of
interval differences of successive @@ intervals greater than 2/ ms and p@@2/ the
proportion derived by dividing @@2/ by the total number of @@ intervals#
Frequency domain analysis
+ccording to 5alliani + et al (199;" fre&uency domain measures of )RV
provide information about the fre&uency distribution of the components of )RV
using :ower -pectral ,ensity analysis (:-,"#
+'selrod et al (1911" introduced power spectral analysis of )RV for
&uantitative evaluation of cardiovascular control# -pectral analysis is the most
popular linear techni&ue used in the analysis of )RV signals (:omeran* B et al
Review of Literature 11
19129 )ilton 5( et al 1999 ?ang < and 5ali' 7//.9 +charya =R et al 7//;"#
-pectral power in :-, analysis provides the basic information of how power (i#e#
variance" distributes as a function of fre&uency (Tas' (orce 199!"#
4eise ( et al 199/9 +charya =R et al 7//; stated that fre&uency domain
analysis overcomes the limitation of time domain by providing information about
parasympathetic ()igh (re&uency )(" and sympathetic (Low fre&uency L(" signals#
(re&uency analysis of )RV is often used as a tool to determine Cautonomic
balanceD or sympathetic and parasympathetic nervous system activity (Lanfranchi
:+ and -omers V8 7//7"# Three main spectral components are distinguished in a
spectrum calculated from short3term recordings of 7 to 2 minutes (-ayers B5 19."
3 the high fre&uency ()(" component (/#12 E /#; )*" is related to vagal activity and
includes the respiratory sinus arrhythmia when the breathing rate is normal# L( (/#/;
E /#12 )*" is a &uantitative mar'er for sympathetic modulations, but in some studies
it is viewed as reflecting both sympathetic and vagal activity (Berntson et al 199"#
The very low fre&uency (VL(" component (/#//.)* E /#/; )*" reflects the
influence of several factors on the heart, including chemoreceptors, thermoreceptors,
the renin3angiotensin system and other non3regular factors# The measurement of
VL(, L( and )( power component is usually made in absolute values of power
(milliseconds s&uared"# L( and )( may also be measured in normali*ed units,
(:agani 5 et al 191!9 5alliani + et al 1991" which represent the relative value of
each power component in proportion to the total power minus the VL( component#
The representation of L( and )( in normali*ed units emphasi*es the controlled and
balanced behaviour of the two branches of the autonomic nervous system# Ratio of
the low fre&uency to high fre&uency (L(F)( ratio" is a measure of sympathetic G
parasympathetic balance (Tas' force 199!"#
Non-linear methods
-tandard time and fre&uency domain methods of )RV have been well
described by the Tas' (orce (199!", but in recent years, new dynamic methods of
)RV &uantification have been used to uncover apparent nonlinear fluctuations in
heart rate# These nonlinear variations would enable the cardiovascular system to
respond more &uic'ly to changing conditions#
Review of Literature 12
The cardiovascular system is too comple% to be linear and it can lead to
better understanding of the system dynamics when it is treating as nonlinear system#
>onventional methods of linear analysis failed to give full information about the
)RV because of the nonlinear origin of )RV (:incus -5 and ?oldberger +L 199;"#
0t has been speculated that analysis of )RV based on the methods of non3
linear dynamics might elicit valuable information for the physiological interpretation
of )RV and for the assessment of the ris' of sudden death (5ansier : et al 199!"#
The most commonly used non3linear method of analysing heart rate
variability is the :oincare plot# $ach data point represents a pair of successive beat,
the %3a%is is the current RR interval, while the y3a%is is the previous RR interval#
)RV is &uantified by fitting mathematically defined geometric shapes to the data
(Brennan 5 et al 7//1"# The shape of the plot can be used to classify the signal into
one of several classes (-chechtman et al 199.9 4oo et al 199;" and the irregular
shapes &uantified from plots, classified as nonlinear# Ather methods used are the
correlation dimension, nonlinear predictability (8anters 68 et al 199;", pointwise
correlation dimension and appro%imate entropy (-torella R6 et al 1991"#
Geometrical methods
+s per the guidelines of Tas' (orce (199!" the series of @@ intervals can
also be converted into a geometric pattern, such as the sample density distribution of
@@ interval durations, sample density distribution of differences between adBacent
@@ intervals, Loren* plot of @@ or RR intervals, etc# The )RV triangular inde% is a
measure, where the length of RR intervals serves as the %3a%is of the plot and the
number of each RR interval length serves as the y a%is# The length of the base of the
triangle is used and appro%imated by the main pea' of the RR interval fre&uency
distribution diagram (+charya =R 7//!"#
+ccording to Tas' (orce (199!" the triangular interpolation of @@ interval
histogram (T0@@" is the baseline width of the distribution measured as a base of a
triangle, appro%imating the @@ interval distribution (the minimum of )RV"#
Triangular interpolation appro%imates the RR interval distribution by a linear
function and the baseline width of this appro%imation triangle is used as a measure
of the )RV inde% (5ali' et al 19199 (arrell T? et al 1991"# This triangular inde%
Review of Literature 13
had a high correlation with the standard deviation of all RR intervals# But it is highly
insensitive to artifacts and ectopic beats, because they are left outside the triangle, so
the need for preprocessing of the recorded data is reduced (5ali' 5 et al 1919"# The
maBor advantage of geometric methods lies in their relative insensitivity to the
analytical &uality of the series of @@ intervals (5ali' 5 et al 199."#
)RV also depends on the age and se%# )RV is influenced by physiologic and
maturational factors# 5aturation of the sympathetic and vagal divisions of the +@-
results in an increase in )RV with gestational age and during early postnatal life
(Van RavenswaaiB >5 et al 1991"# )RV decreases with age (+charya =R et al 7//;9
+charya =R et al 7//;"# This decline starts in childhood (-chwart* 6B et al 1991"#
0nfants have a high sympathetic activity that decreases &uic'ly between ages 2 and
1/ years ((inley 6: et al 191"# The influence of provocation on )RV (i#e#, standing
and fi%ed breathing" is more pronounced at younger ages (-chwart* 6B et al 1991"#
0n adults, an attenuation of respiratory sinus arrhythmia with advancing age usually
predominates (Lipsit* L+ et al 199/9 4eise ( et al 199/"# 0t was shown that
compared to men, women are at lower ris' of coronary heart disease (4ilson :4
and $vans 6> 199."#
:revious studies have assessed gender and age3related differences in time
and fre&uency domain indices (Ramae'ers , et al 1991" and some nonlinear
component of )RV# There also seemed to be a significant difference between day
and night hours when studying )RV indices using spectral and time domain
methods (Ramae'ers , et al 19919 <amasa'i < et al 199!"# )R variation for healthy
subBects from 7/ to / years was studied by Bonnemeir et al (7//.", he found that
the )RV decreases with age and variation is more in the case of female than men#
Thyroid
Thyroid diseases are, arguably, among the commonest endocrine disorders
worldwide# 0ndia too, is no e%ception# +ccording to a proBection from various
studies on thyroid disease, it has been estimated that about ;7 million people in
0ndia suffer from thyroid diseases (8ochupillai @ 7///"# Their manifestations vary
considerably from area to area and are determined principally by the availability of
iodine in the diet#
Review of Literature 14
$pidemiological studies of thyroid dysfunction have limitations, for e%ample
the definition of overt hypothyroidism and subclinical hypothyroidism, the selection
criteria of the sample used, the influence of age, se%, genetic and environmental
factors and the different techni&ues used for the measurement of thyroid hormones
and the relative paucity of incidence data (Vanderpump 5: 7//9"#
Thyroid diseases are different from other diseases in terms of their ease of
diagnosis, accessibility of medical treatment and the relative visibility that even a
small swelling of the thyroid offers to the treating physician# $arly diagnosis and
treatment remains the cornerstone of management (=nni'rishnan +? and 5enon
7/11"#
)yperthyroidism and hypothyroidism are more fre&uent in women
(8ochupillai @ 7///"# This gender3specific prevalence almost certainly results from
the underlying autoimmune mechanism for the most common forms of thyroid
disease, which include both ?raveHs and )ashimotoHs disease (Volpe R 199;"#
)owever, with advancing age, especially beyond the eighth decade of life, the
incidence of disease in males rises to be e&ual to that of females (>anaris ?6 et al
7///"#
Hypothyroidism
)ypothyroidism is a state in which the thyroid gland does not ma'e enough
thyroid hormone# The prevalence of hypothyroidism in the general population
ranges from .#1IE;#!I ()ollowell 6? et al 7//79 Vanderpump 5: et al 19929
Leese ?: et al 7//1"# 0n a 7/1. study =nni'rishnan +? et al found hypothyroidism
to be a common form of thyroid dysfunction affecting 1/#9I of the study
population#
The most common cardiovascular signs and symptoms of hypothyroidism
are diametrically opposed to hyperthyroidism and may include bradycardia, mild
hypertension (diastolic", narrowed pulse pressure, cold intolerance and fatigue
(>rowley 4( et al 19"# Avert hypothyroidism affects J.I of the adult female
population and is associated with increased -VR, decreased cardiac contractility,
decreased cardiac output, accelerated atherosclerosis and coronary artery disease
Review of Literature 15
(-teinberg +, 19!19 >rowley 4( et al 19"# These findings may be the result of
increased hypercholesterolemia and diastolic hypertension in these patients (>appola
+R and Ladenson :4 7//."# )ypothyroid patients have other atherosclerotic
cardiovascular disease ris' factors and an apparent increase in ris' of stro'e as well
(,an*i - and 8lein 0 7//.9 Kureshi +0 et al 7//!"# The blood pressure changes,
alterations in lipid metabolism, decreased cardiac contractility and increased -VR
that accompany hypothyroidism are caused by decreased thyroid hormone action on
multiple organs such as the heart, liver and peripheral vasculature and are potentially
reversible with thyroid hormone replacement (:almieri $+ et al 7//;"#
The effects of hypothyroidism depend on the severity and duration of the
disease and can range from subtle abnormalities to overt and easily recogni*able
manifestations (:oli'ar R et al 199."# 0f undiagnosed or improperly treated,
hypothyroidism status is associated with changes in autonomic regulation of
cardiovascular system and in ventricular repolari*ation# These changes,
characteri*ed by an inhomogeneity of ventricular repolari*ation and cardiovascular
autonomic dysfunction, have been lin'ed to the occurrence of malignant ventricular
arrhythmias and sudden cardiac death (+lgra + et al 199.9 Tas' (orce 199!9 TsuBi )
et al 199!9 Laidi 5 et al 1999 Asborn L+ et al 1999"# )owever, sustained or life3
threatening ventricular ectopy is rarely seen in hypothyroid patients (:oli'ar R et al
199.9 -chenc' 6B et al 7//!"#
Review of multiple cross3sectional studies demonstrates that J./I of
patients with congestive heart failure have low T
.
levels (:ingitore + et al 7//29
-chmidt =5 and +scheim ,, 7//!"# The decrease in serum T
.
is proportional to
the severity of the heart disease as assessed by the @ew <or' )eart +ssociation
functional classification (-chmidt =5 and +scheim ,, 7//!"# The cardiac myocyte
has no appreciable deiodinase activity and therefore relies on the plasma as the
source of T
.
# 0n e%perimental animals the low T
.
syndrome leads to the same
changes in cardiac function and gene e%pression as does primary hypothyroidism
(8at*eff )L et al 199"#
Hyperthyroidism
Review of Literature 16
)yperthyroidism clinically is a condition in which thyroid produce elevated
amount of thyroid hormones# 0t is a type of thyroto%icosis, a hypermetabolic clinical
syndrome with elevated serum levels of thyro%ine (T
;
" and triiodothyronine (T
.
"
(8ittisupamong'ol 4 7//9"# ?raveHs disease is the most common cause of
hyperthyroidism (4eetman +: 7///"# The overall prevalence of hyperthyroidism,
which is appro%imately 1#. percent, increases to ; to 2 percent in older women
()ollowell 6? et al 7//7"#
:atients with hyperthyroidism present with characteristic signs and
symptoms, many related to the heart and cardiovascular system (Biondi B et al
7///9 8lien 0 and ABamaa 8 7//19 Biondi B et al 7//7"# -inus tachycardia, atrial
and ventricular premature beats and reduced heart rate variability are fre&uent
complications of overt and subclinical hyperthyroidism in patients with undetectable
serum T-) (Biondi B and >ooper ,- 7//19 >ooper ,- and Biondi B 7/17"#
)yperthyroidism, e%cessive endogenous thyroid hormone production and
thyroto%icosis, the condition that results from e%cess thyroid hormone, whether
endogenous (hyperthyroidism" or e%ogenous (thyroid hormone treatment" are
associated with palpitations, tachycardia, e%ercise intolerance, dyspnea on e%ertion,
widened pulse pressure and sometimes atrial fibrillation# >ardiac contractility is
enhanced and resting heart rate and cardiac output are increased# >ardiac output may
be increased by 2/I to .//I over that of normal subBects as a result of the
combined effect of increases in resting heart rate, contractility, eBection fraction and
blood volume with a decrease in -VR (8lein 0 and ABamaa 8 7//19 Biondi B et al
7//7"#
-inus tachycardia is the most common rhythm disturbance and it is recorded
in almost all patients with hyperthyroidism (Biondi B et al 7///9 >acciatori V et al
199!"# +n increase in resting heart rate is characteristic of this disease (@ordy'e R+
et al 1911"# )owever, it is atrial fibrillation that is commonly identified with
thyroto%icosis (@a'a*awa ) et al 7///" or most common cardiac complication in
hyperthyroidism (@ordy'e R+ et al 1911"#
+trial fibrillation is a heart malfunction directly related to chronological age,
various cardiac, vascular and some other disorders# $%cess thyroid hormone reduces
Review of Literature 17
the action potential which can be considered as pre3e%isting ris' factor for the
clinical manifestation of atrial fibrillation# 0t seems e%cess thyroid hormone in some
subBects which are prone to hyperthyroidism lead to atrial fibrillation and the
incidence of atrial fibrillation among thyroto%ic patients, are greater than non3
thyroto%ic subBects within the normal society, it is more common among male
hyperthyroid patients, particularly T
.
type of thyroto%icosis (8annel 4B et al 19919
<ue et al 7/119 8amins'i et al 7/17"#
There is e%ercise intolerance in hyperthyroid patients, which may result from
an inability to further increase heart rate and eBection fraction or lower -VR as
would normally occur with e%ercise ((orfar 6> et al 1917"# Respiratory and s'eletal
muscle wea'ness may be the predominant cause of e%ercise intolerance in severe or
long standing disease (Alson B et al 1991"# 0n a study of 7; consecutive patients,
!I of patents had obBective signs andFor symptoms of neuromuscular dysfunction
(,uyff R( et al 7///"#

Subclinical Thyroid Disease
-ubclinical thyroid dysfunction (-T," is an early condition of mild thyroid
hormone e%cess (subclinical hyperthyroidism" or deficiency (subclinical
hypothyroidism", characteri*ed by abnormal serum thyroid stimulating hormone
(T-)" and normal free thyro%ine ((T
;
" and free tri3iodothyronine ((T
.
" (Biondi B
and >ooper ,- 7//19 >ooper ,- and Biondi B 7/17"# :atients of subclinical
hyperthyroidism may have no clinical signs or symptoms9 however, studies show
that they are at ris' for many of the cardiovascular manifestations associated with
overt hyperthyroidism (Biondi B et al 7///"# The prevalence of subclinical
hyperthyroidism appears to increase with advancing age# 0n a 1/3year cohort study
of older patients it was found that low T-) was associated with increased ris' for
cardiovascular mortality (:arle 6V et al 7//1" and atrial fibrillation

(-awin >T et al
199;"#
+n increased cardiovascular ris' is associated with long3term untreated
subclinical hyperthyroidism# -ome studies have demonstrated an increased
prevalence of symptoms and signs of adrenergic overactivity in young and middle3
aged patients with e%ogenous and endogenous subclinical hyperthyroidism (Biondi
Review of Literature 18
B et al 199;9 5ercuro ? et al 7///9 -garbi 6+ et al 7//."# Long3term untreated
subclinical hyperthyroidism may induce changes in cardiac morphology and
function because of the increased cardiac wor'load (Biondi B et al 199;9 5ercuro ?
et al 7///"#
,ecreased heart rate variability on 7;3 hour )olter monitoring was noted in
patients with subclinical and overt hyperthyroidism compared with control patients,
which may predict an increased ris' of subse&uent cardiac events (:etretta 5 et al
7//1"#
(lynn R4 et al (7/1/" reported an increased ris' for cardiovascular
morbidity, mortality and dysrhythmias in a recent large population3based study
among 1,!1; patients with e%ogenous hyperthyroidism (mean age !1#! years"#
8amins'i ? et al (7/17" studied the influence of subclinical hyperthyroidism
(s)T" on blood pressure, heart rate variability and incidence of arrhythmia both
before and after they were restored to the euthyroid state and concluded that s)T in
comparison to euthyroid status may be associated with a statistically significant but
probably clinically insignificant increase of KT interval dispersion, prevalence of
V$-, elevated nocturnal arterial B: and changes in heart rate variability#
The prevalence of subclinical hypothyroidism has been reported to be
between ; and 7/I of the adult population samples (>anaris ?6 et al 7///"#This
wide range reflects some important differences among the populations studied in
terms of race and dietary iodine inta'e, the dissimilar characteristics among the
patients evaluated (age, gender, body mass inde%" and the different methods of T-)
evaluation (T-) cut3off values used to define subclinical hypothyroidism" (Biondi B
et al 7//19 -ur's 50 and Boucai L 7/1/"#
+lthough subclinical hypothyroidism is fre&uently CasymptomaticD many
patients have symptoms of thyroid hormone deficiency ($vered ,> et al 19.9
-taub 66 et al 1997"# Lipid metabolism is altered in subclinical hypothyroidism
(,untas L) 7//79 Ra*vi - et al 7//"# :atients have increased serum cholesterol
levels and lipid levels appear to rise in parallel with serum T-) (>anaris ?6 et al
7///9 -taub 66 et al 1997"# >3reactive protein, a ris' factor for heart disease, is
Review of Literature 19
increased in subclinical hypothyroidism (>hrist3>rain 5 et al 7//."# 0n addition,
atherosclerosis, coronary heart disease and myocardial infarction ris' are increased
in women with subclinical hypothyroidism ()a' +$ et al 7///9 Rodondi @ et al
7//!"#
)a' +$ et al (7///" evaluated in the cross sectional study among 11;9
women with age at least of 22 years that mild subclinical hypothyroidism was
associated with a twofold increased ris' of myocardial infarction and aortic
atherosclerosis#
-ahin 0 et al (7//2" investigated the effect of subclinical hypothyroidism
(-)" on sympathovagal balance using the )RV method# + statistically significant
difference was observed only in time domain parameters of -, of normal to normal
intervals (-,@@" and -, of all 23 min mean normal @3@ intervals (-,+@@"
between subgroup and controls#
HRV and Thyroid
,eviation from normal thyroid status has profound influence on all body
systems including cardiovascular system# >hanges in serum thyroid hormone levels
are usually associated with alteration in autonomic regulation of cardiovascular
activity ((oley >5 et al 7//19 Bhat +@ et al 7//"# The thyroid hormone has direct
effect on e%aggeration of sinus nodal rhythmicity (Valcavi R et al 19979 Asman ( et
al 7//7"#
8lein 0 and ABamaa 8 (199;" studied that thyroid hormones by change at the
level of autonomic nervous system, effect heart and vascular system either directly
or indirectly# ,imier3,avid L et al (199;" studied autonomic dysfunction as a maBor
factor of cardiac diseases# +charya =R et al (7//;" found that )RV analysis can be
used to measure cardiovascular autonomic regulation or asses the activities of the
+@- noninvasively#
0nu'ai T et al (1991" studied the relationship between abnormalities in
autonomic nerve function and the thyroid disorders in patients with autoimmune
thyroid diseases by power spectral analysis (:-+"# They observed in untreated
hyperthyroid patients with ?raveHs disease significantly lower coefficient of
variation of the R3R time intervals >V(R3R", )( and significantly higher L(F)(
Review of Literature 20
ratio than in healthy controls# They also found significantly lower L(F)( ratio in
hypothyroid patients with )ashimotoHs thyroiditis than controls#
>acciatori V et al (7///" e%amined the impact of hypothyroidism on the
cardiovascular autonomic regulation by analysing sympathetic and parasympathetic
influences on the heart# They evaluated )RV by autoregressive power spectral
analysis# They observed sharp reduction in the )( component in hypothyroid (lying,
79#; M 2#; vs ;# M !#. (nu", pN/#/29 standing, 1;#/ M .#2 vs .7#1 M .#! (nu",
pN/#//2"# >onversely the L( component was higher in hypothyroid than in controls
(lying, !1#! M !#; vs ;2#; M !# nu9 standing 1# M 1#/ vs 2.#1 M 2#! nu" difference
being significantly in the standing# They also observed increased L(F)( ratio in
hypothyroid subBects both in lying (7#2 M /#! vs 1#1! M /#.9 pN/#/2" and standing
(1/#/ M .# vs 1#12 M /#.9 pN/#/7"# Total )RV was lower in hypothyroid subBects
than in controls, difference being significant in the lying position# Re3e%amined of
patients after LT
;
therapy, complete normali*ation of cardiovascular parameters was
found (L(F)( ratio, lying standing both pN/#/1 vs baseline values"#
Leong 8- et al (7///" showed that several inde%es of cardiac autonomic
dysfunction, in particular a reduction in sympathetic activity, was present in
symptomatic growth hormone deficient (?)," patients# They proposed that these
changes might be related to abnormalities in cardiac structure or central autonomic
tone and could contribute to the lower blood pressure in these patients# (urthermore,
VL( was lower in ?), patients#
(oley >5 et al (7//1" studied the effect of thyroid status on arterial
barorefle% function and autonomic contributions to arterial pressure and heart rate in
conscious rats# Their results showed that thyroid status alters the balance of
sympathetic to parasympathetic tone in the heart#
>hen 6L et al (7//!" evaluated the impact of hyperthyroidism on the
autonomic nervous system and investigate the relationship between serum thyroid
hormone concentration and heart rate variability in hyperthyroids# They found
significant difference (pN/#//1" in different )RV parameters than controls3 a
decrease in T:, VL(, L(, )( and )( (nu" and an increase in L( (nu", L(F)(#
Review of Literature 21
Bhat +@ et al (7//" investigated autonomic reactivity with altered thyroid
status, they showed that the changes in thyroid hormone levels in both hypothyroids
and hyperthyroids are associated with altered sympathetic reactivity, with no
significant difference in the parasympathetic activity in either hypothyroid or
hyperthyroid subBects as compared to euthyroid controls whereas others observed
that in mar'ed hypothyroidism there is hypofunctional abnormalities in the
parasympathetic system (0nu'ai T et al 199/"#
>hen 6L (7//" e%amined whether the heart rate dynamics of hyperthyroid
patients is different from normal controls by the nonlinear analysis of heart rate
variability ()RV" with correlation dimension (>,"# Their results showed that
hyperthyroid patients and normal controls could be distinguished by >, analysis of
)RV# 0n addition, the decreased >, in hyperthyroid patients implies reduced
comple%ity and impaired tolerance to cardiovascular stresses in hyperthyroidism#

?uasti L et al (7//" found different local @$ concentrations or post3
receptor signaling may be present in patients with thyroid dysfunction# They said
that the neurally mediated influences on the sinus node and the study of intracellular
catecholamine production suggest a reduced sympatho e%citation in hypothyroidism
compared with the treatment phase#
-huvy 5 et al (7//1" e%amined the association of one minute heart rate
variability during deep breathing with sympathovagal imbalance in hyperthyroid
patients with suppressive dose of thyro%ine for thyroid cancer and controls# They
found significantly lower )RV among patients compared to healthy controls (72#! M
1/#2 vs# .;#. M 17#! beatsFmin, pN/#/2", with no significant difference in mean,
ma%imal and minimal heart rate between the groups#
?aletta ( et al (7//1" studied the effect of clinical hypothyroidism on
cardiovascular autonomic function and ventricular repolari*ation in .1 patients (77
females and 9 males9 mean age 2.#! M 11#1 years" with overt hypothyroidism and .1
controls# They observed higher KT dispersion and lower )RV measures in
hypothyroidism than controls# 0n hypothyroids, -,@@ was inversely related to
serum (log" T-) levels, while KT dispersion and KTc dispersion were directly
Review of Literature 22
related to log T-)# +fter ! months of LT
;
3treatment )RV parameters were
improved, with the correction of hypothyroidism whereas KT and KTc dispersion
results were restored partially# -o, they concluded hypothyroidism is associated with
decreased sympatho3vagal modulation of the heart rate, with an increased
inhomogeneity of ventricular recovery times#
0n a 7//9 study La'shmi V et al found the correlation of autonomic indices
as a function of the thyroid status for young females# Basal heart rate variability,
parasympathetic activity ($G 0 Ratio, ./G12 Ratio, Valsalva Ratio" and sympathetic
activity (:ostural >hallenge Test, -ustained )andgrip Test" were done before and
after attainment of euthyroidism# They observed significant increase in
parasympathetic activity on achieving euthyroid state# The sympathetic activity too
significantly improved after L3thyro%ine supplementation# Lipid profile parameters
significantly decreased after achieving euthyroid state#
8arthi' - et al (7//9" studied the role of )RV to assess sympathovagal
imbalance and its association to cardiovascular morbidities in thyroid dysfunction#
They observed significantly lower total power (T:", )( nu in hypothyroid subBects
(pN/#/2" and hyperthyroid (pN/#//1" than controls and increase L( nu, L(F)( ratio
both in hypothyroid (pN/#/2" and hyperthyroid (pN/#//1" than controls# They also
observed statistically high L( nu, L(F)( ratio and low )( nu in hyperthyroids than
hypothyroids which indicates poor cardiovascular health in patients suffering from
thyroid dysfunctions especially in hyperthyroidism#
8abir R et al (7//9" observed the )RV parameters in patients with
hyperthyroidism to find out the influence of e%cess thyroid hormone on cardiac
autonomic nervous activities# 5ean R3R interval was significantly (pN/#//1" lower
but mean heart rate was significantly (pN/#//1" higher, -,@@ and R5--, were
significantly lower in untreated hyperthyroids than those of treated hyperthyroids
(pN/#/1" and euthyroids (pN/#//1"# They concluded that decreased vagal modulation
on heart rate may occur in hyperthyroidism, which may be restored after ade&uate
treatment of the disease#
Thyroid and Creatine inase
Review of Literature 23
Thyroid dysfunctions are often correlated with muscular disorders# >reatine
'inase (>8" is a cytoplasmic and mitochondrial en*yme with wide tissue
distribution (Tsung -) 19!"# -erum >8 was first used as a diagnostic aid in
progressive muscular dystrophy ($bashi - et al 19299 :anag 85,- et al 7/17"#
>reatine 'inase cataly*es the reversible phosphorylation of creatine, a reaction in
which +T: is the donor of the phosphate group (?riffths :, 191!" and creates
phosphocreatine (:>r" and adenosine diphosphate (+,:"#
The dimeric molecule consists of two elongated polypeptide subunits termed
B and 5# The two subunits are very similar# $ach has a relative molecular mass of
;1.//3;./// (:erryman 5B et al 191."# The nomenclature of the subunits is based
on the tissue source of two of the dimeric creatine 'inase isoen*ymesG B for brain
and 5 for muscle (=rdal : et al 191."# Therefore, there are three different
isoen*ymesG >8355, >83BB and >835B#
-'eletal muscle contains the greatest concentration of >8 activity, almost
e%clusively 55 isoen*yme, trace amount of 5B isoen*yme also occurs in adult
s'eletal muscle# 5yocardial tissue contains the second greatest activity, of which !3
1I 55 isoen*yme, 77I 5B isoen*yme and /37I BB isoen*yme# >8 activity in
brain e%clusively attributed to BB isoen*yme (Tsung -) 19!"# ,evelopmentally,
>83BB is the principle isoen*yme of fetal s'eletal muscle during the first and
second month of gestation, but it is gradually replaced by >835B and >8355#
Thus after the si%th month, >83BB is rarely detectable in this tissue# +t term,
s'eletal muscle consists of primarily >8355 isoen*yme ((o%all >, and $mery +$
192"#
+n increase of the >8 activity may be associated to myocardial infarction,
acute cerebrovascular diseases, traumas or diseases involving muscles# +fter
myocardial infarction, >8 level begins to increase in serum between the three and
the si%th hour following the event, reaches a pea' at 7; hours, returns to the normal
range on average by the third day (Rosal'i -B 19/"#
5usculos'eletal disorders often accompany thyroid dysfunctions# 0n addition
to well 'nown observation that musculos'eletal disorders are common in patients
Review of Literature 24
with hypothyroidism, they are also observed in thyroto%icosis and level of >8 is
altered in both these condition (>a'ir 5 et al 7//.9 :ra'ash + et al 7//"#
?iampietro et al (191;" have proved that the creatine 'inase activity is one of
the best indicator of the hypothyroid myopathy# 0t is sensitive for the early detection
of muscle involvement due to the metabolic disorders and is closely correlate to the
metabolic conditions of patients#
>linical studies have also demonstrated a close relationship between the
e%tent of inBury to the myocardium (infarct si*e" following 50 and increased serum
>835B mass concentrations (+pple (- et al 1991"# +round 9/I of >835B is
found in the myocardium but trace amounts are found in small intestine, tongue,
diaphragm and uterus (5annem -R et al 7//9"# >oncentrations of >835B have
been found to be significantly higher in heart muscle of e%perimental animals and
human myocardium with coronary artery disease, aortic stenosis or heart failure,
compared to normal (Vatner ,$ and 0ngwall 6- 191;9 <ounes + et al 19129 0ngwall
6- et al 19129 @ascimben L et al 199!"#
5oderate to mar'ed >835B elevation is also noted in inflammatory
myopathies (eg# polymyositis, dermatomyositis", muscular dystrophies (type 1",
collagen vascular diseases and scleroderma (Larca L6 et al 1911"# 0n these disease
processes, in response to muscle fiber damage, muscle regeneration occurs, mainly
during this regenerative process# -'eletal muscle fibers revert to an embryonic
isoen*yme pattern and >835B is produced leading to increased levels (1/ to 2/I
of total >8" (+dornato BT and $ngel 48 19"#
-u*u'i - et al (199" described ; cases of adult patients with ?raveHs disease
and an abnormal increase in serum >8 concentrations during treatment with +T,
and speculated that the rapid decrease in thyroid hormone resulted in a local
hypothyroid state within the muscle tissue, which may have contributed to the >8
elevations#
+ccording to -trachan -R et al (7///" hypothyroidism is also 'nown to
increase >835B fraction, especially if associated with renal failure# 0t is well
Review of Literature 25
documented that hypothyroidism can cause persistent elevation of cardiac en*ymes,
the cause of which may be the lea'age of the en*ymes from the myocardial cells
secondary to increased cell permeability# These elevated cardiac en*ymes (>8 O
>835B" in patients with hypothyroidism resolve with thyroid hormone
replacement#
Ba&ir < et al (7//." studied serum creatine 'inase activity in thyroid
dysfunction among 27 patients with hypothyroidism (19 males and .. females", 11/
patients with hyperthyroidism (7 males and 1. females" and 11 control subBects
(; males and 1;/ females"# They observed in hypothyroid patients creatine 'inase
activity was significantly higher than controls (pN/#//2"# 0n hyperthyroid patients,
although the serum creatine 'inase activity was significantly lower as compared
with controls, but it was within the normal range# -o they concluded hypothyroidism
should be put into consideration in patients presented with symptoms suggestive of
cardiovascular abnormality without other evidence of myocardial damage and have
raised creatine 'inase activity#
)e'imsoy L and A'tem 08 (7//2" investigated study to determine serum
levels of creatine 'inase (>8" in overt and subclinical hypothyroidism# +
statistically significant elevation of >8 levels was found in patients with overt
hypothyroidism when compared with patients of subclinical hypothyroidism and
control groups#
:ra'ash + et al (7//" studied serum creatine 'inase activity in thyroid
disorder on 2/ patients (./ hyperthyroid and 7/ hypothyroid" they showed that
hypothyroid had significant increase in creatine 'inase and findings were reversed in
hyperthyroid#
5c ?rowder ,+ et al (7/11" analysed serum creatine 'inase and lactate
dehydrogenase activities in patients with thyroid disorders# They found elevated >8
activity in 2 patients (71I, 2F11" with overt hypothyroidism and in 17 patients
(7;#/I, 17F2/" with subclinical hypothyroidism# The mean >8 activity in
subclinical hypothyroid patients was 19#1/ M 172#!1 =FL compared with .19#9/1
M .11#7/ =FL in overt hypothyroid patients, while values for patients with overt and
subclinical hyperthyroidism was 11#. M !9#77 =FL and 1/2#91 M 2#// =FL
Review of Literature 26
respectively# They also observed elevation of L,) in ! patients (..#.I, !F11" with
overt hypothyroidism and in . patients (;#/I, .F2/" with subclinical
hypothyroidism# The mean L,) activity in subclinical hypothyroid patients was
.;/#.1 M 12.#.1 compared with ;71#// M 7/.#91 =FL in overt hypothyroid patients,
while values for patients with overt and subclinical hyperthyroidism were 7..#1/ M
#. =FL and 77#11 M 2;#99 =FL respectively# They concluded significant
elevation in serum >8 and L,) activities indicates that these can be used as
parameters for screening hypothyroid patients but not hyperthyroid patients#
6ungare - et al (7/1." e%amined the role of alternative biochemical
parameter creatine 'inase (>8" in diagnosing thyroid disease among 2/ patients (./
hypothyroid9 7/ hyperthyroid" and 72 age and se% matched persons# They observed
in hypothyroid mean value of T
.
, T
;
, T-), >:8 /#;7 M /#/1, ;#!2 M /#!/, 1.#; M
2#/9 and 197#/. M 19#91 (pN/#///1" and in hyperthyroid ;#1 M 1#.., 12#97 M 7#2.,
/#71 M /#/9 and !/# M 1;#2 (pN/#/1" respectively# 0n control group the mean serum
>8 levels were found to be ;#!1 M 7/#21 and in hypothyroid subBects it was
significantly increased 197#/. M 19#91 (pN/#///1" as compared to controls# The
results showed that there is significant increase in mean >8 levels in hypothyroid
patients and finding were reversed in hyperthyroid patients#
:andey R et al (7/1." evaluated the relationship between thyroid alteration
and serum en*ymes level among 11/ subBects# Thyroid profile and serum en*ymes
were analy*ed using standard 'its# )yperthyroid and hypothyroid cases showed
slight elevation of +-T, +LT and ??T# )owever, the values were higher in
hyperthyroid subBects# +L:, >8 and L,) were mar'edly elevated both in
hyperthyroidism and hypothyroidism as compared to controls# They concluded that
there was a positive association between increased serum +-T, +LT, ??T, >8, +L:
and L,) in hyperthyroidism and hypothyroidism#
5ushta& - et al (7/1;" carried out a study to evaluate myopathy in
hypothyroidism among ./ patients with newly detected overt hypothyroidism and
./ healthy adults as control# They found that mean >8, L,) and -?ATF+-T were
significantly increased in patients with hypothyroidism while the rise in >835B
was statistically insignificant as compared to control subBects# They also observed
Review of Literature 27
positive correlation between >8, >835B, L,) and -?ATF+-T levels with T-)
levels and negative correlation was found with T
.
and T
;
levels# Thus they
concluded that significant elevation of serum >8, L,) and -?AT activities
indicate muscle involvement in hypothyroidism and these en*ymes can be used as
parameters for screening of hypothyroid patients#
Leite ?- et al 7/1. performed a study to chec' any relationship between
mood states heart rate variability ()RV" and creatine 'inase (>8" of Bra*ilian para3
athletes# +nalysis of the data was performed by -pearman correlation# They
observed a relationship between the parasympathetic modulation and the vigor of
the athletes (r P /#2/ to /#2.9 pN/#/2" but >8 was not related with any mar'er#
An e%hausted search, no literature was available to reveal the relationship
between various parameters of heart rate variability ()RV" and creatine 'inase
(>8", creatine 'inase35B (>835B" in thyroid patients#