05-review of literature

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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 192,

$wing et al used short3term )RV measurements as a mar'er of diabetic autonomic

neuropathy# 0n 19, 4olf 55 et al showed that patients with reduced )RV after amyocardial 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 19/s when it was

confirmed that )RV was a strong and independent predictor of mortality following

an acute myocardial infarction (8leiger R$ et al 19 5ali' 5 et al 199 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. :ena* 6 et

al 19! )irsch 6+ and Bishop B 191"#

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#




HRV analysis

8obayashi and 5usha (197" -aul et al (19" <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 adacent RR intervals, -- that is the standard

deviation of differences between adacent 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 (191" 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




192 )ilton 5 et al 199 ?ang < and 5ali' 7//. +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/ +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 19! 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 (LF) 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#




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. 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 199"#

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 adacent

@@ 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&uencydistribution 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 199 arrell T? et al 1991"# This triangular inde%

http://en.wikipedia.org/wiki/Poincar%C3%A9_plot

http://en.wikipedia.org/wiki/Correlation_dimension

http://en.wikipedia.org/wiki/Poincar%C3%A9_plot

http://en.wikipedia.org/wiki/Correlation_dimension




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 199"# The

maor 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 Ravenswaai >5 et al 1991"# )RV decreases with age (+charya =R et al 7//;

+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 19"# 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/ 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 199" 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 199 <amasa'i < et al 199!"# )R variation for healthy

subects 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 proection 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#




$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 environmentalfactors 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 .#IE;#!I ()ollowell 6? et al 7//7 Vanderpump 5: et al 1992

Leese ?: et al 7//"# 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

http://en.wikipedia.org/wiki/Thyroid_gland

http://en.wikipedia.org/wiki/Thyroid_hormone

http://en.wikipedia.org/wiki/Thyroid_gland

http://en.wikipedia.org/wiki/Thyroid_hormone




(-teinberg + 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//. 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. Tas' orce 199! Tsui )

et al 199! aidi 5 et al 199 Asborn L+ et al 1999"# )owever, sustained or life3

threatening ventricular ectopy is rarely seen in hypothyroid patients (:oli'ar R et al

199. -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//2

-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




)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/// 8lien 0 and Aamaa 8 7//1 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// >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 subects as a result of the

combined effect of increases in resting heart rate, contractility, eection fraction and

blood volume with a decrease in -VR (8lein 0 and Aamaa 8 7//1 Biondi B et al

7//7"#

-inus tachycardia is the most common rhythm disturbance and it is recordedin almost all patients with hyperthyroidism (Biondi B et al 7/// >acciatori V et al

199!"# +n increase in resting heart rate is characteristic of this disease (@ordy'e R+

et al 19"# )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 19"#

+trial fibrillation is a heart malfunction directly related to chronological age,

various cardiac, vascular and some other disorders# $%cess thyroid hormone reduces

http://en.wikipedia.org/wiki/Hypermetabolism

http://en.wikipedia.org/wiki/Syndrome

http://en.wikipedia.org/wiki/Serum_(blood)

http://en.wikipedia.org/wiki/Graves'_disease

http://en.wikipedia.org/wiki/Hypermetabolism

http://en.wikipedia.org/wiki/Syndrome

http://en.wikipedia.org/wiki/Serum_(blood)

http://en.wikipedia.org/wiki/Graves'_disease




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

subects 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 subects within the normal society, it is more common among male

hyperthyroid patients, particularly T. type of thyroto%icosis (8annel 4B et al 199

<ue et al 7/11 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 eection fraction or lower -VR as

would normally occur with e%ercise (orfar 6> et al 197"# 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 obective 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// >ooper - and Biondi B 7/17"# :atients of subclinical

hyperthyroidism may have no clinical signs or symptoms 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

http://scialert.net/fulltext/?doi=pjbs.2012.164.176#918680_ja







B et al 199; 5ercuro ? et al 7/// -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; 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 studyamong 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// -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.

-taub 66 et al 1997"# Lipid metabolism is altered in subclinical hypothyroidism

(untas L) 7//7 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/// -taub 66 et al 1997"# >3reactive protein, a ris' factor for heart disease, is




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/// 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//1 Bhat +@ et al 7//"# The thyroid hormone has direct

effect on e%aggeration of sinus nodal rhythmicity (Valcavi R et al 1997 Asman et

al 7//7"#

8lein 0 and Aamaa 8 (199;" studied that thyroid hormones by change at the

level of autonomic nervous system, effect heart and vascular system either directly

or indirectly# imier3avid L et al (199;" studied autonomic dysfunction as a maor

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 (199" 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 LF)




ratio than in healthy controls# They also found significantly lower LF) 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/#/2 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 !# nu standing 1# M #/ vs 2.#1 M 2#! nu" difference

being significantly in the standing# They also observed increased LF) ratio in

hypothyroid subects both in lying (7#2 M /#! vs 1#1! M /#. pN/#/2" and standing

(1/#/ M .# vs 1#2 M /#. pN/#/7"# Total )RV was lower in hypothyroid subects

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 (LF) 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", LF)#




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 subects 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//" 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//" studied the effect of clinical hypothyroidism on

cardiovascular autonomic function and ventricular repolari*ation in .1 patients (77

females and 9 males mean age 2.#! M 11# 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




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 subects

(pN/#/2" and hyperthyroid (pN/#//1" than controls and increase L nu, LF) ratio

both in hypothyroid (pN/#/2" and hyperthyroid (pN/#//1" than controls# They also

observed statistically high L nu, LF) 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




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 1929 :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 : 19!" 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 19."# 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 19."# 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

I 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

http://en.wikipedia.org/wiki/Phosphocreatine

http://en.wikipedia.org/wiki/Adenosine_diphosphate

http://en.wikipedia.org/wiki/Isoenzyme

http://www.ncbi.nlm.nih.gov/pubmed?term=Foxall%20CD%5BAuthor%5D&cauthor=true&cauthor_uid=1117316

http://en.wikipedia.org/wiki/Phosphocreatine

http://en.wikipedia.org/wiki/Adenosine_diphosphate

http://en.wikipedia.org/wiki/Isoenzyme

http://www.ncbi.nlm.nih.gov/pubmed?term=Foxall%20CD%5BAuthor%5D&cauthor=true&cauthor_uid=1117316




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//. :ra'ash + et al 7//"#

?iampietro et al (19;" 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 inury to the myocardium (infarct si*e" following 50 and increased serum

>835B mass concentrations (+pple - et al 199"# +round 9/I of >835B isfound 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- 19; <ounes + et al 192 0ngwall

6- et al 192 @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 191"# 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




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 . females" and 1 control subects

(; 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 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 (7I, 2F1" with overt hypothyroidism and in 17 patients

(7;#/I, 17F2/" with subclinical hypothyroidism# The mean >8 activity in

subclinical hypothyroid patients was 19#/ M 172#! =FL compared with .9#9/1

M .1#7/ =FL in overt hypothyroid patients, while values for patients with overt and

subclinical hyperthyroidism was #. M !9#77 =FL and 1/2#9 M 2#// =FL




respectively# They also observed elevation of L) in ! patients (..#.I, !F1" with

overt hypothyroidism and in . patients (;#/I, .F2/" with subclinical

hypothyroidism# The mean L) activity in subclinical hypothyroid patients was

.;/#. M 12.#. compared with ;71#// M 7/.#91 =FL in overt hypothyroid patients,

while values for patients with overt and subclinical hyperthyroidism were 7..#/ M

#. =FL and 77#1 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 (./

hypothyroid 7/ hyperthyroid" and 72 age and se% matched persons# They observed

in hypothyroid mean value of T., T;, T-), >:8 /#;7 M /#/, ;#!2 M /#!/, 1.#; M

2#/9 and 197#/. M 19#91 (pN/#///1" and in hyperthyroid ;# 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 ;#! M 7/#2 and in hypothyroid subects 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/ subects# 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 subects# +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 subects# They also observed




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. 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#

05-review of literature

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