BLOOD PRESSURE VARIABILITY

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CHAPTER I

INTRODUCTION

The World Health Organization (WHO) has reported that an estimated 17 million

people die from cardiovascular diseases (CVD) each ear (WHO !act "heet# $%%1)&

Coronar arter disease (C'D) continues to e one of the most common chronic

illnesses in most of the developed orld(D*'gostino et al $%%%)& +n ,alasia# heart

diseases ere reported to e the numer one cause of death from 1-.. till 1--7

("outheast 'sian ,edical +nformation Centre/+nternational ,edical !oundation of

0apan "2',+C/+,!03 Health "tatistic# 1---)& +n 1--.# ischemic heart disease as

accounted for causing the highest mortalit rate in ,alasia (.&.-/1%%#%%% population)

and as folloed closel cerero4vascular disease (.&%5/1%%#%%% population)& +t

has een estimated that the ear $%$%# there ill e a tremendous change in the

disease patterns and demograph and that CVD ill e the main cause of death in the

developing countries and ill remain so in the developed countries (,urra and

6opez# 1--7)&

1.1 CIRCADIAN VARIATION OF CARDIOVASCULAR DISEASES

Over the past decade# epidemiological studies have oectivel confirmed the

circadian variation in the onset of cardiac events& "ince 1-5%# it has een 8non that

there is a tendenc for maor cardiovascular episodes to occur during the mid4morning

hours (,uller# 1---)& The onsets of acute mocardial infarction (,uller et al 1-.9:

Willich et al 1-..)# sudden cardiac death (,uller et al 1-.7: Willich et al 1-.7)

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and transient mocardial ischaemia (;ar8er et al 1--


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a8efulness rather than to the time of da& This as illustrated one stud here

the ?; rhthm folloed the inverted ccle of activit in night4shift or8ers ("underg

et al 1-..)& ?; varies aout 9%45% mmHg over a $ual or

greater than 1%E of average datime values) has een reported to e impaired in a

numer of other conditions such as ageing# snoring# ostructive apnea sndrome and

secondar hpertension namel renovascular hpertension# phaeochromoctoma and

Cushing*s sndrome (Coca# 1--


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?;V is reported to correlate ith age& 2lderl suects tend to have higher ?;V as

compared to the ounger ones("ander et al $%%%)& This ma e partl e@plained

the diminished arorefle@ sensitivit associated ith increased arterial stiffness due to

aging (Tan8 et al $%%%)& 'nalsis of suects age groups also revealed that the ?;

level and age independentl affected ?;V("ander et al $%%%)&

1.2.1.2 Sex

There have een contradictor reports regarding the ?;V among se@ distriution& +n

analzing amulator ?; recordings from =9< adolescents (age ranging from 7&$ 4

=%&- ears old) ith tpe + Diaetes ,ellitus# the ?;V as found to e higher in male

compared to the female (einhard et al 1---)& +n contrast# a communit ased stud

in 0apan here the age ranges from $% to 7% ears old# the result as otherise (+mai

et al 1--7)& 'nother stud on atherosclerosis hich involved the elderl (suects of

99 ears and aove)# found no differences among gender("ander et al $%%%)&

1.2.1.3 Physical Activity

The mean level of oth amulator ?; and ?;V decrease during rest (;ic8ering#

1--%)& ;hsical activit has een shon to affect ?; such as changing of posture

from ling to the sitting or standing causes a change in oth sstolic and diastolic ?;

(hione et al 1--=)& Dnamic and static e@ercises are also 8non causes& "pecific

form of e@ercise such as se@ual intercourse can produce a dramatic transient rise in

oth sstolic and diastolic ?;# ut these changes are reversed ithin a fe minutes&

1.2.1.4 Mental Activity

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dietar sodium inta8e# ith some authors reporting ?; variations ith a high salt

inta8e (ichard et al 1-.


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Hoever# it is still not clear hether the ?;V is the cause or the result of the CVD

process& Hence it is important to understand ?;V and the factors regulating it&

1.+ PHYSIOLO,Y OF BLOOD PRESSURE RE,ULATION

?; is a dnamic phsiological function that varies ith each hearteat (0ames et al

1--9)& ?; regulation is an important mechanism to stailize human ?; in different

situations& ?; is regulated mainl the central nervous sstem and the renal sstem&

ecent advances have also led to the discover of other sustances or sstems that aid

in the regulation of ?;&

1.+.1 T'! Rol! Of N!r-os S&st!* In Ra"$ Control Of Bloo$ Pr!ssr!

1.3.1.1 he Autonomic !ervous System

The cardiovascular center or the vasomotor center is responsile for transmitting oth

parasmpathetic and smpathetic impulses& The parasmpathetic impulses are

transmitted from the center mainl to the heart through vagal nerves hereas the

smpathetic impulses travel through the cord to almost all the lood vessels in the

human od& This neurogenic control of oth the heart and the vessels is important in

maintaining normal ?;&

The cardiovascular center is located at the reticular sustance of medulla

olongata& This center regulates the heart rate and contractilit of the heart# the

diameter of the lood vessels and integrates impulses received from higher center

(hpothalamic and limic sstem)& +t consists of three centres: the cardio accelerator

centre (C'C)# the cardio inhiitor centre (C+C) and sensor centre& The neurons of

the C'C secrete norepinephrine here the e@cite the vasoconstrictor neurons of the

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smpathetic nervous sstem& The cardio inhiitor neurons on the other hand have

fiers that proect to the C'C& The C+C on receiving impulses ill inhiit C'C thus

loc8ing the vasoconstriction effect resulting in vasodilatation& The C+C also

transmits inhiitor impulses to the heart via parasmpathetic nerve& The third centre#

hich is the sensor centre# is located at the nucleus tractus solitarius# hich receives

signals from the vagal and glossopharngeal nerves and gives output to control the

activities of oth the C'C and C+C& +n lo ?; condition# the C'C is stimulated ith

reciprocal inhiition of the parasmpathetic vagal signals to the heart& 's a result#

arteries constrict and lead to increase total peripheral resistance& The large veins

constriction ill displace the peripheral lood volume toards the heart increasing

venous return# hence the cardiac output# and the increase in oth heart rate and

contractile force of the heart muscles& These changes ill lead to increase in ?;

(uton and Hall# 1--5)&

1.3.1.2 he "ole o# he Sym$athetic !ervous System in %ardiovascular &isease

2@aggerated smpathetic activities had een associated ith CVD namel the diaetes

(6iao et al 1--9)# hpertension (;i88uamsa et al 1--.: ,ancia et al 1---) and

congestive heart failure (rassi et al 1--9)& egression of left ventricular

hpertroph has also een shon to depend not onl on ?; ut also on the reduction

of cardiac smpathetic drive (,organ and ?a8er# 1--1)& ,icroneurographic approach

has alloed smpathetic nerve traffic to e recorded hich shoed an increase in

smpathetic urst over time in suects ith famil histor of hpertension (Famada

et al 1-..)# in hpertensives (,ar8# 1--5: !loras et al 1--=: 'nderson et al 1-..)#

in isolated sstolic hpertension (rassi et al 1---) as ell as in pregnanc induced

hpertension (reenood et al 1-..)&

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The mechanisms responsile for smpathetic overactivit in high ?; state

have not een conclusivel determined ut one possiilit is that this overactivit

depends on angiotensin ++ ('ng ++)& 'ng ++ has een documented to e@ert e@citator

effects on smpathetic outflo# to facilitate norepinephrine release from adrenergic

nerve endings and to amplif the receptor responsiveness to stimuli (,ancia et al

1---)& Other possiilities include insulin resistance (oe et al 1-.1: 'nderson et

al 1--1: ,asuo et al 1--7) and impairment of arterial arorefle@ (,ancia et al

1--7)&

1.3.1.3 Barorece$tors Activity

,oment4to4moment regulation of ?; is controlled predominantl stretch4activated

(high pressure) aroreceptors located in the all of aortic arch and carotid sinus & This

sstem opposes either increase or decrease in ?; and hence is also 8non as the

pressure uffer sstem& +ncrease in ?; stretches the all of the carotid sinus and

aortic arch and stimulates the aroreceptors# hich send impulses along the afferent

lims of the glossopharngeal nerves and vagal nerves# respectivel# to the sensor

area in the medullar cardiovascular center& The response is# decreased smpathetic

activit# hich decreases contractilit# heart rate and decreased vascular tone causing

vasodilatation# ith reciprocal increased parasmpathetic activit& These receptors

egin to respond at pressures in e@cess of 5% mmHg to a ma@imum of 17% mmHg&

Decreases in ?; have the reverse effect# and these receptors pla an important role in

the response to acute lood loss and shoc8& Hoever# at pressures loer than 5%

mmHg# the aroreceptors loose much of their functional capacit (uton and Hall#

1--5)& The importance of the uffer function of aroreceptors as demonstrated in a

stud in a dog hose aroreceptor nerves have een removed& "imple events of the

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da such as ling don# standing# e@citement# eating and noises cause e@treme

variailit in ?; (Cole et al 1-7


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in lethal condition& +ts function is minimal in our normal da to da ?; regulation

(uton and Hall# 1--5)&

1.+.2 T'! Rol! Of T'! /"$n!& In Lon# T!r* Control Of Bloo$ Pr!ssr!

1.3.2.1 "enin Angiotensin Aldosterone System

enin4angiotensin4aldosterone sstem (''") is the maor renal hormonal sstem

involved in the regulation of ?;& +ts main components are renin# angiotensin + ('ng

+)# angiotensin ++ ('ng ++) and aldosterone& The sstem is involved oth in the

vasoconstriction and the volume4sodium components of ?; control& Once in the

plasma# renin acts on its sustrate angiotensinogen# a glcoprotein that is produced

the liver& Human renin splits a leucl4valine peptide ond and causes release of the

decapeptide angiotensin +& 'ng + itself is an inactive species and its iologic activit

results from its conversion to the active 'ng ++& 'ngiotensin converting enzme

('C2) is a caro@dipeptidase that splits the terminal histidlleucine from 'ng +#

producing the octapeptide 'ng ++# hich is the active peptide in the sstem& 'C2 is

found in the lungs# plasma# and endothelium of vascular eds# including that of the

8idnes (uton and Hall# 1--5)& 'C2 is also responsile for the cataolism of

various iologicall important peptides (eg# sustance ;# rad8inin) into inactive

metaolites&

'lternative 'C24independent pathas for 'ng ++ production also e@ist&

'ngiotensinogen can e converted directl to 'ng ++ enzmes such as tissue

plasminogen activator# cathepsin # and tonin# hereas chmostatin4sensitive 'ng ++4

generating enzme# chmase and cathepsin are ale to catalze the hdrolsis of

'ng + to 'ng ++ (0ohnston and isvanis# 1--7)&

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'ng ++ is one of the vasoconstrictor sustances& +t interacts ith specific

receptors causing smooth muscle contraction# release of aldosterone# prostaccline#

catecholamines# prolactin# adrenocorticotrophic hormone ('CTH) and induces

glcogenolsis (Aavar# 1--7)&

There are at least to maor sutpes of 'ng ++ receptors the 'T1and 'T$

receptors& 'T1 receptor is a 74transmemrane domain receptor hich is coupled to a

guanosine triphosphate inding protein& +t has a signaling patha that involves

phospholipases '# C and D: inositol phosphates# calcium channels# serine and thronine

8inases (de asparo et al $%%%)& +t also mediates increase ?; through intense

vasoconstriction# aldosterone secretion# poldipsia and norepinephrine release into the

snaptic cleft (2dards et al 1--$)& The 'T1 receptor has een implicated in

cardiovascular# renal# and cereral pathologies# such as left ventricular hpertroph#

vascular media hpertroph# cardiac arrthmia# atherosclerosis# glomerulosclerosis#

stro8e and dementia (6ucius et al 1---: Inger et al 1--5)&

The 'T$ receptor is also a 74transmemrane glcoprotein and has

appro@imatel =uence homolog to that of the 'T1receptor (Chung

et al 1--5)& 6ess is 8non aout the 'T$receptor signaling patha& 'T$receptors

are present in high densit in all tissues during fetal development# ut less aundant in

adult tissues& +t is eing e@pressed in high concentrations onl in the adrenal medulla#

uterus# ovar# vascular endothelium and specific areas of the rain (Inger et al

1--.)& 2@pression is up4regulated under certain conditions such as in heart failure#

post4infarct repair# s8in and nervous sstem lesion (6ucius et al 1---: Inger et al

1--5: 6ucius et al 1--.: Aio et al 1--9)& The functions of 'T1and 'T$ receptors

are as summarized in Tale 1&1&

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Tale 1&1

Differential 2ffects ,ediated 'T1and 'T$eceptors

AT1R!c!tor AT2r!c!tor

Vasoconstriction

'ldosterone snthesis and secretion

enal tuular sodium reasorption

+ncreased vasopressin secretion

Decreased renal lood floe

enal renin inhiition

Cardiac hpertroph

Cardiac contractilit

Vascular smooth muscle proliferation

'ugmentation of peripheral

noradrenergic activit

Central osmocontrol

2@tracellular matri@ formation

!etal tissue development

+nhiition of cell groth

Vasodilation

,odulation of e@tracellular matri@

(Aeuronal) regeneration

Cell differentiation

'poptosis

1.3.2.2 "enomedullary (asode$ressor System

ecent phsiological e@periments have estalished that increasing the perfusion

pressure of the 8idne causes the release of vasodepressor sustance from the renal

medulla# the renomedullar interstitial cells (,+C) of the papilla& ,+C secretes

prostaglandins and medullipin +& ,edullipin + is converted in the liver into medullipin

++# its active form& ,edullipin ++ is a vasodilator that suppresses smpathetic tone and

causes diuresis and natriuresis& The sstem action is the reverse of the ''"

(,uirhead# 1--=)&

1.+.+ Rol! Of H*oral S&st!*s In T'! Control Of Bloo$ Pr!ssr!

1.3.3.1 Endothelial Based System

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The endothelial cells lining the vasculature# apart from serving as a diffusion arrier

for solute and fluid e@change# are involved in regulation of vascular function through

the production of various sustances& Cell memrane receptors and memrane ound

ectoenzmes respond to circulating ligands such as sustance ;# leu8otriene# insulin#

thromin and phsical signals such as shear stress# hich lead to the activation of

vasodilator and vasoconstrictor sustances& 2@amples of vasodilators are nitric o@ide

(AO) and prostacclin (;+$)# and e@amples of vasoconstrictors are endothelin (2T)

and thromo@ane (Jimmerman# 1--7)&

AO is a highl reactive free radical that pla a maor role in the cardiovascular#

pulmonar# gastrointestinal# immune# and central nervous sstems (Guo and

"chroeder# 1--9)& +n addition# deranged AO snthesis is the asis for a numer of

pathophsiologic states# such as atherosclerosis# pulmonar hpertension and

hpertension associated ith renal failure& +t is currentl accepted that AO is the

maor phsiological regulator of asal lood vessel tone& AO is released continuousl

the arterial circulation& Vasodilator agents such as acetlcholine and rad8inin

act on endothelial cell4surface receptors to trigger AO release and stimulate solule

guanll cclase# resulting in protein 8inase4dependent rela@ation of vascular smooth

muscle& +n the asence of endothelium# these stimuli lose their vasodilator properties

(,arletta et al 1-..)&

+n renal arteriolar regulation# it is suggested that AO plas a role in renin

release and sodium and ater homeostasis# thus AO plas the 8e role in intravascular

volume and vascular tone (,arsden and ?renner# 1--1)& AO also modulates platelet

adhesion and aggregation# leu8octe adhesion# endothelin generation# plasminogen

activator enzmatic function# and vascular smooth muscle proliferation (Aathan#

1--$)&

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'ltered endothelial production of AO is involved in several states of vascular

dsfunction& Derangement in endothelial AO snthesis ma predispose to the

development of atherosclerosis& 2vidence suggests that AO ma pla an

artheroprotective role inhiiting o@idation of lipoproteins and preventing o@idative

memrane inur free radicals& 6o4densit lipoprotein (6D6) appears to inhiit

AO4dependent vasorela@ation a direct interaction eteen 6D6 and AO& 's a

result# the supero@ide scavenging effect of AO is impaired# and increased amounts of

supero@ide remain availale for o@idation of 6D6& The o@idized 6D6 then initiates

the atherosclerotic process in endothelial and vascular smooth muscle cells& Chronic

endothelial e@posure to o@idized 6D6 causes irreversile inhiition of AO4dependent

vasorela@ation (!lavahan# 1--$: Dinerman et al 1--=)& Vasodilatation is also

impaired in the coronar circulation of smo8ers and children ith familial

hpercholesterolemia (,oncada and Higgs# 1--=)& The results from these studies and

others suggest that endothelial dsfunction in these pathologic states arise from either

impaired release of AO from the endothelium or an alteration in the signal response

characteristics of the vascular smooth muscle&

2T is a $1 amino acid peptide# hich can e@ert in contrast to AO# mar8ed and

long4lasting vasoconstriction& "timulants for 2T production include rad8inin#

adenosine triphosphate# platelet4activating factor# thromin# and shear stress& 2T

infusions reduce renal lood flo and glomerular filtration rate constricting oth

preglomerular and efferent arterioles and eliciting a decrease in the glomerular

filtration rate (Aavar et al 1--5)& +ncreased intrarenal 2T is associated ith

vasoconstriction# sodium retention# and hpertension ("chiffrin# 1--9)&

+t can e concluded that the ?; regulation involves comple@ interactions

among various neural# humoral and haemodnamic mechanisms# as summarized in

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!igure 1&1& 'cute regulator mechanisms act primaril altering the total peripheral

resistance and cardiovascular haemodnamics and are mostl concerned ith the

nervous sstem&

+n contrast# mechanisms over the long term are lin8ed to regulation of sodium

alance and 2C! volume# hich are involved ith the role of 8idnes& While the role

of nervous sstem and 8idne are >uite ell estalished in regulation of ?; and the

pathophsiolog of hpertension# evidences suggesting that humoral mechanisms are

responsile for maintaining the high ?; are still a matter of deate&

6D6 Cholesterol Aorepinephrine 'ng ++ AO HperinsulinemiaDiaetes ,ellitus

"mo8ing

!irinonectin andcollagendeposition

6ipid depositionin media

"mooth ,uscleCell ,igrationand ;roliferation

Clotting

;latelet and

lmphoctesadhesion

2ndothelial dsfunction

At'!roscl!ros"sH&!rt!ns"on0S'!ar str!ss

ot!nt"at!s

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F"#r! 1.1& !actors that predispose to endothelial dsfunction () and the

pathophsiological processes ( that lead to atherosclerosis and hpertension&

1.


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1.3.3.2 !atriuretic Pe$tides

'trial natriuretic peptide ('A;) is a $. amino acid peptide released from electron4

dense granules in atrial moctes in response to overstretch of atrial all as a result of

e@cess lood volume in the condition of high lood pressure (0amison et al 1--$)&

+ts maor actions are to increase natriuresis and diuresis hich ta8e effect in the

8idne glomerular and tuular sstems# decrease sstemic cardiac output and increase

transudation of fluid into the e@tra4vascular space in order to loer the lood pressure&

'part from the aove actions: 'A; inhiits renin release# aldosterone secretion and

endothelin release& +t inhiits aldosterone release directl at the zona glomerulosa of

the adrenal corte@ and loc8s the salt4retaining action of aldosterone at the distal

tuule and collecting duct (Jimmerman# 1--7)&

1.3.3.3 Eicosanoids

2icosanoids are iologicall active products of arachidonic acid that are snthesized

in a variet of tissues and released to act locall on the vasculature& The products of

this cascade e@ert oth vasoconstrictor and vasodilator effects (Chatziantoniou and

'rendshorst# 1--=)& ;rostaglandins hich are formed via ccloo@genase patha

act as vasodilators via stimulation of adenlate cclase and cclic adenosine

monophosphate (c',;)& The vasodilator prostaglandins serve an important

protective function and lessen the influence of vasoconstrictor sustances during

activation of the renin4angiotensin sstem or the smpathetic nervous sstem& +n

some pathophsiologic conditions# there ma e enhanced production of

vasoconstrictor prostanoids# such as thromo@ane& The vasoconstriction induced

thromo@ane is mediated primaril calcium influ@ (?reer et al 1--5)&

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+n contrast# leu8otrienes hich are snthesized via the lipo@genase patha

have een shon to stimulate renin release (Aavar et al 1--5# ?reer et al 1--5)&

'rachidonic acid is also metaolized via ctochrome ;4


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'A ++& (,argolius# 1--5)& +ncreased activit of the 8alli8rein48inin sstem occurs in

conditions of sodium depletion# indicating that it serves as a mechanism to reduce the

effects of enhanced angiotensin ++ levels (,omouli and Vanhoutte# 1--9)&

The ?; regulation involves man interactions among the various neural#

hormonal# and paracrine mechanisms regulating cardiovascular and renal function&

This understandal gives rise to prolems in managing hpertension& +n particular#

short4term changes in ?; are caused a numerous mechanisms that affect cardiac

output# total peripheral resistance# and cardiovascular capacitance& This is mainl

the nervous sstem mechanism&

+n the long term# hoever# most of these actions can e uffered or

compensated appropriate renal adustments of sodium alance# e@tracellular (2C)

fluid volume (through dietar inta8e# insensile loss and urinar e@cretion) and lood

volume& These renal adustments are influenced the ''" and other 8idne

mediated neurohormones& The interaction of these various mechanisms in lood

pressure regulation is shon in !igure 1&$&

1.( ARTERIAL CO)PLIANCE

1.(.1 P'&s"olo#"cal I*ortanc! Of Art!r"al Co*l"anc!

2levated ?; identifies a population at a greater ris8 for cardiovascular events& This is

not ecause ?; itself causes the adverse effect events ut the li8elihood that the

individual has an anormal function or structure of the vasculature (Cohn# 1---)&

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!urthermore# recent advances in non4invasive monitoring and vascular

imaging have led to a numer of indices of arterial function at different levels of the

arterial tree hich are no eing applied as surrogate mar8ers for CVD (,crath#

$%%1)& 'rterial elasticit or compliance# hich is the parameter of interest in this

stud# is one of the indices of arterial function that has een shon to correlate ell

ith cardiovascular ris8 factors such as age ('volio et al 1-.=)#smo8ing(6e8a8is et

al 1--7)#pulse pressure(?enetos et al 1-..) and coronar arter diseases(Watanae

et al 1--=)&

1.4.1.1 Pro$erties and ,unction -# Arteries

The functions of the arteries are: to deliver the lood from the heart to the peripheral

tissues and to dampen the pressure oscillations&

1.4.1.1.1 %onduit ,unction -# Arteries

To perform the conduit function effectivel# large arteries need to deliver the amount

of lood from the heart to the peripheral tissues# as determined the metaolic

activities in the tissues& ' continuous# stead and effectivel constant flo of lood is

re>uired in the arteriolar sstems to ensure efficient metaolic e@change& To maintain

such a stead flo# a constant pressure head (represented mean arterial pressure)

must e applied to overcome resistance to flo caused lood viscosit and friction&

!or a given cardiac output# mean arterial pressure is determined the cross4sectional

area and the numer of arterioles and arteries& This represents peripheral vascular

resistance& Hpertension is classicall thought to e caused the increased

resistance resulting from a reduction in the calier of arterioles and small arteries&

!rom a hemodnamic point of vie# therefore# the conduit function of large arteries is

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dependent on mean arterial pressure# lood flo and the relation eteen them

(6ondon and uerin# 1---)&

1.4.1.1.2 %ushioning E##ect -# Arteries

The principal role of arteries as cushions is to dampen the pressure oscillations that are

caused the intermittent nature of ventricular eection (Aichols and O*our8e#

1--1)& The efficienc of this cushioning function is determined the viscoelastic

properties of the arterial alls descried in terms of compliance# distensiilit or

stiffness& +n performing the cushioning function# the arterial sstem is ale to directl

accommodate the entire volume of lood eected from the heart during sstole&

'rteries store part of the stro8e volume during sstolic eection and drain it during

diastole& This so called KWind8essel functionL thus transforms the pulsatile flo of

central arteries into the stead flo re>uired in the peripheral tissues&

1.(.2 )!c'an"s* Of R!$c!$ Art!r"al Co*l"anc!

'rterial compliance is defined as the change of volume for a given change in pressure&

+t is one of the properties that characterize the pulsatile ehaviour of the vasculature#

esides the pulse pressure& +t is also the reverse of arterial stiffness&

'rterial compliance is vital for an arter to perform the cushioning effect&

This effect simpl means that the arteries dampen the pressure oscillations that are

caused the intermittent nature of the ventricular contraction& ? acting as a

cushion# the arterial sstem is ale to accommodate the entire lood volume eected

from the heart during sstole& The arteries store part of the stro8e volume during

sstolic eection and drain it during diastole& To understand the mechanism of arterial

compliance measurement# the Wind8essel theor assumes the circulation in to as&

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The large arteries hich have the propert of elasticit are the central reservoirs# into

hich the heart pumps and from hich lood travels& The elasticit of the pro@imal

large arteries is the result of the high elastin to collagen ratio in their alls# hich

progressivel declines toards the peripheries& !rom these elastic reservoirs# the

lood travels through the peripheral arteries hich act as the non4elastic conduits to

tissues& "ome researchers (Cohn et al 1--9: +zzo et al $%%1)# refer to the aorta and

its maor ranches as large arteries& This is to differentiate from the more muscular

conduit arteries# such as the radial and rachial# and the smaller predominantl

muscular peripheral arteries& The elasticit of a given arterial segment depends on its

distending pressure& 's the distending pressure increases# there is a reduction of

elasticit as there is greater involvement of the relativel inelastic collagen fiers&

This distending pressure in circulation is determined the mean arterial pressure&

,ean arterial pressure is ta8en into account in arterial stiffness measurement to

differentiate the anticipated effects of distending pressure from the real differences in

the arterial all elasticit&

+n normal phsiological condition# eection of lood from the left ventricle

during sstole initiates an arterial ave that travels toard the peripher& 't the site

here impedance mismatches ta8e place# mainl at the high resistance arterioles#

ave reflections occur& Due to the differences in elastic >ualities as ell as ave

reflection# the shape of the arterial aveform varies throughout the arterial tree& This

shape is formed the sstolic and diastolic pressure aves (refer figure 1&=)& +n the

large compliance arteries# the initial sstolic pressure (;1) travels from the heart to

peripher forming pea8 "?;& eflected pressure aves (;$) arrive at central aorta in

diastole# augmenting D?; and increasing the coronar arter perfusion& +ncreased

arterial stiffness causes the pressure aves to travel faster& 'lso eing termed as

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increasing pulse ave velocit# this causes the pressure aves to arrive at the

peripheral circulation earlier and to e reflected earlier& The reflected aves# instead

of augmenting D?; no augments "?; that result in increasing left ventricular

or8load as ell as compromising the coronar arter lood flo&

The information held ithin the aveforms of the pro@imal aorta is of

interest ecause the lood pressure at this site# rather than peripherall determines the

left ventricular load and coronar arter lood flo& Hoever# peripheral lood

pressure measurement is more common in the maorit of methodologies used&

ecentl# techni>ues ased on the determination of a pressure transfer function

eteen the radial arter and the aorta has een used to provide an estimate of central

pressure ave reflection (Garamanoglu et al 1--9)&

F"#r! 1.+. The shapes of arterial aveforms differ from one arter to another&

'dapted ith permission from Cohn# 1---&

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1.(.+ Factors R!#lat"n# Art!r"al Co*l"anc!

The composition of lood vessels influences the compliance of the vessel all (Co@#

1-.1: 6iu et al 1-.-)& With ageing and hpertension# the arteries stiffen as a result of

degeneration of arterial media ith fractures and fragmentation of elastic lamellae#

increased collagen and calcium content# and dilation and hpertroph of large arteries

and the aorta (O*our8e# 1-.$)& This concept ta8es into account the relation eteen

structure and mechanics of the vessel all in terms of the elastic modular of individual

all components& 'part from the collagen and elastin# arterial all elasticit is also

influenced endothelium (Ginla et al $%%1)# arterial all smooth muscle ul8 and

tone (?an8 et al 1--5: 1---)# endothelin receptor gene (6aemi et al $%%1a) and 'T$

receptor (6aemi et al $%%1)& The functional and structural modifications to the

arterial all have important effects on the cardiovascular sstem increasing the

incidence of fracture# rupture and aneursm formation and the development of

atherosclerosis& !olloing these changes# compliance is reduced# the sstolic and

pulse pressure increase& These cause fatigue of arterial alls# accelerating arterial

damage# thus feeding the vicious ccle&

1.(.( Cl"n"cal I*ortanc! Of Art!r"al Co*l"anc!

'ge dependent decline in large and small arteries compliances# reflecting structural or

functional changes has een demonstrated (,cVeigh et al 1---)& +n disease states

such as hpertension# diaetes and atherosclerosis# the reduction in the compliance is

prominent at the smaller vessel level in arteries sensitive to AO release (Cohn et al

1--9)& Compliance reduction in disease states is a mar8er for the earl stages of

vascular diseases and ma e@plain the underling patholog of ?;V&

1. RIS/ FACTORS IN CARDIOVASCULAR DISEASES

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Clinicians and health authorities for man ears have e@pressed interest in methods of

identifing individuals ho are at increase ris8 of C'D& +n fact# the medical

communit is currentl adopting an individualized approached that specificall

addresses a patient*s individual profile of cardiovascular ris8 factors& 's man as =%%

variales have een listed as the ris8 factors for C'D (Hop8ins and William# 1-.1)

including those outlined the WHO and the !ramingham "tud& ;oulter (1---)# in

his recent revie ased on the = maor studies: the < ears communit follo4up

studies conducted the ?ritish egional Heart "tud group# the ,ultiple is8 !actor

+ntervention Trial (,!+T) involving =95#$$$ 'merican men# and the communit

stud in 0apan# used a standard suggested criteria that had identified maor

cardiovascular ris8 factors into modifiale factors and non4modifiale factors & The

modifiale ris8 factors are high ?;# high 6D6# lo High Densit 6ipoprotein (HD6)#

diaetes (glucose intolerance)# smo8ing# clotting factors# homocsteine level# left

ventricular hpertroph (6VH)# oral contraceptive pills (OC;)# central oesit and

lac8 of e@ercise& The non4modifiale factors are age# gender and famil histor of

hpertension&

1..1 T'! I*ortanc! Of I$!nt"f&"n# R"s3 Factors

+t has een ell estalished that ris8 factors tend to cluster in individuals& When these

ris8 factors coe@ist# the impact on C'D is greater than additive# and is usuall

multiplicative& The current trend hich is toards a more holistic approach in C'D

ris8 evaluation and preventive management has led to the development of several ne

guidelines& The multivariate ris8 formulation from !ramingham "tud (Gannel#

$%%%)# the Ae Jealand uidelines on the management of mild hpertension (Ae

Jealand uidelines roup# 1--


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1-.7) are e@amples of these guidelines hich appl simple methods of evaluating

asolute ris8 ased on consideration of several ris8 factors& is8 factors in an

individual are therefore ecoming essential to e identified and should e ta8en into

consideration in patient*s management&

1..2 Ess!nt"al H&!rt!ns"on

Though hpertension has een 8non for over a centur# its pathophsiolog and

management remain a prolem& +t remains to e the maor reversile ris8 factor for

CVD and renal failure& 'n analsis of the ,odification of Diet in enal Disease

stud (6azarus et al 1--7) revealed that for each 1 mmHg increase in mean arterial

pressure# there is an associated =9E increase in CVD& !or each 9 mmHg increase#

there is an associated increase of =E in left ventricular hpertroph (6VH)& There is

sustantial evidence documenting the linear relationship eteen the degree of

hpertension and the ris8 for cardiovascular and renal diseases in all populations

(Wilson and Culleton# 1--.)& The prevalence of hpertension end organ damage

differs in different areas& +n Western countries hich have high prevalence of

hpertension# mortalit rates of ischaemic heart disease are high (0ones# 1--9)

hereas in 2ast 'sean countries# stro8e is the leading cause of death among

hpertensive communities&

+n ,alasia# it as reported that the proportion of death due to cardiovascular

disease has multiplied more than three4fold since 1-59 (Ghor# 1--


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found to e hpertensive ith 15&.E of them from uran areas compared to 1$&=E

from rural areas& ecent report from The "econd Aational Health and ,oridit

"urve estimated that the overall prevalence of hpertension among adults in

,alasia is $-&- E in 1--5& This figure comprised 1uate ?; control# an important reason

for inade>uate impact on the incidence of C'D is that there ma e multiple features

of hpertension# of hich high ?; is onl one of them& Could ?;V e another

element in hpertension and is it also a feature in hpertensive ,alasian populationM

=%


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1..+ T&! II D"a%!t!s )!ll"ts

+t has een recognized for ears that diaetic patients have to to three fold increased

ris8 for CVD as compared ith their non4diaetic counterparts (Gannel et al 1-7-)&

,uch of the moridit and mortalit associated ith diaetes mellitus (D,) is

attriutale to the macrovascular and microvascular complications of the disease&

Diaetics are at increased ris8 of all cardiovascular events including sto8e# recurrent

hospitalization for mocardial infarct or unstale angina and heart failure&

The prevalence of hpertension in diaetics is at least to fold greater hen

compared to the non4diaetic population (Aational Centre of Health "tatistic# 1-.1)&

The prevalence of complications is also greater in diaetics ith hpertension than

those ho are normotensives& The advent of $< hour '?;, has triggered a lot of

studies tring to identif the ?; load in diaetics that can lead to covert nephropath&

Hansen et al (1--$) used '?;, to stud circadian variation of ?; in suects ith

tpe + D,& The authors found a trend to progressive loss of nocturnal ?; reduction as

aluminuria increased from normoaluminuria to microaluminuria and on to overt

nephropath hen compared ith health control suects& Hoever# despite the

trend# the difference eteen control and normoaluminuric suects did not reach

statisticall significant level& 6ure et al (1--=) on the other hand found a significant

nocturnal ?; lunting in tpe 1 adolescent D, patients and his finding as supported

others (ilert et al 1--


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difference for diastolic ?;V as not significant& The da and night ratio for sstolic

?;# diastolic ?;# heart rate and heart rate variailit ere the same in oth patients

and controls& Come et al (1--=) on the other hand found that the sstolic ?;V and

diastolic ?;V ere significantl increased among the tpe ++ D, suects ith

cardiac autonomic neuropath as compared to the controls& Hoever# the studies did

not ta8e into account other ris8 factors as the diaetic in their suects ere not

controlled for ?; or lipid profile& The aim of this stud is therefore to see the effect of

hperglcemia on ?;V ith as minimal influence as possile from other

cardiovascular ris8 factors&

1..( H&!rl""$a!*"a

Hperlipidaemia also increases the ris8 of C'D and atherosclerotic disease in other

vessels& The role of elevated concentrations of serum cholesterol in the pathogenesis

of atherosclerosis is ell estalished ased on human studies (Verschuren et al 1--9:

Gannel et al 1-7-)# animal e@periment ("chartz# 1--1) and clinical pathological

oservation (Aeman et al 1-.5)& +n the !ramingham "tud# the total cholesterol

level as found to e independent and statisticall significant in relation to the rate of

CHD in oung men# oung and older omen (Castelli# 1-..)&

"ince lipoproteins are the principal carriers of cholesterol in the lood#

intensive investigation as initiated on lipoprotein metaolism& 6D6 levels ere

found to e the lipoprotein most highl correlated ith C'D& The 6ipid esearch

Clinics ;revalence "tud (;e88anen et al 1--%) demonstrated in a 1%4ear follo up

that 6D6 cholesterol as strongl associated ith C'D in men ith or ithout C'D

at the time of entr into the stud& On the other hand the results of 9 randomized

clinical trials involving hdro@methlglutarl coenzme ' (H,4Co') reductase

=$


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inhiitors (statin) therap# had provided evidence that treatment ith simvastatin#

pravastatin or lovastatin resulted in reduction of total cholesterol $%4$9E and 6D6

$94=9E and further decreasing event of C'D (Dons et al 1--.: 6+;+D "tud

roup# 1--.: "ac8s et al 1--5: "candinavian "imvastatin "urvival "tud roup#

1--


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1--9: Ginosian et al 1--


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et al 1--$: "afar et al 1-.7) and increased neuroendocrine hormone such as plasma

insulin# norepinehrine and plasma renin activit (Aeutel et al 1--$)&

+s ?;V then part of the comple@ inherited sndromeM avogli et al (1--%)

has revealed that normotensive suects ith parental hpertension manifested a

significantl higher $


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1..4 H&!rr"ca!*"a

+n recent ears# several ne clinical and epidemiological studies have e@amined the

importance of uric acid as a possile independent cardiovascular ris8 factor& "everal

prospective studies have shon an association eteen hperuricaemia and incidence

of coronar heart disease# CVD and death (?rand et al 1-.9: !reedman et al 1--9:

6evine et al 1-.-: Fano et al 1-.uent

development of coronar heart disease in general# and mocardial infarction in

particular (?rand et al 1-.9)& The relationship ith mocardial infarction as

e>uall strong in oth se@es even after correcting for antihpertensive treatment& The

association hoever as not significant hen diastolic ?; and lood cholesterol ere

adusted for& !reedman and colleagues (!reedman et al 1--9) on the other hand

demonstrated that each 5% mol/6 increment in uric acid level as associated ith a

uez4Vivar et al 1--5) and o@idative stress ('n8er et al 1--7: 6eva et

al 1--.)&

The potential mechanisms here uric acid could contriute to the

pathogenesis of hpertension and cardiovascular end organ damage are also

investigated# though the data are still lac8ing& ' large od of evidence lin8s uric acid

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ith the metaolic sndrome of insulin resistance# oesit# hpertension and

dslipidaemia (eaven# 1--


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as an increase of =&=E compared to the previous surve in 1-.5 (,inistr of Health#

Aational Health and ,oridit "urve# 1--5)&

Cigarette smo8ing is a maor ris8 factor in the development of atherosclerosis

and coronar events& ;revious studies have shon that smo8ing induces immediate

constriction of epicardial coronar arteries and an increase in coronar resistance tone

(,oliternao et al 1--ual mean ?; as compared to non smo8ers (reen et al 1-.5)& +n a control stud

=.


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BLOOD PRESSURE VARIABILITY

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