CHAPTER I

INTRODUCTION

The World Health Organization (WHO) has reported that an estimated 17 million
people die from cardiovascular diseases (CVD) each year (WHO Fact Sheet, 2001).
Coronary artery disease (CAD) continues to be one of the most common chronic
illnesses in most of the developed world (DAgostino et al., 2000). In Malaysia, heart
diseases were reported to be the number one cause of death from 1988 till 1997
(Southeast Asian Medical Information Centre/International Medical Foundation of
Japan [SEAMIC/IMFJ] Health Statistic, 1999) . In 1998, ischemic heart disease was
accounted for causing the highest mortality rate in Malaysia (8.89/100,000 population)
and was followed closely by cerebro-vascular disease (8.06/100,000 population). It
has been estimated that by the year 2020, there will be a tremendous change in the
disease patterns and demography and that CVD will be the main cause of death in the
developing countries and will remain so in the developed countries (Murray and
Lopez, 1997).

1.1 CIRCADIAN VARIATION OF CARDIOVASCULAR DISEASES

Over the past decade, epidemiological studies have objectively confirmed the
circadian variation in the onset of cardiac events. Since 1960, it has been known that
there is a tendency for major cardiovascular episodes to occur during the mid-morning
hours (Muller, 1999). The onsets of acute myocardial infarction (Muller et al., 1985;
Willich et al., 1988), sudden cardiac death (Muller et al., 1987; Willich et al., 1987)

and transient myocardial ischaemia (Parker et al., 1994) tend to occur during the
morning waking hours as compared with the other times of the day. In the case of
acute myocardial infarction, earlier studies have described a circadian periodicity on
the onset of chest pain, based on the subjective reports by the patients (Pell and
DAlonzo, 1963; Thompson et al., 1985).

Muller et al., (1985) had attempted

quantification of the temporal distribution of the acute onset of myocardial infarction

on the basis of objective evidence . The records of 985 patients enrolled in the
Multicenter Investigation of Limitation of Infarct Size (MILIS) trial were analyzed to
determine the time of the onset of infarct according to serial measurements of plasma
creatine kinase-MB activity. It was observed that the frequency of the onset of pain
increased significantly between 6 AM and noon and was associated with increase
enzymes level, which occurred between 5 AM and 2 PM.

This observation is

supported by other reports (Willich et al., 1988). The incidence of acute myocardial
infarction documented from the onset of pain between 6 AM and noon was 1.28 times
greater than the other three six-hour intervals period while the incidence of acute
myocardial infarction confirmed enzymatically was 1.43 times greater between 6 AM
and noon than the other period of the day. The circadian periodicity of the incidence
of stroke has also been reported (Marler et al., 1989).
The reasons for the surge of these events in the early morning hours have not
been confirmed but it is generally known that humans possess an internal time clock
that regulates multiple physiologic factors (chronobiology).

It had been

acknowledged in late 1970 that the blood pressure (BP) together with the heart rate
surge soon after a patient awakens and commences activity, with a clearly
demonstrated trough at night (Craig et al., 1978).

Data from numerous studies

utilizing ambulatory BP monitoring have demonstrated that BP has a very

characteristic and reproducible circadian pattern (Joint National Committee on

Detection, Evaluation and Treatment of High Blood Pressure [JNC VI], 1997;
Staessen et al., 1992). The surge of these cardiovascular events in the early morning
hours is related to the ruptured plaque theory where, a surge in BP in the early
morning would cause rupture of the smooth, relatively stable plaques in the coronary
arteries, which is usually well tolerated and asymptomatic (Davies et al., 1983) . The
irregular surface created by the rupture becomes a nidus for platelet aggregation,
which has also been reported to have increase of activity in the morning (Tofler et al.,
1987). Furthermore, with the increase in blood viscosity, which was documented to
reach its highest value at this period (Ehrly and Jung, 1973), thrombogenesis sets in
and vessel occlusion may occur leading to myocardial infarction or sudden death. In
addition, circulating catecholamine (Tofler et al., 1987), renin (Gordon et al., 1966)
and cortisol (Weitzman et al., 1971) which promote vascular constriction have also
been known to increase steeply during the morning waking hours. These facts have
triggered studies to investigate the role of blood pressure variability (BPV) in CVD.

1.2 BLOOD PRESSURE VARIABILITY

It has been observed that the BP and the heart rate have a definite circadian pattern
(Craig et al., 1978). In most individuals, BP is not constant throughout the day. BP is
highest during the daytime hours, forming a plateau between 1000 hour and 1800 hour
and falls steadily during the evening hours at approximately 0000-0200 hour (Rafferty,
1984). This low nocturnal value then slowly rises again during the early morning
hours (between 0400 and 0600 hour, often while the patient is still asleep) until
approximately 0600 hour after which there is an abrupt and steep increase in BP to the
daytime value (Palatini et al., 1992). BP is closely related to the patterns of sleep and

wakefulness rather than to the time of day. This was illustrated by one study where
the BP rhythm followed the inverted cycle of activity in night-shift workers (Sundberg
et al., 1988). BP varies by about 50-60 mmHg over a 24-hour period (Mancia et al.,
1983). The mean BP falls by about 10%-20% from waking to sleeping (Staessen et
al., 1991).
Blood pressure fluctuations or variability (BPV) is closely related to the
average level of BP, being greatest when pressure is high (Mancia et al., 1983) . In
patients with essential hypertension, the diurnal rhythm and the nocturnal fall in BP
are preserved (Mancia et al., 1983; Staessen et al., 1991) , the pattern being similar to
that of normotensive except that it is shifted upwards (Pickering, 1990a).
The nocturnal fall in BP (which is arbitrarily defined as BP reduction equal or
greater than 10% of average daytime values) has been reported to be impaired in a
number of other conditions such as ageing, snoring, obstructive apnea syndrome and
secondary hypertension namely renovascular hypertension, phaeochromocytoma and
Cushings syndrome (Coca, 1994).

The subgroup of patients who has blunted

nocturnal fall of pressure is called non-dipper. This subgroup is of interest as it is

associated with a higher rate of organ damage and cardiovascular events in
hypertensive women (Verdecchia et al., 1993) and a higher rate of cerebral lacunae
infarct in hypertensive elderly subjects (Shimada et al., 1992).

1.2.1

Factors Influencing Blood Pressure Variability

The factors affecting BP variability are age, sex, physical activity, mental activity,
behavioural and environmental (Coca, 1994).
1.2.1.1

Age

BPV is reported to correlate with age. Elderly subjects tend to have higher BPV as
compared to the younger ones (Sander et al., 2000). This may be partly explained by
the diminished baroreflex sensitivity associated with increased arterial stiffness due to
aging (Tank et al., 2000). Analysis of subjects by age groups also revealed that the BP
level and age independently affected BPV (Sander et al., 2000).

1.2.1.2

Sex

There have been contradictory reports regarding the BPV among sex distribution. In
analyzing ambulatory BP recordings from 354 adolescents (age ranging from 7.2 30.9 years old) with type I Diabetes Mellitus, the BPV was found to be higher in male
compared to the female (Reinhard et al., 1999). In contrast, a community based study
in Japan where the age ranges from 20 to 70 years old, the result was otherwise (Imai
et al., 1997). Another study on atherosclerosis which involved the elderly (subjects of
55 years and above), found no differences among gender (Sander et al., 2000).

1.2.1.3

Physical Activity

The mean level of both ambulatory BP and BPV decrease during rest (Pickering,
1990b). Physical activity has been shown to affect BP such as changing of posture
from lying to the sitting or standing causes a change in both systolic and diastolic BP
(Ghione et al., 1993). Dynamic and static exercises are also known causes. Specific
form of exercise such as sexual intercourse can produce a dramatic transient rise in
both systolic and diastolic BP, but these changes are reversed within a few minutes.

1.2.1.4

Mental Activity

Mood has been reported to be a potent determinant of BP with changes observed

during anxiety, happiness and emotion (Pickering, 1990b). Emotion as one of the
factors affecting BPV, also has its clinical implication as sphygmomanometric BP
measurement by a physician or a nurse are considered an emotional events for the
patient, leading to a rise of BP. This transient pressor response only reaches the
hypertensive values in a subset of patients, called the white coat hypertension . The
white coat hypertension is defined as a condition in which BP is elevated in the
presence of a doctor but falls when the subject leaves the medical environment (JNC
VI, 1997).

Pickering et al., (1988) has reported that as many as 20% of those

diagnosed as hypertensive are actually in this group.

1.2.1.5

Behavioural and Environmental

Behavioral factor such as smoking has been shown to affect BP. In epidemiological
study, the mean BP of smokers when measured casually in the clinic is the same or
lower than the non-smokers (Green et al., 1986).

Ambulatory BP measurement

however showed otherwise. Cellina et al., (1975) reported that smoking increases
about 11 mmHg systolic and 5 mmHg diastolic within a few minutes and lasting for
about 15 minutes in both normotensives and hypertensives. Mann et al., (1991)
showed that in hypertensive patients, smoker with the same clinic BP as the nonsmoker has a significantly higher mean BP than the non-smoker when measured by
using ambulatory BP measurement.
Alcohol intake also increases the BP in both normotensive (Malhotra et al.,
1985) and hypertensive (Potter et al., 1986). The pressor effect of alcohol account for
an average increase of 5 mmHg in both systolic and diastolic 24 hour BP values
(Aguilera et al., 1994). Conflicting results have been reported by the few studies on

dietary sodium intake, with some authors reporting BP variations with a high salt
intake (Richard et al., 1984), but not others (Pickering, 1990b).

1.2.2

The Clinical Significance Of 24 Hour Blood Pressure Measurement

The occurrence of continuous and often pronounced BP fluctuations is not only of

pathophysiological interest, but also has clinical relevance. It has been reported that
the end organ damage in hypertension was closely related to 24-hour mean
ambulatory BP as compared to a single isolated clinic BP measurement (Perloff et al.,
1983). Findings from several cross sectional studies (Parati et al., 1987, Palatini et al.,
1992) have suggested that the degree of BPV during the day and night bears an
independent relationship with the target-organ damage in hypertension. Veerman et
al., (1996) have reported in 33 untreated hypertensive patients, daytime diastolic BPV
was a significant predictor of left ventricular mass index. These evidences are further
supported by Frattola et al., (1993) in a longitudinal study where hypertensive patients
were followed up for 7-8 years after having their ambulatory BP recorded for 24
hours. The degree of overall end organ damage (as quantified by a scoring method) in
this follow up study, was significantly higher in patients who displayed a higher
degree of BPV at the initial evaluation. However, the study though conducted in a
prospective manner did not control for other confounding factors that took place in
between the two periods, for example the development of other cardiovascular risk
factors. Apart from the hypertension end organ damage, the systolic BPV was also
found to be positively associated with the progression of early atherosclerosis in a 3year follow up study (Sander et al., 2000).
All these results suggest that the consequences of hypertension may depend,
not only on the 24-hour average BP values, but also on the magnitude of BPV.

However, it is still not clear whether the BPV is the cause or the result of the CVD
process. Hence it is important to understand BPV and the factors regulating it.

1.3 PHYSIOLOGY OF BLOOD PRESSURE REGULATION

BP is a dynamic physiological function that varies with each heartbeat (James et al.,
1995). BP regulation is an important mechanism to stabilize human BP in different
situations. BP is regulated mainly by the central nervous system and the renal system.
Recent advances have also led to the discovery of other substances or systems that aid
in the regulation of BP.

1.3.1

The Role Of Nervous System In Rapid Control Of Blood Pressure

1.3.1.1

The Autonomic Nervous System

The cardiovascular center or the vasomotor center is responsible for transmitting both
parasympathetic and sympathetic impulses.

The parasympathetic impulses are

transmitted from the center mainly to the heart through vagal nerves whereas the
sympathetic impulses travel through the cord to almost all the blood vessels in the
human body. This neurogenic control of both the heart and the vessels is important in
maintaining normal BP.
The cardiovascular center is located at the reticular substance of medulla
oblongata. This center regulates the heart rate and contractility of the heart, the
diameter of the blood vessels and integrates impulses received from higher center
(hypothalamic and limbic system). It consists of three centres; the cardio acceleratory
centre (CAC), the cardio inhibitory centre (CIC) and sensory centre. The neurons of
the CAC secrete norepinephrine where they excite the vasoconstrictor neurons of the

sympathetic nervous system. The cardio inhibitory neurons on the other hand have
fibers that project to the CAC. The CIC on receiving impulses will inhibit CAC thus
blocking the vasoconstriction effect resulting in vasodilatation.

The CIC also

transmits inhibitory impulses to the heart via parasympathetic nerve. The third centre,
which is the sensory centre, is located at the nucleus tractus solitarius, which receives
signals from the vagal and glossopharyngeal nerves and gives output to control the
activities of both the CAC and CIC. In low BP condition, the CAC is stimulated with
reciprocal inhibition of the parasympathetic vagal signals to the heart. As a result,
arteries constrict and lead to increase total peripheral resistance. The large veins
constriction will displace the peripheral blood volume towards the heart increasing
venous return, hence the cardiac output, and the increase in both heart rate and
contractile force of the heart muscles. These changes will lead to increase in BP
(Guyton and Hall, 1996).

1.3.1.2

The Role of The Sympathetic Nervous System in Cardiovascular Disease

Exaggerated sympathetic activities had been associated with CVD namely the diabetes
(Liao et al., 1995), hypertension (Pikkujamsa et al., 1998; Mancia et al., 1999) and
congestive heart failure (Grassi et al., 1995).

Regression of left ventricular

hypertrophy has also been shown to depend not only on BP but also on the reduction
of cardiac sympathetic drive (Morgan and Baker, 1991). Microneurographic approach
has allowed sympathetic nerve traffic to be recorded which showed an increase in
sympathetic burst over time in subjects with family history of hypertension (Yamada
et al., 1988), in hypertensives (Mark, 1996; Floras et al., 1993; Anderson et al., 1988),
in isolated systolic hypertension (Grassi et al., 1999) as well as in pregnancy induced
hypertension (Greenwood et al., 1988).

The mechanisms responsible for sympathetic overactivity in high BP state

have not been conclusively determined but one possibility is that this overactivity
depends on angiotensin II (Ang II). Ang II has been documented to exert excitatory
effects on sympathetic outflow, to facilitate norepinephrine release from adrenergic
nerve endings and to amplify the receptor responsiveness to stimuli (Mancia et al.,
1999). Other possibilities include insulin resistance (Rowe et al., 1981; Anderson et
al., 1991; Masuo et al., 1997) and impairment of arterial baroreflex (Mancia et al.,
1997).

1.3.1.3 Baroreceptors Activity

Moment-to-moment regulation of BP is controlled predominantly by stretch-activated
(high pressure) baroreceptors located in the wall of aortic arch and carotid sinus . This
system opposes either increase or decrease in BP and hence is also known as the
pressure buffer system. Increase in BP stretches the wall of the carotid sinus and
aortic arch and stimulates the baroreceptors, which send impulses along the afferent
limbs of the glossopharyngeal nerves and vagal nerves, respectively, to the sensory
area in the medullary cardiovascular center. The response is, decreased sympathetic
activity, which decreases contractility, heart rate and decreased vascular tone causing
vasodilatation, with reciprocal increased parasympathetic activity. These receptors
begin to respond at pressures in excess of 60 mmHg to a maximum of 170 mmHg.
Decreases in BP have the reverse effect, and these receptors play an important role in
the response to acute blood loss and shock. However, at pressures lower than 60
mmHg, the baroreceptors loose much of their functional capacity (Guyton and Hall,
1996). The importance of the buffer function of baroreceptors was demonstrated in a
study in a dog whose baroreceptor nerves have been removed. Simple events of the

10

day such as lying down, standing, excitement, eating and noises cause extreme
variability in BP (Cowley et al., 1974). Furthermore, the ability to maintain BP in
response to a challenge such as hemorrhage is markedly reduced following sino-aortic
denervation (Trasher and Keil, 1998).

1.3.1.4 Chemoreceptors Activity

Chemoreceptors are chemosensitive cells sensitive to lack of oxygen, carbon dioxide
(CO2) excess or hydrogen ion excess, located in the carotid bodies found at the
bifurcation of common carotid arteries and aortic bodies. The chemoreceptors, along
with baroreceptors excite nerve fibers through the vagus and glossopharyngeal nerves
to the cardiovascular center.

When the BP is low, the diminished blood flow

stimulated the chemoreceptors as they sense diminished oxygen availability and

excesses of CO2 and hydrogen ion. The chemoreceptors send signals to the
cardiovascular center to elevate the BP by a mechanism similar to the baroreceptor
activity. The chemoreceptors however are not the main BP regulator. It is important
at very low pressure, to prevent further decrease in BP (Guyton and Hall, 1996).
1.3.1.5 Central Nervous System Ischemic Response
The response is initiated only when the blood flow to the cardiovascular center is
reduced causing cerebral ischemia. This causes excesses of CO 2 at the cardiovascular
center which stimulates sympathetic nerves stimulation and elevates BP. The increase
in BP by this mechanism is enormous and can elevate mean BP for as long as 10
minutes and up to 250 mmHg. Owing to the intense arteriolar constriction, the
kidneys will respond by ceasing the production of urine. Despite being one of the
most potent activator of sympathetic vasoconstrictor system, the CNS ischemic
response does not become significant until the pressure falls to 60 mmHg and below

11

in lethal condition. Its function is minimal in our normal day to day BP regulation
(Guyton and Hall, 1996).

1.3.2

1.3.2.1

The Role Of The Kidney In Long Term Control Of Blood Pressure

Renin Angiotensin Aldosterone System

Renin-angiotensin-aldosterone system (RAAS) is the major renal hormonal system

involved in the regulation of BP. Its main components are renin, angiotensin I (Ang
I), angiotensin II (Ang II) and aldosterone. The system is involved both in the
vasoconstriction and the volume-sodium components of BP control. Once in the
plasma, renin acts on its substrate angiotensinogen, a glycoprotein that is produced by
the liver. Human renin splits a leucyl-valine peptide bond and causes release of the
decapeptide angiotensin I. Ang I itself is an inactive species and its biologic activity
results from its conversion to the active Ang II. Angiotensin converting enzyme
(ACE) is a carboxydipeptidase that splits the terminal histidylleucine from Ang I,
producing the octapeptide Ang II, which is the active peptide in the system. ACE is
found in the lungs, plasma, and endothelium of vascular beds, including that of the
kidneys (Guyton and Hall, 1996). ACE is also responsible for the catabolism of
various biologically important peptides (eg, substance P, bradykinin) into inactive
metabolites.
Alternative ACE-independent pathways for Ang II production also exist.
Angiotensinogen can be converted directly to Ang II by enzymes such as tissue
plasminogen activator, cathepsin G, and tonin, whereas chymostatin-sensitive Ang IIgenerating enzyme, chymase and cathepsin G are able to catalyze the hydrolysis of
Ang I to Ang II (Johnston and Risvanis, 1997).

12

Ang II is one of the vasoconstrictor substances. It interacts with specific

receptors causing smooth muscle contraction, release of aldosterone, prostacycline,
catecholamines, prolactin, adrenocorticotrophic hormone (ACTH) and induces
glycogenolysis (Navar, 1997).
There are at least two major subtypes of Ang II receptors: the AT1 and AT2
receptors. AT1 receptor is a 7-transmembrane domain receptor which is coupled to a
guanosine triphosphate binding protein. It has a signaling pathway that involves
phospholipases A, C and D; inositol phosphates, calcium channels, serine and thronine
kinases (de Gasparo et al., 2000). It also mediates increase BP through intense
vasoconstriction, aldosterone secretion, polydipsia and norepinephrine release into the
synaptic cleft (Edwards et al., 1992).

The AT1 receptor has been implicated in

cardiovascular, renal, and cerebral pathologies, such as left ventricular hypertrophy,

vascular media hypertrophy, cardiac arrythmia, atherosclerosis, glomerulosclerosis,
stroke and dementia (Lucius et al., 1999; Unger et al., 1996).
The AT2 receptor is also a 7-transmembrane glycoprotein and has
approximately 34% amino acid sequence homology to that of the AT1 receptor (Chung
et al., 1996). Less is known about the AT2 receptor signaling pathway. AT2 receptors
are present in high density in all tissues during fetal development, but less abundant in
adult tissues. It is being expressed in high concentrations only in the adrenal medulla,
uterus, ovary, vascular endothelium and specific areas of the brain (Unger et al.,
1998). Expression is up-regulated under certain conditions such as in heart failure,
post-infarct repair, skin and nervous system lesion (Lucius et al., 1999; Unger et al.,
1996; Lucius et al., 1998; Nio et al., 1995). The functions of AT1 and AT2 receptors
are as summarized in Table 1.1.

13

Table 1.1
Differential Effects Mediated by AT1 and AT2 Receptors
AT1 Receptor

AT2 receptor

Vasoconstriction

Fetal tissue development

Aldosterone synthesis and secretion

Inhibition of cell growth

Renal tubular sodium reabsorption

Vasodilation

Increased vasopressin secretion

Modulation of extracellular matrix

Decreased renal blood floe

(Neuronal) regeneration

Renal renin inhibition

Cell differentiation

Cardiac hypertrophy

Apoptosis

Cardiac contractility

Vascular smooth muscle proliferation

Augmentation of peripheral
noradrenergic activity

Central osmocontrol

Extracellular matrix formation

1.3.2.2

Renomedullary Vasodepressor System

Recent physiological experiments have established that increasing the perfusion

pressure of the kidney causes the release of vasodepressor substance from the renal
medulla, the renomedullary interstitial cells (RMIC) of the papilla. RMIC secretes
prostaglandins and medullipin I. Medullipin I is converted in the liver into medullipin
II, its active form. Medullipin II is a vasodilator that suppresses sympathetic tone and
causes diuresis and natriuresis.

The system action is the reverse of the RAAS

(Muirhead, 1993).

1.3.3

Role Of Humoral Systems In The Control Of Blood Pressure

1.3.3.1 Endothelial Based System

14

The endothelial cells lining the vasculature, apart from serving as a diffusion barrier
for solute and fluid exchange, are involved in regulation of vascular function through
the production of various substances. Cell membrane receptors and membrane bound
ectoenzymes respond to circulating ligands such as substance P, leukotriene, insulin,
thrombin and physical signals such as shear stress, which lead to the activation of
vasodilator and vasoconstrictor substances. Examples of vasodilators are nitric oxide
(NO) and prostacyclin (PGI2), and examples of vasoconstrictors are endothelin (ET)
and thromboxane (Zimmerman, 1997).
NO is a highly reactive free radical that play a major role in the cardiovascular,
pulmonary, gastrointestinal, immune, and central nervous systems (Kuo and
Schroeder, 1995). In addition, deranged NO synthesis is the basis for a number of
pathophysiologic states, such as atherosclerosis, pulmonary hypertension and
hypertension associated with renal failure. It is currently accepted that NO is the
major physiological regulator of basal blood vessel tone. NO is released continuously
by the arterial circulation. Vasodilatory agents such as acetylcholine and bradykinin
act on endothelial cell-surface receptors to trigger NO release and stimulate soluble
guanylyl cyclase, resulting in protein kinase-dependent relaxation of vascular smooth
muscle. In the absence of endothelium, these stimuli lose their vasodilatory properties
(Marletta et al., 1988).
In renal arteriolar regulation, it is suggested that NO plays a role in renin
release and sodium and water homeostasis, thus NO plays the key role in intravascular
volume and vascular tone (Marsden and Brenner, 1991). NO also modulates platelet
adhesion and aggregation, leukocyte adhesion, endothelin generation, plasminogen
activator enzymatic function, and vascular smooth muscle proliferation (Nathan,
1992).

15

Altered endothelial production of NO is involved in several states of vascular

dysfunction.

Derangement in endothelial NO synthesis may predispose to the

development of atherosclerosis.

Evidence suggests that NO may play an

artheroprotective role by inhibiting oxidation of lipoproteins and preventing oxidative

membrane injury by free radicals. Low-density lipoprotein (LDL) appears to inhibit
NO-dependent vasorelaxation by a direct interaction between LDL and NO. As a
result, the superoxide scavenging effect of NO is impaired, and increased amounts of
superoxide remain available for oxidation of LDL. The oxidized LDL then initiates
the atherosclerotic process in endothelial and vascular smooth muscle cells. Chronic
endothelial exposure to oxidized LDL causes irreversible inhibition of NO-dependent
vasorelaxation (Flavahan, 1992; Dinerman et al., 1993).

Vasodilatation is also

impaired in the coronary circulation of smokers and children with familial

hypercholesterolemia (Moncada and Higgs, 1993). The results from these studies and
others suggest that endothelial dysfunction in these pathologic states arise from either
impaired release of NO from the endothelium or an alteration in the signal response
characteristics of the vascular smooth muscle.
ET is a 21 amino acid peptide, which can exert in contrast to NO, marked and
long-lasting vasoconstriction.

Stimulants for ET production include bradykinin,

adenosine triphosphate, platelet-activating factor, thrombin, and shear stress.

ET

infusions reduce renal blood flow and glomerular filtration rate by constricting both
preglomerular and efferent arterioles and eliciting a decrease in the glomerular
filtration rate (Navar et al., 1996).

Increased intrarenal ET is associated with

vasoconstriction, sodium retention, and hypertension (Schiffrin, 1995).

It can be concluded that the BP regulation involves complex interactions
among various neural, humoral and haemodynamic mechanisms, as summarized in

16

Figure 1.1. Acute regulatory mechanisms act primarily by altering the total peripheral
resistance and cardiovascular haemodynamics and are mostly concerned with the
nervous system.
In contrast, mechanisms over the long term are linked to regulation of sodium
balance and ECF volume, which are involved with the role of kidneys. While the role
of nervous system and kidney are quite well established in regulation of BP and the
pathophysiology of hypertension, evidences suggesting that humoral mechanisms are
responsible for maintaining the high BP are still a matter of debate.

LDL Cholesterol

Ang II

Norepinephrine

Hyperinsulinemia
Diabetes Mellitus

NO

Smoking
Endothelial dysfunction

Fibrinonectin and
collagen
deposition

Smooth Muscle
Cell Migration
and Proliferation

Clotting
Platelet and
lymphocytes
adhesion

Lipid deposition
in media

potentiates

Hypertension/Shear stress

17

Atherosclerosis

Figure 1.1. Factors that predispose to endothelial dysfunction ( ) and the

pathophysiological processes ( ) that lead to atherosclerosis and hypertension.

18

1.3.3.2 Natriuretic Peptides

Atrial natriuretic peptide (ANP) is a 28 amino acid peptide released from electrondense granules in atrial myocytes in response to overstretch of atrial wall as a result of
excess blood volume in the condition of high blood pressure (Jamison et al., 1992).
Its major actions are to increase natriuresis and diuresis which take effect in the
kidney glomerular and tubular systems, decrease systemic cardiac output and increase
transudation of fluid into the extra-vascular space in order to lower the blood pressure.
Apart from the above actions; ANP inhibits renin release, aldosterone secretion and
endothelin release. It inhibits aldosterone release directly at the zona glomerulosa of
the adrenal cortex and blocks the salt-retaining action of aldosterone at the distal
tubule and collecting duct (Zimmerman, 1997).

1.3.3.3 Eicosanoids
Eicosanoids are biologically active products of arachidonic acid that are synthesized
in a variety of tissues and released to act locally on the vasculature. The products of
this cascade exert both vasoconstrictor and vasodilator effects (Chatziantoniou and
Arendshorst, 1993). Prostaglandins which are formed via cyclooxygenase pathway
act as vasodilators via stimulation of adenylate cyclase and cyclic adenosine
monophosphate (cAMP).

The vasodilator prostaglandins serve an important

protective function and lessen the influence of vasoconstrictor substances during

activation of the renin-angiotensin system or the sympathetic nervous system. In
some pathophysiologic conditions, there may be enhanced production of
vasoconstrictor prostanoids, such as thromboxane. The vasoconstriction induced by
thromboxane is mediated primarily by calcium influx (Breyer et al., 1996).

19

In contrast, leukotrienes which are synthesized via the lipoxygenase pathway

have been shown to stimulate renin release (Navar et al., 1996, Breyer et al., 1996).
Arachidonic acid is also metabolized via cytochrome P-450 monooxygenases to
produce several vasoactive agents referred to as epoxyeicosatrienoic acid (EET) and
hydroxyeicosatetraenoic acid (HETE). These substances have been shown to exert
actions on vascular smooth muscle and epithelial tissues (Navar et al., 1996).
In summary, some arachidonic acid metabolites exert antihypertensive
effects, whereas others may contribute to vasoconstriction and hypertension.

At

present, it is accepted that physiologic activation of prostaglandins, in particular those

activated via cyclooxygenase, have vasodilator and renoprotective effects.

1.3.3.4 Kallikrein-kinin system

Plasma and glandular kallikreins are functionally different serine protease enzymes
that act on kininogens (inactive alpha-2 glycoproteins) to form bradykinin or lysylbradykinin (kallidin). The plasma concentrations of kinins are not high enough to
affect BP, so it is thought that kinins act by glandular effects. Within the kidney,
glandular kallikrein and its substrate, kininogen, are located predominately in the
cortex, in association with the distal convoluted and cortical collecting tubules
(Chatziantoniou and Arendshorst, 1993; Bhoola et al., 1992; El-Dahr, 1994).
Bradykinin and kallidin elicit vasodilation and natriuresis and stimulate
formation of prostaglandin E2 (PGE2) and prostacyclin (PGI2) (Carretero and Scicli,
1991).

Bradykinin reduces the vasoconstrictor responses to norepinephrine and

angiotensin II through its potent endothelium-dependent relaxant effects that are

mediated by nitric oxide (NO). Both kinins increase capillary permeability in several
tissues. Kinins are inactivated by ACE, the same enzyme that converts ANG I to

20

ANG II. (Margolius, 1996). Increased activity of the kallikrein-kinin system occurs in
conditions of sodium depletion, indicating that it serves as a mechanism to reduce the
effects of enhanced angiotensin II levels (Mombouli and Vanhoutte, 1995).
The BP regulation involves many interactions among the various neural,
hormonal, and paracrine mechanisms regulating cardiovascular and renal function.
This understandably gives rise to problems in managing hypertension. In particular,
short-term changes in BP are caused by a numerous mechanisms that affect cardiac
output, total peripheral resistance, and cardiovascular capacitance. This is mainly by
the nervous system mechanism.
In the long term, however, most of these actions can be buffered or
compensated by appropriate renal adjustments of sodium balance, extracellular (EC)
fluid volume (through dietary intake, insensible loss and urinary excretion) and blood
volume. These renal adjustments are influenced by the RAAS and other kidney
mediated neurohormones. The interaction of these various mechanisms in blood
pressure regulation is shown in Figure 1.2.

1.4 ARTERIAL COMPLIANCE

1.4.1

Physiological Importance Of Arterial Compliance

Elevated BP identifies a population at a greater risk for cardiovascular events. This is

not because BP itself causes the adverse effect events but the likelihood that the
individual has an abnormal function or structure of the vasculature (Cohn, 1999).

21

Dietary intake
Insensible loss
Urinary excretion
Neurohumoral systems

Net sodium and fluid

balance

ECF

Blood pressure

Mean arterial
pressure

Venous
return

Cardiac output

Autonomic nervous system

Baroreceptor activities
Chemoreceptor activities
CNS ischemic response
RAAS
Renomedullary vasodepressor system
Natriuretic peptides
Eicosanoids
Endothelial based systems
Kallikrein-kinin system

Total peripheral
resistance

Heart rate and

contractility

Vascular capacitance

Figure 1.2. Overview of the interactions of various mechanisms in blood pressure

regulation. Modified from Navar, 1997.

22

Furthermore, recent advances in non-invasive monitoring and vascular

imaging have led to a number of indices of arterial function at different levels of the
arterial tree which are now being applied as surrogate markers for CVD (McGrath,
2001). Arterial elasticity or compliance, which is the parameter of interest in this
study, is one of the indices of arterial function that has been shown to correlate well
with cardiovascular risk factors such as age (Avolio et al., 1983), smoking (Lekakis et
al., 1997), pulse pressure (Benetos et al., 1988) and coronary artery diseases (Watanabe
et al., 1993).

1.4.1.1 Properties and Function Of Arteries

The functions of the arteries are; to deliver the blood from the heart to the peripheral
tissues and to dampen the pressure oscillations.

1.4.1.1.1

Conduit Function Of Arteries

To perform the conduit function effectively, large arteries need to deliver the amount
of blood from the heart to the peripheral tissues, as determined by the metabolic
activities in the tissues. A continuous, steady and effectively constant flow of blood is
required in the arteriolar systems to ensure efficient metabolic exchange. To maintain
such a steady flow, a constant pressure head (represented by mean arterial pressure)
must be applied to overcome resistance to flow caused by blood viscosity and friction.
For a given cardiac output, mean arterial pressure is determined by the cross-sectional
area and the number of arterioles and arteries. This represents peripheral vascular
resistance.

Hypertension is classically thought to be caused by the increased

resistance resulting from a reduction in the caliber of arterioles and small arteries.
From a hemodynamic point of view, therefore, the conduit function of large arteries is

23

dependent on mean arterial pressure, blood flow and the relation between them
(London and Guerin, 1999).

1.4.1.1.2

Cushioning Effect Of Arteries

The principal role of arteries as cushions is to dampen the pressure oscillations that are
caused by the intermittent nature of ventricular ejection (Nichols and ORourke,
1991). The efficiency of this cushioning function is determined by the viscoelastic
properties of the arterial walls described in terms of compliance, distensibility or
stiffness. In performing the cushioning function, the arterial system is able to directly
accommodate the entire volume of blood ejected from the heart during systole.
Arteries store part of the stroke volume during systolic ejection and drain it during
diastole. This so called Windkessel function thus transforms the pulsatile flow of
central arteries into the steady flow required in the peripheral tissues.

1.4.2

Mechanism Of Reduced Arterial Compliance

Arterial compliance is defined as the change of volume for a given change in pressure.
It is one of the properties that characterize the pulsatile behaviour of the vasculature,
besides the pulse pressure. It is also the reverse of arterial stiffness.
Arterial compliance is vital for an artery to perform the cushioning effect.
This effect simply means that the arteries dampen the pressure oscillations that are
caused by the intermittent nature of the ventricular contraction.

By acting as a

cushion, the arterial system is able to accommodate the entire blood volume ejected
from the heart during systole. The arteries store part of the stroke volume during
systolic ejection and drain it during diastole. To understand the mechanism of arterial
compliance measurement, the Windkessel theory assumes the circulation in two ways.

24

The large arteries which have the property of elasticity are the central reservoirs, into
which the heart pumps and from which blood travels. The elasticity of the proximal
large arteries is the result of the high elastin to collagen ratio in their walls, which
progressively declines towards the peripheries. From these elastic reservoirs, the
blood travels through the peripheral arteries which act as the non-elastic conduits to
tissues. Some researchers (Cohn et al., 1995; Izzo et al., 2001), refer to the aorta and
its major branches as large arteries. This is to differentiate from the more muscular
conduit arteries, such as the radial and brachial, and the smaller predominantly
muscular peripheral arteries. The elasticity of a given arterial segment depends on its
distending pressure. As the distending pressure increases, there is a reduction of
elasticity as there is greater involvement of the relatively inelastic collagen fibers.
This distending pressure in circulation is determined by the mean arterial pressure.
Mean arterial pressure is taken into account in arterial stiffness measurement to
differentiate the anticipated effects of distending pressure from the real differences in
the arterial wall elasticity.
In normal physiological condition, ejection of blood from the left ventricle
during systole initiates an arterial wave that travels toward the periphery. At the site
where impedance mismatches take place, mainly at the high resistance arterioles,
wave reflections occur. Due to the differences in elastic qualities as well as wave
reflection, the shape of the arterial waveform varies throughout the arterial tree. This
shape is formed by the systolic and diastolic pressure waves (refer figure 1.3). In the
large compliance arteries, the initial systolic pressure (P 1) travels from the heart to
periphery forming peak SBP. Reflected pressure waves (P 2) arrive at central aorta in
diastole, augmenting DBP and increasing the coronary artery perfusion. Increased
arterial stiffness causes the pressure waves to travel faster. Also being termed as

25

increasing pulse wave velocity, this causes the pressure waves to arrive at the
peripheral circulation earlier and to be reflected earlier. The reflected waves, instead
of augmenting DBP now augments SBP that result in increasing left ventricular
workload as well as compromising the coronary artery blood flow.
The information held within the waveforms of the proximal aorta is of
interest because the blood pressure at this site, rather than peripherally determines the
left ventricular load and coronary artery blood flow. However, peripheral blood
pressure measurement is more common in the majority of methodologies used.
Recently, techniques based on the determination of a pressure transfer function
between the radial artery and the aorta has been used to provide an estimate of central
pressure wave reflection (Karamanoglu et al., 1995).

Figure 1.3. The shapes of arterial waveforms differ from one artery to another.
Adapted with permission from Cohn, 1999.

26

1.4.3

Factors Regulating Arterial Compliance

The composition of blood vessels influences the compliance of the vessel wall (Cox,
1981; Liu et al., 1989). With ageing and hypertension, the arteries stiffen as a result of
degeneration of arterial media with fractures and fragmentation of elastic lamellae,
increased collagen and calcium content, and dilation and hypertrophy of large arteries
and the aorta (ORourke, 1982). This concept takes into account the relation between
structure and mechanics of the vessel wall in terms of the elastic modular of individual
wall components. Apart from the collagen and elastin, arterial wall elasticity is also
influenced by endothelium (Kinlay et al., 2001), arterial wall smooth muscle bulk and
tone (Bank et al., 1996; 1999), endothelin receptor gene (Lajemi et al., 2001a) and AT2
receptor (Lajemi et al., 2001b). The functional and structural modifications to the
arterial wall have important effects on the cardiovascular system by increasing the
incidence of fracture, rupture and aneurysm formation and the development of
atherosclerosis. Following these changes, compliance is reduced, the systolic and
pulse pressure increase. These cause fatigue of arterial walls, accelerating arterial
damage, thus feeding the vicious cycle.

1.4.4

Clinical Importance Of Arterial Compliance

Age dependent decline in large and small arteries compliances, reflecting structural or
functional changes has been demonstrated (McVeigh et al., 1999). In disease states
such as hypertension, diabetes and atherosclerosis, the reduction in the compliance is
prominent at the smaller vessel level in arteries sensitive to NO release (Cohn et al.,
1995). Compliance reduction in disease states is a marker for the early stages of
vascular diseases and may explain the underlying pathology of BPV.
1.5 RISK FACTORS IN CARDIOVASCULAR DISEASES

27

Clinicians and health authorities for many years have expressed interest in methods of
identifying individuals who are at increase risk of CAD.

In fact, the medical

community is currently adopting an individualized approached that specifically

addresses a patients individual profile of cardiovascular risk factors. As many as 300
variables have been listed as the risk factors for CAD (Hopkins and William, 1981)
including those outlined by the WHO and the Framingham Study. Poulter (1999), in
his recent review based on the 3 major studies; the 4 years community follow-up
studies conducted by the British Regional Heart Study group, the Multiple Risk Factor
Intervention Trial (MRFIT) involving 356,222 American men, and the community
study in Japan, used a standard suggested criteria that had identified major
cardiovascular risk factors into modifiable factors and non-modifiable factors . The
modifiable risk factors are high BP, high LDL, low High Density Lipoprotein (HDL),
diabetes (glucose intolerance), smoking, clotting factors, homocysteine level, left
ventricular hypertrophy (LVH), oral contraceptive pills (OCP), central obesity and
lack of exercise. The non-modifiable factors are age, gender and family history of
hypertension.

1.5.1

The Importance Of Identifying Risk Factors

It has been well established that risk factors tend to cluster in individuals. When these
risk factors coexist, the impact on CAD is greater than additive, and is usually
multiplicative. The current trend which is towards a more holistic approach in CAD
risk evaluation and preventive management has led to the development of several new
guidelines.

The multivariate risk formulation from Framingham Study (Kannel,

2000), the New Zealand Guidelines on the management of mild hypertension (New
Zealand Guidelines Group, 1994) and the Oslo Diet Heart Study (Samuelsson et al.,

28

1987) are examples of these guidelines which apply simple methods of evaluating
absolute risk based on consideration of several risk factors.

Risk factors in an

individual are therefore becoming essential to be identified and should be taken into
consideration in patients management.

1.5.2

Essential Hypertension

Though hypertension has been known for over a century, its pathophysiology and
management remain a problem. It remains to be the major reversible risk factor for
CVD and renal failure. An analysis of the Modification of Diet in Renal Disease
study (Lazarus et al., 1997) revealed that for each 1 mmHg increase in mean arterial
pressure, there is an associated 35% increase in CVD. For each 5 mmHg increase,
there is an associated increase of 3% in left ventricular hypertrophy (LVH). There is
substantial evidence documenting the linear relationship between the degree of
hypertension and the risk for cardiovascular and renal diseases in all populations
(Wilson and Culleton, 1998). The prevalence of hypertension end organ damage
differs in different areas.

In Western countries which have high prevalence of

hypertension, mortality rates of ischaemic heart disease are high (Jones, 1995)
whereas in East Asean countries, stroke is the leading cause of death among
hypertensive communities.
In Malaysia, it was reported that the proportion of death due to cardiovascular
disease has multiplied more than three-fold since 1965 (Khor, 1994).

A high

prevalence of hypertension has attributed to this increase. Osman et al., (1984)

reported that among rural Malay adult, out of 359 people examined, 26% had
hypertension which was defined as SBP more than 140 mmHg and DBP more than 90
mmHg. In another study by Kandiah et al., (1980), 14% of 963 respondents were

29

found to be hypertensive with 16.8% of them from urban areas compared to 12.3%
from rural areas. Recent report from The Second National Health and Morbidity
Survey estimated that the overall prevalence of hypertension among adults in
Malaysia is 29.9 % in 1996. This figure comprised 14.0 % of the self-reported
hypertension and 15.9 per cent of undiagnosed hypertension.
Meta-analysis of recent studies that have examined the impact of
hypertension showed that there was a success in decreasing the incidence of stroke
(MacMahon et al., 1986).

However, comparatively it was not the case for the

incidence of CAD (Samuelsson et al., 1987; Grimm et al., 1990). This raised the
questions of whether considering a measurement of 140/90 mmHg to represent
adequately controlled BP is sufficient, for if this criterion is taken, only one quarter of
hypertensive patients are being adequately treated (American Heart Association,
2000). Furthermore, when patients with treated and controlled hypertension were
compared with normotensive subjects with similar levels of BP, there was still an
approximately 30% higher incidence of CAD among hypertensive patients (Havlik, et
al. 1989). It appears that in addition to the inadequate BP control, an important reason
for inadequate impact on the incidence of CAD is that there may be multiple features
of hypertension, of which high BP is only one of them. Could BPV be another
element in hypertension and is it also a feature in hypertensive Malaysian population?

30

1.5.3

Type II Diabetes Mellitus

It has been recognized for years that diabetic patients have two to three fold increased
risk for CVD as compared with their non-diabetic counterparts (Kannel et al., 1979).
Much of the morbidity and mortality associated with diabetes mellitus (DM) is
attributable to the macrovascular and microvascular complications of the disease.
Diabetics are at increased risk of all cardiovascular events including stoke, recurrent
hospitalization for myocardial infarct or unstable angina and heart failure.
The prevalence of hypertension in diabetics is at least two fold greater when
compared to the non-diabetic population (National Centre of Health Statistic, 1981).
The prevalence of complications is also greater in diabetics with hypertension than
those who are normotensives. The advent of 24 hour ABPM has triggered a lot of
studies trying to identify the BP load in diabetics that can lead to covert nephropathy.
Hansen et al., (1992) used ABPM to study circadian variation of BP in subjects with
type I DM. The authors found a trend to progressive loss of nocturnal BP reduction as
albuminuria increased from normoalbuminuria to microalbuminuria and on to overt
nephropathy when compared with healthy control subjects. However, despite the
trend, the difference between control and normoalbuminuric subjects did not reach
statistically significant level. Lurbe et al., (1993) on the other hand found a significant
nocturnal BP blunting in type 1 adolescent DM patients and his finding was supported
by others (Gilbert et al., 1994).
More recent studies have looked into the 24 hours overall mean BP and BPV.
Mitchell et al., (1997) observed that in microalbuminuric type II DM subjects, the 24
hours and daytime systolic BP were significantly higher than controls and this was
supported by earlier studies (White, 1992). Mc Kinlay et al., (1994) found that there
was increased systolic BPV in the type II DM subjects during the day but the

31

difference for diastolic BPV was not significant. The day and night ratio for systolic
BP, diastolic BP, heart rate and heart rate variability were the same in both patients
and controls. Combe et al., (1993) on the other hand found that the systolic BPV and
diastolic BPV were significantly increased among the type II DM subjects with
cardiac autonomic neuropathy as compared to the controls. However, the studies did
not take into account other risk factors as the diabetic in their subjects were not
controlled for BP or lipid profile. The aim of this study is therefore to see the effect of
hyperglycemia on BPV with as minimal influence as possible from other
cardiovascular risk factors.

1.5.4

Hyperlipidaemia

Hyperlipidaemia also increases the risk of CAD and atherosclerotic disease in other
vessels. The role of elevated concentrations of serum cholesterol in the pathogenesis
of atherosclerosis is well established based on human studies (Verschuren et al., 1995;
Kannel et al., 1979), animal experiment (Schwartz, 1991) and clinical pathological
observation (Newman et al., 1986). In the Framingham Study, the total cholesterol
level was found to be independent and statistically significant in relation to the rate of
CHD in young men, young and older women (Castelli, 1988).
Since lipoproteins are the principal carriers of cholesterol in the blood,
intensive investigation was initiated on lipoprotein metabolism. LDL levels were
found to be the lipoprotein most highly correlated with CAD. The Lipid Research
Clinics Prevalence Study (Pekkanen et al., 1990) demonstrated in a 10-year follow up
that LDL cholesterol was strongly associated with CAD in men with or without CAD
at the time of entry into the study. On the other hand the results of 5 randomized
clinical trials involving hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase

32

inhibitors (statin) therapy, had provided evidence that treatment with simvastatin,
pravastatin or lovastatin resulted in reduction of total cholesterol by 20-25% and LDL
by 25-35% and further decreasing event of CAD (Downs et al., 1998; LIPID Study
Group, 1998; Sacks et al., 1996; Scandinavian Simvastatin Survival Study Group,
1994; Shepherd et al., 1995).
It is however debatable as to whether the assessment of LDL or total
cholesterol alone is sufficient and accurate to identify an individual at risk for
myocardial infarction. HDL is the lipoprotein that has an anti atherogenic effect since
it lacks apo-B. HDL confers protection against atherosclerotic CVD and an inverse
relationship between HDL cholesterol and CAD has been established in several
studies (Castelli et al., 1986; Stampfer et al., 1991).
The growing importance of HDL as a predictor of CAD was supported by the
findings in the 26 year follow up Framingham study where 20% of patients with
myocardial infarctions had their cholesterol levels lower than 5.17 mmol/L (200
mg/dl), levels considered safe according to most guidelines. Most of the patients who
had myocardial infarctions at low total cholesterol levels had HDL lower than 0.91
mmol/L (35 mg/dl) emphasizing the importance of the total-to-HDL cholesterol ratio
in determining the atherogenic potential of blood lipids.

Risk of CAD events

increases with the total-to-HDL cholesterol ratio (Castelli, 1988). In the Prospective
Cardiovascular Mnster (PROCAM) study population, patients who had total-to-HDL
cholesterol ratio of less than 5.0 had an incidence of myocardial infarction of 17.3%
over 10 years.

This incidence was greater than that seen in patients with high

triglyceride or LDL cholesterol (Assmann, 2001). This ratio was also found to be a
better predictor of CAD than total cholesterol, LDL, HDL and triglyceride in
Physicians Health Study (Stampfer et al., 1991) and other studies (Grover et al.,

33

1995; Kinosian et al., 1994). Because of the important influence of HDL cholesterol
at even moderate levels of serum total or LDL cholesterol, the total-to-HDL
cholesterol ratio is probably the best guide for therapy with treatment best instituted at
ratios more than 5.0, irrespective of the serum total or LDL cholesterol level (Kannel,
1995). Asmar et al., (1992) had found that patients with and without plasma lipid
abnormality displayed similar 24-hour mean ambulatory BP. However there is no
reported study to evaluate if there is a difference in BPV in hyperlipidemic group (as
defined by total-to-HDL cholesterol less than 5.0) compare to those with normal
serum lipid.

1.5.5

Family History Of Hypertension

Epidemiologic studies revealed that although treating hypertension significantly

reduces the incidence of stroke, a similar reduction in the incidence of coronary artery
disease has been more difficult to achieve (Samuelsson et al., 1987; Grimm et al.,
1990). It is suggested that hypertension is not simply a disease but rather a complex
inherited syndrome of cardiovascular risk factors.
New findings in normotensive patients with family history of hypertension
(FHT) have led to the theory that patients may have coronary artery diseases before
the actual onset of elevated BP. Neutel et al. (1992) showed that cholesterol levels in
subjects with FHT were significantly higher than those without FHT, despite normal
blood pressure.
Normotensive subjects with FHT have also been reported to have significantly
increased left ventricular mass index (Celentano et al., 1988), significant reduction in
ventricular compliance (Graettinger et al., 1991), reduced arterial compliance (Taddei

34

et al., 1992; Safar et al., 1987) and increased neuroendocrine hormone such as plasma
insulin, norepinehrine and plasma renin activity (Neutel et al., 1992).
Is BPV then part of the complex inherited syndrome? Ravogli et al., (1990)
has revealed that normotensive subjects with parental hypertension manifested a
significantly higher 24-hour mean ambulatory BP as compared to those without family
history. The subjects with family history were further dichotomized into those having
both parents with hypertension and those with only single parent with hypertension.
The systolic clinic BP, the mean 24-hour systolic BP, the mean of 24-hour mean
arterial pressure and the left ventricular mass index were always and significantly
higher in those with both parents hypertensive as compared to the normal controls. In
those with one parent hypertensive, only the clinic diastolic and mean arterial pressure
showed significantly higher value than the normal controls.

No difference was

observed with regards to 24 hour mean ambulatory BP in the group where both
parents were hypertensives and those with only a single parent with hypertension.
The study also demonstrated no difference in BP reaction to mental stress tests.
As far as BPV is concern, there have been contradictory results by previous
studies. Manuck et al., (1996) found that there was no difference with regards to BP
reactivity due to mental stress test in subjects with FHT and the matched control.
However, Lemne, (1998) found otherwise. The study showed that even a rather mild
level of heredity for hypertension leads to increase BPV, in particular 24-hour and
daytime systolic BPV apart from increased in BP reactivity to mental stress tests.

35

1.5.6

Hyperuricaemia

In recent years, several new clinical and epidemiological studies have examined the
importance of uric acid as a possible independent cardiovascular risk factor. Several
prospective studies have shown an association between hyperuricaemia and incidence
of coronary heart disease, CVD and death (Brand et al., 1985; Freedman et al., 1995;
Levine et al., 1989; Yano et al., 1984; Lehto et al., 1998; Wannamethee et al., 1997).
Despite the strength of these associations, uric acid has not been established as
a causal risk factor for CVD. Instead, uric acid seems to be linked to hypertension,
dyslipidaemia and disordered glucose metabolism. Several recent reports however
have attempted to dispel this notion. In the Framingham Study, the uric acid values
measured at the fourth biennial examination had predicted the subsequent
development of coronary heart disease in general, and myocardial infarction in
particular (Brand et al., 1985).

The relationship with myocardial infarction was

equally strong in both sexes even after correcting for antihypertensive treatment. The
association however was not significant when diastolic BP and blood cholesterol were
adjusted for. Freedman and colleagues (Freedman et al., 1995) on the other hand
demonstrated that each 60 mol/L increment in uric acid level was associated with a
48% increase in the risk for ischemic heart disease among women. Furthermore, a
growing body of laboratory and clinical evidence suggest that uric acid plays a role in
platelet adhesiveness (Emmerson, 1979; Ginsberg et al., 1977), formation of free
radicals (Vasquez-Vivar et al., 1996) and oxidative stress (Anker et al., 1997; Leyva et
al., 1998).
The potential mechanisms whereby uric acid could contribute to the
pathogenesis of hypertension and cardiovascular end organ damage are also
investigated, though the data are still lacking. A large body of evidence links uric acid

36

with the metabolic syndrome of insulin resistance, obesity, hypertension and

dyslipidaemia (Reaven, 1994). Uric acid may also be an indicator for increased
oxidative stress. Xanthine oxidase, a critical enzyme in the degradation of purines to
uric acid has been shown to be an important source of superoxide free radicals. The
activity of xanthine oxidase increases during ischaemia and intensifies during
reperfusion in coronary endothelial cells (Zweier et al., 1988).

Clinically,

hyperuricaemia occurs during interruption of limb arterial flow (Friedl et al., 1990),
after coronary angioplasty (Huizer et al., 1989), during coronary artery bypass surgery
(Lazzarino et al., 1994) and in other hypoxic states (Sahebjani, 1998; Hayabuchi et al.,
1993).
The relationships between hyperuricaemia and BPV as well as arterial
compliance have not so far been reported.

1.5.7

Cigarette Smoking

The World Health Organization (WHO) estimates that 25% of deaths from CVD at
age 35 to 69 years are attributable to tobacco (World Health Organization, 1999).
Throughout the world, it is estimated that one third of the worlds adult population are
smokers. Death from all tobacco related diseases worldwide are estimated to be 4
million annually and rising (World Health Organization, 1996).

Although the

prevalence of smoking has declined in western countries in recent decades, there has
been a marked increase in tobacco use in less developed countries, with the prevalence
of smoking rising 3.4 % per year (World Health Organization, 1999). In Malaysia,
cigarette smoking accounts for 25% of all death. In 1996, it was reported that the
smoking prevalence was 24.8% among Malaysians over the age of 18 years. There

37

was an increase of 3.3% compared to the previous survey in 1986 (Ministry of Health,
National Health and Morbidity Survey, 1996).
Cigarette smoking is a major risk factor in the development of atherosclerosis
and coronary events. Previous studies have shown that smoking induces immediate
constriction of epicardial coronary arteries and an increase in coronary resistance tone
(Moliternao et al., 1994; Maouad et al., 1986). Kiowski, et al., (1994) showed that
long term smoking is associated with impairment of endothelium dependent
vasodilator response while the short term smoking enhances endothelin-1-induced
vasoconstriction.

Recently, smoking was reported to be associated with acute

deterioration of elastic properties (Stefanadis et al., 1997). The deterioration became

evident even at 1 minute after the initiation of smoking and is maintained for at least
20 minutes. What really cause the abnormal responses of vascular system is not really
known but the toxic components of cigarette smoke may be inducing oxidative stress
and thereby causing endothelial damage. This was supported by McVeigh et al.,
(1997) who showed that smokers have significantly decreased oscillatory (small)
artery compliance but by contrast, similar large arterial compliance and systemic
vascular resistance with the non smokers. This may be the initiating mechanism for
the development of an atherosclerotic plaque. Studies have demonstrated a direct
toxic effect of tobacco smoke on human endothelium associated with an increase in
the number of endothelial cells with nuclear damage in the circulating blood (Davis et
al., 1985). Celermajer et al., (1993) have shown that there is a dose-dependent
impairment of endothelial dysfunction in asymptomatic young smokers and that the
abnormal vasomotion was reversible with smoking cessation. In epidemiological
study, the BP in smokers measured by clinic sphygmomanometer showed a lower or
equal mean BP as compared to non smokers (Green et al., 1986). In a control study

38

however, Mann et al., (1991) reported that the awake ambulatory systolic BP of
smokers was significantly higher than that of non smokers. The awake diastolic BP,
the sleep systolic and diastolic ambulatory BP were not affected by smoking status.
These findings were supported by others (Poulsen et al., 1998; Benowitz et al., 1984).
There has been however very limited data on the effect of smoking on BPV.

1.6 THE SIGNIFICANCE OF THIS STUDY

The growing interest of investigators on the fluctuation of BP is based on the facts that
first, an accurate analysis of BPV during a 24-hour period gives information on the
mechanism involved in BP homeostatic control, both in physiological and
pathological conditions. These include hypertension and other non-CVD. It has been
concluded that risk factors for CVD may mediate their effects by altering the
structure, properties and function of the wall and endothelial components of the
arterial blood vessels that vary between different vascular beds.
Secondly, literatures have shown that not only the 24-hour BP load but also the
BPV has been associated with target organ damage in hypertensive subjects. Data is
still lacking on whether an increase in BPV is also a feature in other disease states
inspite of having a normal BP such as diabetes mellitus, hyperlipidaemia etc. and
whether it will lead to the same consequences.
Finally, a better knowledge of the pattern of BP fluctuations and its association
with arterial compliance in various disease states will be a valuable tool for assessing
the efficacy of antihypertensive drug treatment as well as halting the process of
atherosclerosis.

39