THEORITICAL FRAMEWORK

RISK FACTORS OF CARDIOVASCULAR DISEASE

Epidemiological studies in adults have identified a number of individual characteristics known as

risk factors that predict the probability of individual developing clinical manifestations of CVD

(Dawber et al., 1950). In 2009 WHO published a global health risk report which attributed more

than 15 million (~60%) deaths in middle income countries to CVD risk factors such as

hypertension, tobacco, alcohol use, overweight and obesity, low fruit and vegetable intake and

low physical activity (WHO, 2009). There are two types of risk factors: modifiable risk factors

and non-modifiable risk factors, which are discussed below and summarized in Figure .
Non-Modifiable risk factors:

Non-modifiable risk factors are those that cannot be changed. While we cannot change these

things, they play an important role in CVD development, and also act as indicators of the risk

people face. As a result, these factors may change the way participants are treated for disease.

For CVD, the major non-modifiable risk factors are: Age Gender Ethnicity Family history

Poverty and low education status

Age: Risk of CVD increases with age, mostly occurring in men over 55 years of age and women

over 65 years of age. This is changing, however, and CVD is developing in some people in their

30s and 40s.

Gender: Men are at a 3- to 5-fold higher risk of developing CVD than women until women reach

menopause. Post-menopausal women are at a similar risk as men.

Ethnicity: Risk of CVD changes around the world among ethnic groups.

Family history: Having a parent or sibling that has a history of premature CVD (men

Modifiable risk factors

Modifiable risk factors are those which can be changed, either by the person themselves through

medical therapy, and/or by changing their environment. By altering habits and behaviors, an

individual can reduce their risk of developing CVD and prevent disease. For example, if

someone smokes cigarettes they are at high risk of developing CVD, but they can greatly reduce

their risk by quitting smoking.

Modifiable risk factors can be split into two different components: disease-related risk factors

and lifestyle-related risk factors. These two interact with one another, as changing lifestyle-

related risk factors can alter disease-related risk factors.

Smoking

According to WHO’s global health risk report almost 6 million people die (6% women and 12%

men) annually from tobacco use and exposure (WHO, 2009). It is estimated that by 2030, more

than 10 million people will die annually of cigarette-related afflictions. It is estimated that in

Canada alone, 45,000 people will die prematurely due to tobacco use, and at least 1000 people

will die annually from second hand smoke exposure (109). There are nearly 1.2 billion smokers

worldwide (108,110). Within populations, smoking is especially prevalent among people with a

lower socioeconomic status. Tobacco smoking is the leading preventable killer worldwide. For

example in the Seven Countries study involving more than 12,000 men followed up for 25 years

a clear dose response relationship between smoking and CHD and stroke was reported (Jacobs et

al., 1999). Smoking has been firmly established as one of the most important modifiable CVD

risk factors. The INTERHEART study investigators observed a clear dose-response relationship

between smoking and the risk of acute MI. The harmful effects of smoking were seen even at

relatively low levels, ie, those who smoked one to five cigarettes per day experienced a 40%

increase in MI risk compared with nonsmokers, whereas those who smoked six to 10 cigarettes

per day had a twofold increase in risk, and those who smoked 20 cigarettes per day had a

fourfold increase in risk of heart disease. Cigarette smoking increases the risk of hypertension,

CAD, stroke and peripheral vascular disease. A meta-analysis of 9 cohort studies with up to 39

years follow-up found exposure to environmental tobacco smoke (passive smoking) to increase

risk of death from heart disease in women RR 1.15 (95% CI. 1.03 -1.28) (Kaur et al., 2004).
Smoking induced endothelial dysfunction and inflammation promotes atherosclerotic plaque and

thrombus formation. The three main biologically active ingredients in cigarette smoke that have

been touted as causal constituents for heart disease and stroke are nicotine, carbon monoxide and

oxidant gases. Nicotine causes stimulation of autonomic ganglia and the central nervous system.

By increasing the activity of the sympathetic nervous system, nicotine increases the release of

catecholamines, which in turn elevates heart rate and BP, resulting in wear and tear on the

arterial walls. Carbon monoxide has a high affinity for hemoglobin and competes with oxygen

for uptake by red blood cells. The production of carboxyhemoglobin leads to reduced oxygen

supply to the tissues, thereby producing hypoxemia. To compensate for lowered oxygen uptake,

more red blood cells are generated, leading to polycythemia and increased blood viscosity, and

consequently increasing the risk of thrombus formation. Smoking-induced hypoxemia elevates

the degree of oxidative stress in the body. Oxidative stress is thought to generate free radicals

that contribute to endothelial inflammation and dysfunction, plasma lipid abnormalities through

oxidation of LDL, and platelet adhesion activation. Lipid peroxidation also plays a vital role in

atherogenesis because it leads to the development of foam cells (the initial components of

endothelial plaques). All of these combined actions of cigarette smoking play an important role

in the initiation and development of CVD. A diagram of the pathophysiological actions of

cigarette smoking and acute coronary events is shown in Figure 7 (122).

Nicotine and carbon monoxide in particular are responsible for reduced myocardial oxygen

supply; nicotine raises blood pressure and heart rate predisposing smokers to myocardial

infarction (Lakier, 1992; Smith et al., 2000). Cigarette smoking has also been suggested to play a

mediatory role in oxidative stress and athero-thrombotic disease (Ambrose & Barua, 2004).
Smoking cessation is therefore undoubtedly one of the most important measures in prevention of

CVD (15, 16). Wiggers et al (121) reported that after one year of smoking cessation, the risk of

CAD may be reduced by greater than 50%, and within several years of discontinuation, risk

returns to that of life-long abstainers. This type of evidence clearly suggests that sustained health

benefits may be achieved by quitting smoking and by introducing health promotion and

preventive measures for smoking cessation.

HYPERTENSION

High blood pressure (BP) is one of the most important risk factor for cardiovascular disease

(CVD) (1,2). It effects approximately 15-20% of all adult population worldwide (Wang et al.,

2008) and approximately 54% of strokes and 47% of coronary heart diseases, worldwide, are

attributable to high BP. In the Global Burden of Disease Study in 2010, elevated resting blood

pressure (BP) was estimated to be the leading single risk factor for death and disability adjusted

life years worldwide (17). Globally 40% of the adults have raised blood pressure, and the highest

proportion is in Africa (46%) while the lowest is in the Americas (35%). The WHO attributes 7.1

million (13%) deaths globally, and 64.3 million DALY (disability-adjusted life years) to

hypertension (WHO, 2002) and globally, 51% of stroke and 45% of IHD deaths are attributable

to high systolic blood pressure (WHO, 2011). The Multi Risk Factor Intervention Trial (MRFIT)

in the US showed that hypertension was associated with more than 50% increased risk of death

from CHD (Vaccaro et al., 1998). Treating raised blood pressure has been associated with a 35–

40% reduction in the risk of stroke and at least a 16% reduction in the risk of myocardial

infarction (264).

Hypertension is a common medical condition; its prevalence increases with age,(4,5) and is

estimated to affect 65% of those above 60-years-old.6 The global population is aging, by 2030,

an estimated 20% of the global population will be <65-years-old.7 Therefore, the impact of high

BP on mortality among older adults is expected to grow over the coming decades.

Hypertension was previously defined as a systolic BP of 140 mm Hg or higher or a diastolic BP

of 90 mm Hg or higher, but the new Hypertension Guideline changes the definition of

hypertension, which is now considered to be any systolic BP measurement of 130 mm Hg or

higher or any diastolic BP measurement of 80 mm Hg or higher. This is termed, stage 1

hypertension. Measurements of 140/90 mm Hg or higher are considered stage 2 hypertension.

While individuals with stage 1 or stage 2 hypertension should consult a healthcare provider for

further treatment, extremely high BP (systolic higher than 180 mm Hg or diastolic higher than

120 mm Hg) with target organ damage is considered an emergency.

Hypertension known as silent killer as it showed no symptom. It is probably the single most

important modifiable CVD risk factor.

Alterations in the blood vessels wall that affect the endothelium, the media and the adventitia is

key in the pathophysiology of hypertension. Alterations in the media lead to remodeling of the

vessel wall (Escobales et al., 2005) which leads to an increase in vascular resistance and an

increased arterial blood pressure. Endothelial dysfunction with reduced production of nitric oxide

(NO) will also affect vasodilation, insulin sensitivity, platelet adhesion, and thrombus formation

(37).

Neurogenic and humoral dysfunction cause renal volume retention that lead to increased of

cardiac output and tissue blood flow which can result in an increase in blood volume that can

cause an increase of arterial blood pressure (Navar et al., 1997).

Hypertension can be classified as primary or secondary hypertension. 95% of all hypertension

cases of hypertension are essential hypertension, also known as primary hypertension or

idiopathic hypertension (Carretero et al.,2000). The cause of essential hypertension is still

unknown but it is considered as the sum of interaction between genetic and multiple

environmental factors (Büssemaker et al., 2010).

Environmental factors including obesity, high alcohol intake, high salt intake, insulin resistance,

low potassium intake, aging, sedentary lifestyles, stress, and low calcium intake contribute to the

development of hypertension (Carretero et al., 2000). In the World Health Organisation Global

Burden of Disease 2000 Comparative Risk Analysis study (46), 16% of all hypertensive disease

was attributed to the consumption of alcohol. Associations between body mass index (BMI) and

blood pressure are generally acknowledged (47, 48) and have been found to be almost linear

(49). Some studies suggest that weight gain may account for 65-75 % of the incidence of human

essential hypertension (50). Insulin resistance and diabetes are also serious risk factors for

hypertension, mainly through the blood pressure increasing effect of elevated concentrations of

serum insulin (51, 52). Insulin resistance or diabetes often occurs together with obesity (general

or abdominal), dyslipidemia, and high blood pressure in what is usually known as the metabolic

syndrome (53), and some also consider proinflamatory and prothrombotic states as part of the

syndrome (54). Longitudinal studies show that long-term smoking in fact increases blood

pressure and thus constitutes a serious risk factor for future hypertension (66). It is well

established that the experience of perceived stress is accompanied by an increase in blood

pressure, which is a completely normal physiological adaptation (68). Animal studies show that

chronic stress induces also a permanent blood pressure increase, and some behaviour-based

approaches to stress management, such as meditation, yoga and muscular relaxation, have shown

moderate decreases in elevated blood pressure (69).

Various genes might be involved in the development of hypertension can cause inherited blood

pressure and the influences of these genes have been demonstrated by family studies that showed

high blood pressure are associated among siblings and between parents and children (Carretero

et al., 2000).
Secondary hypertension is hypertension caused other known conditions or by medications.

Medical conditions such as renal parenchymal disease, renal artery stenosis, hyperaldosteronism,

or pheochromocytoma (Grossman et al., 2012) can cause a high blood pressure.. Temporary high

blood pressure also can cause by medications

such as corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), cold medicines and

birth control pills.

The risk of becoming hypertensive in later life is considerable high, as studies from almost all

high-income countries have shown that blood pressure rises with increasing age (16, 17).

Hypertension is simple to diagnose and usually can be controlled by healthy diet, regular

exercise and medication (Campbell et al., 2002). According to large observational studies, raised

blood pressure often coexists with other cardiovascular risk factors, such as tobacco use,

overweight or obesity, dyslipidaemia and dysglycaemia, hyperuricacidemia and carbohydrate

tolerance which increase the cardiovascular risk attributable to any level of blood pressure.

Hypertension affects the structures and functions of small muscular arteries, arterioles and other

blood vessels and can cause damage at variable rate to various target organs including kidney,

brain and eye (Hock et al., 1995; Lee et al., 2010; Escobales et al., 2005).

Observational data support lowering of these systolic and diastolic thresholds (269, 270). Several

trials in patients at high cardiovascular risk (271–273) have confirmed these observational data,

showing reductions in cardiovascular morbidity and mortality in people whose blood pressure is

reduced to levels significantly below 160 mmHg systolic and 90 mmHg diastolic. These trials

support the view that, in patients at high cardiovascular risk, with blood pressures in the range

140–160 mmHg (systolic) and 90–100 mmHg (diastolic), lowering blood pressure reduces the

number of cardiovascular events.

Nearly all of these new patients diagnosed with hypertension, can be treated with lifestyle

modification instead of medications.

Exaggerated or high exercise BP is an important predictor of CV events that are associated with

CV morbidity (Miyai et al. 2000, Nakashima et al. 2004, Sharabi et al. 2001, Singh et al. 1999,

Miyai et al. 2002, Laukkanen et al. 2004,Laukkanen et al. 2006, Kurl et al. 2001)and

mortality(Allison, Cordeiro, et al. 1999, Filipovsky, Ducimetiere, and Safar 1992) in individuals

with or without any signs and symptoms of CVD. Data have shown that individuals identified

with elevated exercise BP may account for 40% of individuals at high risk of CV events.

(Laukkanen et al. 2006) Hypertensive patients have a reduced exercise capacity, which is

attributed to functional and structural changes in CV system.(Lim et al. 1996).

DIABETES

Diabetes mellitus (DM) is defined as elevated fasting plasma glucose ≥7.0mmol/l (126mg/dl) or

a 2-hour plasma glucose (venous plasma after ingestion of 75g oral glucose load) ≥.11.1mmol/l

(200mg/dl) (WHO/IDF, 2006). Globally ~10% of people aged ≥ 25 years have diabetes, and the

highest prevalence is in the Eastern Mediterranean region and the Americas (11%) while the

lowest is in Europe (WHO, 2011). It is estimated that by 2030 about 439 million (7.7%) people

worldwide will have diabetes, and the African region is expected to have the largest proportional

increase of 98% (from 12.1 million to 23.9 million) in adult type 2 diabetes numbers by 2030

(Shaw et al., 2010). Limited data on type II diabetes prevalence in Africa suggest that there has

been a steady increase in diabetes between the 1980s and 1990s with higher rates observed in

urban compared to rural areas (Mbanya et al., 2010). Data from the INTERHEART-Africa study
suggest that diabetes is one of five risk factors that account for almost 90% of initial myocardial

infarction, and suggest that “uncontrolled major CVD risk factors will have a larger impact on

the burden of CVD in Africa than elsewhere” (Steyn et al., 2005).

Insulin is secreted from beta (β) cells of the islets of Langerhans. Insulin is the most important

hormone during the absorptive state, when nutrients are entering the blood from the small

intestine. Insulin stimulates tissues to take up nutrient molecules such as glucose and amino acids

and store them as glycogen, proteins, and fats. Insulin’s best-known role is in the facilitated

diffusion of glucose across cell membranes. A lack of insulin causes an accumulation of glucose

in the plasma because the tissues cannot take it up. The plasma glucose concentration can

become so high that reabsorption mechanisms in the kidney are overwhelmed and glucose is lost

to the urine, taking large volumes of water with it. This is the pathophysiology of diabetes

mellitus

Diabetes mellitus is considered a major risk factor for cardiovascular disease. Results from the

Framingham study comparing participants examined in two time periods (1952-1974 and 1974-

1988) showed that when comparing CVD risk factors over the two time periods, the prevalence

of hypertension, smoking and high cholesterol significantly declined, but the prevalence of DM

(adjusted for age and sex) increased almost 2 fold (figure 1.8) among CVD cases (8.1% versus

14.6%, P=0.0009) (Fox et al., 2007). Diabetes appears amongst all income groups around the

world, and increases the risk of CVD by 2-3 times. In some age groups, people with diabetes

have a two-fold increase in the risk of stroke (8). Cardiovascular disease accounts for about 60%

of all mortality in people with diabetes. The risk of cardiovascular events is 2–3 times higher in

people with type 1 or type 2 diabetes (354, 355) and the risk is disproportionately higher in

women (354, 356). Patients with diabetes also have a poorer prognosis after cardiovascular
events compared with non-diabetics (357, 358). Epidemiological evidence also suggests that the

association between blood glucose and cardiovascular disease begins before diabetes manifests

itself (357–361). In a meta-analysis of non-diabetic subjects, those with the highest blood

glucose levels had a relative risk for cardiovascular disease events of 1.26 compared with those

with the lowest blood glucose. This suggests that cardiovascular risk increases as glucose

tolerance becomes impaired and then progresses to diabetes (362).

Diabetes is the leading cause of renal failure in many populations in both developed and

developing countries. Lower limb amputations are at least 10 times more common in people with

diabetes than in non-diabetic individuals in developed countries; more than half of all non-

traumatic lower limb amputations are due to diabetes (9). Diabetes is one of the leading causes of

visual impairment and blindness in developed countries (10). People with diabetes require at

least two to three times the health-care resources compared to people who do not have diabetes,

and diabetes care may account for up to 15% of national health care budgets (11). In addition,

the risk of tuberculosis is three times higher among people with diabetes (12). High blood sugar

content also causes damage to small blood vessels, mainly affecting the eyes, kidneys, and heart.

The combination of high blood sugar with atherosclerosis further increases the risk of small

blood vessel damage.

Early prevention, detection, and treatment of diabetes are important for reducing the risk of

CVD.
PHYSICAL INACTIVITY

Regular physical activity is required to balance energy output with energy intake from food and

drinks. A lack of regular activity increases the risk of developing obesity and overall CVD risk.

Regular physical activity can be defined as 30 minutes of moderate activity 5 times per week, or

20 minutes of vigorous activity 3 times per week.

In 2008, 31% of adults aged ≥15 years globally had insufficient physical activity with the highest

prevalence of insufficient physical activity found in the Americas and the Eastern Mediterranean

regions where more than 50% of women are insufficiently active. Insufficient physical activity

also increased with level of countries’ income (WHO, 2011). In 2004 physical inactivity was

estimated to be the fourth leading cause of death worldwide with over 3 million deaths and 2.1%

of global DALY attributable to it (WHO, 2009).

Physical inactivity is considered a major independent risk factor for heart disease. About 12% of

the global burden for myocardial infarction is due to physical inactivity after accounting for other

CVD risk factors (Go et al., 2013). The AHA identifies 150 or more minutes of moderate-

intensity activity or 75 or more minutes of vigorous-intensity activity to be a component of ideal

cardiovascular health.

Skeletal muscles act as a regulator of levels of blood glucose by translocation of GLUT4

receptors to the myocyte membrane as a response to insulin and exercise.53,54 The translocation

of GLUT4 receptors is regulated by a plethora of molecular signalling thought to include

calcium, stretch and energy stress signalling. In addition, exercise increases glucose transport-

phosphorylation and glycogen-synthesis related to transport and storage of glucose in the

myocyte.55 Physical activity is also associated with a favourable lipid profile and exercise a

beneficial effect on lipid profile in patients with dyslipidaemia.56, 57

A pivotal element for a normal endothelial function is the presence of the signaling molecule

Nitric Oxide (NO). Thus, a reduction in the bioavailability of NO leads to endothelial

dysfunction that often predates the clinical and/or morphological manifestations of

atherosclerosis.60 Exercise of moderate intensity is known as stimulator of NO-release and cross

sectional studies have shown positive correlations between physical activity and endothelial

function.61, 62 Furthermore, several studies have shown that physical exercise is capable to

restore and improve endothelial function in patients with atherosclerosis, hypertension and

hyperglycaemia.63

Chronic elevation of inflammatory markers such as IL-6, CRP and white blood count is known

as chronic low-grade inflammation. This condition is associated with increased risk of

developing diabetes,64-72 it is a strong, consistent and independent predictor of all-cause and

cardiovascular mortality73-83 and an increase in IL-6 and soluble TNF-α-receptor-2 are

positively correlated to the amount of coronary artery calcification.84

However, a recent meta-analysis of 26 prospective cohort studies followed up for 4-25 years

reported that physical activity offered a significant protection against CHD in individuals who

performed moderate [RR 0.88 (95% CI. 0.83-0.93)] and high [RR 0.73 (95% CI. 0.66-0.80)]

levels of physical activity (Sofi, 2008).

The INTERHEART study, a global case control study including 27 098 participants from 52

countries reported that physical activity was one of the modifiable risk factors associated with

reduced risk of myocardial infarction in women [OR 0.40 (95%CI 0.41-0.57)] and men [OR 0.77

(95%CI 0.71- 0.83)] (Anand et al., 2008).

Each one metabolic equivalent (MET) improvement in aerobic capacity is associated with a 15%

decrease in cardiovascular disease and 12% decrease in mortality risk (Baur et al., 2012; Go et
al., 2013). Physical activity levels are positively associated with levels of HDL and negatively

associated with levels of triglycerides and insulin resistance (Durand et al., 2011). Increasing

aerobic fitness above the NFPA guideline of 12 METS could lower BMI by 1.6 units, increase

HDL by about 5 mg/dL, lower triglycerides by more than 30 mg/dL, and lower blood glucose

levels by about 9 mg/dL (Baur et al., 2011). For every additional MET of CRF, the risk of

metabolic syndrome was reduced by 31% even after adjusting for age (Baur et al., 2012).

Physical activity can 24 also reduce inflammatory markers. A six-week training program was

shown to reduce CRP levels by about 24% (Go et al., 2013).

It is estimated that participation in 150 minutes of physical activity per week reduces risk of

CVD by 30%, and reduces risk of diabetes by 27%. Physical activity protects against type 2

diabetes and persons engaged in regular physical activity of moderate intensity have

approximately 30% lower risk of developing type 2 diabetes than sedentary persons.

ADVANCING AGE

There are several possible explanations for the dominant effect of age on the likelihood for

occurrence of these cardiovascular diseases. One is that aging is synonymous with disease;

however, many people achieve “old age” without evidence of these diseases. Another

explanation is that other defined risk factors co-vary in number or severity with increasing age

and also, increasing age contributes to an increased exposure time to these other age-dependent

risk factors. Age-associated changes in cardiovascular structure and function become “partners”

with pathophysiological disease mechanisms to determine the threshold, severity, and prognosis

of cardiovascular disease occurrence in older persons.

Age-associated changes in the arterial properties of apparently healthy individuals may have

relevance to the steep age-dependent increase in vascular diseases. Cross-sectional studies in

humans have found that wall thickening and dilatation are prominent structural changes that

occur within large elastic arteries during aging.4 Postmortem studies indicate that the aortic wall

thickening that occurs with aging consists mainly of intimal thickening, even in populations with

a low incidence of atherosclerosis.5 Noninvasive measurements made within the context of

several epidemiological studies indicate that the carotid wall intimal media (IM) thickness

increases 2-to 3-fold between 20 and 90 years of age.

It has been argued that the age-associated increase in IM thickness in humans represents an early

stage of atherosclerosis. Age-dependent IM thickening has also been documented in humans in

the absence of atherosclerosis.5 A plethora of other epidemiological studies indicate that

increased IM thickness is an independent predictor of future cardiovascular events and that it

only serves as the foundation for the later development of atherosclerosis.7

Increased Arterial Stiffening

Age-associated increase in IM thickening is accompanied by both luminal dilatation and a

reduction in compliance or dispensability, with an increase in vessel stiffness.2 Pulse wave

velocity (PWV), a relatively convenient, noninvasive index of vascular stiffening, increases with

age both in men and women (Figure 5A). Prominent age associated increases in PWV have been

demonstrated in populations with little or no atherosclerosis, indicating that vascular stiffening

can occur independently of atherosclerosis.15 However, more recent data emerging from

epidemiological studies indicate that increased large vessel stiffening also occurs in the context
of atherosclerosis and diabetes.16,17 Altered mechanical properties of the vessel wall influence

the development of atherosclerosis and the latter, via endothelial cell dysfunction and other

mechanisms, influences vascular stiffness. Evidence now exists that the “primary” increases in

large artery stiffness that accompanies aging gives rise to an increase in large vessel stiffness that

precedes an elevation of arterial pressure.

In addition to stroke volume, arterial pressure is determined by the interplay of peripheral

resistance and central artery stiffness; the former raises both systolic and diastolic pressure to a

similar degree, whereas the latter raises systolic but lowers diastolic pressure. If vascular aging

is a risk factor for disease, then age-associated vascular changes represent a potential target for

treatment and prevention. It is conceivable that drugs that retard or reverse age-associated

vascular wall remodeling and increased stiffness will be preferable to those that lower pressure

without affecting the vascular wall properties.

It is noteworthy that exercise conditioning improves endothelial function in older persons.44 In

addition, there is evidence to indicate that diets low in sodium are associated with reduced

arterial stiffening with aging.45 Retardation or reduction in IM thickness in humans has been

achieved by drug/diet intervention.25–29

HYPERTENSION

High blood pressure (called hypertension) when the Systolic blood pressure (pressure generated

as blood is ejected from the heart during ventricular contraction) and diastolic blood pressure

(pressure generated as the heart ventricle relaxes to take in m ore blood) exceeds 140/90 mm Hg

respectively. Unfortunately, approximately 33% of all adults (>20 years old) in the United States
have hypertension (13). Hypertension is generally classified into one of two categories: (1)

primary, or essential, hypertension and (2) secondary hypertension. The cause of primary

hypertension is multifactorial; that is, there are several factors whose combined effects produce

hypertension. This type of hypertension constitutes 95% of all reported cases in the United

States. Secondary hypertension is a result of some known disease process, and thus the

hypertension is “secondary” to another disease.

Hypertension can lead to a variety of health problems. For example, hypertension increases the

workload on the left ventricle, resulting in an adaptive increase in the muscle mass of the left

heart (called left ventricular hypertrophy). In the early phases of hypertension- induced left

ventricular hypertrophy, the increase in cardiac mass helps to maintain the heart’s pumping

ability. However, with time, this left ventricular hypertrophy changes the organization and

function of cardiac muscle fibers, resulting in diminished pumping capacity of the heart, which

can lead to heart failure. Further, the presence of hypertension is a major risk factor for

developing arteriosclerosis and heart attacks. Finally, hypertension also increases the risk of

kidney damage and the rupture of a cerebral blood vessel resulting in localized brain injury (i.e.,

a stroke).

ATHEROSCLEROSIS

Atherosclerosis is a slow progressive chronic, inflammatory, fibro proliferative disease involving

large and medium-sized conduit arteries, is the primary underlying cause of CVD. Although the

clinical manifestations of CVD occur in middle and late adulthood, the atherosclerotic process

begins in childhood and is accelerated by exposure to established CVD risk factors and their

persistence over time (Berenson et al., 1998).

The disease is characterized by progressive lipid accumulation and the proliferation of smooth

muscle and connective tissue within the sub-endothelial space of primarily large, and medium

sized systemic arteries (Libby et al., 2010). A long incubation period exists between the initial

development of atherosclerosis and clinical manifestations. Vascular endothelial cells are not

only targets, but are also the effectors that actively participate in inflammatory processes

associated with arteriosclerosis. Healthy endothelial cells are selectively permeable and are

primarily antithrombotic, anti-inflammatory and antioxidant due in part, to their production and

release of NO.

High circulating levels of low density lipoprotein cholesterol (LDL-C) and their subsequent

oxidation and accumulation in the subendothelial matrix has been identified as a major triggering

event in the initiation of atherosclerosis. LDL-C normally diffuses passively through endothelial

cell junctions, and its retention in the vessel wall involves interactions between the LDL-C

constituent Apo lipoprotein B (ApoB) and matrix proteins including proteoglycans and other

intimal glycosaminoglycans (GAGs), which have a high affinity for Apo B. This entrapment

increases the residence time of LDL-C in the artery and renders them more susceptible to

oxidation.
Oxidized LDL-C (oxLDL) inhibits the production of NO and stimulates the overlying

endothelial cells to produce endothelial leukocyte adhesion molecules (ELAMs), chemotactic

proteins such as monocyte chemotactic protein-1 (MCP-1), and growth factors such as

macrophage colony-stimulating factor (M-CSF), resulting in the recruitment of monocytes to the

vessel wall and their subsequent proliferation and differentiation into macrophages. Soluble

vascular cell adhesion molecule-1 (sVCAM-1) is responsible for the recruitment of monocytes

and T-lymphocyte by binding to its cognate ligand VLA4 on the leukocyte. Other adhesion

molecules that play a role in the development of atherosclerosis include soluble intercellular

adhesion molecule-1 (sICAM-1), P-selectin and E-selectin.

The monocytes and T-lymphocytes recruited to the sub-intima space are responsible for the

progression of the atherosclerotic lesions and their subsequent complications. In response to

stimulation by macrophage derived IL-1 and TNF- endothelial cells increase their

permeability, produce more adhesion molecules and become more thrombogenic. T-lymphocyte

derived INF-ϒ stimulates macrophages and SMC to express scavenger receptors that bind and

internalise oxLDL resulting in the formation of lipid-rich arterial foam cells.

Stages of atherosclerosis from endothelial damage and fatty streaks (left side) to advanced

atherosclerotic plaque with a ruptured fibrous cap and thrombus formation (right side).

These nascent atherosclerotic lesions are the precursor of more complex plaques. They are called

foam cells because of the foamy appearance under the microscope, due accumulation of lipid

droplets within the cytoplasm. Vascular smooth muscle cells lose their ability to contract and

develop the capacity to proliferate, migrate and to synthesise and secrete extracellular matrix

proteins (EMP). Over time, SMCs migrate to the sub-endothelial layer where they undergo

mitosis and synthesize and release collagen to from a fibrous cap. Macrophages and lymphocytes

may also be present in the fibrous cap.

Macrophages and SMC within foam cells become necrotic and rupture. Their fat content

accumulates and a fibrotic lipid core, a site of chronic inflammation, is formed. Fibrous plaques

eventually increase in size and undergo calcification to become advanced lesions. The dense

fibrous cap may weaken overtime resulting in hemorrhage within the plaque and ultimately
plaque rupture. Thrombosis may result in partial or full occlusion of the artery, the clinical

consequence being myocardial ischemia, infarction or sudden death.

Although the clinical manifestation of CVD occurs in middle and late adulthood, evidence of

atherosclerotic disease is evident from autopsy studies in children and young adults (Enos et al.,

1953, McNamara et al., 1971, McGill et al., 2000). The onset of atherosclerosis in childhood was

first documented by Holman et al., (1957) who reported that grossly visible fatty streaks were

present in the aorta and coronary arteries of US children after the ages of 3 and 10 years

respectively, and that these lesions advanced to fibrous plaques by young adulthood (Holman,

1957). Stary et al., (1989) found that 65% of 12 to 14 year old children had coronary artery

lesions containing foam cells and lipid droplets, and an additional 8% had developed more

advanced pre-atheroma or atheroma stage of atherosclerosis (Stary et al., 1989).

A nation-wide pathology study of atherosclerosis in Japanese youth found that fatty streaks were

present in the aortas of 29% of children <1 year old and 3.1% in the coronary arteries of children

aged between 1 and 9 years of age (Tanaka et al., 1988).

The findings of pathology studies are consistent with the findings from in-vivo studies examining

atherosclerosis in youth (Berenson, 2002, Goar et al., 1992 , Morrison et al., 2010, Tuzcu et al.,

2001). An intravascular ultrasound study on the characterization of atherosclerosis in young

heart transplant recipients found that coronary artery plaques >0.5 mm were present in 17% of

262 asymptomatic heart donors under the age of 20 years (Tuzcu et al., 2001). More recently,

studies using non-invasive ultrasonography to evaluate atherosclerotic plaque development, have

found increased intima media thickness (IMT) of the carotid arteries of both children and young

adults (Berenson, 2002, Morrison et al., 2010).