**2. Risk factors of CVD**

The aetiology of CVD is multifactorial, complex and still not completely understood. However, there is now a general agreement that elevated total cholesterol, LDL-cholesterol and triacyl‐ glycerol levels, low HDL-cholesterol concentrations, smoking, high blood pressure, hyper‐ glycemia and diabetes are all risk factors of CVD. Physical inactivity, obesity, diet and low socio-economic status are thought to be predisposing risk factors which work, at least in part, as promoter on other risk factors. These factors predispose to develop syndrome X or metabolic syndrome, which is characterised by obesity, hypertension, dyslipoproteinaemia, and disturbed glucose tolerance [8]. Some other factors such as elevated prothrombotic factors, markers of inflammation, elevated homocysteine, elevated lipoprotein (a) and some psycho‐ logical factors show associations with CVD [6]. Nevertheless, the aetiology of CVD is far from clear [9], and most factors are unmodifiable while others can be modified through the change of diet habits and lifestyles.

#### **2.1. Unmodifiable risk factors**

#### *2.1.1. Ageing*

Cardiovascular diseases, such as atherosclerosis, coronary heart disease and resultant heart failure reach epidemic proportions among older persons. Aging leads to arterial stiffening that results in aortic dilation and wall thickening along with increased collagen level. Potential ageassociated changes in the tissue levels or responses to growth factors, catecholamines, angiotensin II, endothelin tumor growth factors β ( TGF β) or fibroblast growth factors influences myocardial or vascular cells. Deficit in myocardial beta adregenic receptor signal‐ ling, decline in omega-3 polyunsaturated fatty acids and increased reactive oxygen species generation occur with aging, which enhances Ca2+ influx [10]. The clinical manifestations and prognosis of CVD and resultant heart failure worsen with ageing. Over 83 percent of people who die of coronary heart disease are 65 or older. Thus, age, per se, is the major risk factor for CVD [10].

#### *2.1.2. Gender*

There is a marked difference in CVD risk between sexes [11]. Incidence of CVD was approxi‐ mately 3-fold and mortality about 5-fold greater in men thanin women [12]. Among middleaged people,incidence of coronary heart disease is 2 to 5 times more in men than in women, and this sexratio varies between populations. The role of major risk factors such as lipid abnormalities, high blood pressure, smoking, obesity and diabetes in the development of CVD is well established amongmen (Jousilahti, Vartiainen et al. 1999). In women, significnat shift in their physiological function and heath profiles occurs during and the postmenopausal. When entering into middle ages, women tend to have lower LDL cholesterol and higher HDL cholesterol values than men of similar age. Following menopause, total cholesterol, LDL cholesterol and triglycerides levels increases while HDL levels remain unchanged or decrease slightly. These alterations in lipid values are thought to be related in part to loss of protective effects of estrogen [13].

#### *2.1.3. Heredity (including race)*

**2. Risk factors of CVD**

182 Using Old Solutions to New Problems - Natural Drug Discovery in the 21st Century

of diet habits and lifestyles.

*2.1.1. Ageing*

CVD [10].

*2.1.2. Gender*

**2.1. Unmodifiable risk factors**

The aetiology of CVD is multifactorial, complex and still not completely understood. However, there is now a general agreement that elevated total cholesterol, LDL-cholesterol and triacyl‐ glycerol levels, low HDL-cholesterol concentrations, smoking, high blood pressure, hyper‐ glycemia and diabetes are all risk factors of CVD. Physical inactivity, obesity, diet and low socio-economic status are thought to be predisposing risk factors which work, at least in part, as promoter on other risk factors. These factors predispose to develop syndrome X or metabolic syndrome, which is characterised by obesity, hypertension, dyslipoproteinaemia, and disturbed glucose tolerance [8]. Some other factors such as elevated prothrombotic factors, markers of inflammation, elevated homocysteine, elevated lipoprotein (a) and some psycho‐ logical factors show associations with CVD [6]. Nevertheless, the aetiology of CVD is far from clear [9], and most factors are unmodifiable while others can be modified through the change

Cardiovascular diseases, such as atherosclerosis, coronary heart disease and resultant heart failure reach epidemic proportions among older persons. Aging leads to arterial stiffening that results in aortic dilation and wall thickening along with increased collagen level. Potential ageassociated changes in the tissue levels or responses to growth factors, catecholamines, angiotensin II, endothelin tumor growth factors β ( TGF β) or fibroblast growth factors influences myocardial or vascular cells. Deficit in myocardial beta adregenic receptor signal‐ ling, decline in omega-3 polyunsaturated fatty acids and increased reactive oxygen species generation occur with aging, which enhances Ca2+ influx [10]. The clinical manifestations and prognosis of CVD and resultant heart failure worsen with ageing. Over 83 percent of people who die of coronary heart disease are 65 or older. Thus, age, per se, is the major risk factor for

There is a marked difference in CVD risk between sexes [11]. Incidence of CVD was approxi‐ mately 3-fold and mortality about 5-fold greater in men thanin women [12]. Among middleaged people,incidence of coronary heart disease is 2 to 5 times more in men than in women, and this sexratio varies between populations. The role of major risk factors such as lipid abnormalities, high blood pressure, smoking, obesity and diabetes in the development of CVD is well established amongmen (Jousilahti, Vartiainen et al. 1999). In women, significnat shift in their physiological function and heath profiles occurs during and the postmenopausal. When entering into middle ages, women tend to have lower LDL cholesterol and higher HDL cholesterol values than men of similar age. Following menopause, total cholesterol, LDL cholesterol and triglycerides levels increases while HDL levels remain unchanged or decrease

The prevalence of CVD considerably varies by race/ ethnicity. Genetic predispositions are a result of gene mutations, which alter the biological function expressed by the original genes (polymorphisms) and increases an individual risk for the disease. Several polymorphism and linkage markers have been identified as being correlated to the onset of CVD. For example, M235T polymorphism of the angiotensinogen gene is linked to hypertension and later to the development of CVD [14]. In many developed countries, racial and ethnic minorities bear disproportionate burden of heart disease. Significant differences in socioeconomic status and conventional heart disease risk factors exist among racial/ethnic groups in the United States, Canada and United Kingdom (Ludwig, Ebbeling et al. 2002). The rate of heart disease among the racial and ethnic group in the United States vary widely, with African Americans having rates a half to three fold greater than Asians, depending on the gender [15]. It is also well documented that the prevalence of CVD is higher in several minority populations (Hispanics and African Americans) in comparison to whites. [16]. However, these differences do not fully account for the observed disparities in disease prevalence, suggesting the presence of other biological factors [17].

#### **2.2. Modifiable risk factors**

#### *2.2.1. Obesity*

Obesity is an independent risk factor for CVD. It is a chronic metabolic disorder associat‐ ed with increased morbidity and mortality. Obesity may affect atherosclerosis through many risk factors such as dyslipidemia, hypertension, glucose intolerance, and increased chronic inflammatory and prothrombotic state. Obesity causes a variety of adaptations/ alterations in cardiac structure and function due to excessive adipose tissue accumula‐ tion, even in the absence of comorbidities [18]. Thus, it increases cardiac workload that leads to heart failure, coronary heart disease, sudden cardiac death, and arterial fibrilla‐ tion [19]. In many cases, these events result in mortality and morbidity. By favourably modifying blood lipids, in particular LDL cholesterol, lowering blood pressure, control‐ ling blood sugar, decreasing proinflammatory cytokines and adhesion molecules, weight loss may prevent the progression of atherosclerosis or the occurrence of acute coronary heart events in the obese high-risk populations [18].

#### *2.2.2. High blood cholesterol*

A high concentration of serum cholesterol is a major risk factor for coronary heart disease [20]. The relationship between abnormal plasma cholesterol fractions and increased CVD risk was described 60 years ago [21]. The excessive cholesterol, especially cholesterol transported/ carried by low density lipoproteins that contain protein apolipoprotein (apo) B100 contributes to the formation of atherosclerotic plaques in arteries. Accordingly, cholesterol that is carried by LDL particles is called "bad cholesterol". by contrast, HDL cholesterol which transports esterified cholesterol from the periphery to the liver is considered more cardioprotective and sometimes referred to as "good cholesterol" [22]. The ratio of LDL to HDL cholesterol is more important than LDL or HDL cholesterol concentration and has been widely used to evaluate susceptibility to the development of heart disease. For a healthy person, it is recommended to maintain the LDL/HDL ratio below 3.5.

#### *2.2.3. High blood pressure*

Hypertension is a highly prevalent major contributor to atherosclerotic cardiovascular disease. It accelerates atherogenesis, imparting a 2- to 3-fold coronary heart disease (CHD) and lethal sequel [23]. In most cases, hypertension results from excessive vasoconstriction of the small arterioles throughout the body, raising the diastolic pressure. Because of high peripheral resistance, the heart needs to generate more force to overcome the resistance created by the constricted arterioles and supply adequate blood to the tissues, which leads to a compensatory rise in systolic blood pressure. This excess of systolic and diastolic blood pressures causes excessive vasoconstriction. Thus, increased levels of systolic and diastolic blood pressure are associated with an increased risk of CVD events [24]. When high blood pressures co-exist with obesity, smoking, hypercholesterolemia, and/or diabetes, the risk of heart attack and stroke increases several times.

#### *2.2.4. Physical inactivity*

Sedentary lifestyle is associated with almost twice the risk of developing coronary heart disease compared with their active counterparts. Regular physical activity plays a crucial role in the prevention of CVD. High levels of physical activity are associatedwith substantial reductions in CVD risk, and total mortalitydecreases by 20% to 30% for the increase of every 1000 kcal/wk of energy expenditure resulting from physical activity [25]. Regular exercise has a favourable effect on many of the establishedrisk factors of CVD. Exercisepromotes weight reduction, reduce blood pressure, "bad" cholesterol (LDL level), and total cholesterol,and can raise the "good" cholesterol (HDL) [26].

#### *2.2.5. Diabetes mellitus*

Diabetes has long been recognized to be an independent riskfactor for CVD. Type-1 dia‐ betes ortype-2 diabetes is at high risk for several cardiovasculardisorders: coronary heart disease, stroke, peripheral arterialdisease, cardiomyopathy, and congestive heart failure. Closely linked to type-2 diabetes are several metabolic risk factors such as hypertension, atherogenic dyslipidemia which is associated with insulin resistance that relatedto coro‐ nary heart disease. Cardiovascularcomplications are now the leading causes of illness and death in the diabetic patient. The incidence of diabetes rises with advancing age, obese and overweight persons and in the populations (race/ethnicity) who areparticularly susceptible to diabetes [27].

#### *2.2.6. Tobacco smoke*

by LDL particles is called "bad cholesterol". by contrast, HDL cholesterol which transports esterified cholesterol from the periphery to the liver is considered more cardioprotective and sometimes referred to as "good cholesterol" [22]. The ratio of LDL to HDL cholesterol is more important than LDL or HDL cholesterol concentration and has been widely used to evaluate susceptibility to the development of heart disease. For a healthy person, it is recommended to

Hypertension is a highly prevalent major contributor to atherosclerotic cardiovascular disease. It accelerates atherogenesis, imparting a 2- to 3-fold coronary heart disease (CHD) and lethal sequel [23]. In most cases, hypertension results from excessive vasoconstriction of the small arterioles throughout the body, raising the diastolic pressure. Because of high peripheral resistance, the heart needs to generate more force to overcome the resistance created by the constricted arterioles and supply adequate blood to the tissues, which leads to a compensatory rise in systolic blood pressure. This excess of systolic and diastolic blood pressures causes excessive vasoconstriction. Thus, increased levels of systolic and diastolic blood pressure are associated with an increased risk of CVD events [24]. When high blood pressures co-exist with obesity, smoking, hypercholesterolemia, and/or diabetes, the risk of heart attack and stroke

Sedentary lifestyle is associated with almost twice the risk of developing coronary heart disease compared with their active counterparts. Regular physical activity plays a crucial role in the prevention of CVD. High levels of physical activity are associatedwith substantial reductions in CVD risk, and total mortalitydecreases by 20% to 30% for the increase of every 1000 kcal/wk of energy expenditure resulting from physical activity [25]. Regular exercise has a favourable effect on many of the establishedrisk factors of CVD. Exercisepromotes weight reduction, reduce blood pressure, "bad" cholesterol (LDL level), and total cholesterol,and can

Diabetes has long been recognized to be an independent riskfactor for CVD. Type-1 dia‐ betes ortype-2 diabetes is at high risk for several cardiovasculardisorders: coronary heart disease, stroke, peripheral arterialdisease, cardiomyopathy, and congestive heart failure. Closely linked to type-2 diabetes are several metabolic risk factors such as hypertension, atherogenic dyslipidemia which is associated with insulin resistance that relatedto coro‐ nary heart disease. Cardiovascularcomplications are now the leading causes of illness and death in the diabetic patient. The incidence of diabetes rises with advancing age, obese and overweight persons and in the populations (race/ethnicity) who areparticularly

maintain the LDL/HDL ratio below 3.5.

184 Using Old Solutions to New Problems - Natural Drug Discovery in the 21st Century

*2.2.3. High blood pressure*

increases several times.

*2.2.4. Physical inactivity*

*2.2.5. Diabetes mellitus*

susceptible to diabetes [27].

raise the "good" cholesterol (HDL) [26].

Smokingnearly doubles the risk of heart disease. Smoking acts synergisticallywith other risk factors, substantially increasing the risk ofCVD [28]. The exact toxic componentsof cigarette smoke and the mechanisms involved in smoking-relatedcardiovascular dysfunction are notclearly elucidated, but smoking increasesinflammation, thrombosis, and oxidation of LDLcholesterol. Smokers have significantly higherserum total cholesterol, LDL cholesterol and triacylglycerol levels, while having lower blood concentration of HDL cholesterol than non-smokers [29]. Cigarette smoke exposure increases oxidativestress as a potential mecha‐ nism for initiating cardiovasculardysfunction. Cigarette smoke exposure decreases the plasma activity of paraoxonase, an enzymethat protects against LDL oxidation. Smoking is also found to be an independent predictor of newcoronary lesion formation and thrombosis [30].

In spite of identification of many unmodifiable and modifiable risk factors, there are still several paradoxes in the pathogenesis of CVD that cannot be sufficiently explained; mortality from CVD is relatively low despite a high intake of saturated fatty acids [31] or a high incidence of CVD without having the expected risk indicators [32]. CVD mortality rate in urban popu‐ lations is higher compared with rural populations despite a very low fat intake [33]. All these paradoxes support the assumption that some important factors in the aetiology of CVD are currently unknown. However, it has been well established that elevated blood total cholesterol, especially LDL cholesterol levels is one of the primary risk factors that contribute to the development of atherosclerosis and ultimately CVD. Therefore, in the following sections, we focus mainly on the atherosclerosis, cholesterol metabolism and homeostasis, benefits versus side effects of current cholesterol-lowering products, and our perspectives on the development of future cholesterol-lowering products.
