Prevalence and prevention of cardiovascular disease and diabetes mellitus

Accepted Manuscript Title: Prevalence and prevention of cardiovascular disease and diabetes mellitus Authors: Pitchai Balakumar Khin Maung-U Gowraganahalli Jagadeesh PhD, Senior Expert Pharmacologist PII: DOI: Reference:

S1043-6618(16)30782-4 http://dx.doi.org/doi:10.1016/j.phrs.2016.09.040 YPHRS 3348

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Pharmacological Research

Received date: Revised date: Accepted date:

12-8-2016 28-9-2016 29-9-2016

Please cite this article as: Balakumar Pitchai, Maung-U Khin, Jagadeesh Gowraganahalli.Prevalence and prevention of cardiovascular disease and diabetes mellitus.Pharmacological Research http://dx.doi.org/10.1016/j.phrs.2016.09.040 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Cardiovascular risk factors Non-modifiable risk factors

Age Gender Family history

Global partnership of nationwide public health campaigns should be organized to create awareness among the public with information pertaining to the primary prevention and management of CVDs and diabetes mellitus.

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Modifiable risk factors

Hypertension Tobacco use Diabetes mellitus Physical inactivity Obesity Unhealthy diet Cholesterol and lipids Depression and anxiety Stress

INVITED REVIEW

Prevalence and prevention of cardiovascular disease and diabetes mellitus

Pitchai Balakumar1, Khin Maung-U2,3, Gowraganahalli Jagadeesh2,3,* 1

Pharmacology Unit, Faculty of Pharmacy, AIMST University, 08100 Bedong, Kedah Darul Aman, Malaysia

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Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research, US Food and Drug Administration (FDA), Silver Spring, Maryland 20993, USA

*Correspondence: Gowraganahalli Jagadeesh, PhD Senior Expert Pharmacologist Division of Cardiovascular and Renal Products Office of Drug Evaluation I, Office of New Drugs Center for Drug Evaluation and Research US Food and Drug Administration (FDA) 10903 New Hampshire Avenue Building 22, Room 4128 Silver Spring, MD 20993-0002 USA. E-mail (GJ): [email protected] E-mail (KM-U): [email protected] E-mail (PB): [email protected]

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This article reflects the views of the authors and should not be construed to represent FDA’s views or policies.

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ABSTRACT Noncommunicable diseases (NCDs) have become important causes of mortality on a global scale. According to the report of World Health Organization (WHO), NCDs killed 38 million people (out of 56 million deaths that occurred worldwide) during 2012. Cardiovascular diseases accounted for most NCD deaths (17.5 million NCD deaths), followed by cancers (8.2 million NCD deaths), respiratory diseases (4.0 million NCD deaths) and diabetes mellitus (1.5 million NCD deaths). Globally, the leading cause of death is cardiovascular diseases; their prevalence is incessantly progressing in both developed and developing nations. Diabetic patients with insulin resistance are even at a greater risk of cardiovascular disease. Obesity, high cholesterol, hypertriglyceridemia and elevated blood pressure are mainly considered as major risk factors for diabetic patients afflicted with cardiovascular disease. The present review sheds light on the global incidence of cardiovascular disease and diabetes mellitus. Additionally, measures to be taken to reduce the global encumbrance of cardiovascular disease and diabetes mellitus are highlighted. Keywords: Noncommunicable diseases; cardiovascular risk factors; cardiovascular disease prevalence; diabetes mellitus; disease prevention

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1. Introduction According to the World Health Organization (WHO) report, noncommunicable disease (NCD) deaths have been on the rise from 6.7 million in 2000 to 8.5 million in 2012 in the SouthEast Asia area, and from 8.6 million to 10.9 million in the Western Pacific area [1]. Since 2000, the number of deaths due to NCDs has augmented globally and in every region. While NCDsassociated deaths are higher than all other causes combined, NCD deaths are projected to further increase from 38 million in 2012 to 52 million by 2030 [1]. Cardiovascular diseases (CVDs) constitute the number one cause of mortality at the global level; each year, more people die from CVDs than from any other cause [2]. According to a WHO report, an estimated 17.3 million people died from CVDs in 2008, representing 30% of all global deaths; it was projected that about 23.6 million people will die from CVDs, mainly from heart disease and stroke by 2030 [2]. According to the WHO report, globally in 2012, of 56 million deceases, NCDs killed 38 million people. More than 70% (28 million) deaths happened in low- and middle-income countries [3]. Of note, 16 million deaths due to NCDs occurred before the age of 70, with 82% occurring in low- and middle-income countries [3]. The concept that CVD is a disease of affluence and only rampant in the western society is no longer correct because, the prevalence of CVD is rising fast in the developing countries as well. Among the NCDs, CVDs account for the highest number of NCD deaths (17.5 million people annually); cancers are the second cause of NCD deaths (8.2 million), followed by respiratory diseases (4 million), and diabetes mellitus (1.5 million). These 4 disease groups over all account for 82% of all NCD deaths [3]. 3

In a recently published Medscape Medical News, heart disease (23.4% of all deaths), cancer (22.5%), chronic lower respiratory disease (5.6%), accidents (unintentional injuries; 5.2%), cerebrovascular diseases (5.1%), Alzheimer's disease (3.6%), diabetes mellitus (2.9%), influenza and pneumonia (2.1%), nephritis, nephrotic syndrome, and nephrosis (1.8%), and intentional self-harm (1.6%) were the top 10 areas of death in 2014 in the United States. [57]. Together, these 10 causes of death accounted for 74% of all deaths in the United States [57]. In this article, we review various key cardiovascular risk issues, and the prevalence of CVDs and diabetes mellitus. Additionally, we highlight potential ways to reduce the global burden on CVDs and diabetes mellitus.

2. Cardiovascular risk factors As per the World Heart Federation, cardiovascular risk factors are divided into 2 major classes, viz. non-modifiable and modifiable risk factors [4].

2.1. Non-modifiable risk factors The non-modifiable risk factors include age, gender and family history. Old people are prone to have CVDs because of aging-associated structural and functional anomalies in heart and vessels. Men are at higher risk for cardiac disease than pre-menopausal women, whereas postmenopausal women may have a similar risk just like men [4]. Sudden cardiac death (SCD) often occurs without previous cardiac symptoms. Of note, the high risk of premature death attributed to SCD among men and women is almost 1 in 9 and 1 in 30, respectively. This should serve as a motivator of public health efforts in preventing SCD [58]. Family history of incidence of stroke or coronary heart disease (CHD) is also a vital non-modifiable risk factor for CVD incidence in

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subsequent generation [4]. Regular check-up is highly recommended for people with nonmodifiable risk factors for CVDs. 2.1.1. CVD risk factors unique to the elderly population The prevalence of CHD and morbidity from it increase with the age of population. When evaluating the elderly population, age-specific CHD risk factors such as arterial stiffness, frailty, lipid profiles and depressive symptoms should be considered [31]. As an individual is aging, structural and functional changes in the vascular wall follow, including thickening of the arterial wall and subsequent greater arterial stiffness. The arterial changes could lead to the development of systolic hypertension, which increases left ventricular afterload causing left ventricular hypertrophy [31]. Frailty, which is frequently seen in very old people, is also a risk factor for the development of CHD. The lipid profiles levels affect the CVD risk of the elderly in a different manner from that in a younger population. Neither high total serum cholesterol nor high LDL levels predict cardiovascular mortality in very elderly population (>85 years); however, low HDL level remains a risk factor for CHD death. Lastly, the elderly may suffer from depression for various reasons, which might act as an independent risk factor for CHD in the elderly population [31]. 2.1.2. CVD risk factors unique to women The prevalence of CHD in women is relatively less than men prior to the age of 50. However, their prevalence of CHD rises significantly with age up to almost the prevalence rate in men by the time they are in their seventh decade of life [31]. Almost 50% of women are unaware that heart disease is the leading cause of death in women [31]. It is likely that for women, the traditional methods to evaluate the risk of future coronary events may be inadequate. 5

While considering the cardiovascular risk for a woman, nontraditional factors that could increase the CHD risk of a woman including cardiovascular conditions associated with pregnancy such as preeclampsia, gestational hypertension, gestational diabetes mellitus, menopause-related hormonal changes and autoimmune diseases that are common in women should also be evaluated [31]. Apart from traditional risk factors for CVD (smoking, obesity and metabolic syndrome, hypertension, physical inactivity, high lipids, and diabetes mellitus), the aforementioned nontraditional risk factors for CVD are unique to women. At menopause, the levels of endogenous estrogen fall to about one-tenth of the premenopausal levels, while hormonal changes at menopause could independently produce a negative effect on HDL levels and body fat distribution, and contribute to active progression of atherosclerotic lesions [31]. Women with hypertensive disorders of pregnancy are reported to have a statistically significant augmented risk of cardiomyopathy [32].

2.2. Modifiable risk factors Hypertension, use of tobacco, diabetes mellitus, physical inactivity, unhealthy diet, cholesterol and lipids, and stress among others are collectively included under modifiable risk factors [4]. Yusuf et al. [5] in the INTERHEART study from 52 countries reported potentially modifiable risk factors associated with myocardial infarction that included smoking, raised ApoB/ApoA1 proportion, history of hypertension, abdominal obesity, psychosocial aspects, and regular alcohol ingestion among others. Risk factors are often observed in clusters so that even if a person is detected with just one risk factor such as hypertension, a search for coexisting risk factors such as smoking, central adiposity, hyperlipidemia and diabetes mellitus becomes obligatory, because these risk factors occurring together can increase the risk of CVDs in a multiplicative rather than in an additive manner [6]. 6

2.2.1. Epidemiological data – hypertension Among the risk factors that contribute to the development of CVDs, hypertension is the most important, modifiable and independent risk factor. Hypertension is a persistent elevation of systolic blood pressure of ≥140 mm Hg and a diastolic blood pressure of ≥90 mm Hg. Hypertensive people are to develop diabetic complications at a greater extent. Hypertension is the ‘silent killer’ as it occurs with no warning signs or symptoms; it is regarded as one of the main causes of early death. It is therefore imperative to have a regular blood pressure checkup. High blood pressure is one of the major risk factors for death and for debility worldwide. Hypertension has a negative impact on the function of heart and blood vessels. It is a risk factor for CHD and causes about 50% of ischemic strokes and increases the risk of hemorrhagic stroke [7]. The factors contributing to hypertension are given in BOX 1.

BOX 1: Behavioural factors contributing to hypertension [8] 1.

Nearly half of hypertension may be attributable to consumption of unhealthy diet (nearly 30% to high salt intake, and 20% to low dietary potassium through less consumption of fruits and vegetables).

2.

Physical inactivity is interrelated to nearly 20% of hypertension.

3.

Obesity is correlated to nearly 30% of hypertension.

4.

Excessive intake of alcohol is associated with hypertension. Additionally, quitting tobacco use benefits hypertensive individuals.

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As per the WHO, in 2014, the global prevalence of elevated blood pressure in adults aged 18 years and above was about 22% [1]. Nearly one billion people have hypertension globally from which two-thirds belong to developing countries [9]. About 330 million people in the developed world and around 640 million in the developing world have hypertension. The occurrence of high blood pressure in adults is estimated to reach 1.56 billion in 2025 [7]. About 60% of diabetic people have high blood pressure. Every year, hypertension kills nearly 8 million people globally and nearly 1.5 million people in the South–East Asia section [10].

The

prevalence of hypertension in Indian adults has been estimated to be 30% (34% in urban areas and 28% in rural areas) [11]. In the USA, Centers for Disease Control and Prevention (CDC) estimates that about 1 of 3 adults or about 70 million people have high blood pressure; however, only about half (52%) of them maintain control of their high blood pressure [12]. A recent study suggests that hypertension affects nearly 78 million U.S. adults and is an important modifiable risk factor contributing to other CVDs and stroke [13]. In the data from the National Health and Nutrition Evaluation Survey (NHANES) in 2007 to 2010, while 81.5% of individuals with hypertension were aware of having high blood pressure, and 74.9% were treated, only 52.5% had their high blood pressure under control [13]. Of note, about one fourth of adult population in the U.S have hypertension while another quarter of the population have prehypertension, which is described as systolic blood pressure of 120 to 139 mm Hg or a diastolic blood pressure of 80 to 89 mm Hg [14]. A rising trend in the incidence of hypertension has been reported in a recent epidemiological survey involving several countries and territories [59]. An increase in systolic blood pressure (SBP) was found for both sexes in the regions of Oceania, East Africa, and South 8

and Southeast Asia, and for women in West Africa. SBP was found to be highest for women (mean value of ≥135 mm Hg) in some East and West African countries, and for men (≥138 mm Hg) in Baltic and East and West African countries. In the Western Europe, both men and women demonstrated highest SBP among the high income regions [59]. The key factors to slow the progression of the global prevalence of hypertension include reducing salt intake, alcohol consumption and high dietary fat feasting. Additional factors include eating adequate amount of fruits and vegetables, taking regular mild exercise, instituting measures to reduce body weight in obese and overweight individuals, learning to relieve or cope with stress, and initiating programs to improve socioeconomic status of communities. 2.2.2. Epidemiological data - tobacco use According to the World Heart Federation, smoking is the second leading cause of CVD after hypertension, and is estimated to cause nearly 10% of CVD [15]. The use of tobacco or exposure to secondhand smoke kills nearly 6 million people globally every year. The tobaccorelated deaths have been projected to increase to more than 8 million deaths a year by 2030 [15]. Tobacco use damages blood vessels, temporarily raises blood pressure and lowers exercise tolerance while it also decreases oxygen carrying capacity of blood and increases the clotting tendency of blood, which could cause a range of CVD [15]. Smoking can raise blood triglycerides and decrease the HDL (the good cholesterol) levels. Smoking can damage cells that line the blood vessels and increase the buildup of plaque in blood vessels, causing thickening and narrowing of blood vessels. Breathing secondhand smoke is known to cause stroke and coronary heart disease, including heart attack [16]. Even briefly breathing secondhand smoke could cause damage in the blood vessel linings and cause 9

sticky blood, which could cause a deadly heart attack [16]. The adverse relationship between tobacco use or secondhand smoke and CVD risk is shown in BOX 2.

BOX 2: Tobacco or secondhand smoke and CVD risk [15] 1.

For every cigarette smoked, the risk of a non-fatal heart attack increases by 5.6%.

2.

The risk of heart attack is likely to be more than double by chewing tobacco.

3.

Breathing secondhand smoke increases in non-smokers the risk of developing a CVD by 25–30%.

4.

Secondhand smoke contributes to 600,000 deaths annually, of which 28% are children.

5.

The risk of a heart attack is almost doubled by frequent exposure to tobacco smoke at workplace or home.

In the U.S, the tobacco use has declined markedly; yet, it occupies the place of secondleading cause in total deaths and disability [17]. Nearly one third of CHD deaths are attributed to smoking and secondhand smoke exposure [17]. Smoking is avoidable, and implementation of smoke free exercise and avoidance of smoking habit could prevent associated CVDs. 2.2.3. Epidemiological data - physical inactivity Physical activity is a crucial component of energy outflow, energy balance and weight control. According to World Heart Federation, inadequate physical activity is the fourth leading risk factor contributing to mortality. Insufficient physical activity may be defined as either less 10

than five times of 30 minutes moderate activity per week, or less than three times of 20 minutes vigorous activity per week, or equivalent [18]. The benefits of exercise and physical activity training include reduction in mortality from CVDs, increased exercise capacity and improved quality of life. Undertaking more than 150 minutes of moderate physical activity a week or 60 minutes of vigorous physical activity a week can reduce the risk of CHD by about 30% [19]. Insufficient physical activity could increase the risk of all-cause mortality by 20% to 30% as compared to individuals with at least 150 minutes of moderate intensity physical activity per week, or equivalent [20]. In 2010, worldwide, 23% of adults aged 18+ years did not have sufficient physical activity (men 20% and women 27%). According to the Global Health Observatory (GHO) data of WHO, the highest prevalence of insufficient physical activity was observed in the Eastern Mediterranean region (31%) and the region of the Americas (32%), whereas the lowest prevalence was reported in the South-East Asia (15%) and African (21%) regions [20]. It should be noted that women were less active than men across all regions. In addition, the popularity of decreased physical activity varies with the size of income. In this context, 41% of men and 48% of women from high income countries were inadequately physically active relative to 18% of men and 21% of women from low income countries, according to the Global Health Observatory (GHO) data of WHO [20]. Decreased physical activities have led to a higher incidence of cardiovascular disease, diabetes mellitus, abnormal circulating lipids and obesity (BOX 3).

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BOX 3: Physical inactivity [21] 1.

Decreased physical activity is one of the primary risk factors for CVDs and diabetes mellitus. Inadequate physical activity is one of the ten leading risk factors for death on a worldwide scale.

2.

Globally, one in four adults is not sufficiently active.

3.

Globally, over 80% of the adolescent population is inadequately physically active.

4.

Children and adolescents of age 5 to 17 years need to do at least 60 min/day of moderate to rigorous physical activity.

5.

Adults aged 18–64 years need to do at least 150 min of moderate-intensity physical activity throughout the week, or at least 75 min of vigorous-intensity physical activity throughout the week.

6.

If necessary, for added health benefits, adults could increase their moderate-intensity physical activity to 300 min/week, or equivalent.

2.2.4. Epidemiological data - obesity Obesity is a chronic disease affecting children, adolescents and adults alike. Excess body weight is one of the leading causes of death and disability in the United States and globally; the burden is expected to increase in coming years [17]. Obesity is associated with the chances of developing hypertension, diabetes mellitus, CHD, stroke and osteoarthritis among others. The levels of overweight and obesity are expressed in terms of the body mass index (BMI) of ≥25 kg/m2 and ≥30 kg/m2, respectively [1]. The global prevalence of obesity between 1980 and 2014 has nearly doubled. More than 1.9 billion adults of 18 years and above were overweight in 2014, 12

and of these, over 600 million were obese [22]. By gender, 11% men and 15% women aged 18 years and above were obese in 2014. In 2013, an estimated 42 million children under the age of 5 years were overweight [1]. The incidence of obesity is increasing in all countries. The prevalence of overweight and obesity is highest in the regions of the Americas, i.e., 61% overweight or obese in both sexes. On the other hand, it is lowest in the regions of South-East Asia, i.e., 22% overweight in both sexes [1]. Of note, men are more likely to be less obese than women. In the regions of Americas, Europe and Eastern Mediterranean, more than 50% of women are overweight, and about half of these overweight women are obese (30% in the Americas, 25% in Europe, 24% in Eastern Mediterranean countries) [1]. In the UK, the proportion of obese adults has markedly increased from 13.2% in 1993 to 26.0% in 2013 for men and from 16.4% to 23.8% for women [23]. In the United States, epidemic bursts of obesity declined among those from higher socioeconomic status. On the other hand, it escalated among those from lower socioeconomic status. Moreover, in the US youth especially among adolescent boys, the overall incidence of bursts of obesity continued to increase [17]. Taken together, large intake of high-energy foods, such as refined and processed foods can lead to obesity. An important public health message that must be emphasized to all is to avoid highly processed foods prepared with refined white sugar, flour and saturated fat, and to avoid high calorie foods. 2.2.5. Epidemiological data - unhealthy diet Low consumption of fruits and vegetables and high consumption of saturated fats, transfats and salt can increase cardiovascular risk and weight gain. Low fruits and vegetables intake is 13

believed to account for about 20% of CVD worldwide [24].

According to Global Health

Observatory (GHO) data of WHO, 1.7 million (2.8%) of global deaths may be the result of low consumption of fruits and vegetables [25]. Conversely, adequate consumption of fruits and vegetables could contribute to a reduction in the risk for CVDs, and colorectal and stomach cancers [25]. In addition, WHO recommends less than 5 grams salt per day.

Excess salt

consumption is an important determinant of high blood pressure and cardiovascular risk. It has been suggested that reducing the level of dietary salt intake from 9 to 12 grams per day currently consumed worldwide to the recommended level of 5 grams per day will contribute in a major way to reduce the prevalence of high blood pressure and CVDs [25]. Likewise, consumption of large amounts of saturated fats and trans-fatty acids is adversely associated with heart disease pathology and stroke. The safest strategy to prevent the development of CVDs is through dietary intervention. The major categories of dietary fats include saturated fatty acids (SFA), monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA). High consumption of SFA increases the risk of developing CVDs. On the other hand, MUFA and PUFA are believed to be cardioprotective [26]. Human body synthesizes SFA and MUFA; but, lacks the enzymes to synthesize PUFAs. Therefore, PUFAs are considered essential fatty acids to be taken in the diet [26]. While many reports supporting the cardioprotective effects of omega (n)-3 polyunsaturated fatty acids (PUFAs) exist, there are also reports to the contrary. According to epidemiologic and interventional studies, substituting MUFA-rich foods for SFA-rich foods in the diet might reduce total plasma cholesterol concentrations, but do not lessen the extent of coronary artery atherosclerosis [27]. To precisely understand the claims of

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cardioprotective effect, if any, of MUFA and n-3 PUFA, more studies are to be conducted at the clinical and epidemiological levels. 2.2.6. Epidemiological data - hyperlipidemia Globally, about one third of ischemic heart disease is attributed to elevated cholesterol [28]. The risk of heart disease could be decreased by lowering the raised blood cholesterol. Globally, the socioeconomic status of a country influences the prevalence of elevated total cholesterol. In 2011, about 25% of adults from low-income countries and more than 50% of adults from high-income countries experienced elevated total cholesterol [29]. One of the major risk factors for CVD and stroke is high cholesterol. According to the American Heart Association, one of the seven components of ideal cardiovascular health is that the untreated total cholesterol of <170 mg/dL for children and of <200 mg/dL for adults [30]. Dyslipidemia and disturbances in the homeostatic regulation of lipid and lipoprotein metabolism play a prime role in development of CVD. A reduction in the low-density lipoprotein (LDL)-cholesterol continues to be the primary goal to lessen the progression of CVDs. However, despite maintaining optimal levels of LDL-cholesterol, cardiovascular disease still remain prevalent, suggesting that other lipids and risk factors need to be modulated as well. Current therapies emphasize lowering blood triacylglycerol levels and augmenting high-density lipoprotein (HDL)-cholesterol levels. In addition to these therapeutic approach, lifestyle modifications, especially maintaining a low intake of fats in the diet, will play an important role to prevent CVD.

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2.2.7. Depression as a CVD risk factor Depression appears to be an independent risk factor contributing to the onset of a wide range of CVDs [33]. Proposed biologic mechanisms include altered sympathetic stimulation and changes in lipid metabolism found in association with depression. Other associated behaviors of depression contributing to the development of CVD may be stress, physical inactivity and medication non-adherence. An estimated 15.4 million US adults with CHD have depression and elevated depressive symptoms. About 20% of patients admitted to a hospital for an acute coronary syndrome such as myocardial infarction or unstable angina were suggested to meet the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria for major depression; and even a higher number showed subclinical levels of depressive symptoms [34]. Diabetic patients are suggested to be approximately three times likely to have depression than their nondiabetic counterparts, while diabetic patients are already predisposed to a greater risk for poor cardiovascular health. A recent study suggested that those who were depressed have had higher HbA1c levels and BMIs than those who were not depressed, indicating that depressed diabetic patients are at higher risk of having meager control of cardiovascular risk factors [35]. In addition, a recent study suggested that an association exists between anxiety and increased risk of hypertension [36].

3. Global/regional prevalence of various types of cardiovascular disease Cardiovascular disease refers to diseases of the circulatory system affecting the anatomy and physiology of the heart and blood vessels. The most common types of CVD include hypertension (prevalence information provided in previous sections), ischemic heart disease, 16

cerebrovascular disease (stroke), peripheral vascular disease, heart failure, rheumatic heart disease, valvular heart disease and congenital heart disease.

3.1. Ischemic heart disease Ischemic heart disease (or coronary artery disease) is associated with reduced blood supply to the heart. Ischemic heart disease could develop with high cholesterol, hypertension, chronic diabetes mellitus, abdominal obesity, lack of exercise, not having sufficient fruits and vegetables, large ingestion of alcohol, smoking and stress. According to the WHO, in 2012, ischemic heart disease (7.4 million deaths) has been the leading cause of death in the world, followed by stroke (6.7 million deaths), chronic obstructive pulmonary disease (3.1 million deaths), and lower respiratory infections (3.1 million deaths), among others [37]. Among the 10 leading causes of death by country income group (2012) listed by WHO, ischemic heart disease remains at the top only in lower-middle income countries and in high-income countries [38]. On the other hand, in low-income countries and upper middle-income countries, ischemic heart disease is placed at the 5th and 2nd positions, respectively, among the top 10 causes of death in 2012 [38]. According to the data from the National Health and Nutrition Examination Survey (NHANES) 2009 to 2012, an estimated 15.5 million Americans of age ≥20 years have had CHD, while the prevalence of CHD was 7.6% and 5.0% for men and women, respectively [30].

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3.2. Cerebrovascular disease-Stroke The second leading cause of disability after dementia is stroke. Stroke results from blockade by a clot or from rupture of blood vessel carrying oxygen and nutrients to the brain. Ischemic stroke results from a clot obstructing the blood flow to the brain. A hemorrhagic stroke is the result of a blood vessel rupturing and preventing blood flow to the brain. A transient ischemic attack results from a temporary clot. When looking into the worldwide burden of stroke, the World Heart Federation found that every year 15 million people suffer from a stroke. Nearly six million people die and another five million are left permanently disabled [39]. Disability might include loss of vision and or speech, paralysis and confusion. On a global scale, stroke is the second leading cause of death in people aged >60 years, and the fifth leading cause of death in people aged 15 to 59 years [39]. The incidence of stroke is declining in many developed countries although the actual number of strokes is increasing as a result of the ageing population. It is predicted that stroke mortality in Latin America, Middle East and sub-Saharan Africa might triple in the next 20 years [39]. According to the NHANES 2009-2012 data in the USA, an estimated 6.6 million people of age ≥20 years had a stroke. During this period, the overall stroke prevalence is an estimated 2.6% (NHANES, National Heart, Lung, and Blood Institute-NHLBI). The 2013 data from the Behavioral Risk Factor Surveillance System-Centers for Disease Control and Prevention (BRFSS- CDC) showed that 2.7% of men and 2.7% of women of age ≥18 years have had a history of stroke [30]. On average someone in the US has a stroke every 40 seconds [30]. In 2013, someone died of a stroke on average every 4 minutes. This disease accounted for nearly 1 of every 20 deaths in the US [30]. 18

Recently, Feigin et al [40] systematically analyzed data from the Global Burden of Disease Study 2013 to estimate the population-attributable fraction (PAF) of stroke-related disability-adjusted life-years (DALYs) connected with adjustable environmental, occupational, behavioural, physiological, and metabolic risk factors in different age and sex groups globally and in high-, middle-, and low-income countries during 1990 and 2013. The researchers estimated the disease burden of stroke linked with 17 risk factors in 188 countries. The researchers reported that globally, 90·5% of stroke burden, as measured in DALYs, was attributable to modifiable risk factors with 74·2% due to behavioural factors including smoking, low quality diet, and less physical activity, and suggesting that 90% of stroke burden might theoretically be avoided by controlling these risk factors. Clusters of metabolic factors (elevated SBP, high BMI, high fasting plasma glucose, high total cholesterol, and low glomerular filtration rate; 72·4%) and environmental factors (air pollution and lead exposure; 33·4%) were the second and third largest contributors to DALYs. The percentage contribution of individual risk factors adds up to over 100% because they all interact with each other, and one risk factor is often regulated through other risk factors. It is inferred from the study that greater than 90% of the stroke problem is attributable to modifiable risk factors, while attaining control of behavioural and metabolic risk factors could prevent above three-quarters of the worldwide stroke burden [40].

3.3. Peripheral arterial disease Peripheral arterial disease is common in the legs or lower extremities where narrowing or blockage of the vessels occur mainly because of the buildup of fatty plaque in the arteries (atherosclerosis). While peripheral arterial disease could occur in any blood vessel, it is more common in legs than in arms. Its classic symptom is pain in legs upon exertion which is relieved 19

by resting. Risk factors for peripheral arterial disease mainly include smoking, high blood pressure, atherosclerosis, diabetes mellitus and high cholesterol [41]. The risk factors for peripheral arterial disease are related, but not identical to those for CHD. Cigarette smoking and diabetes mellitus are considered stronger risk factors for peripheral arterial disease than for CHD [30]. In the 21st century, peripheral artery disease has become a worldwide problem. Following coronary artery disease and stroke, lower extremity peripheral artery disease has been the third leading cause of atherosclerotic cardiovascular morbidity [42]. In 2010, there were 202 million individuals afflicted with peripheral artery disease living worldwide, while 69·7% of them were living in low-income or middle-income countries, including 54·8 million from Southeast Asia and 45·9 million from the Western Pacific countries [42]. Peripheral artery disease is associated with high morbidity and mortality affecting about 8.5 million Americans aged ≥40 years [30]. The maximum occurrence of this disease has been observed among aged people. In general, only about 10% of people afflicted with peripheral artery disease have had the classic symptoms of intermittent claudication while around 40% of people did not complain of leg pain [30]. On the other hand, the remaining 50% have had a variety of leg symptoms different from that of classic claudication [30].

3.4. Heart failure Heart failure is a condition in which the heart is unable to pump enough quantity of blood to meet demands of the body. Either the heart cannot fill with enough amount of blood or it cannot pump blood with enough force to supply adequate blood to the circulation. Right-side heart failure occurs when the heart is unable to pump sufficient amount of blood to the lungs for 20

oxygenation/purification, while left-side heart failure occurs when the heart is unable to pump appropriate amount of oxygenated blood to the rest of the body. Globally, heart failure is a major public health problem. Its global prevalence is more than 23 million [43]. Heart failure has been associated with significant mortality, morbidity and healthcare expenditures mainly in people aged ≥65 years [43]. Heart failure is common throughout the sub-Saharan Africa and it strikes individuals in the sub-Saharan Africa at a much younger age than in the United States and Europe [30]. In fact, heart failure has been an imperative contributor to CVD burden in the sub-Saharan Africa for many decades [44]. According to the NHANES 2009 to 2012 data, an estimated 5.7 million Americans aged ≥20 years have had heart failure [30]. It is projected that from 2012 to 2030, the heart failure prevalence will increase 46% resulting in >8 million people aged ≥18 years with heart failure [30]. Furthermore, nearly 50% of people diagnosed with heart failure have been suggested to die within 5 years [30].

3.5. Rheumatic heart disease In the 21st century, rheumatic fever and rheumatic heart disease have remained relatively unheeded diseases in indigent communities. Acute rheumatic fever and subsequent rheumatic heart diseases have been almost eradicated in areas with economic growth and prosperity. However, migration of individuals from low-income countries to high-income regions could contribute to a new wave of an unanticipated prevalence of rheumatic heart disease in highincome countries. World-wide, rheumatic heart disease remains the most prevalent CVD among young people aged <25 years [45].

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Rheumatic heart disease affects over 32 million people worldwide and claims 275,000 lives annually [48]. The most severely affected regions include the sub-Saharan Africa, southcentral Asia, the Pacific and indigenous populations of Australia and New Zealand [46]. Importantly, signs of rheumatic heart disease are found in about 1% of all schoolchildren in Asia, Africa, the Eastern Mediterranean region, and Latin America [46]. In American Samoa, rheumatic heart disease is approximately 10 times more common than in the continental United States and a high prevalence of lifelong morbidity from rheumatic heart disease is projected [47]. In the United States, the annual incidence of acute rheumatic fever declined in the late 20th century to around 0.04–0.06 cases per 1,000 children; rheumatic fever is no longer a notifiable disease in the United States [47]. Recurrent or severe acute rheumatic fever could result in permanent damage to the cardiac valves and rheumatic heart disease [47]. Antibiotics, if administered no more than 9 days after the onset of symptom, can prevent acute rheumatic fever [47]. Long-term benzathine penicillin G injection is effective in averting recurrent acute rheumatic fever attacks and the CDC (Centers for Disease Control and Prevention) recommends it to be given every 3-4 weeks for 10 years or until the age of 21 years to children diagnosed with acute rheumatic fever [47].

3.6. Valvular heart disease Valvular heart disease (VHD) is a structural or functional abnormality of cardiac valves. The main causes of VHD are calcific aortic stenosis in the elderly, floppy mitral valve/mitral valve prolapse associated with mitral regurgitation, bicuspid aortic valve, VHD associated with cardiomyopathy, post-interventional therapy (iatrogenic) and infective endocarditis among others [60]. The incidences of VHD increase over the past few decades probably due to aging 22

population, increased survival in patients afflicted with conditions like ischemic heart disease and inflammatory disease states, and earlier diagnoses due to advanced technologies [61]. The prevalence of VHD is estimated at 2.5% in industrialized countries [62]. A recent trend observed has been a marked increase in the prevalence of valvular disease after the age of 65 years, particularly with regard to aortic stenosis and mitral regurgitation [62]. Rheumatic heart disease represents 22% of VHD in Europe [62]. While Rheumatic heart disease remains an important factor for development of VHD globally, degenerative valve diseases are likely the most common causes of VHD in developed countries [61].

3.7. Congenital heart disease Congenital heart disease is linked with defectiveness in the structure of heart existing at birth. Congenital heart faults could change the normal flow of blood through the heart. Congenital heart disease accounts for about one-third of all major congenital anomalies [49]. The worldwide prevalence of congenital heart disease birth varies and is not available accurately. Asia reported the highest incidence of congenital heart disease birth with 9.3 per 1,000 live births [49]. The total congenital heart disease birth incidence reported in Europe was markedly higher than in North America (8.2 per 1,000 live births vs. 6.9 per 1,000 live births) as per the report of a systematic review and meta-analysis published in 2011 [49]. Major advances in medical and surgical therapies of congenital heart disease over the past 4 decades have enabled many infants born with congenital heart disease to survive to adult and older ages [50], with >85% of children with congenital heart disease surviving to adulthood [51]. The congenital heart disease incidence at birth in any population depends on how a population is studied because before imaging techniques such as echocardiography became 23

available, the incidence has ranged from five to eight cases of congenital heart disease diagnosed per 1000 live births [52]. Following the development of advanced diagnostic procedures in recent years, many milder forms of congenital heart disease were able to be identified; thus, the estimates have ranged from eight to 12 per 1000 live births [52]. The incidence of congenital heart defects in the US is generally reported between 4 and 10 per 1000, clustering around 8 per 1000 live births [30]. Incidence rates over the time might increase because of superior detection during infancy by fetal cardiac ultrasound, screening pulse oximetry and echocardiography [30]. Recent medical advances resulting in improved survival from congenital heart diseases have created a shift in their demographics. From 2000 to 2010, the prevalence of congenital heart disease had increased by 11% only in children but a staggering 57% in adults [63]. In a similar manner, the prevalence in the severe congenital heart disease subgroup had increased by just 19% in children but a large proportion (55%) in adults [63]. Adults have now become a significant patient population constituting a majority of congenital heart disease patients. There is an urgent and growing need to train more physicians who are knowledgeable on adult congenital heart disease and who can assess and manage these patients with complex heart defects.

4. Global/regional prevalence of diabetes mellitus Diabetes mellitus is a chronic disease that happens when the pancreatic beta cells of islets of Langerhans are unable to produce sufficient insulin (type 1 diabetes mellitus, insulindependent, juvenile or childhood-onset diabetes) or when the body ineffectively uses the insulin (type 2 diabetes mellitus, non-insulin-dependent or adult-onset diabetes). Type 2 diabetes 24

mellitus is the most common form of diabetes characterized by elevated blood sugar, insulin resistance and relative lack of insulin. The hormone insulin regulates blood sugar, and thus deficient insulin secretion or its ineffective body’s use could result in hyperglycemia. The precise cause of type 1 diabetes mellitus is not known; its primary symptoms include frequent urination, high level of thirst, weight loss, and fatigue, and, over time, changes in vision, kidney function and sensory/motor nerve function in extremities. The symptoms of type 2 diabetes mellitus might be similar to those of type 1 diabetes mellitus, but are often less marked, and therefore, the presence of type 2 diabetes mellitus may be undiagnosed for many years until complications such as peripheral neuropathy, peripheral vascular disease or kidney disease manifest with symptoms [53]. Chronic and uncontrolled diabetes mellitus is linked to several complications, including retinopathy, neuropathy and nephropathy, among others [54]. Suboptimal control of diabetes mellitus could have damaging effects on multiple systems in the body and could result in life-threatening difficulties [55]. The risk factors for type 2 diabetes mellitus are listed in BOX 4. Globally, the number of adults afflicted with diabetes mellitus has increased from 108 million in 1980 to 422 million in 2014 [53]. The global prevalence of diabetes mellitus in adult population has increased from 4.7% in 1980 to 8.5% in 2014. This indicates that the global prevalence (age-standardized) of diabetes mellitus has nearly doubled since 1980 until 2014 [53]. For the past 10 years, the occurrence of diabetes mellitus has increased in countries with lowand middle-income than in countries with high-income [53].

25

BOX 4: Risk Factors for Type 2 Diabetes Mellitus [56]. The following features are likely to be observed in individuals who develop type 2 diabetes mellitus: 1.

Age ≥45.

2.

Overweight or obese.

3.

Sedentary lifestyle.

4.

Family history with diabetes mellitus.

5.

History of delivering a baby weighing >9 pounds.

6.

Polycystic ovary syndrome; and history of diabetes mellitus during pregnancy.

7.

Elevated blood pressure (≥140/90 mmHg) or being treated for hypertension.

8.

Levels of major lipids: High-density lipoprotein below 35 mg/dL, or triglycerides above 250 mg/dL.

9.

Prediabetes—HbA1C level of 5.7 to 6.4 percent; an elevated fasting plasma glucose test result of 100–125 mg/dL; or a two-hour oral glucose tolerance test result of 140–199 mg/dL.

10.

Acanthosis nigricans presenting with a dark, velvety rash around the neck or armpits.

11.

Current or prior history of CVDs.

In 2012, the total burden of deaths from high blood glucose was 3.7 million. Diabetes mellitus directly caused 1.5 million deaths, while increased risks of cardiovascular and other diseases resulting from higher-than-optimal blood glucose contributed to an additional 2.2 million deaths [53]. Forty three percent of these 3.7 million deaths occurred prior to the age of 70

26

years. The death percentage attributed to either elevated blood glucose or diabetes mellitus that have occurred before the age of 70 years was higher in countries with low- and middle-income than in countries with high-income [53]. In the USA, diabetes mellitus affects 1 in 10 adults with 90% to 95% being type 2 diabetes mellitus [17]. Although type 2 diabetes mellitus has been historically diagnosed mainly in adults of age 40 years and more, it is progressively common in children and youths. In children/youths, its prevalence has been shown to be increased by 30.5% between 2001 and 2009, and it now constitutes nearly 50% of all childhood diabetes mellitus [17]. Diabetes mellitus is generally characterized with shortened life expectancy; men and women afflicted with diabetes mellitus live an average of 7.5 and 8.2 years less, respectively, than those who are devoid of diabetes mellitus [17]. Rampant bursts of childhood and youth obesity through more sedentary lifestyles (such as increased television and computer usage and decreased physical activity) and modifications to nutrition (increasing calorie intake) have led to a higher prevalence of type 2 diabetes mellitus in younger generation. Postponing the early onset of type 2 diabetes mellitus in youngsters will be a major influence on the future burden of the diabetes mellitus, because onset of diabetes at a very young age presages many years of disease and a buildup of the full range of both micro- and macrovascular complications.

27

Reduction in the risk of type 2 diabetes mellitus and improvement of insulin sensitivity and glucose uptake could effectively be achieved by engaging in regular physical activity and having healthy diets, including consumption of dietary fiber foods and substitution of saturated fatty acids with polyunsaturated fatty acids [53]. The WHO and the Food and Agriculture Organization (FAO) recommend limiting the intake of saturated fatty acids to less than 10% of total energy intake, while this intake should be less than 7% for high risk individuals to prevent type 2 diabetes mellitus [53]. It is imperative to achieve adequate intakes of dietary fiber, specifically a minimum daily intake of 20 gram, by regular consumption of wholegrain cereals, legumes, fruits and vegetables [53]. WHO also advises to reduce the ingestion of free sugars to less than 10% of total energy intake and that reduction to 5% could provide additional health benefits [53].

5.

Steps ahead to reduce the global burden of mortality and morbidity from high prevalence of cardiovascular disease and diabetes mellitus Efforts to reduce the global burden of mortality and morbidity from high prevalence of

cardiovascular disease and diabetes mellitus can be focused at the level of the individual or the population. At the individual level, actions needed to prevent and treat CVD appear straightforward: eat a healthy, low-salt, low-fat diet, remain physically active throughout life, preserve normal body weight, do not use tobacco, and seek health care regularly. In reality, however, the actions are much more complex. Behavioral change is difficult, individual choices are influenced and often constrained by broader social and environmental factors, and many people do not have the resources or access to seek appropriate healthcare, education and community-based programs at schools or workplaces.

28

At the level of health management organizations such as the ministries of health or the World Health Organization, awareness and actions in the following areas of providing health care at country and community levels are recommended [64]: (i) Addressing the magnitude of the problem of CVD and diabetes mellitus: The health management organizations need to fully understand the determinants of the growing problems of CVD and diabetes mellitus in the country/community, the proximate risk factors (genomic, biological [hypertension, dyslipidemia] and behavioral [diet, salt intake, physical activity, tobacco]) and the upstream factors such as demographic change, economic development, social variation, education, cultural norms, urbanization trends and globalization [65]. (ii) Active collaboration of health organization in their efforts to improve diets in minimizing the incidence of CVD and diabetes mellitus: The WHO and the World Heart Federation along with governments from developing and developed nations might need to coordinate for cultivating highly effective strategies to improve the regular diet through reduction of dietary intake of salt, sugar and saturated fats [66]. (iii) Accelerating the rates of determination of the burden of CVD and diabetes mellitus in different localities in low- and middle-income countries (LMIC), taking into consideration the change in demographics (population growth and aging) and the prevalence of risk factors (high blood pressure, diabetes mellitus, smoking, obesity, lack of exercise, unhealthy diet and alcohol) is an important measure to reduce the prevalence of CVD and diabetes mellitus [65]. (iv) Availability of essential medicines for CVD and diabetes mellitus: Improve selection of essential medicines and create incentives in public and private sectors to make low-price, quality assured medicines availability. A meta-analysis of surveys from 36 countries for access to 5 29

drugs used to treat CVD (atenolol, captopril, losartan, nifedipine and hydrochlorothiazide) found that these medicines were available in only around 26% of public health facilities and around 57% of private health care facilities [67]. (v) Affordability of essential medicines for CVD and diabetes mellitus: Reduce or abolish taxes on essential medicines, control markups, improve insurance programs to include a basic package of affordable medicines, provide incentives to manufacture quality generic formulations of essential medicines. (vi) Accessibility to essential medicines for CVD and diabetes mellitus: Improve the accessibility by increasing operational hours of clinics, providing free or subsidized clinics, and streamlining clinic procedures to reduce waiting times and improve patient satisfaction. In some countries, long travel times may be required for patients to reach a health facility. (vii) Acceptability of essential medicines for CVD and diabetes mellitus: Improve the acceptability possibly by making available fixed-dose combinations (FDCs, e.g., Polypill), and reporting outcomes of large population-based outcome studies to demonstrate efficacy, safety and acceptability of the FDCs. Inadequate prescription and poor adherence to medication have a marked impact on CVD globally. (viii) Allocation of resources: Governments in LMIC, local communities and NGO donors need to balance many competing priorities when allocating resources. These countries have to recognize and respect the realities of multiple competing priorities in their allocation of resources so that other health priorities (such as AIDS, malaria, tuberculosis) would not be adversely affected as a result of greater attention to CVD.

30

(ix) Advocacy, advertising and education efforts: International advocacy efforts to raise awareness of the growing epidemic of CVD and diabetes mellitus in LMIC have increased in intensity over the past decades. However, these efforts have not yet resulted in established and successful programs to reduce the prevalence of these diseases. There need to be more effective communication of the steps that should be taken for the long term. Strategies using mass media, media advocacy, social marketing, and social mobilization can serve to mobilize support among various other stakeholders in the global health arena. (x) Approach to shared-risk-factor reduction, health promotion, quality health care, and health systems strengthening in an integrated manner is critical. Within this approach there is a need for disease-specific approaches in some areas (such as training the health workforce to effectively implement secondary prevention and treatment), and for investment in scalable CVD-specific diagnostic tools and interventions such as medications for hypertension or dyslipidemia. (xi) Adopting and maintaining suitable environment that leads to lifelong heart-healthy lifestyles, from childhood to adult and old age.

6. Concluding remarks CVDs and diabetes mellitus are the two leading NCDs. They account for most NCD deaths worldwide. The most common types of CVDs are hypertension, CHD, peripheral artery disease, stroke, heart failure, rheumatic heart disease, VHD and congenital heart disease. The development and prevalence of CVDs and their clinical impact and attributable risk are strongly influenced by modifiable and non-modifiable risk factors. Unhealthy diet and insufficient physical activity, the two major current changes in the behavioral pattern of societies worldwide, are common risk factors for both CVDs and diabetes mellitus. Individuals with diabetes mellitus 31

are at increased risk of CVDs; these individuals often have comorbid factors like hyperlipidemia, atherosclerosis, obesity and sedentary life style, which could further contribute to their risk for developing CVDs. There is a need for a detailed, up-to-date understanding of progress of these diseases, reporting programs and control strategies to be available at all levels: global, national and local. Awareness of the prevalence of CVDs and diabetes mellitus among countries and donor organizations worldwide strengthens their efforts in identifying gaps in admittance to appropriate health care and health education, and implementing adequate measures to lessen the burden of CVDs and diabetes mellitus. Furthermore, a global partnership of nationwide public health campaigns should be organized to create awareness among the public with information pertaining to the primary prevention and management of CVDs and diabetes mellitus.

32

Conflict of Interest No conflict of interest exists.

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