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Coronary Artery Disease in South Asians

Coronary Artery Disease in South Asians

Disclosures: No relevant disclosures Address for Correspondence: Mintu P. Turakhia, M.D. M.A.S Palo Alto VA Health Care System Stanford University 3801 Miranda Ave – 111C Palo Alto CA 94304 Tel (650) 858-3932 Fax (866) 756-3025 E-mail: Sources of Funding: Dr. Turakhia was supported by a Veterans Health Services Research & Development Career Development Award (CDA09027-1) and an American Heart Association National Scientist Development Grant (09SDG2250647). Abstract Coronary heart disease is a leading cause of death worldwide, and has been shown to have a high prevalence among South Asians living on and off the Indian subcontinent. This has largely been attributed to both an increased prevalence of traditional risk factors as well as higher levels of novel markers and biomarkers of risk. Compared to Caucasians and most other racial groups, South Asians with coronary heart disease and myocardial infarction tend to present earlier, largely explained by a greater prevalence of risk factors at a younger age. Genetic factors, lifestyle, and urbanization have all been implicated as the reasons for this increased risk and high prevalence of heart disease. New programs aimed at screening younger South Asians have been successful at identifying risk factors for treatment and lifestyle modification. Practitioners should be aware of the increased cardiovascular risk in South Asians, screen for risk factors starting at a younger age, and recommend aggressive medical and lifestyle risk factor modification. Introduction Coronary heart disease(CHD) is a leading cause of death worldwide.1 When compared to other ethnicities, South Asians have a high prevalence of coronary artery disease and associated risk factors.1-3  South Asians are individuals originally from the countries comprising the Indian subcontinent including India, Pakistan, Nepal, Bangladesh and Sri Lanka. The World Health Organization (WHO) reports that CHD will be the largest cause of death and disability by 2020. South Asians make up 25% of the global population, but over 50% of the world’s cardiovascular deaths will be in persons of South Asians origin.1, 2 South Asians have a three to five fold increased risk of myocardial infarction.4 South Asians also present with more severe disease and at an earlier age than Caucasians.5 Because the South Asian population is growing rapidly not only in India, but also abroad, it is important to address and appropriately manage this increased cardiovascular risk.6 Prevalence of coronary disease in South Asians The prevalence of coronary artery disease (CAD) is high among native South Asians as well as migrant South Asians. Prevalence estimates over the last thirty years range from 7.6 to 11% (Table 1).1, 4, 7-10 The Chennai Urban Population Study, which studied subjects in two residential areas in southern India, found an overall CAD prevalence of 11.0%.11 A study of over 2000 subjects in Jaipur, India found an overall prevalence of 7.59% based on standardized questionnaire and electrocardiogram changes.12 A study in Delhi, India of over 13,000 subjects cited a prevalence of 9.7%.13 Similar rates have been reported in studies off the Indian subcontinent as well. The Canadian Study of Health assessment and Risk in Ethnic Groups (SHARE) that South Asians had a CAD prevalence of 10.7%, significantly greater than the prevalence of CAD in the European (4.6%) and Chinese populations (1.7%).14 Mortality attributable to coronary heart disease CHD mortality in South Asians is 40-60% higher compared to the population averages.15 One of the earliest reports of high coronary heart disease rates among South Asians was from Singapore in a study of 9,568 autopsies in the 1950s, which reported a seven-fold higher incidence of coronary heart disease among South Asians in comparison to the Chinese population.16 The 1994 WHO report stated that cardiovascular mortality in individuals less than 70 years of age was 52.2% in India compared to 26.5% in developed countries.17Similar results were found in an analysis of cause-specific death rates among Canadians of European, South Asian, and Chinese origin which showed that those of South Asian and European origin had significantly higher death rates from ischemic heart disease when compared to those of Chinese origin.18 This was confirmed by a study in the UK which reported higher mortality ratios from ischemic heart disease among South Asians compared to European controls.19 The Study of Health Assessment and Risk in Ethnic groups trial (SHARE) based in Canada compared individuals of South Asian, Chinese and European origin, and found subclinical atherosclerosis to be more prevalent among South Asians than the Chinese and European populations. South Asian origin was also an independent predictor of cardiovascular mortality.14  This has also been validated in the United States South Asian population. An analysis of the California Mortality Database between 1990 and 2000 found that both South Asian men and women had higher proportional mortality ratios when compared to six other ethnicities.20Furthermore, South Asians present with myocardial infarction and coronary disease up to 10 years earlier than Caucasians and other racial groups further contributing to increased prevalence in this group.3, 21, 22 There are two leading explanations for the high disease burden in South Asians. The first is that South Asians have a high prevalence of traditional risk factors, which leads to developing coronary disease at a young age. The second is that South Asians have novel risk factors, usually biomarker based, that account for the variation in risk independent of traditional risk factors. Traditional Risk factors While it is well established that South Asians have a higher burden of cardiovascular mortality, studies attribute this increased prevalence to an increased prevalence of cardiovascular risk factors including age, hypertension, hyperlipidemia, diabetes and smoking, based on the Framingham population. However, the Framingham risk score, when applied to South Asians, results in underestimation of cardiovascular risk among South Asians because of the statistical bias towards age when calculating the Framingham score. South Asians present with coronary artery disease at a younger age than their ethnic counterparts, largely explained by increased prevalence of risk factors at a young age.21 In Western populations, it has been found that CAD occurs up to 10 years earlier in South Asians when compared to the general population.3, 21-23 Acute myocardial infarction (AMI) has also been reported at a younger age in South Asian emigrants vs. South Asian natives largely explained by the increased prevalence of risk factors at an earlier age among South Asians.9, 22, 24 25 Absence of risk factors during adolescence, and rapid development of risk factors during ages 30-39 suggesting a need for active screening of South Asians early to prevent disease.26 Another study by Ismail et al found similar results, attributing the increased prevalence of myocardial infarction at a younger age in South Asians to an increased prevalence of cardiovascular risk factors including tobacco use, ghee intake, elevated fasting glucose, high cholesterol, paternal history of cardiovascular disease, low income and low level of education.22 The INTERHEART case control study analyzed risk factors for acute myocardial infarction (AMI) in 52 countries across various ethnicities including South Asians. Compared to controls, in patients with AMI across all regions, 90% of the attributable risk of MI was from nine risk factors including:  smoking, increased apolipoprotein B/apolipoprotein A-I ratio, hypertension, diabetes mellitus, abdominal obesity, and psychosocial stress. The study concluded that >90% of the global risk of cardiovascular disease is preventable by appropriately managing these nine risk factors.9 Furthermore because these risk factors were more prevalent at an earlier age this can partially explain the increased prevalence of AMI in a younger age among South Asians. Diabetes and Metabolic Syndrome Diabetes mellitus has a high prevalence among South Asians and is a predictor of cardiovascular mortality.27, 28 A study of urban South Indians found that diabetic subjects had twofold higher mortality rates when compared to those without diabetes.29 The SHARE study found glucose intolerance or diabetes in one-third of the South Asian population studied, markedly higher than other ethnicities.14 A study in Atlanta, Georgia found that type II diabetes was prevalent in 18.3% of South Asian immigrants which was significantly greater than the local Caucasian, African American and Hispanic populations.30 South Asians in the UK are three to five-fold more likely to have diabetes than their ethnic counterparts.31 Furthermore South Asian diabetics are thought to have a two to four-fold greater mortality than European diabetics.32, 33 Metabolic syndrome has been recognized as a set of risk factors for CAD including dyslipidemia, low HDL, hypertension, glucose intolerance, and abdominal obesity.34, 35 Metabolic syndrome has been associated with a twofold greater risk of CAD and a five-fold greater risk of developing diabetes.36 South Asians have a strikingly high prevalence of metabolic syndrome and glucose intolerance both on the Indian subcontinent and off the subcontinent.25, 28, 37, 38 In India the prevalence of metabolic syndrome was 41.1% in a study of 475 individuals aged 20-75 years of age.39 A study in the UK showed that metabolic syndrome among British South Asians was 39%, significantly greater than the 20% prevalence noted in British Caucasians.40 A study of South Asians living in California found a 27% prevalence of metabolic syndrome.28 The high prevalence of metabolic syndrome among South Asians can be explained by the “adipose tissue overflow hypothesis” which suggests that subcutaneous adipose tissue is less developed in South Asians causing earlier utilization of visceral adipose tissue resulting in an increased atherogenic profile at similar BMIs when compared to Caucasians.9, 41, 42 Dyslipidemia An abnormal lipid profile is a strong predictor of cardiovascular disease. Increased total cholesterol, increased LDL levels, increased triglycerides, and low levels of HDL increase cardiovascular risk. 17, 43 Total cholesterol levels correlate with increased risk of cardiovascular events. Serum cholesterol levels are relatively high in the economically privileged in India, and are higher in South Asian migrants when compared to Caucasian controls.15, 44 In the SHARE study, total cholesterol levels were found to be significantly higher in South Asians, when compared to the Chinese and European controls.14 High LDL is a risk factor for cardiovascular disease, however LDL levels in South Asians are comparable to other populations.4, 45 The SHARE study found slightly increased LDL levels in South Asians when compared to Europeans and Chinese. Small dense LDL particles are also an important risk factor for atherogenesis.46-48 Elevated levels of small, dense LDL are associated with a two to threefold higher risk of cardiovascular disease and atherogenesis.48Among South Asians, the prevalence of small dense LDL particles ranges from 35-45%.44, 46, 49 While Kulkarni et al found elevated levels of small, dense LDL particles in South Asians when compared to their ethnic counterparts, another study found no statistically significant difference.44, 46 This data must be validated with further studies given conflicting studies. Patients with high triglyceride levels also may be at increased risk for cardiovascular disease. High triglycerides promote elevated levels of small, dense LDL, which are atherogenic.50 Patel et al reported that elevated triglycerides are associated with a more atherogenic lipid profile, with higher cholesterol levels, lower HDL levels, and smaller and denser LDL particles.51 South Asians have higher triglyceride levels when compared to other ethnicities.43, 44, 52-55  In Fiji, South Asians had 30% higher triglyceride levels in comparison to the native population.56 HDL is a lipid subparticle thought to participate in reverse cholesterol transport. Low levels of HDL have been defined as a cardiovascular risk factor.14, 45 South Asians have lower HDL when compared to their ethnic counterparts potentially explaining increased atherogenesis in this population.3, 4, 14, 27, 57, 58 Anand et alfound significantly lower levels of HDL in South Asians when compared to the European  and Chinese populations.14 High levels of small, less protective HDL have also been seen among South Asians, and is cited as a possible explanation for increased cardiovascular risk seen among South Asians.4, 44 Smoking Smoking is widely prevalent among South Asians, especially on the Indian subcontinent. More than one-third of South Asian native men, a few percent of women use tobacco, and there are estimated to be 120 million smokers in India.59 A recent national study found a strikingly high prevalence of smoking and attributed smoking to be the cause of death in 5% of women and 20% of men in India.60 A study by Pais et al found cigarette smoking to be the strongest predictor of first acute myocardial infarction on the Indian subcontinent.61 However, the prevalence of CAD remains high in South Asian migrants despite decreased prevalence of smoking when compared to their ethnic counterparts, suggesting the need to study other risk factors.1, 3, 17 Emerging Risk Factors In addition to traditional risk factors, over the last two decades several biomarkers thought to predict cardiovascular risk and myocardial infarction have been identified. These biomarkers include lipoprotein(a), apolipoprotein B100, and CRP levels. These biomarkers have been primarily studied among Caucasians, however there are have been some reports of increased prevalence of these novel risk factors in the South Asian population. Lipoprotein(a) has identified as an independent risk factor for early development of coronary artery disease independent of diet.2, 4, 62-65It has also been cited as a predictor of development of premature coronary artery disease.62 South Asians off the Indian subcontinent have been found to higher levels of lipoprotein(a) when compared to their ethnic counterparts.58, 66, 67 South Asian migrants have higher lipoprotein(a) levels than South Asian natives.58 Apolipoprotein-B100 to apolipoprotein-AI ratio can predict atherogenesis, and is more prevalent in South Asians vs. other ethnicities.68, 69 In the INTERHEART study, Joshi et al found that the prevalence of elevated apolipoprotein-B100 to apolipoprotein –AI ratio to be higher among South Asians with MI when compared to subjects from other countries (61.5% vs. 48.3%).21 Elevated CRP has been shown to be a marker of atherogenesis and vascular inflammation, as well as a predictor of plaque rupture and cardiovascular risk.2, 70, 71 CRP levels are higher in South Asians vs. Caucasian patients suggesting a pro-inflammatory state. A study in the UK of over 1,000 healthy adults found increased levels of CRP among South Asians vs. European whites; furthermore, the study suggested that increased levels of CRP were also associated with traditional cardiovascular risk factors.72  This was validated by a study in Canada which found CRP levels to be significantly elevated in South Asians vs. Chinese and European populations in a study of 1250 subjects in Canada.14 Lifestyle factors Urbanization and lifestyle factors may contribute to increased incidence of CAD and risk factors. It was observed as early as 1962 that there is an increased prevalence of disease and risk factors in urban India when compared to rural India.8-10, 73, 74 This suggests that urbanization may contribute to increased cardiovascular risk as evidenced by the increased prevalence of disease and cardiovascular risk factors in urban vs. rural India including increased BMI, low HDL, high triglycerides, diabetes, hypertension and lifestyle factors including exercise and calorie intake.7, 13, 75, 76 Studies showed lower rates of diabetes mellitus among rural South Asians vs. urban South Indians as well.30, 77 In a review of studies reporting serum cholesterol levels,  high average serum cholesterol values were more prevalent in urban South Asians of a high socioeconomic strata vs. a low socioeconomic strata and in South Asians overseas vs. South Asians on the Indian subcontinent.15 Hypertension however, was reported as having a consistently high prevalence between urban and rural South Asian patients.78 Generally, however this increased prevalence of cardiovascular risk factors in urban South Asians holds true in South Asian migrants as well. Furthermore South Asians tend to be more physically inactive than their ethnic counterparts. Physical inactivity is another risk factor highly prevalent among South Asians.9  In a study based in Delhi of 276 newly diagnosed CHD patients, sedentary lifestyle was characteristic of 97% of the cohort.79 In a study based in the UK, South Asian patients were more likely to be sedentary vs. white patients (47.0% vs. 28.1%), and this physical inactivity explained >20% of excess coronary heart disease mortality among South Asians after adjustment for confounders.80 Advances to address public health burden Risk scores to estimate short and long-term risk of heart disease or cardiovascular events have been derived to estimate risk at point of clinical care. The Framingham Risk Score is the most commonly used of these.81The risk score is a weighted sum of age, gender, total cholesterol, HDL cholesterol, smoking status and systolic blood pressure and can estimate the 10-year risk of CHD. However, the Framingham score markedly underestimates cardiovascular risk in South Asians, primarily because of the statistical bias towards advanced age. Therefore, South Asian individuals below age 50 or 60 have a marked underestimation of CHD risk, even though they have a high prevalence of CHD risk factors at younger ages. Recognizing this risk, Bainey et alproposed an algorithm to actively screen for CAD among South Asians living off the Indian subcontinent by addressing the need for modification of the traditional Framingham risk factors, and by advocating that the Framingham score be multiplied by 1.4 to accurately assess cardiovascular risk.17 The South Asian Heart Center (SAHC), located in the Bay Area in California is an organization dedicated to addressing this strikingly high prevalence of cardiovascular disease South Asians face.  Through education, lifestyle changes, risk factor screening, and consistent follow up, SAHC aims to provide cardiovascular care catered to the Bay Area South Asian population. Awareness is the first step to addressing this epidemic, and more organizations like SAHC are needed to appropriately treat and prevent heart disease among South Asians.28 There is a high prevalence of cardiovascular disease and cardiovascular risk factors among South Asians. In order to prevent premature disease and decrease the prevalence of disease, both awareness and action is necessary.  Thus, to prevent CAD among South Asians, preventative measures such as education, dietary and lifestyle modification, screening for metabolic syndrome, cardiovascular risk factor reduction and regular follow up with care providers is paramount.17, 21, 82


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Table 1: Prevalence of Coronary Heart Disease in South Asians*

Author Year Location Prevalence
Padmavati S74 1962 Delhi, India 1.04%
Sarvotham SG83 1968 Chandigarh 6.60%
Chadha SL13 1990 Delhi, India 9.67%
Gupta R12 1995 Jaipur, India 7.59%
Mohan V29 2001 Chennai, India 11.00%
Gupta R84 2002 Jaipur, India 8.12%
Anand SS14 2000 Canada 10.7%

*Adapted from Gupta, et al24

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