Clinical Feature: South Asian Ethnicity - An Underappreciated Cardiovascular Risk

South Asians are defined as individuals who derive their ethnic origin from the Indian subcontinent. Nearly 3.4 million South Asians currently reside in the United States experiencing a growth of 81% from 2000 to 2010.¹ Interestingly, while South Asians account for only 25% of the world’s population, they account for a disproportionate 60% of the world’s cardiovascular disease burden.² Amongst South Asians who live in the western world, rates of coronary heart disease are greater than 10% of the population with mortality rates in the United States nearly two times that of any other major ethnic group.^3,4 Traditional risk factors, as defined by ATP III Framingham based risk calculators, often fall short of identifying South Asians for their more aggressive, earlier onset, and often more fatal forms of heart disease. While the specific etiologies that define South Asian cardiovascular risk is a subject of continuous investigation, current data suggests that a unique combination of lipid and metabolic abnormalities contribute to this disease burden.

Beyond Traditional Lipid Measurements
The South Asian lipid profile is characterized by elevated LDL and triglycerides with depressed HDL (SHARE Study) when comparing South Asian lipid profiles to those of Caucasians and Chinese living in Canada. In the SABRE Study comparing South Asians to Europeans this is also observed (see table).^3,5 This profile often fails to raise red flags in most Framingham based cardiovascular risk calculators that emphasize total cholesterol and HDL. The landmark INTERHEART Study looked at 15,152 first time acute myocardial infarction cases across 52 countries compared to a nearly equal number of age matched non-myocardial infarction controls. Of the acute myocardial infarction cases studied, 1,732 cases were of South Asian descent across 5 countries. One key finding was that both the prevalence and value of ApoB100/ ApoA-1 ratio was statistically greater in South Asian cases compared to other ethnicities.⁶ Furthermore, the ApoB100/ ApoA-1 ratio was found to be a much stronger indicator of cardiovascular disease risk than traditional LDL, HDL, and LDL/ HDL ratios.^2,6-10

Small lipid particle size creates a more atherogenic LDL particle that is prone to oxidation and a HDL particle that is rendered less protective. KR Kulkarni et al found a two times greater frequency of small, dense LDL particles among Asian Indian men compared to Caucasian men. NC Bhalodkar et al found that Asian Indian men had significantly higher levels of small HDL particles when compared to predominantly Caucasian men in the Framingham Offspring Study group.^11,12 The National Asian Indian Heart Disease Project found individuals of Asian Indian descent had significantly lower levels of HDL2b, implying an impaired reverse cholesterol transport system may also contribute to the atherosclerotic disease risk in this population.¹³

Lipoprotein (a) [Lp(a)]
Lipoprotein (a) has long been associated with elevated cardiovascular risk independent of LDL-C, non-HDL-C, and the presence of other cardiovascular risk factors.¹⁴ High Lp(a) levels (greater than 40 mg/dl) in the setting of total cholesterol/HDL ratios greater than 5.8 increase the odds of premature coronary artery disease by a factor of 2.95.¹⁵ Since South Asians are often characterized by low HDL levels compared to total cholesterol values and are known to have markedly elevated Lp(a) (greater than 30 mg/dl) levels compared to their Caucasian counterparts, it is reasonable to presume that excess Lp(a) levels might play a role in the severe and high premature rates of coronary artery disease amongst this ethnic population.^3,16 Evidence suggests that once coronary disease has been intervened upon with either coronary artery bypass surgery or coronary angioplasty in South Asians who possess Lp(a) levels between 20 and 30 mg/dl, there is a two to threefold increase in acute myocardial infarctions and restenosis.^2,17-19 Lp(a) is being considered as a screening tool to identify those South Asians at most risk for premature heart disease.

Metabolic Syndrome
Patients with metabolic syndrome have a 50-60% greater risk of cardiovascular disease and a two to threefold greater risk of cardiovascular mortality.^2,20,21 The relationship between insulin resistance and obesity, cornerstones of the metabolic syndrome definition, seems to be somewhat different amongst South Asians. The “thin-fat phenotype”, a body structure consistent with high visceral fat to low lean muscle ratios, is often found in the South Asian body habitus.^22,23 As a result of this, South Asians have demonstrated evidence of diabetes and insulin resistance at BMI values as low as 23 kg/m2.24 For this reason, many have favored the use of waist circumference or waistto-hip ratio as a more precise measure of South Asian obesity and therefore as a practical measurement to screen for metabolic syndrome. INTERHEART found South Asian men and women with acute myocardial infarctions often had significantly higher waist-to-hip ratios (42.7% and 52.4% respectively) compared to control subjects (27.9% and 39.9% respectively).⁶ McKeigue et al found Asian Indians in the United Kingdom to have higher waist-to-hip ratios compared to their European counterparts despite comparable BMIs. Furthermore, this same group of South Asians were found to have a fourfold increase in diabetes and a twofold increase in post-glucose insulin levels for every 0.04 unit rise in waist-tohip ratio.^25,26 Such characteristics have led to nearly a third of South Asians studied in trials within the United States and Canada to be diagnosed as diabetic.^3,22,27 These factors are overlooked by lay and medical professionals within and outside the South Asian community because vegetarianism, which is thought to be heart healthy, is a common hallmark of the South Asian community’s diet. The INTERHEART study demonstrated only 20% of South Asian acute myocardial infarction cases and 26.5% of South Asian controls consumed more than one serving of fresh fruits and vegetables daily.⁶ This illustrates a major nutritional misconception of South Asians whose diet is actually dominated by prolonged cooking of vegetables^6,28 as well as a high consumption of cooked carbohydrates and fats.

Homocysteine
Treatment of hyperhomocysteinemia (>15 μM) in the setting of coronary artery disease for the purposes of primary and secondary prevention has failed to show significant benefit.^2,29 These studies however, failed to include South Asians and a number of other ethnic groups. Boushey et al reported that for every 1 μM increase in homocysteine in the setting of hyperhomocysteinemia there exists a 12% and 16% greater coronary artery disease risk among men and women respectfully.^2,30 Furthermore, evidence exists that among South Asians in the United Kingdom, elevated homocysteine levels contributed to twice as many cardiovascular deaths compared to their European counterparts. Studies also concluded that this elevated homocysteine level was largely due to vitamin B12 and folate deficiency suggesting a possible reversible mechanism to curb the cardiovascular disease incidence in this high risk community.^2,31 Further study regarding benefit of therapy in this population is required.

Adipokines
There is strong evidence linking inflammation to cardiovascular disease and this has often been thought to be another component of the South Asian cardiovascular risk profile. The SHARE study demonstrated that South Asians possessed elevated (age- and sex-adjusted) hs-CRP levels compared to those of Chinese and European descent.³ Raji et al demonstrated that Asian Indians were found to have depressed levels of adiponectins, which were associated with endothelial dysfunction, diminished fibrinolysis capacity, and increased insulin resistance.^22,32 When looking at the inverse relationship of leptin and insulin sensitivity amongst non-diabetic South Asians, significantly higher levels of leptin with lower insulin sensitivity were noted compared to Caucasian and Chinese participants. Ethnicity was the only statistically significant variable associated.^22,33 Elevated inflammatory markers mechanistically may be important with regards to the South Asian cardiovascular epidemic. The study of novel biomarkers may assist in the early identification of cardiac risk in South Asians.

Conclusion
South Asians are a major ethnic community within the United States. They face a higher risk of acute myocardial infarction and prevalence of coronary artery disease at a much younger age. This community demonstrates a more atherogenic lipid profile, a body habitus with higher visceral fat content rendering them more prone to insulin resistance, and a unique level of inflammatory markers that make them more susceptible to thrombosis and coronary plaque buildup. More than one out of ten South Asians are affected by heart disease with a mortality rate that is twice the general population. This community can ill afford the effects of false negative screening measures provided by traditional cardiovascular risk stratification tools.^2,22 European based guidelines such as the United Kingdom’s NICE lipid modification measures explicitly state that South Asians are more likely to develop cardiovascular disease at a younger age and estimates of cardiovascular risk by Framingham based calculators should be increased by a factor of 1.4.³⁴ Unfortunately, NHLBI pooled cohort risk estimators do not take South Asian ancestry into account. Health care providers need to become much more aware of risk in this minority group. Earlier and more aggressive use of non-medication and medication interventions should be considered. Advanced lipid testing might be more valid and clinically useful for predicting risk in the South Asian community. Clearly, research investigating both novel testing and treatment in this high risk community is both necessary and lacking. Public education measures should be adopted that inform South Asians of their risk and advise on lifestyle changes, dietary habits, and the utility of preventive care services in a culturally competent manner. Finally, an understanding within the ranks of South Asian community organizations must be attained so appropriate public health campaigns can be initiated and validated as truthful by trusted community leaders. In the end, it is a multidisciplinary approach of public health, education, clinical prevention, and investigation that will curb this cardiovascular epidemic that deeply affects this significant community in the United States and abroad.

Disclosure statement: Dr. Sitafalwalla and Dr. Norris have no disclosures to report. References are listed on page 27.