South Asian Ancestry Linked to Increased Risk for Heart Disease

Will Pass

July 12, 2021

Individuals of South Asian ancestry face twice the risk of heart disease, compared with individuals of European descent, yet existing risk calculators fail to account for this disparity, according to the results of a new study.

These findings confirm previous reports and practice guidelines that identify South Asian ancestry as a risk enhancer for atherosclerotic cardiovascular disease (ASCVD), suggesting that earlier heart disease screening and prevention is warranted in this patient population, lead author Aniruddh P. Patel, MD, research fellow at the Center for Genomic Medicine, Massachusetts General Hospital, Boston, and colleagues said.

"Previous studies in multiple countries have estimated a 1.7- to 4-fold higher risk of ASCVD among South Asian individuals, compared with other ancestries, but have important potential limitations," Patel and colleagues wrote in the paper on their prospective cohort study, published in Circulation.

The INTERHEART case-control study, for example, which assessed risk factors for acute myocardial infarction among more than 15,000 cases from 52 countries, is now 2 decades old, and "may not reflect recent advances in cardiovascular disease prevention," the investigators wrote.

Most studies in the area have been small and retrospective, they added, and have not adequately assessed emerging risk factors, such as prediabetes, which appear to play a relatively greater role in the development of heart disease among South Asians.

Methods and Results

To address this knowledge gap, Patel and colleagues analyzed data from the UK Biobank prospective cohort study, including 449,349 middle-aged participants of European ancestry and 8,124 similarly aged participants of South Asian descent who did not have heart disease upon enrollment. Respective rates of incident ASCVD (i.e., MI, ischemic stroke, or coronary revascularization) were analyzed in the context of a variety of lifestyle, anthropometric, and clinical factors.

After a median follow-up of 11.1 years, individuals of South Asian descent had an incident ASCVD rate of 6.8%, compared with 4.4% for individuals of European descent, representing twice the relative risk (adjusted hazard ratio, 2.03; 95% CI, 1.86-2.22; P < .001). Even after accounting for all covariates, risk of ASCVD remained 45% higher for South Asian individuals (aHR, 1.45; 95% CI, 1.28-1.65; P < .001). This elevation in risk was not captured by existing risk calculators, including the American College of Cardiology/American Heart Association Pooled Cohort Equations, or the QRISK3 equations.

The findings were "largely consistent across a range of age, sex, and clinical subgroups," and "confirm and extend previous reports that hypertension, diabetes, and central adiposity are the leading associations in this observed disparity," the investigators wrote.

Two Diabetes Subtypes Are More Prevalent in South Asians

Hypertension, diabetes, and central adiposity do not fully explain South Asians' higher risk for ASCVD, wrote Namratha R. Kandula, MD, of Northwestern University Medical Center, Chicago, and Alka M. Kanaya, MD, of the University of California, San Francisco, in an accompanying editorial published in Circulation.

Some of the undetected risk may stem from unique diabetes disease factors, Kandula and Kanaya added.

"Newer data have demonstrated distinct subtypes of type 2 diabetes, with South Asians having a higher prevalence of both a severe insulin resistant with obesity subtype and a less recognized severe insulin deficient subtype," they wrote. "Importantly, both of these more prevalent diabetes subtypes in South Asians were associated with a higher incidence of coronary artery calcium, a marker of subclinical atherosclerosis and strong predictor of future ASCVD, compared to other diabetes subtypes."

Diabetes Rate Is Higher for South Asians in the US

Although the present study was conducted in the United Kingdom, the findings likely apply to individuals of South Asian ancestry living in the United States, according to principal author Amit V. Khera, MD, associate director of the precision medicine unit at the Center for Genomic Medicine, Massachusetts General Hospital.

"There are already more than 5 million individuals of South Asian ancestry in the U.S. and this represents one of the fastest-growing ethnic subgroups," Khera said in an interview. "As in our study of individuals in the U.K., South Asians in the U.S. suffer from diabetes at much higher rates – 23% versus 12% – and this often occurs even in the absence of obesity."

Khera noted that the 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease identify South Asian ancestry as a risk-enhancing factor, calling this a "stopgap measure." More work is needed, he said, in the research arena and in the clinic.

Zero South Asians Included in Studies Used to Develop Risk Estimator

"I think the first step is to simply acknowledge that the risk estimators we use in clinical practice have important limitations when it comes to diverse patient populations," Khera said in an interview. "We saw this in our study, where – despite a more than doubling of risk – the predicted risk based on the equations used in primary care showed no difference. This risk estimator was developed based on legacy cohort studies, in [which] zero South Asians were included. Despite important differences across race/ethnicity, the current state-of-the-art in the U.S. is to use one equation for Black individuals and another for all other ethnicities."

Experts Suggest Steps for Reducing Heart Disease Risk

While risk modeling remains suboptimal, Khera suggested that clinicians can take immediate steps to reduce the risk of heart disease among individuals with South Asian ancestry.

"Despite all of the uncertainty – we still don't have a complete understanding of why the risk is so high – there are still several things primary care doctors can do for their patients," Khera said.

Foremost, he recommended lifestyle and dietary counseling.

"Dietary counseling is particularly effective if put in the context of cultural norms," Khera said. "Many South Asians consider fruit juices or white rice to be healthy, when they lead to rapid spikes in blood sugar."

Khera also advised earlier heart disease screening, such as coronary calcium scanning "sometime between age 40-50 years," noting that positive test results may motivate patients to start or adhere to medications, such as cholesterol-lowering therapies. If necessary, clinicians can also refer to heart centers for South Asian patients, which are becoming increasingly common.

According to Cheryl A.M. Anderson, PhD, chair of the AHA's Council on Epidemiology and Prevention, and professor and dean of the Herbert Wertheim School of Public Health and Human Longevity Science at the University of California, San Diego, the current study suggests that heart disease management strategies for South Asian patients may be lacking.

"We have had a tradition of preventing or trying to treat heart disease in a fashion that doesn't yet account for the increased risk that might be prevalent in those of South Asian ancestry," Anderson said in an interview.

She suggested that improving associated risk-analysis tools could be beneficial, although the tools themselves, in the context of race or ethnicity, may present their own risks.

"We want to be mindful of potential adverse implications from having everything linked to one's ancestry, which I think this tool doesn't do," Anderson said, referring to the AHA/ACC Pooled Cohort Equations. "But in sort of the bigger picture of things, we always want to expand and refine our toolkit."

According to Rajesh Dash, MD, PhD, associate professor, cardiologist, and director of the South Asian Translational Heart Initiative (SSATHI) Prevention Clinic and CardioClick Telemedicine Clinic at Stanford (Calif.) HealthCare, the science supports more active risk mitigation strategies for South Asian patients, and the AHA and the ACC "are the two entities that need to lead the way."

"Certainly the American Heart Association and the American College of Cardiology should be taking a more active leadership role in this," Dash said in an interview.

In 2018, the AHA issued a scientific statement about the elevated risk of ASCVD among South Asian individuals, "but it did not rise to the level of specific recommendations, and did not necessarily go as far as to incorporate new screening parameters for that population," Dash said. He also noted that the most recent AHA/ACC guideline identifies South Asian ancestry as a risk-enhancing feature, a statement similarly lacking in actionable value.

"That does not definitively lead someone like a primary care physician to a decision to start a statin, or to be more aggressive with a diagnostic workup, like a stress test, for instance, for a patient who they otherwise would not have done one in had they not been South Asian," Dash said.

The steps taken by the AHA and the ACC are "a healthy step forward," he noted, "but not nearly the degree of attention or vigilance that is required, as well as the level of action that is required to change the narrative for the population."

At the SSATHI Prevention Clinic, Dash and colleagues aren't waiting for the narrative to change, and are already taking a more aggressive approach.

The clinic has an average patient age of 41 years, "easily 15 years younger than the average age in most cardiology clinics," Dash said, based on the fact that approximately two-thirds of heart attacks in South Asian individuals occur under the age of 55. "We have to look earlier."

The SSATHI Prevention Clinic screens for both traditional and emerging risk factors, and Dash suggested that primary care doctors should do the same.

"If you have a South Asian patient as a primary care physician, you should be aggressively looking for risk factors, traditional ones to start, like elevated cholesterol, hypertension, diabetes, or – and I would argue strongly – prediabetes or insulin resistance."

Dash also recommended looking into family history, and considering screening for inflammatory biomarkers, the latter of which are commonly elevated at an earlier age among South Asian individuals, and may have a relatively greater prognostic impact.

To encourage broader implementation of this kind of approach, Dash called for more large-scale studies. Ideally, these would be randomized clinical trials, but, realistically, real-world datasets may be the answer.

The study was supported by the National Heart, Lung, and Blood Institute; the Broad Institute at MIT and Harvard; the National Human Genome Research Institute; and others. The investigators disclosed relationships with IBM Research, Sanofi, Amgen, and others. Dash disclosed relationships with HealthPals and AstraZeneca. Anderson reported no relevant conflicts of interest.

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