By Ariaratnam Gobikrishna –

Ariaratnam Gobikrishna MD

It has been nearly sixteen years since the MASALA Study (Mediators of Atherosclerosis in South Asians Living in America) was launched. This longitudinal study began with a simple binary question: Are South Asians at higher risk? That question was quickly settled. It then moved to quantification—how much higher is that risk? From there, it turned inward: Why does this excess risk exist? Now, the study has entered its most consequential phase—the one that matters most to patients and clinicians alike: how to predict this risk accurately, detect it early, and intervene meaningfully.

Let’s jump to the question of why. There are multiple, still largely hypothesis-driven explanations for why South Asians appear to develop and die from cardiovascular disease earlier than many other ethnic groups. No single mechanism has been definitively proven, but several consistent biological patterns have emerged.

One long-standing idea is the “thrifty gene” hypothesis, which proposes that populations exposed to historical cycles of famine may have developed a metabolic tendency to efficiently store energy. In modern environments of caloric abundance, this may manifest as preferential deposition of fat in metabolically harmful locations—visceral fat around the liver and pancreas, intramuscular fat, and relatively less lean muscle mass. Clinically, this translates into a phenotype often described as central adiposity, or a “thin–fat” or “pot-belly” appearance, even at relatively low BMI. This phenotype, particularly in muscle and liver, disrupts insulin signaling at multiple levels. Fat deposition within already limited lean muscle leads to inefficient fatty acid oxidation, with accumulation of intermediates such as diacylglycerols and ceramides that disrupt insulin signaling and impair glucose uptake. In the liver, similar lipid overload blunts insulin’s ability to suppress glucose production, resulting in continued glucose output despite elevated insulin levels.

Alongside this body composition pattern, South Asians tend to have lower levels of adiponectin, the protective adipokine secreted by fat tissue that improves insulin sensitivity, reduces inflammation, and supports endothelial health. Reduced adiponectin may contribute to an earlier onset of insulin resistance. As a result, again prediabetes and type 2 diabetes tend to develop at lower BMI thresholds. This is not only due to insulin resistance but also to earlier and more pronounced beta-cell dysfunction (insulin secreting cells in pancreas), limiting the pancreas’s ability to compensate for rising glucose levels. The consequence is often earlier-onset diabetes with more persistent hyperglycemia.

Inflammatory signaling also appears to be upregulated, with higher levels of systemic inflammation contributing to a chronic pro-atherogenic state. This arises from the overflow of fat storage from subcutaneous depots into ectopic sites, leading to adipocyte dysfunction. These stressed and inflamed fat cells release pro-inflammatory cytokines such as leptin, tumor necrosis factor-alpha and interleukin-6, which in turn drive hepatic production of C-reactive protein (CRP).

In addition, South Asians exhibit a characteristic pattern of dyslipidemia often referred to as Atherogenic Dyslipidemia. Finally, a higher proportion of individuals in South Asian populations carry elevated levels of lipoprotein(a), a genetically influenced bad cholesterol strongly associated with atherosclerotic cardiovascular disease.

Before we go further, we must confront the LDL (bad cholesterol) question—central to the very fabric of Atherogenic Dyslipidemia.

In many South Asian patients, the typical pattern is not isolated LDL elevation, but a triad of relatively “normal” LDL cholesterol, elevated triglycerides, and low HDL cholesterol.

In states of insulin resistance and relative insulin deficiency, fat tissue begins to break down more than usual, releasing free fatty acids into the bloodstream. These fatty acids are taken up by the liver and converted back into triglycerides, leading to increased production and release of VLDL particles—the main carriers of triglycerides in the blood.

Once in circulation, this excess VLDL is not only converted into IDL and LDL but also takes part in lipid exchange through Cholesteryl Ester Transfer Protein (CETP), a process that may be up to 30% more active in South Asian populations (This observation, described in 2015, helped explain the long-standing riddle of South Asian atherogenic dyslipidemia). During this exchange, VLDL gives away triglycerides and takes cholesterol from LDL and HDL, leaving both of them enriched with triglycerides. These triglyceride-rich LDL and HDL particles now become targets for lipases, resulting in smaller, denser LDL particles and smaller HDL particles. These smaller, dysfunctional HDL particles are not only taken up more rapidly by the liver but are also small enough to be excreted by the kidneys, contributing to lower HDL levels. This also explains why LDL cholesterol (LDL-C) may appear normal or even low. Each LDL particle now carries less cholesterol, but the number of particles has increased —and it is this particle number, rather than the cholesterol content per particle, that drives atherogenesis.

As you may recall, one of the key roles of HDL (good cholesterol)is reverse cholesterol transport—the removal of cholesterol from tissues, including the walls of arteries. When HDL levels are low and its function is weakened, this protective process is reduced, adding to the overall risk of plaque buildup.

What about triglycerides? It is not the triglycerides themselves that are the problem—it is the particles that carry them. More specifically, not all triglyceride-rich particles are atherogenic. Large particles like chylomicrons and very large VLDL are simply too big to penetrate the arterial wall. The real concern lies with their smaller, cholesterol-enriched remnants—chylomicron remnants, VLDL remnants, and IDL. These particles are small enough to enter the arterial intima and contribute to plaque formation.

However, there is another crucial concept in atherogenesis: residence time. Chylomicron remnants remain in circulation for only minutes; VLDL remnants and IDL persist for several hours; whereas LDL particles remain for days—particularly the smaller LDL particles, which persist even longer. As a result, at any given moment, the majority—sometimes more than 90%—of circulating atherogenic particles are LDL, many of which are small and dense in South Asians, making them more numerous and more prone to arterial penetration, oxidation, and retention. Compounding this further, South Asians also have a higher burden of remnant lipoproteins— VLDL remnants, and IDL—adding an additional layer of atherogenic risk.

Now that we have belabored the “why”—particularly the LDL question, which sits at the center of this story—it is worth pausing on a striking paradox. In a population with one of the highest risks of premature coronary disease, uncertainty and debate around LDL still persist, particularly among physicians of South Asian descent. Unfortunately, some of these voices have become highly visible and influential within the South Asian community through social media, where they often spew misinformation under the rubric of a “pharmaceutical conspiracy,” easily swaying many against statin use and the concept of reducing saturated fat intake.

With that in mind, the next question is: If this disease begins early and progresses rapidly toward premature events, isn’t early detection paramount? Investigators from the MASALA study have even suggested that South Asians be screened for atherosclerosis as early as age 18—irrespective of diabetes status or BMI. Yet how we do this remains the million-dollar question. Despite significant advances in understanding the “why,” we still lack consensus-driven, practically actionable strategies for early detection.

What we do have, instead, are surrogate measures. These include routine blood tests for glucose and lipids—along with a one-time measurement of lipoprotein(a), even though targeted therapies for Lipo(a)are still in progress. Anthropometric thresholds have been lowered, with reduced BMI and waist circumference cutoffs aimed at capturing the so-called “thin–fat” phenotype. Coronary artery calcium (CAC) screening has been pushed earlier, from age 40 to 35 in higher-risk individuals. There is also a growing shift toward using Apolipoprotein B levels rather than traditional LDL cholesterol, in an effort to reconcile the disconnect between LDL concentration and particle number.

On the intervention front, lifestyle modification has taken center stage. A culturally adapted “South Asian Mediterranean diet” has been proposed—one that replaces refined starches with whole foods and substitutes saturated fats such as coconut oil, palm oil, and ghee with mono- and polyunsaturated fats.  Overcooking, deep frying, and the repeated reuse of cooking oils have been discouraged. So are processed carbohydrates and sugars, along with the incorporation of regular physical activity, particularly resistance training. For those deemed to be at high risk, earlier initiation of statin therapy and CAC/CCTA (Coronary Computed Tomography Angiography)-guided risk stratification are recommended.

In the meantime, the MASALA Study is expanding to include a second generation, now in their 30s, who are already being followed. What has emerged from this work, however, is sobering. Even in the absence of a singular breakthrough or “magic bullet,” the investigators have made some inroads; they have identified our vulnerabilities and liabilities, and we now know that lifestyle will make a significant difference—and that change must begin very early, the earlier the better. Yet, as they turn to the next generation, they are confronted with a cruel irony: what they had hoped to secure for future generations now appears not merely stalled, but reversed.

In many ways, this younger, next-generation cohort seems to have inherited the worst of both worlds: retaining the calorie-dense, starch-heavy, oil-laden dietary patterns of traditional South Asian culture, while simultaneously adopting the excesses of the modern West—processed red meats, larger portion sizes, sedentary living, and, increasingly, e-cigarette use. They have effectively added obesity into the mix, while acquiring dyslipidemia at an early age.

But here lies another problem: the very study tracking these changes is not designed to establish causality. The MASALA study is not a randomized controlled trial but a longitudinal observational study. So far, it has shown that individuals who adhere more closely to a South Asian–adapted Mediterranean diet tend to have lower rates of diabetes. However, there are currently no published data on hard cardiovascular endpoints—such as myocardial infarction or stroke—linked to any specific lifestyle pattern, early detection strategy, or statin use within this cohort. Even if such data emerge, they will likely demonstrate association rather than causation.

What we need, therefore, are large-scale randomized controlled trials to substantiate recommendations that currently rest on smaller studies and observational data. After more than 16 years, we are left with a problem: on the one hand, an inspiring body of scientific data explains why we, as a group, are more prone to this scourge; on the other, we still lack concrete interventions validated by rigorous scientific standards.

Compounding this is an emerging and somewhat paradoxical problem: the next generation appears to be intensifying the very risk factors at the center of the storm, making an already complex challenge even harder to tackle.