Risk Factors for Acute Coronary Syndrome in Indians: A Reappraisal

Cardiovascular disease (CVD) is the leading cause of mortality in India, and its prevalence continues to rise unabatedly.^{1, 2} The rising prevalence of CVD in India necessitates urgent and effective steps to halt this epidemic. At the population level, it is required to educate people about the menace of CVD, emphasize upon them the need and the benefits of prevention, and teach them the ways to prevent CVD. At the individual level, strategies are needed to identify those at risk for developing CVD and then institute aggressive risk reduction strategies in them. Fundamental to both the approaches is a thorough understanding of the risk factors causing CVD in India.

The mechanisms underlying CVD among Indians have been a matter of considerable debate. Indians (and in general South Asians) not only have a higher incidence of CVD, but they also tend to develop the disease at a younger age and have more severe and extensive disease.^3–5 Greater genetic propensity has been postulated to be one of the important reasons underlying this excess CVD risk among Indians. This assumption is supported by the consistently higher CVD morbidity and mortality seen among the migrant South Asians residing in the UK or US, as compared to the respective native populations.⁶⁻⁸

In contrast, the famous INTERHEART study showed that even among South Asians, almost 90% of the acute myocardial infarctions could be explained by the nine conventional and non-conventional risk factors, namely, abnormal lipids, smoking, hypertension, diabetes mellitus (DM), abdominal obesity, psychosocial factors, lack of regular physical activity, consumption of alcohol, and lower intake of fruits and vegetables. ⁵ It was further shown that the South Asians tended to develop these harmful factors at a younger age, and this led to the higher incidence and earlier onset of myocardial infarctions in them. ⁹ The INTERHEART study thus relegated genetic factors to only a minor contributor toward excess CVD risk among South Asians. In a way, it is a reassuring finding since it allows us an opportunity to intervene through appropriate preventive strategies.

The risk factor profile among South Asians and Indians has certain characteristic features. Visceral adiposity is particularly common, which promotes insulin resistance, inflammation, and a host of metabolic abnormalities that eventually culminate into DM and CVD^10–12. Visceral adiposity and insulin resistance are also responsible for “atherogenic dyslipidemia,” the unique pattern of lipid abnormalities observed in the South Asians. ¹³ It is characterized by low levels of high-density lipoprotein cholesterol (HDL-C), relatively normal levels of low-density lipoprotein cholesterol (LDL-C) but with a greater proportion of small-dense LDL particles, and a higher prevalence of elevated triglycerides and lipoprotein (a). Thus, visceral adiposity and insulin resistance seem to play a central role in the pathogenesis of CVD among South Asians. ¹²

The above mentioned findings suggest that visceral adiposity and associated abnormalities should have a prominent place in any risk reduction strategy conceived for Indian patients. However, it is observed that in the busy clinical practice, most of the emphasis is on a few easily identifiable and important risk factors such as DM, smoking, hypertension, and elevated LDL-C. Since these four risk factors account for a substantial proportion of CVD, focusing predominantly on these risk factors appears reasonable and effort-effective. However, is it really justified to ignore other potentially relevant risk factors such as visceral adiposity, low HDL-C, and elevated triglycerides? What role do these risk factors play in the causation of CVD among Indians in the contemporary scenario? Do they have any incremental value over the four major risk factors mentioned earlier?

To answer some of these questions, Rao et al. recently conducted a large study among patients presenting for the first time with an acute coronary syndrome (ACS). ¹⁴ This study, titled MERIFACS (MEtabolic Risk factors In First Acute Coronary Syndrome), recruited a total of 2,153 patients and 1,210 controls from 15 participating centers, mostly from South India. Propensity score matching was performed to yield a matched population of 1,193 cases with 1,210 controls. The authors termed DM, hypertension, elevated LDL-C, and smoking as major conventional risk factors (CRFs) and compared their association with ACS with that of a set of relatively less emphasized risk factors such as obesity [defined using both body mass index (BMI) and waist-hip ratio (WHR)], low HDL-C, elevated triglycerides, and glycosylated hemoglobin > 7% (considered a marker of inadequately controlled DM). The authors labeled these secondary risk factors as specific metabolic risk factors (MRFs). It was found that these specific MRFs were collectively as prevalent as the major CRFs. Furthermore, the risk of ACS conferred by some of these MRFs (high WHR, low HDL-C, and high HbA1c) was comparable to that of the CRFs. ¹⁴

Several important messages can be derived from this study. First, given the high prevalence of some of the MRFs and their association with ACS, it would be a grave mistake to not sufficiently address them in the clinical practice. Nearly two-thirds of the controls had elevated WHR and 42.8% had low HDL-C. With the odds ratios of 2.4 and 2.2, respectively (similar to that of high LDL-C), these two risk factors have the potential to contribute significantly to the burden of CVD. These two risk factors were also among the nine important risk factors for myocardial infractions identified by the INTERHEART study. ⁵ The MERIFACS study, performed nearly two decades after the INTERHEART study, has thus reiterated the same findings in a more contemporary cohort. This study proves that increased WHR and low HDL-C continue to be highly relevant to the pathogenesis of CVD in Indians, necessitating appropriate efforts to tackle them effectively.

Metabolic syndrome is an entity described to lay emphasis on the abnormalities that are commonly associated with visceral adiposity. Several different criteria exist for diagnosing metabolic syndrome, but all of them rely on recognizing the following five key abnormalities: abdominal obesity, impaired fasting glucose, hypertension, low HDL-C, and elevated serum triglycerides.^15–17 Individually, the relationship of these risk factors with CVD is only modest. However, it is hypothesized that metabolic syndrome identifies an unhealthy metabolic milieu that, in the long-term, culminates in frank DM and/or CVD. Early recognition of this unhealthy constellation affords an excellent opportunity to intervene in a timely manner. However, despite being an intuitively appealing concept, its adoption in routine clinical practice has been only suboptimal. There are several reasons for this. First, the incremental value of metabolic syndrome as an entity for predicting CVD risk has remained highly debated. Many studies have shown that the presence of metabolic syndrome is associated with increased risk of adverse cardiovascular events beyond the risk imparted by the individual risk factors alone.^18–20 However, at the same time, there are other studies that have shown that the entity “metabolic syndrome” is no better than its individual components as a cardiovascular risk marker.^21–23 The second problem is that there have been multiple criteria proposed for diagnosing metabolic syndrome with different threshold values recommended for its components for different population groups.^15–17,24 This greatly adds to the confusion, especially for the practicing clinicians. Against this background, the findings of the MERIFACS study assume significance. This study reinforces the pathogenic relevance of many of the components of metabolic syndrome in causation of ACS in India and calls for greater attention to these risk factors, either individually or in the form of metabolic syndrome. Previous studies have already shown that metabolic syndrome is common among Indian patients with coronary artery disease and is associated with more advanced disease.^{25, 26}

The second important message from the MERIFACS study is that WHR and not BMI is the most appropriate obesity parameter for assessing CVD risk. Similar findings were reported by the INTERHEART study also, which had shown that WHR had a graded and highly significant association with myocardial infraction risk. ²⁷ In contrast, BMI only had a modest association, which was substantially reduced after adjustment for WHR. These findings seem quite logical since visceral adiposity is a much stronger risk factor for CVD as compared to overall obesity and WHR quantifies visceral adiposity much better than BMI. Unfortunately, in the busy clinical practice, BMI is virtually the only obesity metric used because of the ease of measurement. However, it is high time we realized the important of WHR, especially in a country like India where visceral adiposity is highly prevalent.

Third, the study by Rao et al. showed that HbA1c >7% had an independent association with ACS, over what was imparted by the diagnosis of DM alone. This implies that in routine clinical practice, just enquiring about the presence or absence of DM is not sufficient. We must also endeavor to ensure adequate control of DM.

Lastly, the MERIFACS study provides yet another reconfirmation of the fact that Indians tend to develop CVD at a much younger age. The mean age of the participants in this study was 56 years, which is much less than the usual age of presentation in the western countries. ⁵

The MERIFACS study had many limitations as well that warrant attention. It was a cross-sectional study, limited mainly to centers from South India. The population-attributable risks for individual risk factors were not estimated to provide an assessment of their actual contribution to ACS in this study. Also, it is not possible to ascertain from this study whether the ratio of LDL-C to HDL-C could provide a more accurate assessment of lipid-related ACS risk, than the individual lipid components. It would be informative if the authors could provide some of these answers by performing additional analysis of their data. Nevertheless, despite these limitations, the primary message from this study is quite clear. We, the clinicians in India, must widen our approach toward CVD prevention by going beyond the major CRFs and including those MRFs that are especially relevant for our population. Elevated WHR, low HDL-C, and uncontrolled DM are the main candidates. High prevalence of these risk factors in the general population is a matter of great concern. It is time to take cognizance of these facts and institute effective strategies to control these risk factors to curb the burgeoning CVD epidemic in India. We cannot continue to ignore these risk factors anymore.