Expanding statin use for prevention of ASCVD in Indians: Reasoned and simplified proposals.

Atherosclerosis, a systemic disease, is the predominant cause of cardiovascular disease (CVD) that far exceeds other causes (egs: congenital, hypertension, arrhythmia). CVD is the leading cause of mortality globally (18 million lives, including 9 million from coronary artery disease (CAD) annually).1 The Global Burden of Disease study reported that in the year 2017, India had one of the highest mortality, most of them premature, from CVD (2.64 million, women 1.18, men 1.45) and CAD (1.54 million, women 0.62, men 0.92) in the world.2 A systemic disease of this magnitude and impact warrants a proactive preventive strategy and not a reactive, invasive and focal approach. In this editorial, we call for a wider use of statins in Indians, explain our rationale based on risk factors and risk-enhancing factors, and present a simplified and cost effective approach to combat CVD.

Lipoprotein(a): An underrecognized genetic risk factor for malignant coronary artery disease in young Indians.

Malignant coronary artery disease (CAD) refers to a severe and extensive atherosclerotic process involving multiple coronary arteries in young individuals (aged <45 years in men and <50 years in women) with a low or no burden of established risk factors. Indians, in general, develop acute myocardial infarction (AMI) about 10 years earlier; AMI rates are threefold to fivefold higher in young Indians than in other populations. Although established CAD risk factors have a predictive value, they do not fully account for the excessive burden of CAD in young Indians. Lipoprotein(a) (Lp(a)) is increasingly recognized as the strongest known genetic risk factor for premature CAD, with high levels observed in Indians with malignant CAD. High Lp(a) levels confer a twofold to threefold risk of CAD-a risk similar to that of established risk factors, including diabetes. South Asians have the second highest Lp(a) levels and the highest risk of AMI from the elevated levels, more than double the risk observed in people of European descent. Approximately 25% of Indians and other South Asians have elevated Lp(a) levels (≥50 mg/dl), rendering Lp(a) a risk factor of great importance, similar to or surpassing diabetes. Lp(a) measurement is ready for clinical use and should be an essential part of all CAD research in Indians.

Lipoprotein(a): An independent, genetic, and causal factor for cardiovascular disease and acute myocardial infarction.

Lipoprotein(a) [Lp(a)] is a circulating lipoprotein, and its level is largely determined by variation in the Lp(a) gene (LPA) locus encoding apo(a). Genetic variation in the LPA gene that increases Lp(a) level also increases coronary artery disease (CAD) risk, suggesting that Lp(a) is a causal factor for CAD risk. Lp(a) is the preferential lipoprotein carrier for oxidized phospholipids (OxPL), a proatherogenic and proinflammatory biomarker. Lp(a) adversely affects endothelial function, inflammation, oxidative stress, fibrinolysis, and plaque stability, leading to accelerated atherothrombosis and premature CAD. The INTER-HEART Study has established the usefulness of Lp(a) in assessing the risk of acute myocardial infarction in ethnically diverse populations with South Asians having the highest risk and population attributable risk. The 2018 Cholesterol Clinical Practice Guideline have recognized elevated Lp(a) as an atherosclerotic cardiovascular disease risk enhancer for initiating or intensifying statin therapy.

Cardiometabolic-Renal Disease in South Asians: Consensus Recommendations from the Cardio Renal Society of America.

BACKGROUND: Rates of cardiometabolic-renal disease are extremely high among South Asians (India, Pakistan, Bangladesh, Sri Lanka, Bhutan, the Maldives, and Nepal) residing in their home countries and worldwide. The Cardio Renal Society of America, National Kidney Foundation of Arizona, and Twinepidemic Inc. convened a task force to examine evidence and reach consensus regarding cardiometabolic-renal disease prevention in South Asians. The task force distilled the findings from 5 years of face-to-face and virtual meetings addressing questions derived from expert reviews of published data using the Delphi technique to create these consensus statements. SUMMARY: Several high-quality observational studies document the high and increasing incidence and prevalence of cardiometabolic-renal disease among South Asians, starting well before adulthood, owing to genetic, cultural, and environmental factors. Despite the need for additional prospective studies, especially randomized trials, of educational, screening, and other prevention efforts, sufficient information is already available to expand and intensify ongoing efforts in professional and lay education to help control this epidemic. The task force proposes to provide this expansion over the next 10 years through scientific and lay publications and other educational programs to promote more effective action among the public, health care professionals, payers, and regulators in screening for and treating cardiometabolic-renal risk factors and preventing disease in South Asians, starting at an early age. Key Messages: These consensus statements describe risk factors and prognoses characteristic of South Asians regarding cardiometabolic-renal diseases, to aid physician decision-making, health care system delivery, and research initiatives to improve the quality of care for South Asians worldwide.

Lipoprotein(a) Levels and the Risk of Myocardial Infarction Among 7 Ethnic Groups.

BACKGROUND: Lipoprotein(a) [Lp(a)] levels predict the risk of myocardial infarction (MI) in populations of European ancestry; however, few data are available for other ethnic groups. Furthermore, differences in isoform size distribution and the associated Lp(a) concentrations have not fully been characterized between ethnic groups. METHODS: We studied 6086 cases of first MI and 6857 controls from the INTERHEART study that were stratified by ethnicity and adjusted for age and sex. A total of 775 Africans, 4443 Chinese, 1352 Arabs, 1856 Europeans, 1469 Latin Americans, 1829 South Asians, and 1221 Southeast Asians were included in the study. Lp(a) concentration was measured in each participant using an assay that was insensitive to isoform size, with isoform size being assessed by Western blot in a subset of 4219 participants. RESULTS: Variations in Lp(a) concentrations and isoform size distributions were observed between populations, with Africans having the highest Lp(a) concentration (median=27.2 mg/dL) and smallest isoform size (median=24 kringle IV repeats). Chinese samples had the lowest concentration (median=7.8 mg/dL) and largest isoform sizes (median=28). Overall, high Lp(a) concentrations (>50 mg/dL) were associated with an increased risk of MI (odds ratio, 1.48; 95% CI, 1.32-1.67; P<0.001). The association was independent of established MI risk factors, including diabetes mellitus, smoking, high blood pressure, and apolipoprotein B and A ratio. An inverse association was observed between isoform size and Lp(a) concentration, which was consistent across ethnic groups. Larger isoforms tended to be associated with a lower risk of MI, but this relationship was not present after adjustment for concentration. Consistent with variations in Lp(a) concentration across populations, the population-attributable risk of high Lp(a) for MI varied from 0% in Africans to 9.5% in South Asians. CONCLUSIONS: Lp(a) concentration and isoform size varied markedly between ethnic groups. Higher Lp(a) concentrations were associated with an increased risk of MI and carried an especially high population burden in South Asians and Latin Americans. Isoform size was inversely associated with Lp(a) concentration, but did not significantly contribute to risk.

South Asian Cardiovascular Disease & Cancer Risk: Genetics & Pathophysiology.

South Asians (SAs) are at heightened risk for cardiovascular disease as compared to other ethnic groups, facing premature and more severe coronary artery disease, and decreased insulin sensitivity. This disease burden can only be partially explained by conventional risk factors, suggesting the need for a specific cardiovascular risk profile for SAs. Current research, as explored through a comprehensive literature review, suggests the existence of population specific genetic risk factors such as lipoprotein(a), as well as population specific gene modulating factors. This review catalogues the available research on cardiovascular disease and genetics, anthropometry, and pathophysiology, and cancer genetics among SAs, with a geographical focus on the U.S. A tailored risk profile will hinge upon population customized classification and treatment guidelines, informed by continued research.

Benefits & risks of statin therapy for primary prevention of cardiovascular disease in Asian Indians - a population with the highest risk of premature coronary artery disease & diabetes.

Several reviews and meta-analyses have demonstrated the incontrovertible benefits of statin therapy in patients with cardiovascular disease (CVD). But the role for statins in primary prevention remained unclear. The updated 2013 Cochrane review has put to rest all lingering doubts about the overwhelming benefits of long-term statin therapy in primary prevention by conclusively demonstrating highly significant reductions in all-cause mortality, major adverse cardiovascular events (MACE) and the need for coronary artery revascularization procedures (CARPs). More importantly, these benefits of statin therapy are similar at all levels of CVD risk, including subjects at low (<1% per year) risk of a MACE. In addition to preventing myocardial infarction (MI), stroke, and death, primary prevention with statins is also highly effective in delaying and avoiding expensive CARPs such as angioplasties, stents, and bypass surgeries. There is no evidence of any serious harm or threat to life caused by statin therapy, though several adverse effects that affect the quality of life, especially diabetes mellitus (DM) have been reported. Asian Indians have the highest risk of premature coronary artery disease (CAD) and diabetes. When compared with Whites, Asian Indians have double the risk of CAD and triple the risk of DM, when adjusted for traditional risk factors for these diseases. Available evidence supports the use of statin therapy for primary prevention in Asian Indians at a younger age and with lower targets for low-density lipoprotein cholesterol (LDL-C) and non-high density lipoprotein (non-HDL-C), than those currently recommended for Americans and Europeans. Early and aggressive statin therapy offers the greatest potential for reducing the continuing epidemic of CAD among Indians.

Intensive statin therapy for Indians: Part-I. Benefits.

The underlying disorder in the vast majority of cases of cardiovascular disease (CVD) is atherosclerosis, for which low-density lipoprotein cholesterol (LDL-C) is recognized as the first and foremost risk factor. HMG-CoA reductase inhibitors, popularly called statins, are highly effective and remarkably safe in reducing LDL-C and non-HDL-C levels. Evidence from clinical trials have demonstrated that statin therapy can reduce the risk of myocardial infarction (MI), stroke, death, and the need for coronary artery revascularization procedures (CARPs) by 25-50%, depending on the magnitude of LDL-C lowering achieved. Benefits are seen in men and women, young and old, and in people with and without diabetes or prior diagnosis of CVD. Clinical trials comparing standard statin therapy to intensive statin therapy have clearly demonstrated greater benefits in CVD risk reduction (including halting the progression and even reversing coronary atherosclerosis) without any corresponding increase in risk. Numerous outcome trials of intensive statin therapy using atorvastatin 80 mg/d have demonstrated the safety and the benefits of lowering LDL-C to very low levels. This led the USNCEP Guideline Committee to standardize 40 mg/dL as the optimum LDL-C level, above which the CVD risk begins to rise. Recent studies have shown intensive statin therapy can also lower CVD events even in low-risk individuals with LDL-C <110 mg/dL. Because of the heightened risk of CVD in Asian Indians, the LDL-C target is set at 30 mg/dL lower than that recommended by NCEP. Accordingly, the LDL-C goal is < 70 mg/dL for Indians who have CVD, diabetes, metabolic syndrome, or chronic kidney disease. Intensive statin therapy is often required in these populations as well as others who require a > or = 50% reduction in LDL-C. Broader acceptance of this lower LDL-C targets and its implementation could reduce the CVD burden in the Indian population by 50% in the next 25 years. Clinical trial data support an extremely favorable benefit-to-risk ratio of intensive statin therapy with some but not all statins. Atorvastatin 80 mg/d is 100 times safer than aspirin 81 mg/d and 10 times safer than diabetic medications. Intensive statin therapy is more effective and safe compared to intensive control of blood sugar or blood pressure in patients with diabetes.

Reducing the burden of coronary artery disease in India: challenges and opportunities.

UNLABELLED: Asian Indians--living both in India and abroad--have one of the highest rates of coronary artery disease (CAD) in the world, three times higher than the rates among Caucasians in the United States. The CAD among Indians is usually more aggressive at the time of presentation compared with whites or East Asians. The overall impact is much greater because the CAD in Asian Indians affects the "younger" working population. This kind of disproportionate epidemic among the young Indians is causing tremendous number of work days lost at a time when India is experiencing a dizzying economic boom and needs a healthy populace to sustain this boom. While the mortality and morbidity from CAD has been falling in the western world, it has been climbing to epidemic proportions among the Indian population. Various factors that are thought to contribute to this rising epidemic include urbanization of rural areas, large-scale migration of rural population to urban areas, increase in sedentary lifestyle, abdominal obesity, metabolic syndrome, diabetes, inadequate consumption of fruits and vegetables, increased use of fried, processed and fast foods, tobacco abuse, poor awareness and control of CAD risk factors, unique dyslipidemia (high triglycerides, low HDL-cholesterol levels), and possible genetic predisposition due to lipoprotein (a) [Lp(a)] excess. The effect of established, as well as novel, risk factors is multiplicative, not just additive (total effect>sum of parts). The management would require aggressive individual, societal, and governmental (policy and regulatory) interventions. Indians will require specific lower cut-offs and stricter goals for treatment of various risk factors than is currently recommended for western populations. To this end, the First Indo-US Healthcare Summit was held in New Delhi, India on December 14 and 15, 2007. The participants included representatives from several professional entities including the American Association of Physicians of Indian origin (AAPI), Indian Medical Association (IMA), Medical Council of India (MCI), and Government of India (GOI) with their main objective to address specific issues and provide precise recommendations to implement the prevention of CAD among Indians. The summary of the deliberations by the committee on "CAD among Asian Indians" and the recommendations are presented in this document. OBJECTIVES: Discussion of demographics of CAD in Indians-both in India and abroad, current treatment strategies, primordial, primary, and secondary prevention. Development of specific recommendations for screening, evaluation and management for the prevention of CAD disease epidemic among Asian Indians. Recommendations for improving quality of care through professional, public and private initiatives.

The metabolic syndrome and dyslipidemia among Asian Indians: a population with high rates of diabetes and premature coronary artery disease.

South Asians have high rates of diabetes and the highest rates of premature coronary artery disease in the world, both occurring about 10 years earlier than in other populations. The metabolic syndrome (MS), which appears to be the antecedent or "common soil" for both of these conditions, is also common among South Asians. Because South Asians develop metabolic abnormalities at a lower body mass index and waist circumference than other groups, conventional criteria underestimate the prevalence of MS by 25% to 50%. The proposed South Asian Modified National Cholesterol Education Program criteria that use abdominal obesity as an optional component and the South Asian-specific waist circumference recommended by the International Diabetes Federation appear to be more appropriate in this population. Furthermore, Asian Indians have at least double the risk of coronary artery disease than that of whites, even when adjusted for the presence of diabetes and MS. This increased risk appears to be due to South Asian dyslipidemia, which is characterized by high serum levels of apolipoprotein B, lipoprotein (a), and triglycerides and low levels of apolipoprotein A1 and high-density lipoprotein (HDL) cholesterol. In addition, the HDL particles are small, dense, and dysfunctional. MS needs to be recognized as a looming danger to South Asians and treated with aggressive lifestyle modifications beginning in childhood and at a lower threshold than in other populations.

Dyslipidemia in South Asian patients.

South Asians around the globe have the highest rates of coronary artery disease (CAD). These rates are 50% to 300% higher than other populations, with a higher risk at younger ages. These high rates of CAD are accompanied by low or similar rates of major traditional risk factors. The prevalence of diabetes is three to six times higher among South Asians than Europeans, Americans, and other Asians but does not explain the "South Asian Paradox." A genetic predisposition to CAD, mediated by high levels of lipoprotein(a), markedly magnifies the adverse effects of traditional risk factors related to lifestyle and best explains the South Asian Paradox. Although the major modifiable risk factors do not fully explain the excess burden of CAD, they are doubly important and remain the foundation of preventive and therapeutic strategies in this population. A more aggressive approach to preventive therapy, especially dyslipidemia, at an earlier age and at a lower threshold is clearly warranted.

Accuracy of the ratio of triglycerides to high-density lipoprotein cholesterol for predicting low-density lipoprotein cholesterol particle sizes, phenotype B, and particle concentrations among Asian Indians.

Asian Indians have unusually high rates of coronary artery disease. Small low-density lipoprotein (LDL) particle predominance (phenotype B) is associated with a fourfold atherogenic risk. This study examined the accuracy of a triglyceride/high-density lipoprotein cholesterol (HDL) ratio of > or =3.8 (determined from the Adult Treatment Panel III guidelines, normal triglycerides <150 mg/dl and HDL >40 mg/dl) for predicting phenotype B in Asian Indians. Fasting blood samples were collected from 150 healthy Asian Indians. LDL size analysis was performed by nuclear magnetic resonance spectroscopy. The triglyceride/HDL cholesterol ratio correlated inversely with the LDL size and positively with the particle concentration. A triglyceride/HDL cholesterol ratio of > or =3.8 had 76% sensitivity, 93% specificity, and 83% positive and 89% negative predictive values for predicting phenotype B.

Effect of leisure time exercise on high-density lipoprotein cholesterol, its subclasses, and size in Asian Indians.

Asian Indians have a greater prevalence and incidence of coronary artery disease than other ethnic groups, despite similar routine lipid profiles. High-density lipoprotein (HDL) cholesterol, particularly the large subclass, is predominantly associated with coronary artery disease protection. Exercise reduces coronary artery disease risk by improving HDL cholesterol levels. The effect of exercise on HDL cholesterol concentrations, subclasses, and size, measured by nuclear magnetic resonance spectroscopy, was assessed in 388 healthy Asian Indians. Exercise was associated with significantly greater concentrations of total HDL cholesterol, entirely due to significant increases in the cardioprotective large HDL subclass and larger HDL cholesterol particle sizes.

Comparison of high-density and low-density lipoprotein cholesterol subclasses and sizes in Asian Indian women with Caucasian women from the Framingham Offspring Study.

BACKGROUND: Asian Indian women have a higher rate of coronary artery disease (CAD) than do other ethnic groups, despite similar conventional risk factors and lipid profiles. Smaller high-density lipoprotein cholesterol (HDL-C) particle size is associated with reduced cardiac protection or even an increased risk of CAD. Exceptional longevity correlates better with larger HDL-C particle sizes. HYPOTHESIS: Higher rates of CAD among Asian Indian women may partly be explained by the differenes in the prevalence of atherogenic HDL-C and low-density lipoprotein cholesterol (LDL-C) sizes and their subclass concentrations among Asian Indian women compared with Caucasian women. METHODS: We measured HDL-C concentrations and sizes by nuclear magnetic resonance spectroscopy in 119 relatively healthy Asian Indian women and compared them with those of 1752 Caucasian women from the Framingham Offspring Study (FOS). RESULTS: Asian Indian women were significantly younger (47.9 +/- 11.2 vs. 51.0 +/- 10.1 years, p = 0.0001), leaner (body mass index 24.0 +/- 4.7 vs. 26.0 +/- 5.6, p = < 0.0002), less likely to be postmenopausal (32 vs. 54%, p = < 0.0001), or smoke (< 1 vs. 20%, p = < 0.0001); nevertheless, prevalence of CAD was higher in Asian Indian women (4.2 vs. 1%, p = 0.0006). Asian Indian women had similar HDL-C (53 +/- 13 vs. 53 +/- 13 mg/dl, p = 0.99), smaller HDL-C particle size (8.9 +/- 0.35 vs. 9.4 +/- 0.44 nm, p = < 0.0001), higher total cholesterol (209 +/- 40 vs. 199 +/- 42 mg/dl, p = 0.01), and similar triglyceride (120 +/- 77 vs. 108 +/- 110 mg/d, p = 0.24) levels. Low-density lipoprotein cholesterol, particle concentrations and sizes, as well as prevalence of pattern B were similar. CONCLUSIONS: Compared with the FOS, Asian Indian women have significantly smaller overall HDL particle size and similar levels of HDL-C, which may reflect impaired, reverse cholesterol transport. Total cholesterol was higher, whereas triglyceride and LDL-C levels were similar. This may partly explain the higher CAD rates in Asian Indian women. Further large scale, prospective, long-term studies are warranted.

High-density lipoprotein subclass distribution in individuals of Asian Indian descent: the National Asian Indian Heart Disease Project.

Individuals of Asian Indian descent have significantly higher cardiovascular event rates as compared with other ethnic groups. The authors investigated the prevalence of metabolic disorders linked to coronary artery disease in an Asian Indian male population compared with non-Asian Indian males. Standard lipid measurements did not discriminate between groups, and the Asian Indian group exhibited less of the high coronary artery disease risk small low-density lipoprotein trait. Despite less of the small low-density lipoprotein trait in the Asian Indian group and no difference in high-density lipoprotein cholesterol, the Asian Indian group had a significantly higher prevalence (p < 0.0002) of low high-density lipoprotein 2b, implying impaired reverse cholesterol transport. This observation remained significant in the subgroup of patients with high-density lipoprotein cholesterol over 40 mg/dL, a region felt not to reflect impaired reverse cholesterol transport. Low high-density lipoprotein 2b combined with the higher lipoprotein(a) in the Asian Indian group may help explain the high prevalence of coronary artery disease in this ethnic population.