Risk Factors for Early Myocardial Infarction in South Asians Compared With Individuals in Other Countries FREE

The South Asian countries of India, Pakistan, Bangladesh, Sri Lanka, and Nepal account for about a quarter of the world's population and contribute the highest proportion of the burden of cardiovascular diseases compared with any other region globally.^1- 3 South Asian migrants living in several countries have higher death rates from coronary heart disease (CHD) at younger ages compared with the local population despite apparently lower levels of conventional risk factors.^4- 8 Deaths related to cardiovascular disease also occur 5 to 10 years earlier in South Asian countries than they do in Western countries.^9- 10 This has raised the possibility that South Asians exhibit a special susceptibility for acute myocardial infarction (AMI) that is not explained by traditional risk factors.

Among individuals living in the United Kingdom, the earlier onset of CHD among South Asian migrants is not an artifact of differences in the population distribution because the higher incidence of CHD is most marked in those younger than age 40 years (about a 3-fold difference), whereas it is less marked in those older than 60 years (about a 1.5-fold difference) based on an analysis of UK mortality data.⁸ Despite documenting the higher rates of earlier CHD in South Asians, few studies have been able to shed light on its reasons. Most studies do not include information on diet, physical activity, abdominal obesity, psychosocial factors or apolipoprotein levels, and do not have sufficiently large numbers of clinical events to reliably assess the comparative effects of the various risk factors at various ages in South Asians compared with other ethnic groups.^11- 13

The INTERHEART study is uniquely positioned to address the reasons for the higher rates of CHD in native South Asians compared with those from other parts of the world because of its standardized protocol with extensive data collection and inclusion of a large number of cases from South Asian countries and other parts of the world.

Details of the study methods, including inclusion and exclusion criteria, have been published.¹⁴ Briefly, INTERHEART enrolled 15 152 cases of first AMI and 14 820 age-matched (±5 years) and sex-matched controls from 262 centers in 52 countries between February 1999 and March 2003. Of these, 1732 AMI cases and 2204 controls were recruited from 15 centers in 5 South Asian countries (India: 470 cases, 940 controls; Pakistan: 637 cases, 655 controls; Bangladesh: 228 cases, 238 controls; Sri Lanka: 153 cases, 132 controls; Nepal: 244 cases, 239 controls) and 10 728 cases and 12 431 controls were enrolled from other countries. Among individuals from South Asian countries, 252 AMI cases (14.6%) and 307 controls (13.9%) were women. All patients presenting within 24 hours of onset of chest pain were screened and the center attempted to enroll consecutive eligible cases. The majority of participants provided written informed consent. In a few centers, after approval by either the ethics committee or the institution, oral consent was obtained. The study was approved by the ethics committee at each hospital.

Information about demographic factors, socioeconomic status, tobacco smoking, physical activity, dietary patterns, personal and family history of cardiovascular disease and risk factors, and measures of stress were obtained through interviewer-administered structured questionnaires. Height, weight, and waist and hip circumferences were measured using standardized protocols.¹⁴ Waist-to-hip ratio (WHR) was used to measure abdominal obesity. Staff were trained using standardized manuals, videotapes, and instructions provided at meetings or site visits. Only self-reported history of hypertension was used in the analysis because blood pressure levels may be lowered by AMI or its treatment.

Nonfasting blood samples (20 mL) were obtained from each case and control, which were centrifuged, separated, and frozen immediately at −20°C or −70°C. Samples were shipped in nitrogen vapor tanks to a central blood storage site and stored at −160°C in liquid nitrogen. Blood samples were analyzed for apolipoprotein B₁₀₀ (ApoB₁₀₀) and apolipoprotein A-I (ApoA-I) using standardized immunoturbidimetric assays (Roche/Hitachi 917 analyzer with Tina-quant ApoB₁₀₀ version 2 kits, Roche Diagnostics, Mannheim, Germany). The ratio of ApoB₁₀₀ to ApoA-I was used as a marker of dyslipidemia because apolipoprotein concentrations are not affected by fasting state, which is unlike the estimation of triglycerides or calculated low-density lipoprotein cholesterol levels, and it has been shown to be superior to other measures in several^15- 19 but not all²⁰ large prospective studies in predicting cardiovascular disease.

Current smokers were defined as individuals who smoked cigarettes or beedis (a form of smoking indigenous to South Asian countries) in the previous 12 months. Individuals who had quit smoking more than a year earlier were classified as former smokers. For the WHR and ApoB/ApoA-I ratio, tertiles were calculated using the overall control data. For WHR, tertiles were calculated separately for men and women. Participants were classified as physically active if they reported moderate (walking, cycling) or strenuous exercise (jogging, football, vigorous swimming) for 4 or more hours per week. Regular alcohol use was defined as consumption at least once per week.

Data were transferred to the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario. Data on smoking were missing for 5.7% of the participants; diabetes, 1.3%; hypertension, 1.4%; WHR, 2.9%; depression, 13.6%; stress at work or home, 4.2%; physical activity, 1.7%; diet, 2.5%; and alcohol use, 1.9%. Blood samples were available for 1227 AMI cases and 1593 controls from South Asia.

Calculation of age-standardized prevalence of risk factors, odds ratios (ORs), 95% confidence intervals (CIs), and the population attributable risks (PARs) was previously described.¹⁴ Means or medians were calculated to summarize variables and compared using the t test or an appropriate nonparametric test. Unconditional logistic regression was used to compute the ORs and 95% CIs; all models were adjusted for age, sex, and smoking status. The results presented herein are derived from models fitted with unconditional logistic regression and adjusted for the matching criteria.

Perfect matching was not possible in all cases and controls. This matching also was not possible when data on a risk factor were missing for a case or a control. Therefore, to include as many individuals as possible for a subgroup analysis, we widened the age-matching criteria and used frequency matching of cases and controls using age and sex strata. The results are comparable between conditional logistic regression, mixed models, and unconditional logistic regression, with adjustment for matching criteria. The estimated ORs and 95% CIs that had been calculated using the different methods were within 5% of each other. There was a slight underestimation of the effects compared with those obtained by the fully matched analysis.

Data on individual risk factors are presented separately for India and Pakistan. The data from Bangladesh, Nepal, and Sri Lanka are combined to provide more stable estimates of ORs and PARs because there were fewer participants from these countries. We also compared the prevalence of risk factors between native South Asians and those from other countries and between controls and cases in each age strata (<40 years, 40-49 years, 50-59 years, and >60 years). Within the cases, we used a logistic model to predict the occurrence of AMI at a younger age (<40 years). Predicted probabilities of first AMI before age 40 years are presented as unadjusted and adjusted for the 9 risk factors. We used SAS statistical software version 9.1 (SAS Institute Inc, Cary, NC) to analyze the data, IRAP software version 2.2 (National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, Md) to compute all PARs and 95% CIs for various risk factors using a method based on unconditional logistic regression.²¹

The PARs presented are adjusted for confounders in a similar manner to the corresponding logistic regression models for OR estimates and are stratified by subgroup of interest. For simple dichotomous exposure and disease and no adjustment for confounding, the usual formula for PAR was used. For estimating variance, the methods of Benichou and Gail²² were used to calculate the 95% CIs using a logistic transformation approach. However, when the PAR estimates were negative, conventional Wald-type 95% CIs were used. S-Plus software (Insightful, Seattle, Wash) was used to prepare the figures. The effect of combining all of the exposures was estimated by summation of model coefficients and their antilogs.

The majority (59%) of the participants were from low- or middle-income areas (China, 21%; Southeast Asia, 8%; Africa, 5%; Middle Eastern countries, 13%; South America, 12%), while 26% were from high-income areas (Western Europe, 5%; Eastern Europe, 14%; North America, 2%; Australia, 5%). A total of 702 of 1675 cases (41.9%) and 656 of 2202 controls (29.8%) from South Asia had 8 or fewer years of education compared with 3109 cases (39.5%) and 3169 controls (35.4%) from other countries with the same level of education. Low educational level was strongly associated with increased risk of AMI in native South Asians and in individuals from other countries (P<.001).

The mean (SD) age of first AMI was lower in native South Asians (53.0 [11.4] years) than in participants from other countries (58.8 [12.2]; P<.001). South Asian female cases were 5.6 years older than male cases (mean [SD] age, 58.6 [11.6] years vs 53.0 [11.2] years). Striking variations in the mean age of presentation of cases were observed between countries within South Asia. The youngest patients lived in Bangladesh and had a mean (SD) age of 51.9 (11.0) years and the oldest patients lived in Nepal and had a mean (SD) age 58.9 (11.8) years (Table 1).

The prevalence of protective risk factors (leisure time physical activity, regular alcohol intake, and daily intake of fruits and vegetables) were markedly lower (all P<.001), while that of harmful risk factors such as elevated ApoB₁₀₀ /ApoA-I ratio was higher in South Asian cases and controls compared with those cases and controls from other countries (P<.001; Figure 1).

Current and former smoking, history of hypertension, history of diabetes mellitus, high WHR, elevated ApoB₁₀₀ /ApoA-I ratio (top vs lowest tertile), and adverse psychosocial factors were strongly associated with increased risk of AMI (P<.001) in native South Asians. Daily intake of fruits and vegetables (P<.001) and physical activity (P = .03) were protective against AMI. Among individuals from other areas, regular alcohol consumption was protective (OR, 0.79; 95% CI, 0.74-0.85) but it was not protective among native South Asians (OR, 1.06; 95% CI, 0.85-1.30; P for interaction = .02).

Compared with individuals from other areas, native South Asians had significantly higher PARs associated with WHR but lower PARs for history of hypertension and psychosocial stress. The risk factors associated with the highest PARs among South Asians were elevated ApoB₁₀₀/ApoA-I ratio (46.8%), WHR (37.7%), and current and former smoking (37.5%) (Figure 1).

In participants younger than 60 years, the prevalence of the 3 metabolic risk factors of ApoB₁₀₀ /ApoA-I ratio, diabetes, and WHR was higher in South Asian cases and controls and consumption of fruits and vegetables, physical activity, and alcohol use were lower compared with their counterparts from other areas (Table 2). However, after adjusting for all of the 9 risk factors among the cases, the predicted probability of having an AMI at a younger age (<40 years) was similar among native South Asians and individuals from other areas (Figure 2). This analysis suggests that an AMI at an earlier age among South Asians can be largely explained by higher levels of these metabolic risk factors at younger ages.

Although all risk factors (with the exception of alcohol consumption in both sexes, and physical activity in women) were significantly associated with AMI in both sexes in native South Asians, there was considerable heterogeneity in the prevalence, ORs, and PARs between the sexes (Figure 3). The prevalence of current and former smoking and alcohol consumption were markedly lower in women compared with men. Regular physical activity was extremely low in both cases and controls, particularly in women and this paralleled the higher rates of abdominal obesity in women.

Among women, the PARs associated with the following risk factors were significantly higher: high WHR (P = .02), lack of exercise (P<.001), lack of daily intake of fruits and vegetables (P = .01), psychosocial factors (P = .005), history of hypertension (P = .001), and history of diabetes (P<.001). Among men, the PARs associated with the following risk factors were significantly higher: current and former smoking (P<.001) and elevated ApoB₁₀₀ /ApoA-I ratio (P = .006).

The combined OR for all 9 risk factors was similar for native South Asians (123.3; 95% CI, 38.7-400.2) and for individuals from other countries (125.7; 95% CI, 88.5-178.4). This OR explained a high and similar degree of PAR for AMI of 85.8% (95% CI, 78.0%-93.7%) among native South Asians and 88.2% (95% CI, 86.3%-89.9%) among individuals from other areas.

Current and former smoking, elevated ApoB₁₀₀ /Apo-I ratio, history of hypertension, and history of diabetes showed consistently significant associations with AMI in all South Asian countries (Table 3). Bangladesh had the highest prevalence for the most risk factors among the controls: current and former smoking (59.9%), elevated ApoB₁₀₀ /Apo-I ratio (59.7%), abdominal obesity (43.3%), self-reported history of hypertension (14.3%), and depression (43.0%). However, Bangladesh had the lowest prevalence for regular physical activity (1.3%) and daily intake of fruits and vegetables (8.6%). A history of diabetes was highest among Indians (11.9%). Increasing levels of these risk factors were related to increased AMI risk in all countries.

Consumption of alcohol was not associated with AMI in South Asians. Among Indians, there was a significant harmful association between alcohol consumption and AMI (OR, 1.64; 95% CI, 1.21-2.27). The prevalence of alcohol consumption was very low in the predominantly Muslim countries of Pakistan (1.5% in controls) and Bangladesh (2.1% controls).

Our study demonstrates that the majority of AMI risk in native South Asians can be explained by 9 potentially modifiable risk factors with similar collective impact as in other countries. Previous studies including analyses of national mortality data in Singapore, the United Kingdom, and Canada indicate that natives of South Asian countries experience fatal CHD at younger ages compared with individuals of European or Chinese ethnicity living in the same country.^6- 8 Moreover, there are no major causes of non-CHD deaths that are more common in middle-aged natives of South Asian countries that could distort the age structure. These considerations suggest that the earlier onset of AMI among native South Asians is not an artifact due to differences in the age distribution of the populations under study. In our study, we observed that South Asians had a lower age at presentation of first AMI, which is consistent with previous studies.^6- 8 The younger age of first AMI among the South Asian cases in our study appears to be largely explained by the higher prevalence of risk factors in native South Asians.

The 4 main risk factors, which showed consistently significant associations across all South Asian countries in both sexes were current and former smoking, high ApoB₁₀₀ /Apo-I ratio, history of hypertension, and history of diabetes. Alcohol consumption did not appear to be protective in native South Asians and this may be related to lower prevalence or differences in patterns of drinking (binge drinking in South Asians vs regular drinking in other countries).

The higher PAR due to low daily consumption of fruits and vegetables, lack of regular exercise, and high WHR observed among native South Asians compared with individuals from other countries contributes to the higher rates of CHD observed in South Asians. The 9 risk factors collectively explained 86.0% of the risk in South Asians and suggests that modifying behavior related to known risk factors could lead to a substantial impact. The role of other novel risk factors such as lipoprotein(a) or homocysteine, which are elevated in South Asians, in causing CHD is unclear. Recent randomized trials of homocysteine lowering have not demonstrated a reduction in CHD.^23- 25 Thus, the role of novel risk factors as an important cause for CHD in South Asians is likely to be small.

The rates of consumption of fruits and vegetables were surprisingly lower in South Asian controls compared with controls from other areas despite vegetarianism being common among Indians. Consumption of green leafy vegetables and fruits are associated with lower risk of CHD^26- 29 and a gradient toward lower risk is associated with a greater number of servings consumed (P for trend <.001).²⁷ The consumption of fruits and vegetables was lowest in Bangladesh (8.6% in controls), which is the country that had the youngest age of AMI occurrence. In South Asian households, prolonged cooking of vegetables is a common practice, which may destroy 90% of the folate content.³⁰ A similar inverse association between intake of vegetables and AMI has been reported in a case-control study from India.³¹ These data collectively provide the basis for public health education aimed at substantially increasing consumption of fruits and vegetables.

Although physical activity was protective in native South Asians, the proportion of South Asians who regularly exercised was low compared with other regions. Leisure time physical activity is culturally unacceptable for most Muslim women. A recent study³² from 2 Indian cities indicates that daily moderate-intensity exercise such as brisk walking for 35 to 40 minutes was associated with more than a 50% reduction in risk for CHD. Physical activity increases insulin sensitivity and high-density lipoprotein cholesterol, lowers blood pressure, improves endothelial function, and reduces the risk of type 2 diabetes mellitus, hypertension, and central adiposity^32- 36; these risk factors are highly prevalent in South Asians. Hence, there is an urgent need to promote moderate-intensity physical activity for South Asians. Adverse psychosocial factors (depression and stress at work or home) were found to be significantly associated with AMI, consistent with the global data³⁷ and data from other studies.^38- 42

Within the 5 South Asian countries studied, Bangladeshis had the highest prevalence of most risk factors. Similar observations also have been made in migrant Bangladeshis living in the United Kingdom.⁴³ Whether this is related to lower income and educational levels in Bangladesh compared with other South Asian countries is unclear and needs to be examined. The striking variation observed in the lower age of presentation of first AMI in South Asians, with Bangladeshis being the youngest and Nepalese the oldest, indicates that the onset of AMI could be delayed by modifying these risk factors.

The main strength of our study is the large size, which enabled a high power level for analysis by sex and comparisons across the South Asian countries. We also have assessed ApoB₁₀₀ /Apo-I ratio as a more powerful marker of dyslipidemia than the usual lipoproteins, the psychosocial factors of depression and stress at home or work, diet, and exercise; all of which have not been assessed previously in South Asian populations.^11- 13

Case-control studies are potentially susceptible to biases. We minimized these by paying careful attention to the design and analysis. Selection bias was reduced by enrolling incident cases of first AMI, thereby minimizing any biases resulting from changes in lifestyle adopted by individuals with previous coronary artery disease. We also recruited cases and controls from the same source population. We selected both hospital-based and community-based controls and their separate analyses yielded similar results indicating the absence of major selection biases.¹⁴ Furthermore, our previous analysis indicated similar results in those who died in the hospital compared with those who were discharged. We minimized measurement biases by using uniform, standardized methods of data collection by trained research assistants for both the cases and the controls. Although our study is the largest study including South Asian women, there were only 252 female cases so sex differences should be cautiously interpreted. We did not study the intake of ghee (a common form of saturated fat consumed in South Asia), which has been reported to be associated with AMI.¹² Although we did not directly measure insulin resistance, which may be the underlying factor in the high rates of CHD in native South Asians,⁴⁴ we assessed factors (high WHR and lack of exercise) that lead to insulin resistance. Similarly, the effect of newer risk factors associated with AMI,⁴⁵ such as prothrombotic (fibrinogen, plasminogen activator inhihitor-1)⁴ or proinflammatory factors (C-reactive protein, lipoprotein[a], homocysteine), were not studied. However, given that the 9 risk factors we studied collectively explained 86% of the PAR for AMI, the unmeasured risk factors are unlikely to play a major independent role.

Native South Asians consume fewer fruits and vegetables, exercise less, have higher WHRs, elevated ApoB₁₀₀ /ApoA-I ratios, and consume alcohol less regularly. It is likely that the recent increase in CHD in South Asians is due to lifestyle changes associated with urbanization, perhaps interacting with a genetic predisposition that leads to abdominal obesity, dysglycemia, and dyslipidemia. Because larger hips also appeared to be protective,⁴⁶ it is possible that there is a loss of lower body muscle mass, which may influence glucose homeostasis and insulin resistance. The higher levels of risk factors in both cases and controls younger than age 60 years may explain why South Asians have earlier onset of CHD.

Eight INTERHEART risk factors account for the majority of AMI cases in South Asian countries and throughout the world. These data suggest that lifestyle changes implemented early in life have the potential to substantially reduce the risk of AMI in South Asians.