We used existing baseline and follow-up data from the Mediators of Atherosclerosis in South Asians Living in America (MASALA) study.¹⁷ Being initiated in 2010, over a 3-year period, investigators recruited 906 South Asians living in San Francisco and the greater Chicago areas using surname-based methods. A follow-up examination was conducted in 2015–2018 and included 749 participants. All participants underwent interviews and clinical examinations at the study sites (University of California, San Francisco, and Northwestern University). Information on sociodemographic characteristics, dietary intake, physical activity, acculturation status, psychosocial factors, physical exam, and 12-hour fasting laboratory tests were collected. The MASALA study protocol was approved by the institutional review boards of University of California, San Francisco, and Northwestern University, and all participants signed an informed consent prior to undergoing study procedures. Investigators at the George Washington University were provided deidentified extant data and had no access to identifiers or study participants; therefore, the George Washington University deemed this project as not human subject research.

For our regression analysis, we excluded participants missing a component of the summary cumulative biological risk index at baseline (n = 20), or those who were not first-generation immigrants (n = 19), or missing baseline coronary artery calcium (CAC) information (n = 9). The final analytic sample included 858 South Asians at baseline, among whom, 669 (78%) South Asians had repeat CAC data at the follow-up examination approximately 5 years later.

The univariate analysis for associations between sociodemographic characteristics and CAC categories at baseline is shown in Table 1. All participants included in the analyses were foreign born (first-generation immigrants). The mean age of the participants at baseline was 56 years with 46% women. The majority of cohort had high education levels, family income more than $75,000, were married, and reported being non-smokers. More than half of the study participants had a CAC score of 0, 35% had a CAC score between 0 and 400, and 8% had a CAC score ≥400. Participants with a higher CAC score were older (P < 0.001), more likely to be men (P < 0.001), had lower family income (P = 0.002), had government insurance (P < 0.001), had lived in the US for a longer time (P < 0.001), were widowed, separated, or divorced (P = 0.005), and identified as being a current smoker (P < 0.001) or non-vegetarian (P = 0.016). About 7% of study participants had a cumulative biological risk score of 0 (Fig. 1). Among individuals with no CAC, 10% had 0 score for cumulative biological risk, while only less than 4% of individuals with CAC had a score of 0. Compared to CAC score = 0, individuals with CAC tend to have higher cumulative biological risk score (P < 0.001).

Table 2 shows the adjusted associations between cumulative biological risk with common and internal CIMT, at baseline. Individuals with 1 point higher cumulative biological risk score had a 0.01 mm higher common CIMT (95% confidence interval [CI]: 0.01–0.02, P < 0.001). A significant interaction with age at the median (55 years) as cutoff was observed for the association between cumulative biological risk and internal CIMT (P = 0.002), and hence stratified results are reported. Among individuals less than 55 years old, a 1 point increase of cumulative biological risk score was associated with 0.02 mm higher internal CIMT (95% CI: 0.01–0.04, P = 0.003), and 0.07 mm higher among individuals ≥ 55 years (95% CI: 0.04–0.09, P < 0.001).

The adjusted associations between cumulative biological risk score and CAC are shown in Table 3. At baseline, study participants with 1 point increase of cumulative biological risk score had 26% higher odds of CAC score between 0 and 400 (odds ratio [OR] = 1.26, 95% CI: 1.14–1.39, P < 0.001) and 41% higher odds of CAC ≥ 400 (OR = 1.41, 95% CI: 1.17–1.69, P < 0.001) compared to those with CAC score = 0. A 1 point increase of the cumulative biological risk score at baseline was associated with 30% higher odds of having new CAC (CAC score > 0) at the follow-up examination among individuals with CAC = 0 at baseline (OR = 1.30, 95% CI: 1.10–1.53, P = 0.002). For any CAC progression, a 1 point increase of cumulative biological risk score at baseline was associated with 17% higher CAC score increment, indicating more progression of CAC at follow-up visit with additionally adjusting for baseline CAC (rate ratio = 1.17, 95% CI: 1.10–1.24, P < 0.001).

Our study investigated the associations between cumulative biological risk and subclinical atherosclerosis in the MASALA study, a cohort of middle- and older-aged South Asian immigrants in the US. Higher cumulative biological risk score was associated with higher risk of subclinical atherosclerosis assessed by both internal CIMT and CAC at baseline as well as CAC progression after 5 years of follow-up.

Evidence from our study is consistent with previous investigations that have examined the associations between cumulative biological risk or allostatic load with CVD. Cross-sectional analysis using data from the Boston Puerto Rican Health Study showed that higher allostatic load based on biomarkers, including serum dehydroepiandrosterone-sulfate (DHEA-S), urinary cortisol, urinary norepinephrine and epinephrine, systolic and diastolic blood pressures, plasma high-density lipoproteins (HDLs) cholesterol and total cholesterol, glycosylated hemoglobin, and waist circumference, was associated with higher risk of CVD assessed by self-reported heart disease, heart attack, or stroke in Puerto Ricans aged 45–75 years (72% of women) living in Boston, MA.¹¹ Seeman et al. also demonstrated that a higher allostatic load score summarized by biomarkers of systolic blood pressure, diastolic blood pressure, waist-to-hip ratio, total cholesterol to HDL cholesterol ratio, glycated hemoglobin, urinary cortisol, urinary norepinephrine and epinephrine, HDL cholesterol, and DHEA-S was associated with higher incidence of CVD events after a 7 years of follow-up among men and women aged 70–79 years (51% women and 81% non-Hispanic white) living in Durham, NC, East Boston, MA, and New Haven, CT, in the MacArthur Successful Aging Study.²⁶ Additionally, using data from Jackson Heart Study, higher allostatic load (summarized score of waist circumference, triglyceride to HDL ratio, low-density lipoproteins (LDLs) cholesterol, glycated hemoglobin, heart rate, systolic and diastolic blood pressures, CRP, serum cortisol, and aldosterone) was associated with increased incident of coronary heart disease among African American adults aged 21–94 years (66% women) after a median 9.9 years of follow-up.²⁷ In the general US population, higher allostatic load score assessed by systolic and diastolic blood pressures, pulse, HDL and total cholesterol, waist-to-hip ratio, glycated hemoglobin, CRP, and albumin was associated with higher risk of CVD-specific mortality among individuals aged 25 years and older (84% non-Hispanic white) using data from the National Health and Nutrition Examination Survey III.²³

In this cohort, about three quarters of South Asian participants had cumulative biological risk score ≥2, indicating having at least two factors at high risk. In our study, it is not possible to identify social determinants of this increased cumulative biological risk score as has been proposed in other studies, one possible reason could be immigration-related stress. Migration is a life-altering event that can have a lasting impact on multiple health domains. The vast majority of South Asian Americans are immigrants²⁸ and are exposed to social and cultural stressors and discrimination after immigrating to the US resulting in an increased risk of dysregulation in multiple physiological processes.^29,30 A potential pathway for higher cardiometabolic risk among South Asian immigrants could be higher psychosocial and environmental stress due to less social support, acculturative stress, and perceived discrimination.^29,30 Stress and life event changes can activate hypothalamic–pituitary–adrenal axis and sympathetic–adrenal–medullary systems in multiple interdependent regulatory systems to cope with stressors and changes in order to achieve allostasis.³¹ Increased stress could result in high allostatic load, reflected in the aggregated total of systemic dysregulations across multiple physiologic regulatory systems including the cardiovascular, metabolic, immune, and neuroendocrine systems.³¹

To our knowledge, this is the first investigation examining cumulative biological risk and its association with subclinical atherosclerosis and its progression in South Asian immigrants. The MASALA study is the first large community-based South Asian cohort in the US, a minority that is not as extensively studied. We≈were able to account for several confounders in these analyses since carefully collected detailed information on covariates was available, and included traditional cultural beliefs, an important factor that influences lifestyle and acculturative stress in South Asian immigrants.

While there is a lack of a gold standard definition for components to include in the measurement for allostatic load, typically, indices include biomarkers across several domains including neuroendocrine, cardiovascular/autonomic, immune, and metabolic.³¹ Studies examining allostatic load include between 9 and 11 biomarkers,²⁰ and in our analyses, we incorporated nine biomarkers, including systolic and diastolic blood pressure, triglycerides and total cholesterol, BMI, CRP, albumin, eGRF, and glycosylated hemoglobin; however, being limited to variables that had already been collected or measured in the cohort, our summary measure of cumulative biological risk included only secondary response biomarkers to stress, and primary stress mediators such as catecholamines and cortisol were not included in these analyses.

In addition, it is important to note that participants of the MASALA study were well educated with relatively high incomes and, therefore, may not have experienced the same stressors as less educated immigrants with lower incomes, and as such these associations may have been underestimated in our analyses. Another limitation is that among the MASALA study participants, mean years spent living in the US were27 years (SD = 10.8). Given the relatively longer length of stay, these findings may also not be generalizable to recent South Asian immigrants.

Cumulative biological risk was positively associated with prevalent subclinical atherosclerosis, and higher cumulative biological risk score was associated with progression of CAC in middle- and older-aged South Asian immigrants. Future studies focused on psychosocial and lifestyle factors associated with cumulative biological risk in immigrants are needed to better understand the underlying mechanisms for these increased risks.