Mediation of the effects of obesity on coronary heart disease in a bi-ethnic cohort: the Atherosclerosis Risk in Communities (ARIC) Study

Excess adiposity is associated with physiologic risk factors for coronary heart disease (CHD), including dyslipidemia, high blood pressure and insulin resistance, however few studies have analyzed mediation of the obesity-CHD relationship by individual physiologic risk factors. Mediation can be examined using structural equation modeling (SEM), which has several advantages over standard regression for analyses of mediation, including significance-testing of the individual indirect (mediated) effects. We used data from the Atherosclerosis Risk in Communities (ARIC) Study, a longitudinal cohort of 15,792 African American and White adults aged 45-64 years at baseline (1987-1989) and followed through 2005, to examine mediation of the effects of body mass index (BMI) on CHD hazard. Physiologic risk factors examined included total and high density lipoprotein (HDL) cholesterol, triglycerides, systolic and diastolic blood pressure (SBP, DBP) and insulin resistance. The overall effect of BMI on CHD was curved, with a steeper slope at lower compared to higher BMI levels. Mediated effects of BMI on CHD tended to be strongest through HDL cholesterol and insulin resistance. Mediation was more moderate through total cholesterol and SBP, and was null through DBP and triglycerides. In models that included all 6 hypothesized mediators, BMI was not directly associated with CHD. We found no differences in mediation by race or gender. Because antihypertensive medication use is highly prevalent in this cohort (31% at baseline), we explored the impact of medication use on our analyses involving blood pressure. The associations of BMI with blood pressure and with CHD were markedly attenuated in participants taking antihypertensive medication compared to participants not taking antihypertensive medications, though the association of blood pressure with CHD was not different between the two groups. When associations of BMI with SBP and DBP were compared in the same individuals before and after initiating treatment with antihypertensive medications, no differences were found. Overall, these results highlight the complexity of analyses of blood pressure in persons being treated with antihypertensive medication and underscore the importance of traditional physiologic risk factors, particularly HDL cholesterol and insulin resistance, as mediators of the effect of obesity on CHD