Circulating Branched-Chain Amino Acids and Incident Cardiovascular Disease in a Prospective Cohort of US Women

Background: Circulating branched-chain amino acids (BCAAs; isoleucine, leucine, and valine) are strong predictors of type 2 diabetes mellitus (T2D), but their association with cardiovascular disease (CVD) is uncertain. We hypothesized that plasma BCAAs are positively associated with CVD risk and evaluated whether this was dependent on an intermediate diagnosis of T2D. Methods: Participants in the Women’s Health Study prospective cohort were eligible if free of CVD at baseline blood collection (n=27 041). Plasma metabolites were measured via nuclear magnetic resonance spectroscopy. Multivariable Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for BCAAs with incident CVD (myocardial infarction, stroke, and coronary revascularization). Results: We confirmed 2207 CVD events over a mean 18.6 years of follow-up. Adjusting for age, body mass index, and other established CVD risk factors, total BCAAs were positively associated with CVD (per SD: HR, 1.13; 95% CI, 1.08–1.18), comparable to LDL-C (low-density lipoprotein cholesterol) with CVD (per SD: HR, 1.12; 95% CI, 1.07–1.17). BCAAs were associated with coronary events (myocardial infarction: HR, 1.16; 95% CI, 1.06–1.26; revascularization: HR, 1.17; 95% CI, 1.11–1.25), and borderline significant association with stroke (HR, 1.07; 95% CI, 0.99–1.15). The BCAA–CVD association was greater (P interaction=0.036) among women who developed T2D before CVD (HR, 1.20; 95% CI, 1.08–1.32) versus women without T2D (HR, 1.08; 95% CI, 1.03–1.14). Adjusting for LDL-C, an established CVD risk factor, did not attenuate these findings; however, adjusting for HbA1c and insulin resistance eliminated the associations of BCAAs with CVD. Conclusions: Circulating plasma BCAAs were positively associated with incident CVD in women. Impaired BCAA metabolism may capture the long-term risk of the common cause underlying T2D and CVD.