Branched‐Chain Amino Acids in Computed Tomography–Defined Adipose Depots and Coronary Artery Disease: A PROMISE Trial Biomarker Substudy

BACKGROUND: The interplay between branched‐chain amino acid (BCAA) metabolism, an important pathway in adiposity and cardiometabolic disease, and visceral adipose depots such as hepatic steatosis (HS) and epicardial adipose tissue is unknown. We leveraged the PROMISE clinical trial with centrally adjudicated coronary computed tomography angiography imaging to determine relationships between adipose depots, BCAA dysregulation, and coronary artery disease (CAD). METHODS AND RESULTS: The PROMISE (Prospective Multicenter Imaging Study for Evaluation of Chest Pain) trial randomized 10 003 outpatients with stable chest pain to computed tomography angiography versus standard‐of‐care diagnostics. For this study, we included 1798 participants with available computed tomography angiography data and biospecimens. Linear and logistic regression were used to determine associations between a molar sum of BCAAs measured by nuclear magnetic resonance spectroscopy with body mass index, adipose traits, and obstructive CAD. Mendelian randomization was then used to determine if BCAAs are in the causal pathway for adipose depots or CAD. The study sample had a mean age of 60 years (SD, 8.0), body mass index of 30.6 (SD, 5.9), and epicardial adipose tissue volume of 57.3 (SD, 21.3) cm(3)/m(2); 27% had HS, and 14% had obstructive CAD. BCAAs were associated with body mass index (multivariable beta 0.12 per SD increase in BCAA [95% CI, 0.08–0.17]; P=4×10(−8)). BCAAs were also associated with HS (multivariable odds ratio [OR], 1.46 per SD increase in BCAAs [95% CI, 1.28–1.67]; P=2×10(−8)), but BCAAs were associated only with epicardial adipose tissue volume (odds ratio, 1.18 [95% CI, 1.07–1.32]; P=0.002) and obstructive CAD (OR, 1.18 [95% CI, 1.04–1.34]; P=0.009) in univariable models. Two‐sample Mendelian randomization did not support the role of BCAAs as within the causal pathways for HS or CAD. CONCLUSIONS: BCAAs have been implicated in the pathogenesis of cardiometabolic diseases, and adipose depots have been associated with the risk of CAD. Leveraging a large clinical trial, we further establish the role of dysregulated BCAA catabolism in HS and CAD, although BCAAs did not appear to be in the causal pathway of either disease. This suggests that BCAAs may serve as an independent circulating biomarker of HS and CAD but that their association with these cardiometabolic diseases is mediated through other pathways.