Beschreibung:
Background. Visceral adipose depots such as hepatic steatosis (HS) and epicardial fat (EAT) have been implicated as markers for CVD. Higher BCAA have been implicated in HS progression, but the interplay between BCAA, different adipose tissue depots (ATDs) and CAD has not been evaluated. We leveraged the PROMISE clinical trial with centrally adjudicated coronary CTA imaging to determine relationships between ATDs, BCAA dysregulation and CAD. Methods. The PROMISE trial randomized 10,003 outpatients with stable chest pain to CTA vs. standard of care diagnostics. We included 4,019 participants with available CTA and biospecimens. ATDs (HS [presence/absence] and EAT volume) and CAD were determined by a CT core lab. NMR spectroscopy was used to measure serum BCAA (total). We determined association between (1) BMI and ATDs with obstructive CAD ( > 50% stenosis in a major epicardial coronary vessel); (2) BCAA and ATDs; and (3) BCAA and CAD, using univariate and multivariate regressions. Association between BCAA with time-to-incident CVD events (all-cause death, myocardial infarction, or unstable angina hospitalization) was performed using Cox proportional hazard models. Individual BCAA SNPs were used as the instruments for Mendelian randomization (MR) analyses to evaluate if BCAA are in the casual pathway for HS or CAD. Results. The population had a mean age of 60 years, BMI of 30.8, was 53% female, 27.1% had HS, 13.9% had CAD, and 15.4% had high risk coronary plaque. EAT was associated with CAD in the multivariate models (OR 1.004, 95% CI [1.00-1.01], p=0.019). HS was not associated with CAD. Total BCAA levels were associated with HS in multivariate models (OR 1.46, 95% CI [1.28-1.67], p<0.001), but BCAA were not associated with EAT. BCAA were associated with CAD in univariate (OR 1.18, CI 1.04-1.34, p<0.001), but were not associated with incident events. Mendelian randomization did not support the role of BCAA as in the casual pathway of HS or CAD. Conclusions. Leveraging a large clinical trial, we found that CTA-derived ATDs are associated with CAD. We further established the role of dysregulated BCAA catabolism in HS, although this relationship did not seem to be associated with or in the causal pathway of CAD.