Validation of the association between a branched chain amino acid metabolite profile and extremes of coronary artery disease in patients referred for cardiac catheterization

Abstract

Objective To validate independent associations between branched-chain amino acids (BCAA) and other metabolites with coronary artery disease (CAD). Methods We conducted mass-spectrometry-based profiling of 63 metabolites in fasting plasma from 1983 sequential patients undergoing cardiac catheterization. Significant CAD was defined as CAD index ≥ 32 (at least one vessel with ≥95% stenosis; N = 995) and no CAD as CAD index ≤ 23 and no previous cardiac events (N = 610). Individuals (N = 378) with CAD severity between these extremes were excluded. Principal components analysis (PCA) reduced large numbers of correlated metabolites into uncorrelated factors. Association between metabolite factors and significant CAD vs. no CAD was tested using logistic regression; and between metabolite factors and severity of CAD was tested using linear regression. Results Of twelve PCA-derived metabolite factors, two were associated with CAD in multivariable models: factor 10, composed of BCAA (adjusted odds ratio, OR, 1.20; 95% CI 1.05–1.35, p = 0.005) and factor 7, composed of short-chain acylcarnitines, which include byproducts of BCAA metabolism (adjusted OR 1.30; 95% CI 1.14–1.48, p = 0.001). After adjustment for glycated albumin (marker of insulin resistance [IR]) both factors 7 (p = 0.0001) and 10 (p = 0.004) remained associated with CAD. Severity of CAD as a continuous variable (including patients with non-obstructive disease) was associated with metabolite factors 2, 3, 6, 7, 8 and 9; only factors 7 and 10 were associated in multivariable models. Conclusions We validated the independent association of metabolites involved in BCAA metabolism with CAD extremes. These metabolites may be reporting on novel mechanisms of CAD pathogenesis that are independent of IR and diabetes.

Plasma Branched-Chain Amino Acids and Incident Cardiovascular Disease in the PREDIMED Trial

“…Our results are consistent with several previous studies of baseline BCAAs and CVD (4,6, 13), however our study represents the first longitudinal assessment with repeated measurements of BCAA concentrations. Shah, et al (4) found a direct cross-sectional association between a principal component-derived factor with BCAAs and related catabolites and prevalent myocardial infarction.…”

Metabolomics and Metabolic Diseases: Where Do We Stand?

“…Similarly, metabolomics profiling of 447 metabolites in 2204 female subjects in the TwinsUK cohort found a strong association of BCAA and their metabolites with type 2 diabetes and impaired fasting glucose levels (Menni et al, 2013). Several groups have also shown that BCAA and related metabolites are associated with coronary artery disease (CAD), even when controlled for diabetes (Shah, et al, 2010; Magnusson et al, 2013; Bhattacharya et al, 2014). …”

Metabolic Dysfunction in Heart Failure: Diagnostic, Prognostic, and Pathophysiologic Insights From Metabolomic Profiling

“…The metabolome, now in its third decade of characterization in life sciences research, has solidified its position in the top echelon of well-established ‘omes [1]. Featured in over 13,000 publications since 1998, metabolomic investigations have led to advances in numerous fields ranging from sickle cell disease to autism, to type 2 diabetes, to coronary artery disease [2–7]. Despite the many successes of metabolomic profiling in elucidating molecular mechanisms and developing diagnostic or prognostic models, it has been employed to a limited extent in the setting of heart failure (HF).…”