Abstract
BACKGROUND: Subclinical alterations in left ventricular (LV) structure, diastolic function, and metabolic disturbances are associated with coronary heart disease (CHD) risk, but their relationships remained unclear. Large-scale longitudinal metabolomic profiling of LV measures is lacking. METHODS: Using untargeted metabolomics, we quantified 563 fasting plasma metabolites from 1799 American Indian individuals attending 2 exams (~5.5 years apart). We examined associations between metabolites and measures of LV structure (LV mass index, relative wall thickness), and diastolic function (peak early filling velocity to peak late filling velocity, isovolumic relaxation time, and deceleration time) using generalized estimating equation model. Findings were then replicated in an independent biracial cohort. Frailty Cox proportional hazards models were used to examine whether LV-related metabolites are associated with the risk of CHD over a 20-year follow-up. Pathway enrichment analysis was performed to identify relevant metabolic pathways. RESULTS: We identified 173 metabolites (47 named; q<0.05) associated with LV structure or diastolic function in the SHFS (Strong Heart Family Study), and some metabolites were confirmed in the biracial cohort. Three metabolites were additionally associated with incident CHD. Aspartic acid and palmitoleic acid were associated with lower LV mass index and peak early filling velocity to peak late filling velocity ratio and lower CHD risk (hazard ratios [HRs], 0.75 [95% CI, 0.56-0.99] to 0.81 [95% CI, 0.67-0.99]), whereas isothreonic acid was associated with higher relative wall thickness and higher CHD risk (HR, 1.15 [95% CI, 1.01-1.32]). LV-related metabolites were enriched in arginine biosynthesis, alanine-aspartate-glutamate metabolism, and starch and sucrose metabolism. CONCLUSIONS: We identified metabolomic markers of LV structure and diastolic function, several of which that were independently associated with CHD risk, providing insight into metabolic pathways underlying LV subclinical changes and CHD.