Metabolomic signatures of cardiac remodelling and heart failure risk in the community

Abstract

Aims: Heart failure (HF) is associated with several metabolic changes, but it is unknown whether distinct components of the circulating metabolome may be related to cardiac structure and function, and with incident HF in the community.

Methods and results: We assayed 217 circulating metabolites in 2336 Framingham Study participants (mean age 55 ± 10 years, 53% women) without HF at baseline. We used linear and Cox regression to relate concentrations of metabolites to left ventricular (LV) diastolic dimension, LV wall thickness, LV ejection fraction, left atrial dimension, LV ventricular mass, and aortic root size cross-sectionally and to incident HF prospectively. Bonferroni-adjusted P-values <0.05 denoted statistical significance. Circulating concentrations of kynurenine [β = -0.12 cm per standard deviation (SD) increment in normalized residual of metabolite, P = 7.3 × 10^-8 ] and aminoadipate (-0.11 cm per SD increment, P = 2.61 × 10^-5 ) were associated with left ventricular diastolic dimension, phosphatidylcholine (carbon:double bound = 38:6) with left atrial dimension (0.10 cm per SD increment, P = 9.7 × 10^-6 ), and cholesterol ester (carbon:double bound = 20:5) with left atrial dimension (0.10 cm per SD increment, P = 1.4 × 10^-5 ) in multivariable-adjusted models. During an average follow-up of 15.8 (range 0.02-23.2) years, 113 participants (5%) were diagnosed with HF with reduced ejection fraction and 106 individuals (5%) with HF with preserved ejection fraction. In multivariable analyses, concentrations of phosphatidylcholine (hazard ratio 0.63, P = 1.3 × 10^-5 ) and ornithine (hazard ratio 1.44, P = 0.00014) were associated with HF with reduced ejection fraction.

Conclusions: Several metabolites, including the vasoactive metabolite kynurenine, were related to cardiac structure and function in our sample. Additional research is warranted to confirm our observations and investigate if these metabolites can risk stratify ambulatory individuals.

Keywords: Echocardiography; Heart failure risk; Metabolomics.

Figure 1

Association of selected metabolites and echocardiographic measures. Only variables that were significant at a false discovery rate level of ≤0.10 in one or more of the echocardiographic measures are presented. The y axis presents −log(P‐value). Dotted line represents a Bonferroni‐corrected P‐value of <0.05. AOR, aortic root; FS, fractional shortening; LAD, left atrial dimension; LVDD, left ventricular diastolic dimension; LVM, left ventricular mass; LVWT, left ventricular wall thickness. Metabolite abbreviations: SM, sphingomyelin; CE, cholesterol ester; DAG, diacylglycerol; TAG, triacylglycerol. C stands for carbon:double bond; for example, C16_1_SM is sphingomyelin (carbon:double bond = 16:1).