Plasma Metabolite Associations with Incident Heart Failure with Reduced and Preserved Ejection Fraction

Background: Prior studies on metabolite associations with incident heart failure (HF) used billing code-based definitions and lacked the data on left ventricular ejection fraction needed to determine associations with HF with reduced (HFrEF) and preserved (HFpEF) ejection fraction. Objectives: Identify potentially causal plasma metabolite associations with HFrEF and HFpEF, ascertained using a validated machine learning- and natural language processing-based algorithm, in up to 38,000 individuals. Methods: We included MGB Biobank participants who had available metabolomics data and no history of HF at baseline. The primary exposures were plasma levels of 42 metabolites measured using a H1 nuclear magnetic resonance platform. The primary outcome was incident HF, ascertained by a validated machine learning- and natural language processing-based algorithm. Multivariable Cox proportional hazards regression to quantify the associations between a 1-SD difference in metabolite level and the time to incident HF. Mendelian randomization analysis was used test the potential causality of each metabolite-HF association. Results: The final analytical cohort included 38,628 individuals with a mean age of 63 years (56% women). Higher plasma levels of glutamine associated with a higher risk of incident HF (HR [95% CI]: 1.21 [1.07-1.35]) while higher levels of docosahexaenoic acid (an omega-3 fatty acid) (0.85 [0.75-0.95]), phosphatidylcholines (0.85 [0.75-0.97]), phosphoglycerides (0.86 [0.76-0.97]) and total cholines (0.85 [0.75-0.97]) associated with a lower HF risk. Docosahexaenoic acid and total omega-3 fatty acids associated with HFpEF. Associations with HFpEF tended to be stronger than with HFrEF for several fatty acids, including omega-3 fatty acids, in individuals with obesity, but not coronary artery disease or diabetes. Mendelian randomization analysis supported causal associations between higher levels of docosahexaenoic acid and omega-3 fatty acids with a higher risk of HF and greater left ventricular mass index. Conclusions: Dysregulated omega-3 fatty acid metabolism may be causally associated with a higher risk of incident HFpEF.