Abstract 9085: Phenome-Wide Association Study (phewas) Identifies Clinical Factors Associated With Plasma Ketones from Four Large Studies

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Background: Ketosis is an adaptive mechanism to the stress imposed by cardiovascular disease, including heart failure (HF), with ketones constituting a more efficient myocardial fuel. Contributing factors to the development of ketosis and its association with adverse events have not been well studied. Methods: We performed a phenome-wide association study (PHeWAS) for serum ketone (beta-hydroxybutyrate [BHB]) levels in four cohorts with a total of 6,508 participants across a broad array of cardiovascular health, including CATHGEN (N=4,374), RELAX (N=161), TECOS (N=995), and EXSCEL(N=978). On cross-sectional analysis, we performed a random effects meta-analysis relating clinical and echocardiographic predictor variables to log transformed BHB using linear regression (with false discovery rate adjusted p-values). The relationship between BHB and HF metrics (HF history, ejection fraction, right ventricular systolic pressure [RSVP]) with markers of insulin resistance was assessed in each cohort. The association between BHB and death or HF hospitalization was assessed using Cox regression. Results: The mean age was 62 years, 36% female, and 75% white. Log BHB was associated with higher heart rate (beta-coefficient 0.009, p=0.001), HF (0.188, p=0.02), ejection fraction < 55% (-0.138, p=0.008), RVSP (0.010, p=0.02), ischemic heart disease (-0.094, p=0.002), and statin use (-0.13, p=0.002). The association between HF phenotypes and BHB was not explained by markers of insulin resistance. Higher BHB levels were associated with increased risk for death and HF hospitalization ( Figure ), driven primarily by death. Conclusions: We identified several novel non-diabetic associations between ketosis and clinical measures in patients with cardiovascular disease. The link between ketosis and HF was independent of insulin resistance. BHB is a powerful predictor of outcomes, particularly death, across a spectrum of cardiovascular disease, including HF.