Abstract
BACKGROUND AND AIM: Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with heart failure with preserved ejection fraction (HFpEF), independent of shared risk factors. The aim of this study was to discover metabolic pathways associated with HFpEF in individuals with MASLD to explore shared mechanisms and identify biomarkers of risk. METHODS: We examined HFpEF cases and non-HF controls in the Duke CATHeterization GENetics (CATHGEN) study. HFpEF was defined as left ventricular ejection fraction (LVEF) ≥ 45%, diastolic dysfunction grade ≥ 1 on transthoracic echocardiogram (TTE), and history of clinical heart failure. MASLD was phenotyped using ICD codes or hepatic steatosis index (HSI) > 36, in the presence of ≥ 1 metabolic risk factor. Metabolomic profiling was performed in fasting plasma using targeted tandem flow injection (absolute quantification, n = 60) and non-targeted (relative quantification, n = 210) mass spectrometry. Logistic regression models tested the association between metabolite factors and HFpEF. An interaction term analyzed the influence of MASLD on associations between metabolites and HFpEF. RESULTS: A total of 430 participants were included; 247 (57.4%) had HFpEF. In participants with MASLD (N = 222, 51.6%), a factor composed of markers of kidney function, acylcarnitines, and modified amino acids was associated with HFpEF (OR: 2.2, 95% CI: 1.5-3.2, FDR-adjusted p-value = 0.002). The association of a PC composed primarily of ketoglutarate and phenyl sulfate with HFpEF was modified by MASLD (unadjusted p-value = 0.03). CONCLUSIONS: Markers of kidney function and mitochondrial metabolism were associated with HFpEF in participants with MASLD. Mitochondrial energy pathways may link MASLD to HFpEF.