Short-Chain Fatty Acids in Heart Failure with Preserved Ejection Fraction: Pathophysiological Roles and Therapeutic Potential

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by typical heart failure symptoms, left ventricular ejection fraction (LVEF) ≥50%, elevated natriuretic peptides, and impaired diastolic function. HFpEF constitutes a heterogeneous clinical syndrome with increasing prevalence worldwide and limited therapeutic options. Short-chain fatty acids (SCFAs), generated by gut microbial fermentation of dietary fibers, have recently been implicated as modulators of cardiovascular physiology and pathology. In this narrative review, we synthesize evidence linking SCFAs and SCFA-related signaling to HFpEF pathophysiology, with attention to the distinction between direct HFpEF evidence and findings extrapolated from broader cardiovascular and metabolic models. Although HFpEF-specific data remain limited, available evidence suggests that SCFAs may be relevant to several disease-associated processes, including systemic inflammation, adipokine dysregulation, endothelial dysfunction, myocardial stiffness, and metabolic derangement. We further discuss receptor-mediated and histone deacetylase-dependent mechanisms, consider differences among acetate, propionate, and butyrate, and evaluate the current limitations and therapeutic implications of SCFA-related pathways in HFpEF. At present, SCFA-directed interventions should be viewed as investigational rather than established therapeutic strategies for HFpEF.