Orchestrating HFpEF: How Noncoding RNAs Drive Pathophysiology and Phenotypic Outcomes

Heart Failure with Preserved Ejection Fraction (HFpEF) is an increasingly prevalent clinical syndrome that poses a significant public health challenge due to its complex pathophysiology, diagnostic limitations, and lack of effective therapies. Central to its development are multifactorial and interrelated mechanisms, including left ventricular diastolic dysfunction, myocardial fibrosis, inflammation, endothelial dysfunction, and cardiomyocyte hypertrophy. In recent years, noncoding RNAs (ncRNAs)—particularly microRNAs (miRNAs) and long noncoding RNAs (LncRNAs)—have emerged as critical regulators of these cellular and molecular pathways. This review outlines the major pathophysiological mechanisms underlying HFpEF and highlights the noncoding RNAs most extensively studied in this context. Several ncRNAs have shown promise as biomarkers for the diagnosis and prognosis of HFpEF, owing to their tissue specificity, stability in circulation, and involvement in disease-relevant pathways. However, their integration into routine clinical practice remains limited. Importantly, the regulatory functions of ncRNAs in HFpEF pathophysiology also position them as potential therapeutic targets. Early experimental studies demonstrate encouraging results, suggesting that ncRNA-targeted interventions may support the development of personalized treatment strategies tailored to the diverse clinical phenotypes observed in HFpEF.