miRNA-Orchestrated Fibroinflammatory Responses in Heart Failure with Preserved Ejection Fraction: Translational Opportunities for Precision Medicine.

Heart failure with a preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases. It continues to impose a significant global cardiovascular burden due to its rising prevalence, complex pathophysiology, and limited treatment options. The absence of effective disease-modifying therapies is primarily attributable to the complex and heterogeneous pathophysiology underlying HFpEF. The hallmark of HFpEF is systemic inflammation, mostly originating from extracardiac comorbidities, which initiates and sustains the process of myocardial fibrosis, resulting in diastolic dysfunction. Recent evidence has identified specific micro ribonucleic acids (miRNAs) as key regulatory molecules in this inflammation-fibrosis cascade. Particularly, miR-21 and miR-29 play a central role in modulating these pathological processes by regulating the post-transcriptional expression of genes involved in inflammation, cardiac fibrosis, and remodeling. The inflammation-fibrosis axis in HFpEF offers multiple therapeutic opportunities ranging from direct anti-fibrotic strategies to the modulation of inflammation and fibrosis-related miRNA signatures. Such targeted approaches, especially miRNA modulation, hold potential to disrupt fundamental molecular mechanisms driving disease progression, moving beyond conventional HFpEF management. This narrative review explores the roles of miRNAs in modulating inflammation and fibrosis in HFpEF, critically assesses their potential as diagnostic and prognostic biomarkers, and evaluates their therapeutic application. Given the urgent clinical need for efficient HFpEF treatment strategies, understanding miRNA-mediated regulation of the inflammation-fibrosis axis is essential for developing personalized, mechanism-based therapies for HFpEF that could fundamentally change the HFpEF management paradigm.