The Dark Side of Vascular Aging: Noncoding Ribonucleic Acids in Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) represents a growing global public health challenge, now accounting for approximately half of all heart failure cases and often linked to a systemic pathophysiological process in older adults with multiple comorbidities. Despite increasing recognition of the vascular contributions to HFpEF, the precise molecular mechanisms, particularly the role of noncoding Ribonucleic Acids (ncRNAs) in mediating vascular aging and subsequent cardiac dysfunction, remain incompletely understood. This review provides a comprehensive overview of the mechanistic link between vascular aging and HFpEF, with a specific focus on the pivotal roles of ncRNAs in this complex interplay. We delineate the classification of vascular aging, its cellular hallmarks, including endothelial senescence, vascular smooth muscle cell phenotypic switching, and extracellular matrix remodeling, and its systemic implications, such as inflammaging, oxidative stress, and reduced nitric oxide bioavailability. We then detail how these vascular alterations, including increased ventricular afterload and impaired myocardial perfusion due to coronary microvascular dysfunction, contribute to HFpEF pathophysiology. The review extensively discusses recent findings on how diverse classes of ncRNAs, notably microRNAs, long noncoding RNAs, and circular RNAs, along with emerging evidence for PIWI-interacting RNAs, small nuclear RNAs, small nucleolar RNAs, and tRNA-derived small RNAs, regulate these vascular aging processes and serve as molecular bridges connecting vascular dysfunction to heart failure. In conclusion, understanding the regulatory landscape of ncRNAs in vascular aging may reveal novel biomarkers and therapeutic avenues, offering new strategies for precision medicine in HFpEF.