The Potential Connection Between Mechanical Stress and Heart Failure with Preserved Ejection Fraction: Mechanistic Insights and Therapeutic Potential

Heart failure with preserved ejection fraction (HFpEF) represents a complex clinical syndrome characterized by limited therapeutic options, which are largely due to its intricate pathophysiology. The role of mechanical stress is pivotal in maintaining cardiovascular homeostasis; conversely, its dysregulation may precipitate the progression of cardiovascular diseases. In HFpEF, both macroscopic structural alterations and intricate molecular processes might be influenced by mechanical stress. This review examines the potential associations between mechanical stress and HFpEF, exploring the pathophysiological underpinnings to the effects of mechanotransduction effectors on cardiac remodeling and the progression of heart failure, providing novel insights into the pathological mechanisms of HFpEF. Therapeutic strategies targeting these mechanotransduction effectors have shown promise in mitigating pathological cardiac remodeling in models of metabolic-associated heart failure, underscoring their potential as innovative treatments for HFpEF. Considering the clinical heterogeneity of HFpEF, it is imperative to pursue phenotype-specific personalized treatments to optimize therapeutic efficacy.