Unfolding Discoveries in Heart Failure

This editorial explores evolving pathophysiologic insights into heart failure with preserved ejection fraction (HFpEF). Once considered a benign precursor to systolic heart failure, HFpEF is now recognized as a persistent condition with high prevalence and limited treatment success. The article reviews three major contributors to left ventricular diastolic stiffness: myocardial fibrosis driven by coronary microvascular inflammation, reduced cardiomyocyte elasticity due to altered titin phosphorylation, and a newly proposed mechanism involving suppression of the unfolded protein response (UPR). Mouse models combining metabolic dysfunction and nitric oxide synthase inhibition recapitulated HFpEF features and responded to targeted interventions restoring UPR. These findings suggest distinct mechanistic subtypes of HFpEF, advocating for precision-based therapeutic strategies aligned with underlying pathology antifibrotic, anti-inflammatory, or protein stabilizing approaches.

This editorial explores evolving pathophysiologic insights into heart failure with preserved ejection fraction (HFpEF). Once considered a benign precursor to systolic heart failure, HFpEF is now recognized as a persistent condition with high prevalence and limited treatment success. The article reviews three major contributors to left ventricular diastolic stiffness: myocardial fibrosis driven by coronary microvascular inflammation, reduced cardiomyocyte elasticity due to altered titin phosphorylation, and a newly proposed mechanism involving suppression of the unfolded protein response (UPR). Mouse models combining metabolic dysfunction and nitric oxide synthase inhibition recapitulated HFpEF features and responded to targeted interventions restoring UPR. These findings suggest distinct mechanistic subtypes of HFpEF, advocating for precision-based therapeutic strategies aligned with underlying pathology antifibrotic, anti-inflammatory, or protein stabilizing approaches.