Unravelling the Pathogenesis of Heart Failure with Preserved Ejection Fraction: The Pivotal Role of Autophagy and...

Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases and is associated with high morbidity and mortality. Despite its prevalence, effective therapies remain elusive due to its complex and multifactorial pathophysiology, including systemic inflammation, microvascular dysfunction, myocardial fibrosis and diastolic dysfunction. Recent evidence has highlighted the central role of cellular stress responses (particularly autophagy and endoplasmic reticulum stress) in the progression of HFpEF. This review examines current evidence on the roles of autophagy and endoplasmic reticulum stress in HFpEF, focusing on their interplay and associated biomarkers, including light chain 3 (LC3), Beclin-1, GRP78 and CHOP. Dysregulated autophagy and endoplasmic reticulum stress have been shown to promote vascular senescence, inflammation, fibrosis and further remodelling in HFpEF. The targeting of autophagy and endoplasmic reticulum stress offers new diagnostic and therapeutic avenues. Future research should prioritise biomarker development and personalised therapies to shift HFpEF management from symptom control to molecular targeting.