Heart Failure with Preserved Ejection Fraction as a Multisystem Syndrome: A Mechanistically Anchored Endotype Framework for Precision Therapy.

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure cases worldwide and remains associated with substantial morbidity, mortality, and limited therapeutic efficacy. This persistent therapeutic gap reflects not only clinical heterogeneity but also a fundamental conceptual limitation: HFpEF has been approached as a myocardial disorder despite mounting evidence that it represents a multisystem syndrome. In this perspective, we integrate current pathophysiological and clinical evidence into a mechanistically anchored endotype framework based on dominant biological axes. We propose four overlapping endotypes-cardiorenal, fibrotic-inflammatory, metabolic-adiposity, and microvascular-energetic-and align contemporary and emerging therapies with these domains. We further outline a pragmatic roadmap for biomarker-guided stratification and propose principles for next-generation clinical trial design based on mechanistic enrichment. This framework provides a clinically actionable structure for biomarker-guided stratification and supports mechanism-based therapeutic selection in HFpEF. Aligning dominant biological drivers with targeted interventions generates testable hypotheses for endotype-enriched clinical trials and precision treatment strategies. Prospective validation of this approach may facilitate a transition from uniform management toward individualized, biology-driven care.