Molecular Pathways, Target Landscape, and Translational Models in Heart Failure with Preserved Ejection Fraction

Abstract

Highlights What are the main findings? HFpEF’s clinical heterogeneity is attributable to underlying interconnected molecular pathways that drive the disease, and the therapeutic landscape is evolving toward phenotype-specific interventions. Current animals and in vitro HFpEF fail to fully recapitulate the mechanistic complexity of the disease spectrum, and thus there is a major need for improving phenotype dependent translational fidelity. What are the implications of the main findings? Advancing the effectiveness of HFpEF will likely rely on improved phenotype-based patient stratification strategies, which remains a key area of investigation. Innovation in drug discovery and clinical translation requires prioritization of human-relevant, multifactorial HFpEF models with integration of high-throughput functional assays, multi-omics profiling, and machine-learning approaches to improve patient-specific therapeutic outcomes. Abstract Heart failure with preserved ejection fraction (HFpEF) is a substantial global health burden and the greatest unmet medical need for cardiovascular diseases. It is marked by pronounced clinical heterogeneity and complex multi-system pathophysiology with limited therapeutic options. Progress in developing effective therapeutics is constrained by the inadequacy of experimental models to fully recapitulate the multifactorial nature of the disease. Recent evidence underscores the significant involvement of inflammatory, oxidative, and mitochondrial pathways in the pathogenesis of HFpEF, with non-coding RNAs and epigenetic regulation serving as crucial modulators and prospective therapeutic targets. This review maps the HFpEF target landscape, while critically assessing the mechanistic contributions, translational fidelity, and limitations of existing in vivo and in vitro models. Further, advances are noted among the in vitro technologies, including human cardiac organoids and engineered heart tissues integrated with high-throughput multi-omics and computational modeling, enabling in-depth examination of HFpEF mechanisms. Finally, we underscore the necessity of integrative, systems-level approaches and multi-marker strategies to enhance translational relevance, improve risk stratification, and accelerate development of mechanism-based therapies. Collectively, this review supports phenotypic-guided and mechanism-informed therapeutic development for HFpEF, and provides a roadmap for next generation model development and therapeutic innovation.