Villalba-Orero, MaríaLópez-Olañeta, MarinaCampos-Olmo, BelénJimenez-Carretero, DanielSánchez, LucíaSánchez-Cabo, FátimaAusiello, AntonellaCañas-Álvaro, RodrigoCamafeita, EmilioVázquez, JesúsGarcía-Pavía, PabloPascual-Figal, DomingoLara-Pezzi, Enrique2026-04-092026-04-092025-01Circ Heart Fail. 2025 Jan;18(1):e011724.https://hdl.handle.net/20.500.12105/27407Heart failure with preserved ejection fraction (HFpEF) is a major public health problem characterized by multiple simultaneous comorbidities whose specific contribution is challenging to disentangle in humans, leading to a generalized therapeutic approach that may not account for the underlying pathology. We followed distinct mouse models of major HFpEF comorbidities for 2.5 years to unveil their specific contribution to the syndrome. All comorbidities contributed to HFpEF through partially distinct routes. Aging alone resulted in HFpEF in old age, with delayed left ventricular relaxation and kidney fibrosis. Obesity induced a faster deterioration of relaxation associated with enlarged left ventricle and liver fibrosis. Hypertension caused delayed ventricular relaxation independent from structural changes that preceded left atrial dilatation linked to aortic stiffness and increased fibrosis in myocardium and kidney. Chronic intermittent hypoxia led to HFpEF and relaxation impairment associated with pulmonary hypertension. Hyperglycemia accelerated diastolic dysfunction and HFpEF onset associated with reduced arterial flow and left ventricular remodeling. Therefore, the pathological substrates contributing to HFpEF included cardiac and noncardiac alterations with differential features for each comorbidity. Critically, the characteristics linked to diastolic dysfunction and HFpEF across the various comorbidities agreed with phenogroups observed in human patients. The identification of time-dependent pathological features provides a comprehensive picture of HFpEF progression associated with each comorbidity.This study was supported by grants PID2021-124629OB-I00, TED2021- 129774B-C22, and PLEC2022-009235 from the Ministerio de Ciencia In- novacion y Universidades (MICIU; AEI/10.13039/501100011033), the European Union's NextGenerationEU/PRTR ("Plan de Recuperacion, Transformacion y Resiliencia de Espana"), and Fondo Europeo de Desarrollo Regional to Dr Lara-Pezzi, PEJ-2019-TL/BMD-12831 from Comunidad de Madrid to Dr Lara-Pezzi, and Juan de la Cierva Incorporacion Grant (IJCI-2016-27698) to Dr Villalba-Orero. Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by Instituto de Salud Carlos III, Ministerio de Ciencia Innovacion y Universidades, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (grant CEX2020-001041-S funded by MICIU/AEI/10.13039/501100011033).engAMhttp://creativecommons.org/licenses/by-nc-nd/4.0/agingheart failure, diastolichyperglycemiahypertensionobesityAttribution-NonCommercial-NoDerivatives 4.0 International39611257CIRCULATION-HEART FAILUREopen access