Key result
Following mouse models for 2.5 years revealed that distinct comorbidities (aging, obesity, hypertension, hypoxia, hyperglycemia) contributed to HFpEF through partially distinct pathological routes.
Why the study?
The specific contribution of multiple simultaneous comorbidities in HFpEF is challenging to disentangle in humans, leading to generalized therapies that may not account for underlying pathology.
This preclinical study demonstrates that different comorbidities drive HFpEF through distinct pathophysiological mechanisms, supporting the existence of specific HFpEF phenogroups.
Supports distinct HFpEF phenogroups by comorbidity in animals; leaves open clinical translation and targeted therapies.
BACKGROUND: Heart 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. METHODS: We followed distinct mouse models of major HFpEF comorbidities for 2.5 years to unveil their specific contribution to the syndrome. RESULTS: 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. CONCLUSIONS: The identification of time-dependent pathological features provides a comprehensive picture of HFpEF progression associated with each comorbidity.
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Villalba‐Orero et al. (2024) studied Heart failure with preserved ejection fraction (HFpEF). Major HFpEF comorbidities (aging, obesity, hypertension, chronic intermittent hypoxia, hyperglycemia) was evaluated on Contribution to HFpEF and diastolic dysfunction. Following mouse models for 2.5 years revealed that distinct comorbidities (aging, obesity, hypertension, hypoxia, hyperglycemia) contributed to HFpEF through partially distinct pathological routes.
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