Two-Hit Swine Model of Heart Failure With Preserved Ejection Fraction Mimics Cardiac and Systemic Pathologies

Heart failure with preserved ejection fraction (HFpEF) accounts for over 50% of heart failure cases and is associated with significant morbidity and mortality. Developing preclinical models that recapitulate the cardiac and systemic pathologies of HFpEF is critical for advancing treatment.

Large animal models offer translational relevance due to physiological similarities to humans, but few capture both cardiac and extracardiac features of HFpEF. The authors aimed to develop a swine model of HFpEF using a 2-hit intervention combining high-salt diet with infrarenal aortic banding.

Female swine were subjected to this intervention and evaluated longitudinally over 20 weeks. Echocardiography and invasive pressure-volume (PV) loop analysis assessed cardiac remodeling and diastolic dysfunction. Histopathology was performed on cardiac and extracardiac tissues, including lungs, liver, and kidneys.

The 2-hit intervention induced a progressive HFpEF phenotype over 20 weeks, as evidenced by echocardiographic increases in left ventricular mass, wall thickness, left atrial volume, and diastolic dysfunction with preserved systolic function. PV loop analysis revealed a steeper end-diastolic PV relationship, indicating increased left ventricular stiffness and reduced compliance. Histology showed early myocardial fibrosis at 4 weeks, with atrial-to-ventricular progression of cardiomyocyte hypertrophy culminating in global cardiac hypertrophy by 20 weeks. Extracardiac findings included pulmonary and hepatic congestion with associated structural remodeling and fibrosis, and renal remodeling accompanied by elevated serum creatinine, consistent with systemic HFpEF pathophysiology.

This novel 2-hit swine model replicates key cardiac and systemic pathologies of human HFpEF and provides a robust platform for elucidating underlying mechanisms and evaluating potential therapies.