A porcine model of hypertensive cardiomyopathy: implications for heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFPEF) evolves with the accumulation of risk factors. Relevant animal models to identify potential therapeutic targets and to test novel therapies for HFPEF are missing. We induced hypertension and hyperlipidemia in landrace pigs (n=8) by deoxycorticosteroneacetate (DOCA, 100 mg/kg, 90d-release subcutaneous depot) and a western diet (WD) containing high amounts of salt, fat, cholesterol and sugar for 12 wks. Compared to weight-matched controls (n=8), DOCA/WD treated pigs showed left ventricular (LV) concentric hypertrophy and left atrial (LA) dilatation in the absence of significant changes in LV ejection fraction or symptoms of heart failure at rest. The LV end-diastolic pressure-volume relationship (EDPVR) was markedly shifted leftwards. During simultaneous right atrial pacing and dobutamine infusion, cardiac output reserve and LV peak inflow velocities were lower in DOCA/WD treated pigs at higher LV end-diastolic pressures. In LV biopsies, we observed myocyte hypertrophy, a shift towards the stiffer titin isoform N2B and reduced total-titin phosphorylation. LV superoxide production was increased, in part due to nitric oxide synthase (NOS) uncoupling, while AKT and NOS isoform expression and phosphorylation were unchanged. In conclusion, we developed a large animal model where loss of LV capacitance was associated with a titin isoform shift and dysfunctional NOS, in the presence of preserved LV ejection fraction. Our findings identify potential targets for the treatment of HFPEF in a relevant large animal model.