Abstract 14305: Diastolic Dysfunction and Activation of Ventricular and Atrial Unfolded Protein Response in a Novel Gottingen Miniswine Model of Heart Failure With Preserved Ejection Fraction

Abstract

Introduction: During cardiac hypertrophy, the unfolded protein response (UPR) is activated which includes upregulation of chaperones to assist with protein folding and protein ubiquination for proteolytic degradation. We investigated the expression level of a key chaperone Hspa5 (heat shock protein A5) and ubiquinated protein levels in left ventricular (LV) and atrial (LA) tissue obtained from a preclinical porcine model heart failure with preserved ejection fraction (HFpEF) involving obesity and hypertension. Methods: Female Gottingen minipigs were fed standard or western diet (WD) for 20 weeks to induce obesity and metabolic syndrome and subsequent HFpEF. Those fed WD were also administered 11-deoxycorticosterone acetate (DOCA) (50 mg/kg, SQ) to induce hypertension. LV functional assessment was performed via transthoracic echocardiography and invasive hemodynamics at 20 weeks. In addition, UPR and proteasomal function were assayed following 20 weeks of HFpEF in ventricular and left atrial extracts via RT-qPCR and immunoblot. Results: Minipigs fed WD+DOCA demonstrated hypercholesterolemia, hypertension, LV hypertrophy and increased LVEDP. LVEF was >50% in HFpEF and control groups. We observed significant LV diastolic dysfunction as measured by E/e’ and LA dysfunction as decreased LA fractional area of change (LAFAC) at 20 weeks. LV extracts from HFpEF swine demonstrated a marked increase in Hspa5 without measurable increases in standard fetal genes (e.g. Myh7 ). LA extracts from HFpEF swine exhibited robust accumulation of ubiquitylated proteins compared to control swine. There was a positive correlation between Hspa5 and E/e’ ratio, and the inverse for LA ubiquitylated proteins and LA function. Conclusions: Coordinate with myocardial stiffening, hypertrophy and functional decline, HFpEF robustly augments proteostasis in both LV myocardium and LA recapitulating the clinical presentation of HFpEF patients.