Cardiac reverse remodelling in a mouse model with many phenotypical features of heart failure with preserved ejection fraction: effects of modifying lifestyle.

Multiple factors cause heart failure with preserved ejection fraction (HFpEF) and involve various systems. HFpEF prevalence is rapidly rising, and its prognosis remains poor after the first hospitalization. Adopting a more active lifestyle has been shown to provide beneficial clinical outcomes for HFpEF patients. Using a two-hit HFpEF murine model, we studied cardiac reverse remodelling (RR) after stopping the causing stress and introducing voluntary exercise (VE). We checked in 2-month-old male and female C57Bl6/J mice the heart's response to angiotensin II (AngII; 1.5 mg/kg/day for 28 days) fed or not with a high-fat diet (HFD). Then, AngII and/or the HFD were stopped, and VE was started for an additional four weeks. AngII and AngII+HFD (metabolic-hypertensive stress or MHS) caused cardiac hypertrophy (CH) and myocardial fibrosis, left ventricular (LV) concentric remodelling, atrial enlargement, and reduced exercise capacity. HFD alone induced CH and LV concentric remodelling in female mice only. CH and LV concentric remodelling were reversed four weeks after stopping AngII, starting VE, and a low-fat diet. Left atrial enlargement and exercise capacity were improved but differed from controls. We performed bulk LV RNA sequencing and observed that MHS upregulated 58% of the differentially expressed genes (DEGs) compared to controls. In the RR group, compared to MHS animals, 60% of the DEGs were downregulated. In an HFpEF mouse model, we show that correcting hypertension, diet, and introducing exercise can lead to extensive cardiac reverse remodelling.