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

Abstract

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.

A murine model of hypertensive heart disease in older women

“…It was unsuspected that AngII infusion in old Ovx mice would tend to normalize the expression of clock genes towards levels measured in young females instead of the opposite. We recently observed in young female mice treated with combined AngII and a high-fat diet that expression of Arntl, Ciart, and Per2 was all modulated in the opposite direction we observed here ( Aidara et al, 2024 ). The current knowledge of the control of cardiac clock genes does not provide much to explain this observation, and further studies are needed to both confirm and understand it better.…”

“…Sham surgery was performed without the placement of a vehicle-filled osmotic minipump in all animals. Previous studies have shown that this had not caused differences in the heart ( Matsiukevich et al, 2023 ; Aidara et al, 2024 ).…”

“…One important addition that our model will probably need in the future is the inclusion of a metabolic stressor. Previous publications of HFpEF murine models ( Withaar et al, 2021a ; Schiattarella et al, 2019 ; Withaar et al, 2021b ; Tong et al, 2019 ; Matsiukevich et al, 2023 ; Aidara et al, 2024 ) added a high-fat diet to hypertensive stress. We recently observed in young female mice that the high-fat diet alone was sufficient to cause significant levels of CH, comparable to AngII.…”

“…We did not submit the animals to exercise exhaustion protocols, and lung weight remained within the normal range. We did not incorporate metabolic stress such as a high-fat diet as in other recently developed HFpEF models ( Withaar et al, 2021a ; Schiattarella et al, 2019 ; Withaar et al, 2021b ; Tong et al, 2019 ; Matsiukevich et al, 2023 ; Aidara et al, 2024 ).…”

“…The study used male and female animals but did not emphasize sex-based differences. We recently proposed our HFpEF mouse model, which combined AngII and HFD for four weeks, and it was amenable in both young and older animals, either male or female ( Aidara et al, 2024 ).…”