Relative contribution of correcting the diet and voluntary exercise to myocardial recovery in a two-hit murine model of heart failure with preserved ejection fraction

Using a two-hit murine model of heart failure with preserved ejection fraction (HFpEF), we studied cardiac reverse remodeling (RR) after stopping the causing stress [Angiotensin II (AngII) + high-fat diet (HFD); metabolic and hypertensive stress (MHS)] and then introducing voluntary exercise (VE) and feeding the animals with a low-fat diet. This led to extensive left ventricle (LV) RR. We then studied the relative contribution to RR of only correcting the diet or allowing VE after stopping AngII. We next evaluated myocardial recovery after an extended period (12 wk instead of four) by exposing the animals to a second MHS. Our observations revealed a sex-specific response. Stopping AngII but continuing the HFD blocked RR in females, not males. Correcting the diet or implementing VE normalized most gene markers of LV hypertrophy or extracellular matrix remodeling, irrespective of sex. Twelve weeks of recovery were associated with normal LV morphology and function, except for several abnormal diastolic echocardiographic parameters. A second MHS after these 12 wk led to a loss of ejection fraction in males. The response of females was like that after the first MHS, suggesting a better myocardial recovery. The MHS likely changed myocardial glucose metabolism. Pyruvate dehydrogenase (PDH) activity, which is responsible for pyruvate entry in the mitochondria, was reduced after MHS, and this was accompanied by an increase in PDH phosphorylation and pyruvate dehydrogenase kinase 4 content. RR normalized these. Our results suggest sex-specific RR after stopping the MHS and that myocardial anomalies remaining make males more sensitive to a second HFpEF-inducing stress.<b>NEW & NOTEWORTHY</b> Most new mouse models of heart failure with preserved ejection fraction (HFpEF) are based on the combination of hypertension and metabolic alterations. These models provide a better approximation of the complexity of the processes involved in human HFpEF. Here, we show that the extent of reverse remodeling and myocardial recovery after stopping the causal stress in a mouse model depends on the biological sex, recovery duration, and diet correction.