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

Abstract We recently proposed a new two-hit murine model of heart failure with preserved ejection fraction (HFpEF) amenable for both male and female animals. Using this model, we studied cardiac reverse remodelling (RR) after stopping the causing stress (Angiotensin II (AngII) + High-fat diet; MHS) after 28 days, and then introducing voluntary exercise (VE) and feeding the animals with a low-fat diet. We showed this could lead to extensive cardiac left ventricle (LV) RR. Revisiting this HFpEF model, we studied the relative contribution to RR of correcting the diet and/or starting VE after stopping AngII. We also evaluate the extent of myocardial recovery after an extended period (12 weeks instead of four) by exposing the animals to a second MHS. Our observations revealed a sex-specific response. Discontinuing AngII but continuing the HFD blocked RR in females, not males. Removing AngII and correcting either the diet or implementing VE normalized most tested gene markers of LV hypertrophy or extracellular matrix, irrespective of sex. Twelve weeks of recovery was associated with normal LV morphology and function, except for abnormal diastolic echocardiographic parameters. A second MHS after these 12 weeks led to a loss of ejection fraction in males and LV dilatation. The response of females was like that after the first MHS, suggesting a better recovery. The MHS changed markers of myocardial glucose metabolism. Pyruvate dehydrogenase (PDH) activity responsible for pyruvate entry in the mitochondria was reduced after MHS, and this was accompanied by an increase of PDH phosphorylation and pyruvate dehydrogenase kinase 4 content. RR mostly normalized these. Our results suggest sex-specific RR after stopping the MHS and that myocardial anomalies remaining in males make them more sensitive to a second HFpEF-inducing stress. Competing Interest Statement The authors have declared no competing interest.