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

Abstract

Using a two-hit murine model of heart failure with preserved ejection fraction (HFpEF), we studied cardiac reverse remodelling (RR) after stopping the causing stress (Angiotensin II (AngII) + High-fat diet (HFD); 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 weeks 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 remodelling, irrespective of sex. Twelve weeks of recovery was associated with normal LV morphology and function, except for several abnormal diastolic echocardiographic parameters. A second MHS after these 12 weeks 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.