Moderate intensity exercise training ameliorates the heart failure with preserved ejection fraction phenotype in a preclinical model by improving cardiometabolic fitness

Abstract Introduction and Aim Exercise intolerance is a hallmark feature of patients with heart failure with preserved ejection fraction (HFpEF).While clinical evidence suggests potential benefits of exercise training in HFpEF, its mechanisms remain largely unknown.In this study, we used a translationally relevant murine model of cardiometabolic HFpEF(1) to assess whether moderate intensity continuous training(MICT) can ameliorate the HFpEF phenotype in mice and promote cardiometabolic health. Methods Twenty-five adult, male C57BL/6N were fed with the combination of high fat diet(HFD;D12492,Research diet)and L-NAME(0.5 g/L,in drinking water) for 15 weeks to elicit HFpEF as previously described(1).After the establishment of the HFpEF phenotype, mice were randomized in two groups:sedentary(SED,n= 10) and exercised(MICT,n=15)mice.MICT was carried out according to the protocol:running on 10-degree positive inclination treadmill for 8 consecutive weeks,5 times/week,60 minutes/day,at a speed gradually increasing from 0.1 to 0.2 m/sec on a weekly basis.Morphometry, echocardiography(TTE),isoproterenol-induced stress echocardiography(SE),time domain nuclear magnetic resonance, and treadmill exhaustion tests were performed at the beginning and end of MICT.Additionally, at the end of MICT blood and tissues were collected for proteomics analysis(Fig1).Non-trained male C57BL/6N mice(37w) were used as controls for the HFpEF mice. Results Before randomization, all HFpEF mice were similar in terms of phenotypic characteristics. Compared to SED mice, MICT induced a significantly decrease in body weight driven by a reduction of total fat mass with an increased in lean mass(Fig2A+B).Interestingly, MICT had no impact on skeletal muscle mass for all different muscle groups evaluated (extensor digitorum longus, soleus and tibialis anterior).Importantly, MICT led to a significant improvement in exercise capacity in HFpEF mice, as shown by increased running distance and time, surpassing even the running distance seen in non-HFpEF mice (SED:62.8±18.7,MICT:305.7±13.9,non-HFpEF mice: 129.72±15.2meters,p