Background: Patients with heart failure and preserved ejection fraction (HFpEF), accounting for 50% of all heart failure patients, exhibit reduced exercise capacity probably due to molecular changes in the skeletal muscle. Recently the angiotensin receptor-neprilysin inhibitor (ARNI) Sacubitril/Valsartan (Sac/Val) has been shown to increase exercise capacity in patients suffering from heart failure with reduced ejection fraction (HFrEF). So far it is unknown if Sac/Val also has some beneficial impact on skeletal muscle function and molecular changes in HFpEF. This study aimed to address the question whether Sac/Val affects molecular alterations and skeletal muscle function in a rat model of HFpEF. 

Methods: Starting at an age of 20 weeks female obese ZSF-1 rats received Sac/Val as a daily oral gavage over a time period of 12 weeks (HFpEF-ARNI). The treated animals were compared age-matched untreated lean (healthy) and obese (HFpEF control) ZSF-1rats. At an age of 32 weeks skeletal muscle function of EDL and soleus muscle (absolute and specific muscle force) was assessed and skeletal muscle tissue was harvested for molecular and histological analysis. In addition, echocardiography was used to verify the development of HFpEF in these animals.

Results: The 12 weeks of ARNI supplementation to ZSF-1 obese animals resulted in an improvement of cardiac parameters like E/È, LVEDP and myocardial mass. With respect to muscle function the development of HFpEF induced a reduction in absolute (EDL by 10%, soleus by 16%) and specific force (EDL by 18%, soleus by 12%) generation and a loss of muscle mass (TA muscle, con: 14.14±0.1 mg/mm; HFpEF: 12.84±0.2 mg/mm; p<0.05). Oral application of ARNI for 12 weeks resulted in a small improvement of muscle mass of the EDL (5%) muscle and the absolute muscle force of the EDL (7%). No impact of ARNI on specific muscle force was observed. At the molecular level the development of HFpEF is associated with an elevated protein expression of the atrogen MuRF1 and ubiquitinylated proteins in the skeletal muscle. No effect of ARNI on these molecular changes was detected.

Conclusions: In the present animal model of HFpEF the oral application of ARNI for 12 weeks had only small effects on skeletal muscle. Therefore, the beneficial effects of ARNI are probably due to positive effects on other organs like the myocardium.