Abstract
The angiotensin receptor/neprilysin inhibitor Sacubitril/Valsartan (Sac/Val) has been shown to be beneficial in patients suffering from heart failure with reduced ejection fraction (HFrEF). However, the impact of Sac/Val in patients presenting with heart failure with preserved ejection fraction (HFpEF) is not yet clearly resolved. The present study aimed to reveal the influence of the drug on the functionality of the myocardium, the skeletal muscle, and the vasculature in a rat model of HFpEF. Female obese ZSF-1 rats received Sac/Val as a daily oral gavage for 12 weeks. Left ventricle (LV) function was assessed every four weeks using echocardiography. Prior to organ removal, invasive hemodynamic measurements were performed in both ventricles. Vascular function of the carotid artery and skeletal muscle function were monitored. Sac/Val treatment reduced E/é ratios, left ventricular end diastolic pressure (LVEDP) and myocardial stiffness as well as myocardial fibrosis and heart weight compared to the obese control group. Sac/Val slightly improved endothelial function in the carotid artery but had no impact on skeletal muscle function. Our results demonstrate striking effects of Sac/Val on the myocardial structure and function in a rat model of HFpEF. While vasodilation was slightly improved, functionality of the skeletal muscle remained unaffected.
Highlights
Patients suffering from heart failure with preserved ejection fraction (HFpEF) take a large share of all heart failure (HF) patients and account, based on the underlying definition, for 22–73% of all cases [1], thereby predominantly affecting female patients and the elderly [2]
We documented the development of HFpEF in adult ZSF1-obese animals based on diastolic dysfunction and clinical signs of chronic heart failure despite preserved left ventricular ejection fraction (LVEF) at an age of 20 weeks, suggesting the ZSF1 rat to serve as an ideal model for studying HFpEF and potential therapies [5]
HFpEF compared to their age-matched lean control group (Table 1)
Summary
Patients suffering from heart failure with preserved ejection fraction (HFpEF) take a large share of all heart failure (HF) patients and account, based on the underlying definition, for 22–73% of all cases [1], thereby predominantly affecting female patients and the elderly [2]. One promising candidate is the ZSF1 (Zucker fatty and spontaneously hypertensive) obese rat [5]. It was developed by crossing rat strains with two separate leptin receptor mutations (fa and facp ), the lean female ZDF rat (+/fa), and the lean male SHHF (spontaneously hypertensive heart failure) rat (+/facp ). We documented the development of HFpEF in adult ZSF1-obese animals based on diastolic dysfunction and clinical signs of chronic heart failure despite preserved left ventricular ejection fraction (LVEF) at an age of 20 weeks, suggesting the ZSF1 rat to serve as an ideal model for studying HFpEF and potential therapies [5]
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