Neprilysin Inhibition to Reduce Myocardial Fibrosis in Heart Failure With Preserved Ejection Fraction

Cardiac magnetic resonance imaging (MRI) measures of myocardial interstitial fibrosis (MIF) are elevated in heart failure with preserved ejection fraction (HFpEF) patients and associated with poor prognosis. Extracellular volume (ECV) is the most reproducible and best validated cardiac MRI measure of MIF. Sacubitril/valsartan reduces histological MIF in mice and levels of some extracellular matrix regulatory proteins in humans with HFpEF. However, the effect of sacubitril/valsartan on robust measures of MIF in humans is unknown. Demonstrating reductions in ECV with sacubitril/valsartan would clarify the mechanism of this approved medication. Given the borderline reduction in heart failure hospitalizations with sacubitril/valsartan and the heterogeneity of HFpEF pathophysiology, this result would suggest that neprilysin inhibition may particularly benefit HFpEF patients with greater MIF. The investigators propose a proof-of-concept clinical trial to evaluate the effect of neprilysin inhibition (sacubitril/valsartan vs valsartan alone) on cardiac MRI measures of fibrosis (principally ECV) and circulating protein levels.

Inclusion Criteria: * Adults aged 50 years or older * Able to provide informed consent, as assessed by a physician investigator, and willing to comply with the study * Clinically confirmed diagnosis of heart failure * Left ventricular ejection fraction greater than or equal to 45% within 1 year by echocardiogram, cardiac MRI, or nuclear scan Exclusion Criteria: * Contraindication to MRI (metal prosthesis, implantable cardiac device, or severe claustrophobia) * Systolic blood pressure \< 100mm Hg, or \5.2mmol/L within 60 days of enrollment, or \>5.0 mmol/L for patients not taking an ACE inhibitor or angiotensin receptor blocker * Myocardial infarction within 6 months of enrollment * Infiltrative or hypertrophic cardiomyopathy * History of cirrhosis, biliary cirrhosis, or cholestasis * History of angioedema * Pregnancy, planning pregnancy, or breastfeeding * Active treatment with lithium or a direct renin inhibitor