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.

Study Overview

• Status: Not yet recruiting
• Conditions: Myocardial Fibrosis; Heart Failure With Preserved Ejection Fraction
• Intervention / Treatment: Drug: Sacubitril-valsartan; Drug: Valsartan

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jonathan Cunningham, MD; Phone Number: 671-732-5524; Email: jcunningham3@bwh.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 <110 mm Hg for patients not taking an ACE inhibitor or angiotensin receptor blocker
• symptomatic hypotension
• eGFR < 30 mL/min/1.73m2 within 60 days of enrollment
• Serum potassium >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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sacubitril/valsartan; Patient randomized to the interventional arm will be treated with sacubitril/valsartan	Drug: Sacubitril-valsartan; Sacubitril-valsartan titrated to maximally targeted dose; Other Names: Entresto
Active Comparator: Valsartan; Patient randomized to the active comparator arm will be treated with valsartan	Drug: Valsartan; Valsartan titrated to maximally targeted dose; Other Names: Diovan

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in extracellular volume by cardiac MRI	The primary outcome is to evaluate the change in extracellular volume (ECV), measured by cardiac MRI, from baseline to one year, in the sacubitril/valsartan arm compared to the valsartan arm	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in left ventricular native T1 time	Measured by cardiac MRI	1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in left ventricular mass	Measured by cardiac MRI	1 year
Change in left atrial size		1 year

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital

Publications and helpful links

General Publications

• Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, Martinez F, Packer M, Pfeffer MA, Pieske B, Redfield MM, Rouleau JL, van Veldhuisen DJ, Zannad F, Zile MR, Desai AS, Claggett B, Jhund PS, Boytsov SA, Comin-Colet J, Cleland J, Dungen HD, Goncalvesova E, Katova T, Kerr Saraiva JF, Lelonek M, Merkely B, Senni M, Shah SJ, Zhou J, Rizkala AR, Gong J, Shi VC, Lefkowitz MP; PARAGON-HF Investigators and Committees. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2019 Oct 24;381(17):1609-1620. doi: 10.1056/NEJMoa1908655. Epub 2019 Sep 1.

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): September 1, 2029

Study Registration Dates

• First Submitted: July 26, 2024
• First Submitted That Met QC Criteria: July 30, 2024
• First Posted (Actual): August 2, 2024

Study Record Updates

• Last Update Posted (Actual): February 25, 2026
• Last Update Submitted That Met QC Criteria: February 24, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Heart Failure; Fibrosis; Amino Acids, Peptides, and Proteins; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Amino Acids; Amino Acids, Essential; Tetrazoles; Valine; Amino Acids, Branched-Chain; Valsartan; sacubitril and valsartan sodium hydrate drug combination
• Other Study ID Numbers: 2024P001894; 1K23HL168163-01A1 (U.S. NIH Grant/Contract: National Heart Lung and Blood Institute)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Deidentified participant data will be made available according to NHLBI and institutional regulations

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes