PROJECT SUMMARY / ABSTRACT Heart failure with preserved ejection fraction (HFpEF) affects 2.5 million Americans and is associated with high morbidity and mortality. Few effective treatments are available. This proposal will investigate an important cause of HFpEF: myocardial interstitial fibrosis (MIF). Hypertension, diabetes, and systemic inflammation lead to MIF by activating fibroblasts, which secrete regulatory proteins that deposit, process, and cross link collagen fibers in the myocardial extracellular matrix. Treatment of MIF is a potential strategy to prevent or treat HFpEF, but will require scalable diagnostic tests and proven anti-fibrotic therapies. Dr. Cunningham, a heart failure cardiologist and early career investigator at Brigham and Women’s Hospital in Boston, proposes to study MIF using cardiac MRI, large-scale proteomics, and clinical trial methods. Preliminary data show that inhibition of neprilysin (an enzyme which degrades natriuretic peptides) by the heart failure drug sacubitril/valsartan reduces plasma levels of several extracellular matrix regulatory proteins. These results suggest that neprilysin inhibition may attenuate MIF. However, it remains unknown 1) whether plasma levels of extracellular matrix regulatory proteins are associated with MIF, 2) which extracellular matrix regulatory proteins are modified by neprilysin inhibition, and 3) whether neprilysin inhibition reduces or slows progression of MIF. In this proposal, Dr. Cunningham hypothesizes that plasma levels of extracellular matrix regulatory proteins identify MIF and that neprilysin inhibition reduces MIF through its effect on these proteins. In Aim 1, he will evaluate whether plasma levels of pre-specified extracellular matrix regulatory proteins are associated with MIF measured by cardiac MRI in community participants from the UK Biobank. In Aim 2, he will investigate the effect of neprilysin inhibition on plasma levels of these proteins in a previously conducted HFpEF randomized trial. In Aim 3, he will conduct a pilot randomized trial directly assessing the effect of neprilysin inhibition on the most reproducible marker of MIF, extracellular volume measured by contrast cardiac MRI. If successful, these studies will form the foundation for future R01 applications identifying patients with MIF using proteomics and cardiac imaging and evaluating the benefit of neprilysin inhibition or other anti-fibrotic therapies in these patients. These specific aims are part of a comprehensive career development program designed to provide Dr. Cunningham with the skills to become an independent R01-funded physician-scientist. Dr. Scott Solomon, an expert in heart failure clinical trials at Brigham and Women’s Hospital, and Dr. Patrick Ellinor, an expert in cardiovascular epidemiology at the Broad Institute, will mentor Dr. Cunningham. Dr. Cunningham will develop expertise in the biostatistical analysis of large-scale physiological data, the interpretation of cardiac MRI, ...