Advanced Cardiac Therapies for Heart Failure Patients Research Overview

Pediatric Cardiac Metabolic and Biomarker Profiling in Health and Disease

With arterial and cardiac vein blood acquired during elective pediatric procedures from patients with preserved function and those being considered for heart transplant, including ventricular assist device (VAD)-supported patients at both pre- and post-VAD placement timepoints, we will use comprehensive metabolomics and proteomics for comparisons to adult data from our recent Science publication as a reference. For the first time, we will evaluate 1) how basal cardiac fuel use differs between children and adults, 2) pediatric-specific metabolic alterations in heart failure that may represent novel therapeutic targets, and 3) pediatric-specific heart failure biomarkers.

Conduct Deep Molecular Profiling of the Failing Right Ventricle

We will employ global metabolomics, single nuclei RNAseq, and targeted proteomics to comprehensively define the right ventricular failure (RVF) profile in 1) the murine pulmonary artery banding model and 2) pediatric RVF heart tissue collected at the time of ventricular assist device implantation or transplant. In parallel, we will complete metabolic, gene, and protein expression profiling of previously banked human adult failing RVs and compare those profiles with those from nonfailing RVs to establish a comparative benchmark and enable pediatric-specific pathway identification.

Test Potential Therapies in a Pre-clinical Model

We will use the pulmonary artery banding (PAB) research model of RVF, developed in part by Jonathan Edwards, MD, to test potential therapies. These efforts will first focus on drug repurposing of newer therapies with recently established efficacy for adult LVF, which have yet to be tested in RVF, including 1) empagliflozin, a metabolic modulator that inhibits the sodium-glucose pump SGLT2 and 2) omecamtiv, a direct activator of myosin, the principal heart contractile protein. If data supports efficacy in the PAB model, we will move forward with external grant submission to support a clinical trial in pediatric RVF. In parallel, we will leverage the deep profiling detailed above to identify and test a novel therapeutic target; if preliminary data is encouraging, we will initiate investigational new drug-enabling studies.