Abstract 12182: Cardiac Transcriptome Remodeling and Impaired Bioenergetics in Single Ventricle Congenital Heart Disease

Abstract

Introduction: Single Ventricle congenital heart disease (SV) encompasses a group of cardiac abnormalities where improper development of the heart results in only one functional pumping chamber. From a molecular standpoint, how the myocardium adapts to the chronic altered hemodynamic conditions of SV physiology, and the mechanisms implicated in the transition to heart failure (HF) which is common in the SV population, are poorly understood. Here, we test the hypothesis that metabolic remodeling represents a pathophysiologic mechanism of heart failure progression in SV. Methods: We performed comprehensive multi-omics analysis (transcriptomics, metabolomics, and lipidomics) of the SV myocardium from both failing (SVHF, N=15) and non-failing (SVNF, N=9) SV subjects, compared with biventricular non-failing controls (BVNF, N=4). Furthermore, we assessed functional components of mitochondrial bioenergetics in each of these populations. Results: Integrated multi-omics analysis demonstrated dysregulation of multiple metabolic pathways in the failing SV heart (A). Functional cardiac bioenergetics analysis revealed decreased mitochondrial carnitine palmitoyl transferase activity (B) and mitochondrial dysfunction (C), with corresponding decreases in tricarboxylic acid cycle metabolites, high energy phosphates, and lipid intermediates in the failing SV heart. Moreover, some of these bioenergetic perturbations precede the onset of overt failure, and are seen in the non-failing SV heart (B-C). Conclusions: Our findings indicate that SV physiology induces myocardial metabolic alterations that limit mitochondrial fatty acid β-oxidation and decrease cardiac energy generation. Together, these data suggest SV patients may be uniquely vulnerable to changes in energetic demand and may benefit from therapeutic strategies aimed at preserving cardiac bioenergetics and preventing cardiometabolic remodeling for the treatment or prevention of HF.