Abstract 235: Hypertrophic Cardiomyopathy, a Disease of Altered Cardiac Energetics

Abstract

Hypertrophic cardiomyopathy (HCM) is a complex disease, the phenotypes of which are only partly explained by the biomechanical effects of individual genetic variants. At the cellular level, HCM sarcomeric mutations generally enhance maximal force production ultimately leading to higher energy demands. Despite significant advances in elucidating sarcomeric structure-function relationships, there is limited knowledge on the link between altered cardiac energetics and HCM phenotypes. In this work, we test the hypothesis that changes in cardiac energetics are a common pathway leading to the clinical pathophysiological phenotypes of HCM. We performed a comprehensive multi-omic study of the molecular, ultrastructural, and functional features of HCM energetics using septal myectomy samples from 27 HCM patients and 13 normal controls (donor hearts). Combined mass spectrometry and RNA-Seq revealed dramatic alterations in multiple metabolic pathways,with major dysregulation in fatty acid metabolism leading to reduced acylcarnitines and accumulation of free fatty acids. Additionally, HCM hearts showed clear signs of global energetic decompensation manifested by a decrease in high energy phosphate metabolites (ATP, ADP, and PCr) and reduction in several mitochondrial genes involved in creatine kinase and ATP synthesis machinery. Quantitative electron microscopy showed a marked increase in severely damaged mitochondria with reduced cristae density, affecting 10-12% of total mitochondria, coinciding with reduced citrate synthase (CS) activity and mitochondrial respiration. These mitochondrial abnormalities were associated with elevated ROS and reduced antioxidant defenses along with insufficient mitophagic clearance. Overall, our findings suggest that perturbed metabolic signaling and mitochondrial dysfunction are common pathogenic mechanisms in HCM. A central role for compromised energetics in HCM could also help explain the delayed age of onset of the clinical phenotype and present novel drug targets for attenuation of the clinical disease through reducing mitochondrial injury and improving function.