1177Insights on mitochondrial energetics in obstructive hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy, heterogeneous in phenotype and clinical course. The genotype-phenotype relationship and associated molecular mechanisms are still incompletely understood. In the HCM milieu, increased energy cost of force production, impairing performance and mitochondrial function, may be associated to patients' genotype and/or phenotype. Purpose To determine abnormalities in mitochondrial energetics in HCM and their possible relationship with genotype and clinical phenotype of patients. Methods Septal myectomies from characterized patients with obstructive HCM (HOCM, n=18) and donor hearts discarded from transplantation (CTRL, n=8) have been compared. HOCM patients were screened and demographic, clinical and instrumental data (routine ECG, echocardiography and cardiac magnetic resonance-CMR) were collected. Genetic analysis was performed on total DNA extracted from myectomies by NGS on MiSeq platform using the TruSight Cardio Sequencing kit and testing a panel of 26 genes. Activity and amount of mitochondrial enzymes generating/scavenging reactive oxygen species were investigated. Results Within the HOCM cohort 30% of patients was bearing mutations in sarcomeric genes associated with HCM. The amount and/or activity of mitochondrial Complex I NADH dehydrogenase, of SOD2 and (m)-aconitase were upregulated in HOCM vs. CTRL. NADH dehydrogenase level was inversely correlated with the degree of mitral valve regurgitation and mitral valve backward volume by CMR (Spearman R=−0.5 and −0.8, respectively). The Complex V enzyme ATP synthase activity decreased, whilst its amount was comparable in HOCM vs. CTRL. Analogously the SOD1 activity was similar in HOCM and CTRL. No difference in mitochondrial DNA (mtDNA) copy number was found. Results were unrelated to HCM-associated mutations. Conclusions HOCM hearts are characterized by mitochondrial hyperactivity aimed at quenching reactive oxygen species, but decreased ATP synthase activity. Overall, these data suggest an abnormal mitochondrial activity in the myocardium of HOCM patients independent of the presence of HCM-associated mutations. Moreover, our results underpin the markedly abnormal cellular energetics of HOCM, identifying potential therapeutic targets. Acknowledgement/Funding NET-2011-02347173, Italian Minister of Health