Abstract 15746: Intrinsic Cardiomyocyte Mitochondrial Defects Underlie Cardiac Dysfunction and Heart Failure Risk Associated With Hypoplastic Left Heart Syndrome

• Published in: Circulation (New York, N.Y.) N.Y.), 2018-11, Vol.138 (Suppl_1 Suppl 1), p.A15746-A15746
• Main Authors: Xu, Xinxiu, Tan, Tuantuan, Lin, Jiuann-Huey Ivy, Adams, Phillips, Liu, Xiaoqin, Timothy N, Feinstein, Khalifa, Omar, Porter, George A, Shiva, Sruti S, Lo, Cecilia
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539

IntroductionHypoplastic left heart syndrome (HLHS) is a complex congenital heart disease with high morbidity/mortality and high risk of heart failure. Based on findings from the Ohia HLHS mouse model, we hypothesize intrinsic cardiomyocyte defects may drive poor clinical outcome and heart failure risk in HLHS.MethodsInduced pluripotent stem cells (iPSC) were generated from 10 HLHS patients and differentiated into cardiomyocytes (iPSC-CM). Cell proliferation, and apoptosis were quantified. CM differentiation was analyzed by confocal imaging. Mitochondrial function was assayed with the Seahorse analyzer and mitochondrial membrane potential was assessed with TMRE staining.ResultsThe iPSC-CM from 6 of the 10 HLHS patients and from the HLHS mutant mice showed reduced cell proliferation (39.0% decrease; p=0.014), increased apoptosis (6.9 fold increase; p=0.0286) and sarcomere disorganization (Fig 1A) with calcium transient defects (29.9% decrease, p=0.0333) and reduced the frequency of CM beating (17.8% decrease, p=0.0119). These same HLHS patient iPSC-CM also showed reduced mitochondrial membrane potential (44.0% decrease, p=0.05), indicating a permeability transition pore closure and/or electron transport chain defect. Assessment of mitochondrial respiration showed diminished oxygen consumption rate (Fig.1B). Importantly, the patients with CM mitochondrial and differentiation defects also showed poor clinical outcome with 4 cardiac deaths (3 deaths, 1 heart transplant), and 2 suffering severe right ventricular dysfunction. In contrast, 4 other HLHS patients with iPSC-CM exhibiting normal proliferation and differentiation and normal mitochondrial function had favorable clinical outcomes with good myocardial function.ConclusionOur findings suggest intrinsic mitochondrial dysfunction may compromise cardiac function and contribute to heart failure risk in HLHS patients, a new paradigm that warrants further investigation.