Abstract 16339: Mitochondrial Function in Animal and Novel Human Disease Models of Tachycardiomyopathy

Abstract

Introduction: Clinical significance of tachycardiomyopathy (TCM) increased with trials on catheter ablation therapy. Myocardial biopsies from patients show disturbed mitochondrial architecture. Hypothesis: TCM involves mitochondrial dysfunction. Methods: First, TCM was investigated in an animal model: pacemaker implantation in 7 rabbits was followed by tachypacing for 30 days (TCM), 7 animals served as sham-operated controls (SHAM). Second, results of the animal study were evaluated for their translational perspective for human disease using a novel model of induced pluripotent stem cell-derived cardiomyocytes (iPS-CM), derived from 4 healthy donors. IPS-CM were paced with 120 bpm (TACH) or 60 bpm (CTRL) for 7 days in vitro. Targeted transcriptomics, high-resolution respirometry and flow cytometry (MitoSOX Red) were performed. To account for variations between cell differentiations, experiments on iPS-CM were carried out in a paired design. Results: TCM showed LV dilatation and dysfunction (ΔLVEDD +5.3±0.2mm; ΔFS -19±8%; TCM-SHAM; p<0.001). Histological findings resembled human disease entailing cardiomyocyte hypertrophy (CSA 519±32μm 2 vs. 413±21μm 2 , p<0.01) without fibrosis (hydroxyproline content, p=0.52). Mitochondrial transcriptome of TCM was characterized by downregulation of 10 antioxidative enzymes (e.g. GPX3, fold change (FC) 0.4; TCM/SHAM; p<0.05) as well as mitochondrial carriers, including ADP/ATP- and NADH-shuttling (SLC25A4, FC 0.7; SLC25A12, FC 0.8; p<0.01). As transcriptomics implied impaired substrate import, respirometry was performed in whole tissue. In support of our findings on the transcriptome level, mitochondrial oxidative phosphorylation capacity decreased in TCM (133±13 vs. 170±16 pmol·O 2 ·s -1 ·mg -1 ·tissue, p<0.05). Similarly, oxidative phosphorylation was reduced in iPS-CM (995±738 vs. 1838±901 pmolO 2 ·s -1 ·IU -1 citrate synthase activity, TACH vs. CTRL, p<0.01). Concurrently, tachypacing increased mitochondrial superoxide emission in iPS-CM (MFI 491±206 vs. 301±119, p<0.05). Conclusions: Persistent tachycardia alters two mitochondrial key functions in an animal and a novel human ex vivo model: oxidative phosphorylation capacity is reduced, while superoxide emission increases.