Abstract 15846: Impaired Contraction and High Susceptibility to Arrhythmias in a Mouse Model of Desmoplakin-Mediated Arrhythmogenic Cardiomyopathy

Abstract

Introduction: Desmoplakin (DSP) is a key protein for cardiac myocyte cell-to-cell adhesion that connects the desmosomes present in intercalated discs to the cytoplasmic network of desmin intermediate filaments. Pathogenic variants of the human DSP gene often lead to left ventricular (LV)-dominant and biventricular forms of arrhythmogenic cardiomyopathy characterized by a dilated LV, arrhythmias, and an elevated risk of sudden cardiac death. Nonetheless, the pathophysiological pathways triggered by DSP variants remain unknown. Hypothesis: We hypothesized that DSP pathogenic variants modify cardiomyocyte excitation-contraction coupling leading to life-threatening ventricular arrhythmias. Methods: We created a novel knock-in mouse model based on the human DSP p.S2859LfsX5 variant that leads to a murine protein truncated from its last 9 amino-acids. We compared one-year-old sedentary heterozygous (Dsp +/- ) animals to WT littermates and defined histologic, cellular, and molecular outcomes of the variant. Results: Western blotting revealed 50% Dsp reduction (N= 5 hearts/group; P < 0.05) in mutant right ventricle (RV) indicating mutant protein instability. Histologic assessments of Dsp +/- hearts revealed LV chamber enlargement and RV wall thinning in the absence of fibrosis and lipid infiltration. Dsp +/- myocytes isolated from LV and RV free walls and field stimulated at 3 Hz exhibited 30-40% reduction in sarcomere shortening (n= 17-25 myocytes/ventricle/3-4 hearts/group; P < 0.05), while their Ca 2+ handling properties remained normal. Pacing of Dsp +/- isolated myocytes (LV and RV) in the presence of (100 nmol/L) isoproterenol provoked a 20-30% increase in Ca 2+ release due to sarcoplasmic reticulum Ca 2+ overload (n= 15-20 myocytes/ventricle/3-4 hearts/group; P < 0.05). Finally, surface ECGs showed that activation of the sympathetic pathway (isoproterenol + caffeine) in 6-month-old Dsp +/- mice increased mutant heart susceptibility to ventricular arrhythmias. Conclusions: The pathogenic variant p.S2859LfsX5 promotes biventricular dysfunction due to the loss in myocyte contraction capacity and catecholaminergic-mediated ventricular arrhythmias from cardiomyocyte Ca 2+ overload.