Abstract 15946: Ipsc-Derived Cardiomyocytes From Myotonic Dystrophy Type 1 Patients Reveal Sodium and Calcium Channels Dysfunction

Myotonic dystrophy type 1 (DM1), an autosomal dominant multi-systemic disorder, is the most common adult form of muscular dystrophy. DM1 is caused by the expression of DMPK mutant RNAs containing CUG repeats that sequester muscleblind-like proteins (MBNL), leading to misregulation of alternative splicing. Cardiac complications such as conduction abnormalities and tachyarrhythmias are the main cause of death in individual with DM1. We hypothesized that dysfunctional ion channels are responsible for the electrophysiological abnormalities seen in DM1 patients. Here, we developed a disease model using iPSC-derived cardiomyocytes from a control individual and two DM1 patients with different CTG repeats length and clinical history to study the pathogenetic mechanism behind the cardiac manifestations. The first patient, a 27-years old man with a CTG repeat of 1300 (DM1-1300), has a pacemaker implanted as a result of a third-degree atrioventricular bloc. The second patient, a 38-years old man with a CTG repeat of 300 (DM1-300), has no cardiac complications reported. We confirmed the presence of toxic RNA foci in DM1 cardiomyocytes and as expected, MBNL1/2 transcripts were found mis-spliced using Alternative Splicing-PCR (ASPCR). We identified a switch in the cardiac sodium channel SCN5A and the calcium channel CACNA1D from adulthood to fetal isoform. The down regulation of adult SCN5A isoforms is consistent with sodium current, INa shift of steady-state activation to depolarized potentials seen in iPSC-CMs from DM1-1300 patient. L-type calcium current (ICaL) densities were increased in iPSC-CMs from DM1-1300, consistent with the overexpression of CaV1.2 transcript and proteins in these iPSC-CMs from DM1-1300. Importantly, INa and ICaL dysfunction resulted in prolonged action potential, slower velocity and decreased overshoot in iPSC-CMs from DM1 patients. Finally, optical mapping analysis revealed a slower conduction velocity in iPSC-CMs monolayer from DM1-1300. These abnormalities were not seen in iPSC-CMs from a healthy family related control. In conclusion, patient-specific iPSC-CMs is a powerful model of cardiac disease in DM1 and demonstrated the mechanism underlying the electrical cardiac abnormalities observed in DM1 patients.