Bipolar Patient–Specific In Vitro Diagnostic Test Reveals Underlying Cardiac Arrhythmia Phenotype Caused by Calcium Channel Genetic Risk Factor

A common genetic risk factor for bipolar disorder is the CACNA1C gene, a gene also critical for cardiac rhythm. The impact of CACNA1C mutations on bipolar patient cardiac rhythm is unknown. Here we report the cardiac electrophysiological implications of a bipolar disorder associated genetic risk factor in CACNA1C using patient induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). Results indicate the CACNA1C bipolar disorder related mutation causes cardiac electrical impulse conduction slowing mediated by impaired intercellular coupling via connexin43 gap junctions. In vitro gene therapy to restore connexin43 expression increased cardiac electrical impulse conduction velocity and protected against thioridazine induced QT-prolongation. Patients positive for bipolar disorder CACNA1C genetic risk factors may have elevated proarrhythmic risk for adverse events to psychiatric medications that slow conduction or prolong the QT interval. This in vitro diagnostic tool enables psychiatric patient specific cardiac testing to determine patients' sensitivity to off target effects of psychiatric medications.