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

ABSTRACT

A common genetic risk factor for bipolar disorder is CACNA1C, a gene that is 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. Results indicate that the CACNA1C bipolar disorder-related mutation causes cardiac electrical impulse conduction slowing mediated by impaired intercellular coupling via connexin 43 gap junctions. In vitro gene therapy to restore connexin 43 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 in response to psychiatric medications that slow conduction or prolong the QT interval. This in vitro diagnostic tool enables cardiac testing specific to patients with psychiatric disorders to determine their sensitivity to off-target effects of psychiatric medications.

Bipolar disorder (BD) is associated with genetic risk factors that present as mutations in specific genes. One gene commonly associated with BD is the calcium channel gene CACNA1C, found in the brain and the heart. The impact of CACNA1C mutation on cardiac function in patients with BD is unclear. Here, we created a BD CACNA1C mutant patient "heart in a dish" using patient-specific stem cells. Gene editing was also used to correct the mutation to create an isogenic control cell line. We found that the BD calcium gene mutation caused slow electrical impulse propagation, reduced the function of the calcium channel, and was associated with low intercellular communication channels called connexin. Using connexin gene therapy in vitro, the the cardiac dysfunction could be corrected and cured. This new approach offers patient-specific hearts-in-a-dish that can be used to ensure that medications will not cause heart racing or arrhythmias.