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

Area of Science:

• Cardiovascular Genetics
• Neuropsychiatric Disorders
• Stem Cell Biology

Background:

• CACNA1C is a genetic risk factor for bipolar disorder and crucial for cardiac function.
• The effect of CACNA1C mutations on bipolar disorder patient cardiac rhythm remains unclear.
• Investigating CACNA1C's role in cardiac electrophysiology is vital for understanding patient risks.

Purpose of the Study:

• To investigate the cardiac electrophysiological consequences of a bipolar disorder-associated CACNA1C genetic risk factor.
• To explore the potential of gene therapy to correct CACNA1C mutation-induced cardiac defects.
• To assess the proarrhythmic risk in bipolar disorder patients with CACNA1C mutations.

Main Methods:

• Utilized patient-derived induced pluripotent stem cells (iPSCs) differentiated into cardiomyocytes.
• Examined the impact of CACNA1C mutations on cardiac electrical impulse conduction and intercellular coupling.
• Assessed the efficacy of in vitro gene therapy targeting connexin 43 expression.
• Evaluated protection against thioridazine-induced QT prolongation.

Main Results:

• The CACNA1C bipolar disorder-related mutation significantly slowed cardiac electrical impulse conduction.
• Impaired intercellular coupling via connexin 43 gap junctions was identified as the mechanism.
• In vitro gene therapy restored connexin 43 expression, increasing conduction velocity.
• Gene therapy also protected against thioridazine-induced QT prolongation.

Conclusions:

• Bipolar disorder-associated CACNA1C mutations impair cardiac electrical conduction through connexin 43.
• Patients with these mutations may face increased proarrhythmic risk from psychotropic medications affecting QT interval.
• An in vitro diagnostic tool can identify cardiac sensitivity to off-target drug effects in psychiatric patients.