Abstract 10197: Cavin1, a Novel Actor in Drug Induced Long Qt

Abstract

Introduction: Many drugs have been pulled from the market due to their undesirable effect in prolonging the QT interval by altering cardiac ion currents, notably I Kr generated by hERG. This cardiotoxic impact is however extremely variable between individuals and the mechanisms underlying this variability remain undiscovered. Previously, we identified a higher expression of CAVIN1, an essential protein for caveolae biogenesis, in cardiomyocytes (CM) derived from individuals with high susceptibility to develop sotalol-induced long QT. Hypothesis: CAVIN1 can modulate cardiomyocytes’ response to drugs. Methods: We used induced pluripotent stem cells-derived-CM (iCM) from 3 subjects with the highest sensitivity (HS) to sotalol (ie, those with the highest increase in QTc) and 3 others with the lowest sensitivity to sotalol (LS). Results: cardiac repolarization and I Kr were similar between HS-iCM and LS-iCM at baseline. However, HS-iCM displayed a significantly higher prolongation of the repolarization phase along with a decrease in I Kr in response to sotalol and other drugs targeting hERG (E4031, vandetanib, and clarithromycin). CAVIN1 mRNA and protein levels were increased by 2-fold in the HS-iCM. Overexpressing CAVIN1 in the LS-iCM using adenovirus induced higher sensitivity to sotalol and the other hERG blockers. In contrast, CAVIN1 knockdown using siRNA in the HS-iCM switched their phenotype to a lower sensitivity to hERG blockers. We observed that CAVIN1 overexpression in LS-iCM and HEK cells changed hERG distribution within cells with accumulation at the membrane. We applied Methyl-β-cyclodextrin, a detergent that removes caveolae from membranes, and found that caveolae depletion induced prolonged repolarization associated with a decrease in CAVIN1 and hERG sarcolemmal expression, and their accumulation in the cytoskeleton. In contrast with the LS-iCM, sotalol application in the HS-iCM promoted hERG internalization into the cytoskeleton. Conclusions: We identified CAVIN1 as a novel modulator of cardiac repolarization in response to drug by promoting hERG internalization. This represents a novel mechanism sustaining the inter-individual variability in response to drugs.