Elucidating the role of Cavin1 in drug-induced long QT syndrome (diLQTS)

Abstract

Several drugs can induce QT prolongation by altering cardiac ion currents, notably I Kr . The cardiotoxic response to a drug is however extremely variable between individuals. The molecular mechanisms underlying this variability remain unclear. Previously, we reported higher expression levels of Cavin1, an essential protein for caveolae formation, in cardiomyocytes (CM) derived from patients with high susceptibility to develop sotalol-induced LQT. To investigate whether Cavin1 could sway the cardiac repolarization response to drugs. We used induced pluripotent stem cells-CM (iPS-CM) from 2 subjects with the highest sensitivity (HS) to sotalol (ie, those with the highest increase in QTc) and 2 individuals with the lowest sensitivity to sotalol (LS). HS iPS-CM were similar to LS-iPS-CM at baseline but displayed significant prolongation in action potential and field potential (FPD) durations after the application of 30 and 50 μM of sotalol. They also displayed higher sensitivity to other drugs targeting hERG (E4031, vandetanib, and clarithromycin). Cavin1 mRNA and protein levels were increased by 2 fold in the HS iPS-CM. Overexpressing Cavin1 in the LS-iPS-CM using adenovirus induced a higher sensitivity to sotalol as only 10 μM was sufficient to induce 12% longer FPD. Likewise, the infection with Cavin1 increased the sensitivity of LS-CM to the other hERG blockers. In contrast, siRNA against Cavin1 reduced its expression by 60% in HS iPS-CM and switched their phenotype to a lower sensitivity to sotalol and the other hERG blockers. Finally, manipulating Cavin1 levels changed the repolarization duration beside any pharmacological stimulation, suggesting a role of Cavin1 in modulating hERG sarcolemmal expression. This will be further validated in HEK cells co-expressing hERG and Cavin1. Altogether, this work identified Cavin1 as a novel modulator of cardiomyocyte response to hERG blockers and a potential risk factor for diLQT.