Arrhythmias & electrophysiology
CAVIN1-Mediated hERG Dynamics: A Novel Mechanism Underlying the Interindividual Variability in Drug-Induced Long QT
Authors' conclusion
Our study identifies unbridled turnover of the potassium channel hERG as a mechanism supporting the interindividual susceptibility underlying diLQT development and demonstrates how this phenomenon is finely tuned by CAVIN1.
Study context
- Population
- iPS-CMs derived from patients with highest or lowest sensitivity to sotalol administration in vivo (maximal change in QT interval 3 hours after administration)
- Comparison
- Highest sensitivity (HS) vs lowest sensitivity (LS) iPS-CMs; CAVIN1 knockdown and CAVIN1 overexpression
- Outcome
- Electrophysiological activity and cellular distribution of hERG channels after hERG blocker treatment
Methodological detailspatient-specific iPS-CMs, small interfering RNA knockdown, adenoviral overexpression
- Patient-specific iPS-CMs
- Small interfering RNA knockdown
- Adenoviral overexpression
Main finding
As reported in the abstract
CAVIN1 expression in HS vs LS iPS-CMs
2× more highly expressed in HS
Further findings
Sotalol-induced hERG translocation and caveolae
- Sotalol promoted translocation of hERG from plasma membrane to cytoskeleton fractions, dependent on CAVIN1 expression
- CAVIN1 silencing reduced the number of caveolae at the membrane and abrogated hERG translocation in sotalol-treated HS iPS-CMs
Responses to other hERG blockers
- CAVIN1 also controlled cardiomyocyte responses to E4031, vandetanib and clarithromycin
Original publication
CAVIN1-Mediated hERG Dynamics: A Novel Mechanism Underlying the Interindividual Variability in Drug-Induced Long QT. Circulation. Published 29 April 2024. doi:10.
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