Why the study?
In a long QT syndrome patient carrying KCNQ1 and TRPM4 dual mutations, conventional medication and ICD implantation had limited success, motivating patient-specific iPSC cardiomyocyte drug screening.
Do verapamil and lidocaine shorten the QT interval in iPSC-derived cardiomyocytes from a patient with KCNQ1/TRPM4 dual mutation long QT syndrome?
Do verapamil and lidocaine shorten the QT interval in iPSC-derived cardiomyocytes from a patient with KCNQ1/TRPM4 dual mutation long QT syndrome?
Patient-specific iPSC-derived cardiomyocytes can be used to identify effective personalized pharmacological treatments, such as verapamil and lidocaine, for long QT syndrome patients with complex mutations.
Verapamil may reduce defibrillator shocks in this dual-mutation LQTS case; leaves open whether iPSC-CM screening predicts response in broader populations.
Congenital long QT syndrome is a type of inherited cardiovascular disorder characterized by prolonged QT interval. Patient often suffer from syncopal episodes, electrocardiographic abnormalities and life-threatening arrhythmia. Given the complexity of the root cause of the disease, a combination of clinical diagnosis and drug screening using patient-derived cardiomyocytes represents a more effective way to identify potential cures. We identified a long QT syndrome patient carrying a heterozygous KCNQ1 c.656G>A mutation and a heterozygous TRPM4 c.479C>T mutation. Implantation of implantable cardioverter defibrillator in combination with conventional medication demonstrated limited success in ameliorating long-QT-syndrome-related symptoms. Frequent defibrillator discharge also caused deterioration of patient quality of life. Aiming to identify better therapeutic agents and treatment strategy, we established a patient-specific iPSC line carrying the dual mutations and differentiated these patient-specific iPSCs into cardiomyocytes. We discovered that both verapamil and lidocaine substantially shortened the QT interval of the long QT syndrome patient-specific cardiomyocytes. Verapamil treatment was successful in reducing defibrillator discharge frequency of the KCNQ1/TRPM4 dual mutation patient. These results suggested that verapamil and lidocaine could be alternative therapeutic agents for long QT syndrome patients that do not respond well to conventional treatments. In conclusion, our approach indicated the usefulness of the in vitro disease model based on patient-specific iPSCs in identifying pharmacological mechanisms and drug screening. The long QT patient-specific iPSC line carrying KCNQ1/TRPM4 dual mutations also represents a tool for further understanding long QT syndrome pathogenesis.
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Wang et al. (2022) studied this question.
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