Abstract
Short QT syndrome (SQTS) is associated with tachyarrhythmias and sudden cardiac death. So far, only quinidine has been demonstrated to be effective in patients with SQTS type 1(SQTS1). The aim of this study was to investigate the mechanisms of disopyramide underlying its antiarrhythmic effects in SQTS1 with the N588K mutation in HERG channel. Human-induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) from a patient with SQTS1 and a healthy donor, patch clamp, and calcium imaging measurements were employed to assess the drug effects. Disopyramide prolonged the action potential duration (APD) in hiPSC-CMs from a SQTS1-patient (SQTS1-hiPSC-CMs). In spontaneously beating SQTS1-hiPSC-CMs challenged by carbachol plus epinephrine, disopyramide reduced the arrhythmic events. Disopyramide enhanced the inward L-type calcium channel current (ICa-L), the late sodium channel current (late INa) and the Na/Ca exchanger current (INCX), but it reduced the outward small-conductance calcium-activated potassium channel current (ISK), leading to APD-prolongation. Disopyramide displayed no effects on the rapidly and slowly activating delayed rectifier and ATP-sensitive potassium channel currents. In hiPSC-CMs from the healthy donor, disopyramide reduced peak INa, ICa-L, IKr, and ISK but enhanced late INa and INCX. The results demonstrated that disopyramide may be effective for preventing tachyarrhythmias in SQTS1-patients carrying the N588K mutation in HERG channel by APD-prolongation via enhancing ICa-L, late INa, INCX, and reducing ISK.
Highlights
Short QT syndrome (SQTS) is a rare, inheritable cardiac channelopathy associated with abbreviated corrected QT interval (QTc), tachyarrhythmias and sudden cardiac death (SCD) (Gussak et al, 2000; Brugada et al, 2004)
Disopyramide has been shown to prolong action potential duration and suppress arrhythmias in SQTS cells, we checked both effects in our SQTS type 1 (SQTS1)-human iPS cells (hiPSCs)-CMs before investigating its ionic mechanisms
For the first time, we investigated the ionic mechanism underlying the action potential duration (APD)-prolonging and antiarrhythmic effects of disopyramide in hiPSC-CMs from a patient with SQTS type 1
Summary
Short QT syndrome (SQTS) is a rare, inheritable cardiac channelopathy associated with abbreviated corrected QT interval (QTc), tachyarrhythmias and sudden cardiac death (SCD) (Gussak et al, 2000; Brugada et al, 2004). Worldwide more than 200 SQTS-patients with different gene mutations have been reported and different types of SQTS have been described (Bjerregaard, 2018; Campuzano et al, 2018). SQTS types 1–3 are linked to a gain of function of potassium channels led by mutations in the KCNH2 (SQTS1), KCNQ1 (SQTS2), and KCNJ2 (SQTS3) gene. SQTS types 4-6 are linked to a loss of function of calcium channels resulting from mutations in CACNA1C (SQTS4), CACNB2 (SQTS5), and CACNA2D1 (SQTS6) gene. Implantable cardioverter defibrillator (ICD) can be useful for terminating arrhythmias in SQTS-patients, ICD cannot be used for every patient (Giustetto et al, 2006; Mazzanti et al, 2014). Pharmacotherapy is required at least for some SQTS-patients
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