2026-07-08 | Ca2+ current involvement in a KCNH2 mutation's phenotype and its modulation by estrogen.
Estrogens affect repolarization and may act as phenotype modifiers in long QT syndrome (LQTS). In a LQT2 patient with the G628S-KCNH2 mutation (normal CACNA1C genes) the occurrence of arrhythmia-related symptoms followed 17-β estradiol (E2) administration. This study aims to test whether a mechanistic link can be established between the two events. Membrane potential, ICaL and IKr were measured from mutant (LQT2) and wild-type (WT) hiPS-CMs exposed to 10 nM E2. Adequacy of E2 effects in accounting for patient's electrical phenotype was tested by in silico simulations using a "population" approach. Molecular characterization was carried out by qPCR and immunocytochemistry. LQT2 hiPS-CMs were characterized by marked prolongation of action potential duration (APD) and susceptibility to early afterdepolarizations (EADs), thus recapitulating the LQT2 phenotype. In LQT2 hiPS-CMs, IKr was absent, the ICaL window was increased and the recovery from inactivation was delayed. E2 reversed mutation's effects on APD and ICaL window, but failed to restore IKr and reduce EADs prevalence. E2 also introduced a fast component in ICaL recovery which contributed to ICaL availability during the AP plateau. E2 did not change the expression of KCNH2 channels, E2 receptors (GPER) and CaV1.2 channels (CACNA1C). Simulations indicate that the changes in ICaL gating are a major determinant of APD prolongation and EADs associated with the KCNH2 mutation. The KCNH2 mutation was associated with ICaL gating abnormalities crucially contributing to APD prolongation, which were largely corrected by E2. However, by accelerating ICaL recovery, E2 facilitated EADs despite APD shortening.
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2026-07-03 | Combined Leadless Pacing and Subcutaneous ICD Therapy in Long QT Syndromes.
Congenital long QT syndrome (LQTS) is associated with ventricular arrhythmias and increased risk of sudden cardiac death. Beta-blockers are first-line therapy, although intolerance may occur. We report a case of a 50-year-old man with LQTS and subcutaneous implantable cardioverter-defibrillator (S-ICD) who experienced recurrent appropriate therapies and beta-blocker intolerance due to bradycardia. An atrial leadless pacemaker was implanted while maintaining the S-ICD, achieving a double-device strategy without intracardiac leads. This approach resulted in QTc shortening, symptom improvement, and complete suppression of further ICD therapies. This strategy may represent a feasible and effective alternative in selected LQTS patients requiring atrial pacing.
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2026-06-18 | C-terminal long-QT type 1 R562S-Kv7.1 variant, the first variant in helix C impairing β-adrenergic response of the slow delayed rectifier K+ channel.
Kv7.1 variants, associated with long QT syndrome type 1 (LQT1) and altering the function of the slow delayed rectifier K+ (IKs) channel, may result in arrhythmias, especially during exercise. This study focused on complex analysis of the R562S-Kv7.1 variant located in helix C of the Kv7.1 C terminus, which was identified in four putatively unrelated families in the Czech Republic. The clinical and genetic investigation was followed by functional analysis (whole-cell patch clamp, confocal microscopy, computational simulations) and structural modelling. The genetic analysis suggested that R562S-Kv7.1 might be a founder LQT1 variant in Central Europe. R562S carriers showed a significantly prolonged corrected QT (QTc) interval at rest and a significantly higher QTc prolongation after exercise vs. healthy relatives. The functional analysis of R562S channels demonstrated their preserved membrane localization, a significant decrease in IKs with a rightward shift of the voltage dependence of activation, and, importantly, a lack of responsiveness to β-adrenergic stimulation. The latter seems to be related to a modified interaction of the modulatory KCNE1 subunit with Kv7.1. The pro-arrhythmic potential of R562S dysfunction, mediated by delayed afterdepolarizations during β-adrenergic stimulation, could be effectively prevented by mild (5%) inhibition of L-type Ca2+ current (ICa). R562S-Kv7.1 is the first variant in helix C causing an impaired response of IKs channel to β-adrenergic stimulation, likely due to altered interactions between channel subunits, namely Kv7.1 and KCNE1. Mild ICa inhibition was suggested as a new treatment option.
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