J Mol Cell Cardiol. 2026 Aug;217:176-188. doi: 10.1016/j.yjmcc.2026.07.004. Epub 2026 Jul 7.
ABSTRACT
BACKGROUND: 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.
METHODS: Membrane potential, I and I 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.
RESULTS: 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, I was absent, the I window was increased and the recovery from inactivation was delayed. E2 reversed mutation's effects on APD and I window, but failed to restore I and reduce EADs prevalence. E2 also introduced a fast component in I recovery which contributed to I 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 I gating are a major determinant of APD prolongation and EADs associated with the KCNH2 mutation.
CONCLUSIONS: The KCNH2 mutation was associated with I gating abnormalities crucially contributing to APD prolongation, which were largely corrected by E2. However, by accelerating I recovery, E2 facilitated EADs despite APD shortening.
PMID:42413688 | DOI:10.1016/j.yjmcc.2026.07.004