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, I_CaL and I_Kr 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, I_Kr was absent, the I_CaL window was increased and the recovery from inactivation was delayed. E2 reversed mutation's effects on APD and I_CaL window, but failed to restore I_Kr and reduce EADs prevalence. E2 also introduced a fast component in I_CaL recovery which contributed to I_CaL 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_CaL gating are a major determinant of APD prolongation and EADs associated with the KCNH2 mutation.

The KCNH2 mutation was associated with I_CaL gating abnormalities crucially contributing to APD prolongation, which were largely corrected by E2. However, by accelerating I_CaL recovery, E2 facilitated EADs despite APD shortening.