Ca²⁺ current involvement in a KCNH2 mutation's phenotype and its modulation by estrogen

Area of Science:

• Cardiovascular Electrophysiology
• Molecular Cardiology
• Genetics of Arrhythmia

Background:

• Estrogens can modify cardiac repolarization and influence Long QT Syndrome (LQTS) phenotypes.
• A specific LQT2 patient with a KCNH2 mutation experienced arrhythmia symptoms after 17-β estradiol (E2) administration.

Purpose of the Study:

• To investigate the mechanistic link between E2 administration and arrhythmia symptoms in an LQT2 patient with a G628S-KCNH2 mutation.
• To determine how E2 affects cardiac ion channel function and electrical activity in LQT2 models.

Main Methods:

• Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from LQT2 patients and wild-type controls were used.
• Measurements included membrane potential, L-type calcium current (I_CaL), and rapid delayed rectifier potassium current (I_Kr) with and without E2 exposure.
• In silico simulations and molecular analyses (qPCR, immunocytochemistry) were performed.

Main Results:

• LQT2 hiPSC-CMs exhibited prolonged action potential duration (APD) and early afterdepolarizations (EADs), with absent I_Kr and altered I_CaL kinetics.
• E2 partially reversed APD prolongation and I_CaL window changes but did not restore I_Kr or reduce EADs.
• E2 accelerated I_CaL recovery, potentially increasing calcium channel availability during the action potential plateau.

Conclusions:

• KCNH2 mutations can cause I_CaL gating abnormalities contributing to APD prolongation and EADs in LQT2.
• E2 partially corrects these abnormalities but its acceleration of I_CaL recovery may promote EADs despite APD shortening.
• The findings highlight complex interactions between sex hormones and genetic mutations in LQTS.