Sex-specific IKAS activation in rabbit ventricles with drug-induced QT prolongation

Abstract

Background: Female sex is a known risk factor for drug-induced long QT syndrome (diLQTS). We recently demonstrated a sex difference in apamin-sensitive small-conductance Ca²⁺-activated K⁺ current (I_KAS) activation during β-adrenergic stimulation.

Objective: The purpose of this study was to test the hypothesis that there is a sex difference in I_KAS in the rabbit models of diLQTS.

Methods: We evaluated the sex difference in ventricular repolarization in 15 male and 22 female Langendorff-perfused rabbit hearts with optical mapping techniques during atrial pacing. HMR1556 (slowly activating delayed rectifier K⁺ current [I_Ks] blocker), E4031 (rapidly activating delayed rectifier K⁺ current [I_Kr] blocker) and sea anemone toxin (ATX-II, late Na⁺ current [I_NaL] activator) were used to simulate types 1-3 long QT syndrome, respectively. Apamin, an I_KAS blocker, was then added to determine the magnitude of further QT prolongation.

Results: HMR1556, E4031, and ATX-II led to the prolongation of action potential duration at 80% repolarization (APD₈₀) in both male and female ventricles at pacing cycle lengths of 300-400 ms. Apamin further prolonged APD₈₀ (pacing cycle length 350 ms) from 187.8±4.3 to 206.9±7.1 (P=.014) in HMR1556-treated, from 209.9±7.8 to 224.9±7.8 (P=.003) in E4031-treated, and from 174.3±3.3 to 188.1±3.0 (P=.0002) in ATX-II-treated female hearts. Apamin did not further prolong the APD₈₀ in male hearts. The Ca_i transient duration (Ca_iTD) was significantly longer in diLQTS than baseline but without sex differences. Apamin did not change Ca_iTD.

Conclusion: We conclude that I_KAS is abundantly increased in female but not in male ventricles with diLQTS. Increased I_KAS helps preserve the repolarization reserve in female ventricles treated with I_Ks and I_Kr blockers or I_NaL activators.

Keywords: Calcium transient; Optical mapping; Potassium and late sodium currents; Repolarization reserve; SK current.