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 Ca(2+)-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 (APD(80)) in both male and female ventricles at pacing cycle lengths of 300-400 ms. Apamin further prolonged APD(80) (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 APD(80) in male hearts. The Ca(i) transient duration (Ca(i)TD) was significantly longer in diLQTS than baseline but without sex differences. Apamin did not change Ca(i)TD. 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.