Abstract 1354: Estrogen predisposes prepubertal Long QT Syndrome 2 (LQT2) rabbits to cardiac arrhythmias
Introduction: Adult women with LQT2 are at higher risk for clinical events and sudden cardiac death (SCD) than men. We have created transgenic LQT2 rabbits selectively over-expressing a pore mutant of the human HERG in the heart. All episodes of SCD in these LQT2 females occurred after sexual maturation. We hypothesize that sex hormones modulate cardiac repolarization and incidence of polymorphic VT in female LQT2 rabbits.
Methods: In this ongoing study, prepubertally ovariectomized females were implanted with 90 day-release-pellets of estradiol (EST, 150mg), or dihydrotestosterone (DHT, 200mg), or placebo (OVX). A fourth group consisted of sham-operated females (SHAM). All groups underwent telemetric ECG monitoring, surface ECG after 30 days of hormone treatment, and in vivo electrophysiological studies (EPS) under isoflurane (2–5%) after 60 days.
Results: EST steepened the QT/RR slope of prepubertal rabbits mimicking the adult LQT2 female phenotype (baseline: 0.608 ± 0.09, after 4 weeks: 0.69 ± 0.1, n=5, p<0.05; SHAM females: 0.699 ± 0.07, n=4). In contrast, DHT decreased the QT/RR slope (baseline: 0.739 ± 0.11, after 4 weeks: 0.521 ± 0.08, n=3, p=0.02). A smaller decrease was seen in OVX: 0.677 ± 0.01 vs. 0.599 ± 0.08, n=2. EST prolonged QT- and QTpeak-index compared to DHT rabbits. (EST, n=2: QT: 112.6% ± 1.5; QTp: 95.8% ± 1.6 vs. DHT, n=2: QT: 105.4% ± 4.1, p=0.07; QTp: 87.6% ± 0.9, p<0.05 vs. SHAM females, n=2: QT: 123.4% ± 9.5; QTp: 102.3% ± 2.5) EPS revealed a longer AERP and VERP in EST than in DHT rabbits - and a trend towards longer refractoriness than in OVX - reaching similarly prolonged refractoriness as in SHAM females (EST, n=2: AERP: 165.0 ± 35.4ms; VERP: 225.0 ± 25.0ms vs. DHT, n=3: AERP: 90.00 ± 5.8ms, p=0.03; VERP: 193.3 ± 8.8ms, p=0.07 vs. OVX, n=2: AERP: 125.0 ± 25.0ms, VERP: 205.0 ± 5.0ms, vs. SHAM females, n=2: AERP: 145.0 ± 5.0ms, VERP: 220.0 ± 20.0ms). One out of four EST-treated prepubertal rabbits died at the age of 96 days of spontaneous polymorphic VT.
Conclusion: EST increases the QT/RR slope and prolongs QT and cardiac refractoriness mimicking the adult LQT2 female phenotype, whereas DHT decreases the QT/RR slope and shortens QT and refractoriness mimicking a male phenotype. EST predisposes prepubertal LQT2 rabbits to spontaneous polymorphic VT.