Abstract 2292: Epinephrine Challenge in Mice Carrying the Human +/N629D Mutation in the KCNH2 Channel
Introduction: Mutations in human ERG1 potassium channel (hERG/KCNH2/Kv11.1) underlie the Long QT2 Syndrome. Adrenalin challenge is used clinically to unmask long QT, to provoke syncope or arrhythmias but the pathobiology of response to adrenalin is not understood.
Methods: To elucidate precursors to sudden death we created a mouse model of LQT2 by inserting the missense N629D human LQT2 mutation into the orthologous mouse gene, mERG by homologous recombination in embryonic stem cells.
Results: Under vivarium conditions, lifespan of +/N629D mice is normal. However, epinephrine ip (2 mg/kg) resulted in 12/12 adult +/N629D mice abruptly loosing consciousness, 6/12 spontaneously died rapidly and an additional 6/12 mice were euthanized because of a persistent neurologic defect by 24 hours. Abrupt spontaneous deaths were asystolic. Of these 6 euthanized +/N629D mice, 2 regained locomotion but 1 had paralysis of a forelimb and one had spontaneous tremors. In comparison 1/17 +/+ wild type mice died spontaneously (p<0.01). At onset of unconsciousness profound sinus bradycardia was associated with modestly prolonged QT but Torsade or VF never occurred. Profound ST segment elevation occurred in 11/12 +/N629D mice just before unconsciousness associated with abrupt decreases in myocardial performance, aortic flow and fractional shortening. Blood pressure was not measureable using tail cuff recordings. This was observed in 0/17 +/+ mice (p<0.001). To further elucidate vascular biology in +/N629D mice, response of pressurized mesenteric arteries to epinephrine was evaluated. In 5/5 +/N629D mice epinephrine at 10−7 M produced greater vasoconstriction than seen with 135 mM KCL; whereas in +/+ mice, smaller response only occurred at high concentrations.
Conclusion: In +/N629D mice, epinephrine-induced vasospasm is the immediate precursor to decreased cardiac output, neurologic impairment and asystolic sudden death. Epinephrine induced vasospasm in this LQT2 model may be an under-recognized precursor of sudden death, as has been observed in some families with the Long QT2 Syndrome.