Abstract 1248: Effect of β-adrenergic Stimulation or Parasympathetic Stimulation in deltaKPQ-SCN5A Mice with Long QT Syndrome 3
Arrhythmias in long QT Syndrome 3 (LQT3) occur predominantly at rest. Antiarrhythmic therapy is of debate. We performed telemetric Holter ECGs and electrophysiologic studies in mice and isolated beating hearts with the heterozygeous knock-in deletion ΔKPQ-SCN5A (LQT3) and wildtype (WT) littermates at baseline and during parasympathetic and sympathetic stimulation with or without β adrenoreceptor (ar) blocker pretreatment. Carbachol (0.5 mg/kg i.p.) provoked bigemini or torsades de pointes (TdP) during bradycardia in freely roaming LQT3 mice (6/6, p<0.05 vs. WT 0/6 Fig⇓.), isoprenaline (2 mg/kg i.p.) or atropine (0.5 mg/kg i.p.) did not. Propranolol (3.5 mg/d p.o.) aggravated bradycardia and provoked pauses (n=10, 11 ± 1 pauses / 15min, p<0.05 vs. WT 3 ± 0.4, maximal duration 903 ms vs. WT 347). Pretreatment with propranolol did not prevent carbachol induced arrhythmias. Of 55 LQT3 isolated hearts, 17 developed afterdepolarizations (EAD) and TdP, associated with markedly prolonged monophasic action potential duration (APD) in hearts with TdP, 60 ± 1 ms, p < 0.05 vs. without TdP 45 ± 1. β(ar) stimulation (orciprenaline 1.7 μM) suppressed EAD & TdP (TdP in 0/16 hearts, p<0.05 vs. 4/13 hearts at baseline) and decreased APD and dispersion of APD, dispersion 9 ± 1 ms, p<0.05 vs. baseline 19 ± 2 ms. βar blockade (propranolol or esmolol 10-7 - 10-5 M) did not suppress EAD or TdP, but aggravated bradycardia and prolonged APD. Conclusions: Parasympathetic stimulaton provokes arrhythmias in this model of LQT3. βar stimulation suppresses EAD & TdP in this model of LQT3 by decreasing APD, dispersion of APD and pauses. These beneficial effects are suppressed by β ar blockade.