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Apamin induces early afterdepolarizations and torsades de pointes ventricular arrhythmia from failing rabbit ventricles exhibiting secondary rises in intracellular calcium

  • Author(s): Chang, PC
  • Hsieh, YC
  • Hsueh, CH
  • Weiss, JN
  • Lin, SF
  • Chen, PS
  • et al.
Abstract

Background A secondary rise of intracellular Ca2+(Cai) and an upregulation of apamin-sensitive K+current (IKAS) are characteristic findings of failing ventricular myocytes. We hypothesize that apamin, a specific IKASblocker, may induce torsades de pointes (TdP) ventricular arrhythmia from failing ventricles exhibiting secondary rises of Cai. Objective To test the hypothesis that small conductance Ca2+activated IKASmaintains repolarization reserve and prevents ventricular arrhythmia in a rabbit model of heart failure (HF). Methods We performed Langendorff perfusion and optical mapping studies in 7 hearts with pacing-induced HF and in 5 normal control rabbit hearts. Atrioventricular block was created by cryoablation to allow pacing at slow rates. Results The left ventricular ejection fraction reduced from 69.1% [95% confidence interval 62.3%-76.0%] before pacing to 30.4% [26.8%-34.0%] (N = 7; P <.001) after pacing. The corrected QT interval in failing ventricles was 337 [313-360] ms at baseline and 410 [381-439] ms after applying 100 nmol/L of apamin (P =.01). Apamin induced early afterdepolarizations (EADs) in 6 ventricles, premature ventricular beats (PVBs) in 7 ventricles, and polymorphic ventricular tachycardia consistent with TdP in 4 ventricles. The earliest activation site of EADs and PVBs always occurred at the site with long action potential duration and large amplitude of the secondary rises of Cai. Apamin induced secondary rises of Caiin 1 nonfailing ventricle, but no EAD or TdP were observed. Conclusions In HF ventricles, apamin induces EADs, PVBs, and TdP from areas with secondary rises of Cai. IKASis important in maintaining repolarization reserve and preventing TdP in HF ventricles. © 2013 Heart Rhythm Society.

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