title: Apamin induces early afterdepolarizations and torsades de pointes ventricular arrhythmia from failing rabbit ventricles exhibiting secondary rises in intracellular calcium.
abstract: BACKGROUND
  A secondary rise of intracellular Ca(2+) (Cai) and an upregulation of apamin-sensitive K(+) current (I(KAS)) are characteristic findings of failing ventricular myocytes. We hypothesize that apamin, a specific I(KAS) blocker, may induce torsades de pointes (TdP) ventricular arrhythmia from failing ventricles exhibiting secondary rises of Cai.
  
  
  OBJECTIVE
  To test the hypothesis that small conductance Ca(2+) activated IKAS maintains 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 Ca(i). Apamin induced secondary rises of Ca(i) in 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 Ca(i). I(KAS) is important in maintaining repolarization reserve and preventing TdP in HF ventricles.
authors.affiliation: Krannert Institute of Cardiology and the Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Second Section of Cardiology, Department of Medicine, Chang Gung Memorial Hospital and Chang Gung University School of Medicine, Taoyuan, Taiwan.
authors.forename: Po-Cheng
authors.initials: PC
authors.lastname: Chang
authors.forename: Yu-Cheng
authors.initials: YC
authors.lastname: Hsieh
authors.forename: Chia-Hsiang
authors.initials: CH
authors.lastname: Hsueh
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
authors.forename: Shien-Fong
authors.initials: SF
authors.lastname: Lin
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
mesh_terms: D000200:Action Potentials; D000818:Animals; D001030:Apamin; D054537:Atrioventricular Block / Q000209:etiology / Q000503:physiopathology; D002118:Calcium / Q000502:physiology*; D002304:Cardiac Pacing, Artificial; D004195:Disease Models, Animal; D006333:Heart Failure / Q000139:chemically induced* / Q000503:physiopathology; D026902:Potassium Channel Blockers; D011817:Rabbits; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology; D018487:Ventricular Dysfunction, Left / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D026902:Potassium Channel Blockers; D001030:Apamin; D002118:Calcium
keywords: APD; AV; Action potential duration; Apamin; Ca(i); EAD; HF; I(Ca,L); I(KAS); L-type Ca(2+) current; LV; Optical mapping; PCL; PVB; Potassium channels; QTc; SK; TdP; Torsades de pointes; V(m); action potential duration; apamin-sensitive K(+) current; atrioventricular; corrected QT; early afterdepolarization; heart failure; intracellular Ca(2+); left ventricular; membrane potential; pacing cycle length; premature ventricular beat; small conductance Ca(2+) activated K(+); torsades de pointes