Apamin induces early afterdepolarizations and torsades de pointes ventricular arrhythmia from failing rabbit ventricles exhibiting secondary rises in intracellular calcium.
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.
['Chang|Po-Cheng|PC|', 'Hsieh|Yu-Cheng|YC|', 'Hsueh|Chia-Hsiang|CH|', 'Weiss|James N|JN|', 'Lin|Shien-Fong|SF|', 'Chen|Peng-Sheng|PS|']
D000200:Action Potentials D000818:Animals D001030:Apamin D054537:Atrioventricular Block D002118:Calcium D002304:Cardiac Pacing, Artificial D004195:Disease Models, Animal D006333:Heart Failure D026902:Potassium Channel Blockers D011817:Rabbits D016171:Torsades de Pointes D018487:Ventricular Dysfunction, Left
Apamin early afterdepolarization Torsades de pointes Torsades de pointes intracellular Ca(2+) apamin-sensitive K(+) current I(KAS) TdP heart failure HF Optical mapping atrioventricular left ventricular corrected QT EAD premature ventricular beat PVB Action potential duration Action potential duration Ca(i) APD AV I(Ca,L) L-type Ca(2+) current LV PCL Potassium channels QTc SK V(m) action potential duration membrane potential pacing cycle length small conductance Ca(2+) activated K(+) torsades de pointes