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 Ca2+ (Cai) and an upregulation of IKAS are characteristic findings of failing ventricular myocytes. We hypothesize that apamin, a specific IKAS blocker, may induce torsades de pointes (TdP) ventricular arrhythmia from failing ventricles exhibiting secondary rises of Cai. Objectives To test the hypothesis that small conductance Ca2+ activated apamin sensitive K+ current (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 (AV) 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]% pre-pacing to 30.4 [26.8–34.0]% (N=7, p<0.001) post-pacing. The QTc in failing ventricles was 337 [313–360] ms at baseline and 410 [381–439] ms after applying 100 nmol/L of apamin (p=0.01). 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 the EADs and PVBs always occurred at the site with long APD and large amplitude of the secondary rises of Cai. Apamin induced secondary rises of Cai in 1 non-failing ventricles, but no EAD or TdP were observed. Conclusion In HF ventricles, apamin induces EADs, PVBs and TdP from areas with secondary rises of Cai. IKAS is important in maintaining repolarization reserve and preventing TdP in HF ventricles.

Small‐Conductance Calcium‐Activated Potassium Current in Normal Rabbit Cardiac Purkinje Cells

“…Apamin induced very little change of APD 80 in VMs at PCLs between 500 and 1000 ms. APD 80 prolongation was observed with 2000 and 4000 ms PCLs. The latter finding is consistent with a previous study which showed that apamin increased APD 80 of Langendorff‐perfused normal rabbit ventricles only when the PCL was ≥800 ms 21. For all cells studied, apamin prolonged APD 80 of PCs (n=9) from 228±12 to 244±17 ms (6.63% increase) at 2000 ms PCL, from 203±18 to 226±3 ms (9.22% increase) at 1000 ms PCL, from 190±26 to 199±16 ms (5.58% increase) at 600 ms PCL and from 171±16 to 177±25 ms (2.2% increase) at 500 ms PCL.…”

Apamin Does Not Inhibit Human Cardiac Na+ Current, L-type Ca2+ Current or Other Major K+ Currents

“…Subsequent investigations showed that the apamin-sensitive potassium current ( I KAS ) is present in the atria [5]–[12]. In addition, while normal ventricles paced at physiological cycle lengths do not express significant I KAS [13], we and others found that I KAS expression is upregulated in failing, ischemic or infarcted human, rabbit and rat ventricles and in normal rabbit ventricles with complete atrioventricular block [14]–[19]. A common criticism of all these studies is that the specificity of apamin in cardiac type ion channels has not been well established.…”

Down-regulation of the Small Conductance Calcium-activated Potassium Channels in Diabetic Mouse Atria

“…It is envisioned that the electrophysiological changes resulting from K ϩ channel down-regulation promote the development of "atrial torsade de pointes" for AF initiation. Indeed, a recent report showed that apamin induces early after-depolarizations and torsade de pointes in failing rabbit ventricles, confirming that suppression of SK channels is proarrhythmic (32).…”