A secondary rise of intracellular Ca²⁺ (Ca_i) 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 Ca_i.

To test the hypothesis that small conductance Ca²⁺ activated I_KAS maintains repolarization reserve and prevents ventricular arrhythmia in a rabbit model of heart failure (HF).

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.

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.

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.