Small-Conductance Calcium-Activated Potassium Channel and Recurrent Ventricular Fibrillation in Failing Rabbit Ventricles

Abstract

Rationale Fibrillation-defibrillation episodes in failing ventricles may be followed by action potential duration (APD) shortening and recurrent spontaneous ventricular fibrillation (SVF). Objective We hypothesized that activation of apamin-sensitive small-conductance Ca2+-activated K+ (SK) channels are responsible for the postshock APD shortening in failing ventricles. Methods and Results A rabbit model of tachycardia-induced heart failure was used. Simultaneous optical mapping of intracellular Ca2+ and membrane potential (Vm) was performed in failing and non-failing ventricles. Three failing ventricles developed SVF (SVF group), 9 did not (no-SVF group). None of the 10 non-failing ventricles developed SVF. Increased pacing rate and duration augmented the magnitude of APD shortening. Apamin (1 μmol/L) eliminated recurrent SVF, increased postshock APD80 in SVF group from 126±5 ms to 153±4 ms (p<0.05), in no-SVF group from147±2 ms to 162±3 ms (p<0.05) but did not change of APD80 in non-failing group. Whole cell patch-clamp studies at 36°C showed that the apamin-sensitive K+ current (IKAS) density was significantly larger in the failing than in the normal ventricular epicardial myocytes, and epicardial IKAS density is significantly higher than midmyocardial and endocardial myocytes. Steady-state Ca2+ response of IKAS was leftward-shifted in the failing cells compared with the normal control cells, indicating increased Ca2+ sensitivity of IKAS in failing ventricles. The Kd was 232 ± 5 nM for failing myocytes and 553 ± 78 nM for normal myocytes (p = 0.002). Conclusions Heart failure heterogeneously increases the sensitivity of IKAS to intracellular Ca2+, leading to upregulation of IKAS, postshock APD shortening and recurrent SVF.

Calcium-Voltage Coupling in the Genesis of Early and Delayed Afterdepolarizations in Cardiac Myocytes

“…Late I Na is another candidate because it may slowly inactivate (58). Finally, the gradual rise in [Ca] i may also activate other outward currents, such as the Ca-activated Cl current (I Cl(Ca) ) (59) or small conductance Ca-activated K current (60). Because I Ks has a very low density in mouse ventricular myocytes, one or more of these currents may be responsible for the slow process that is causing the long plateau shown in the experimental recordings in Fig.…”

“…It is well known that Cadependent signaling pathways, such as CaMKII signaling, can affect many ionic currents as well as Ca cycling properties (70), which can have much more complex effects on EADs and DADs. Our AP model does not include some of the Ca-dependent ionic currents, such as I ns(Ca) (71,72) and the small conductance Ca-activated K channel (60) (38). Therefore, a dynamic [Na] i may have additional effects on EADs and DADs.…”

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

“…An extremely high rate of activation, such as that which occurs during ventricular fibrillation, is known to activate I KAS and shorten the postshock APD. These changes facilitate the recurrence of ventricular fibrillation in failing rabbit ventricles 15, 31. Hsieh et al7 tested the importance of pacing rates on the expression of I KAS in the same rabbit heart failure model.…”

“…Large variations of I KAS densities have also been observed in VMs 8, 15, 35. The mechanisms by which some cells had more I KAS than others remain unclear.…”

“…Drugs that block I KAS may be proarrhythmic by removing the repolarization reserve. On the other hand, an excessive amount of I KAS may shorten the action potential duration (APD) and promote recurrent ventricular fibrillation 15. Therefore, I KAS blockade may be either proarrhythmic or antiarrhythmic, depending on the mechanisms of arrhythmia 5.…”