KATP vs Purkinje fibers: Which should we shoot first, or should we?

Abstract

backs. 4 ICDs, which are widely used to prevent arrhythmic SCDs, can also deliver inappropriate shocks that can not only damage the diseased heart but also provoke arrhythmias. In spite of these shortcomings, ICDs are the only available therapy that can effectively terminate VF soon after it initiates. Moreover, select antiarrhythmic medications such as beta-blockers and amiodarone are used to reduce the frequency of ICD shocks but are associated with undesirable side effects. 5 Additionally, ablation of proarrhythmic ventricular tissue can decrease the number of ICD shocks but does not significantly alter mortality rate and potentially can result in multiple complications 6 possibly due to electroporation damage. 7 Therefore, identifying novel mechanisms and therapeutic strategies to effectively treat malignant arrhythmias such as VF is an absolute necessity to improve prognosis for the growing population with cardiac disease. One important approach to achieve this goal is to determine the cellular basis of these fatal arrhythmias. Historically, ion channels that maintain normal electrical homeostasis across the cell membrane are the primary candidates to treat arrhythmias. The ATP-sensitive potassium current IK(ATP) is one such ion current that plays an important role in cardiac repolarization and contraction during both physiologic and especially pathologic conditions. 8 Specifically, KATP channels are known to play a cardioprotective role during myocardial ischemia and hypoxia, wherein the increased potassium efflux causes a reduction in action potential duration. Although beneficial, the anatomically heteterogeneous decrease in action potential duration and hence dispersed refractoriness also can increase the propensity for VF. 9–11 Experimental manipulation of the KATP channels using channel openers (e.g., pinacidil and diazoxide) and inhibitors (e.g., glibenclamide) has clearly established the channel’s role in the induction and maintenance of VF in different animal models, 8,12 explanted human hearts, 9 and in non–insulin-dependent diabetic patients during transient ischemia. 13 Clearly, activation of KATP channels could be one mechanism of ischemia-induced VF, especially in diseased, metabolically challenged hearts. Another important player implicated in VF development is the Purkinje fiber system (PS), where triggered activity has been proposed to initiate as well as maintain VF. 14,15 Premature beats originating in the PS may initiate VF, and ablation focused on these fibers can reduce the arrhythmic burden in patients with idiopathic VF. 14 In the canine heart,