Advances in Arrhythmia and Electrophysiology Advances in Cardiac ATP-Sensitive K Channelopathies From Molecules to Populations

ATP-sensitive K (KATP) channels are nucleotide-gated bioenergy sensors that enable high-fidelity feedback communication between cellular energy dynamics and membrane electric activity.1–4 Particularly dense in cardiac sarcolemma where they are composed through heteromultimeric assembly of inwardly rectifying K channel pores, typically KCNJ11-encoded Kir6.2 proteins, and regulatory ATPbinding cassette (ABC) proteins, namely ABCC9-encoded SUR2A subunits, KATP channels are increasingly recognized as integral to tissue energy conservation and optimization of energy use.5 Integrated with intracellular energy pathways, sarcolemmal KATP channels are established cardioprotectors implicated in the sustenance of wellness.6–8 Knockout of the Kir6.2 KATP channel pore induces inefficient cardiac energetics associated with altered metabolic fuel selection and remodeling of the myocardial proteome, highlighting a distinct role of the channel in heart energy homeostasis.9,10 KATP channel ablation alters the expression of one tenth of largely metabolism-related protein species, exposing within the KATP channel-deficient ventricle markers of cardiovascular disease susceptibility.9,11 Indeed, disruption of the Kir6.2 KATP channel compromises cardiac protection afforded by ischemic preconditioning, impairs myocardial tolerance to sympathetic surge, and aggravates the impact of endurance challenge or hemodynamic overload precipitating heart failure under stress.12 Conversely, overexpression of channel subunits generates a protective phenotype at cellular and organ levels.13,14 High-throughput molecular technologies applied to phenotypically characterized patient and population cohorts have contributed to the deciphering of human KATP channelopathies, disease entities caused by genetic disruption of ion channel function.15–19 In cardiovascular medicine, mutations in the regulatory SUR2A subunit have been linked to KATP channelopathy-associated electric and cardiomyopathic disorders, namely the syndromes of adrenergic atrial fibrillation and dilated cardiomyopathy with tachycardia.19–21 Moreover, in clinical heart failure, a common polymorphism in the Kir6.2 KATP channel pore subunit has been identified as a robust biomarker for impaired performance in stress test.22 Furthermore, the Kir6.2 K23 allele, present in more than half of the population, has been pinpointed as an independent risk factor for susceptibility to maladaptive cardiac remodeling in hypertension.23 Cardiovascular disorders associated with genetic variation in KATP channel genes also include myocardial infarction and ventricular fibrillation. Collectively, advances in molecular medicine have enabled a growing understanding of genetically determined channel function and malfunction, underscoring the broadening awareness of the impact of the KATP channel complex on individual and public cardiovascular health.