Advances in cardiac ATP-Sensitive K⁺ channelopathies from molecules to populations

Deficient cellular energetics set by aberrant K_ATP channel function increasingly is implicated in a spectrum of conditions underlying metabolic imbalance and electric instability.⁵ Indeed, cardiac K _ATP channelopathies are emerging as a recognized disease entity underlying heart failure and arrhythmia. ¹⁹ Understanding the molecular structure and function of K_ATP channel subunits, ⁸ and their relationship to cellular metabolic signaling, ⁹⁹ has been instrumental in interpreting the pathophysiology of channel malfunction associated with heart disease predisposition (Figure 3).¹² From individual patients to populations, variants in K _ATP channel genes now have been documented in human dilated cardiomyopathy²¹ and atrial fibrillation²⁰ and as risk factors for electric instability,^93,94 adverse cardiac remodeling,²³ impaired performance under stress,²² or myocardial infarction.⁹⁸ Beyond the initial deciphering of genotype-phenotype relationships, development and application of high-throughput platforms to screen for disrupted coding and regulatory sequences in cardioprotective K_ATP channel genes as well as diagnosis of corrupted interactions within the cellular milieu would advance current knowledge regarding this homeostatic channel complex and its implications in cardiovascular medicine. In particular, deconvolution of altered metabolic pathways and signaling cascades associated with pathogenic K_ATP channel mutation may offer unique opportunities to pinpoint lesions that stratify the consequences of genetic variation on disease traits.¹⁸ In this regard, it can be anticipated that systems biology and network medicine strategies increasingly will be deployed to resolve the K_ATP channel interactome.¹¹ Mapping of the systems integration of molecules and their respective biological networks in health versus disease will, in turn, guide the judicious development of prognostic discriminators of disease variability and selection of treatment response predictors.^100-102 Advances in the molecular medicine of K_ATP channelopathies thus are poised to offer new perspectives in the diagnosis and therapy of individuals and populations.^103-107.