K_ATP channels operate as an energy-sparing system limiting muscle energy expenditure during propagation of action potentials [7, 8, 33, 56]. Defined as the most densely expressed K⁺ channels in the myocardium, K_ATP channels are critical in cardiac energy homeostasis and electrical stability across a spectrum of stress conditions, from acute ischemia to chronic exertion and heart failure [12, 19, 57].

In ischemia, K_ATP channel opening shortens cardiac action potential duration and controls Ca²⁺ influx [58, 59]. Sarcolemmal K_ATP channel activation is responsible for the electrical current that underlies ST-segment elevation of transmural ischemic injury, and has been implicated in protection afforded by ischemic preconditioning [12]. Specifically, in the Kir6.2-knockout mouse following transmural anterior myocardial infarction, absence of significant and sustained ST-segment change contrasts the wild-type counterpart that demonstrates prompt and pronounced ST-segment elevation following ischemic injury [60]. Moreover, K_ATP channels have been implicated in the ischemic preconditioning mechanism by which exposure to brief ischemia preceding a sustained ischemic insult reduces subsequent infarct size [61]. Analogous to ischemic preconditioning, pharmacologic activation by K_ATP channel openers has also protective benefit [62, 63]. Both ischemic and pharmacologic preconditioning are abolished in the absence of Kir6.2-containing K_ATP channels [64, 65]. Absence of sarcolemmal K_ATP channel activity has negative effects on cardiac relaxation and contractility under acute ischemic stress. In parallel, knockout of Kir6.2 negates protection afforded by ischemic preconditioning on myocardial energy generation, transfer and utilization [66]. Total ATP turnover, a global parameter of energy demand, fails to increase in the ischemic-preconditioned K_ATP channel knockout as opposed to the wild-type, correlating with failure of preconditioned hearts lacking K_ATP channels to functionally recover [66]. The K_ATP channel-dependent cardioprotective potential is underscored by improved myocardial function during post-ischemic reperfusion following introduction of the SUR2A transgene into the SUR2 null cardiomyocyte [67].

Beyond protection against ischemia, K_ATP channels appear central to cardiac participation in the general adaptation syndrome [57]. In the “fight-or-flight” response, metabolic adaptations in bodily functions achieve a superior level of performance necessary to cope with the demands of imposed stress. The sustenance of augmented performance requires energy-controlling mechanisms, such as the K_ATP channel, ensuring that the reaction to stress itself does not become harmful [57]. A common trigger of the general adaptation syndrome is systemic sympathetic stimulation that augments cardiac contractility and heart rate, and thereby provides the necessary higher cardiac output to meet demand. Enhanced cardiac output imposes a significant metabolic load on the heart. A compensatory increase in outward K⁺ current activates when the sustained augmentation of heart muscle performance competes with the ability of cellular energetics to maintain contractile and electrical stability. The K_ATP channel-mediated action potential shortening limits actomyosin ATP consumption by reducing Ca²⁺ influx, restraining energy utilization to ensure functional and structural cellular integrity [68]. Under sympathetic distress, hearts without K_ATP channels lack stress-induced cardiac action potential shortening predisposing to cytosolic Ca²⁺ overload associated with contractile dysfunction, and possibly death [68]. On autopsy, contraction bands, pathognomonic of cytosolic Ca²⁺ loading, are visible throughout the myocardium of the Kir6.2-knockout but not wild-type counterpart [68]. Measurement of oxygen consumption has revealed that increased workloads produce only moderate elevation of energy expenditure, in line with K_ATP channel-dependent shortening of action potential duration [56]. Conversely, absence of K_ATP channel-driven action potential shortening in K_ATP channel-deficient hearts precipitates significant elevation in oxygen consumption [56].

Under catecholamine challenge, action potential prolongation remains uncompensated in the absence of K_ATP channel function, predisposing the myocardium to early afterdepolarizations [69]. This deficit in repolarization reserve translates into a high risk for induction of triggered activity and ventricular dysrhythmia [69]. Proarrhythmogenic features and lack of adaptation to stress in transgenic mice with cardiac myocyte-specific ablation of K_ATP channels verifies that these features are intrinsic to the myocardium [70]. Moreover, K_ATP channels may provide a vital feedback element for cardiovascular tolerance in sepsis, where the systemic inflammatory response to infection imposes a high demand for bodily adaptation [71]. The exaggerated susceptibility provoked by disruption of Kir6.1-containing channels was linked to progressive deterioration in cardiac activity, ischemic myocardial damage, and contractile dysfunction [71]. K_ATP channels, harnessing the ability to recognize alterations in the cellular energy state and to translate this information into changes in membrane excitability, therefore provide a necessary link for maintaining myocardial well being in the face of stress-induced energy demanding augmentation in performance.

Exercise training elicits an array of metabolic responses that underlie fitness. Mice lacking K_ATP channels when challenged with a regimented training protocol failed to manifest improved exercise capacity [72]. Repetitive exercise-stress unmasks a survival disadvantage in the Kir6.2-knockout associated with cardiac damage, implicating K_ATP channel activity in achieving physiologic benefits of exercise training without accumulating deficits [72]. Exercise intolerance has also been documented in the setting of ablation of the regulatory SUR2 subunit [73], ­underscoring the role of K_ATP channels in ensuring optimal performance. Beyond physical exercise, in distinct hyperadrenergic states exemplified by cocaine abuse, K_ATP channel deletion amplifies poor cardiovascular outcome while promotion of channel activity by potassium channel opening drugs improves survival [74, 75].

Intact K_ATP channels prevent transition from a state of disease risk to that of overt organ failure. In hypertension induced by volume overload, knockout of Kir6.2 K_ATP channels predisposes to heart failure and death [76]. Defective decoding of hypertension-induced metabolic distress signals in the K_ATP channel knockout sets in motion pathological Ca²⁺ overload and aggravates cardiac remodeling through a calcium/calcineurin-dependent cyclosporine-sensitive pathway [76]. Similarly, in models of pressure overload, such as that imposed by transverse aortic constriction, compromised K_ATP channel function renders the heart vulnerable to poor outcome [77]. The constricted K_ATP channel knockout displays biventricular congestive heart failure, characterized by exercise intolerance, cardiac contractile dysfunction, hepatopulmonary congestion and death. Surviving K_ATP channel knockouts develop sequelae, including exaggerated fibrotic myocardial hypertrophy associated with nuclear up-regulation of calcium-dependent pro-remodeling MEF2 and NF-AT pathways, precipitating chamber dilatation [77]. Moreover, it has been documented that disease-induced K_ATP channel metabolic dysregulation, even in the absence of channel gene defect, is a contributor to the pathobiology of heart failure, illustrating a mechanism for acquired channelopathy [78].

Genetically-determined K_ATP channel malfunc­tion was originally linked to insulin secretory disorders, namely congenital hyper­insulinism and neonatal diabetes [4, 17–19, 79, 80]. Beyond isolated failure of pancreatic β-cells, K_ATP channel mutations are also pathogenic in the DEND syndrome, characterized by varying degrees of delayed speech/motor development, epilepsy, neonatal diabetes, muscle hypotonia, and ­balance issues [17–19]. An even broader role in disease pathogenesis has been realized with the discovery of K_ATP channel malfunction in human ­skeletal myopathies [81, 82]. In cardiovascular medicine, K_ATP ­channelopathies have been ­associated with atrial fibrillation and dilated cardiomyopathy with tachycardia, as well as phenotypic modifiers of preclinical and overt heart disease [1, 19].

Atrial fibrillation is increasingly recognized as having genetic underpinnings [83, 84]. A case in point is the early onset cases in a subset of patients attributable to monogenic defects. The paradigm of a heritable basis for atrial fibrillation is exemplified by reports of familial disease attributed to gain-of-function or loss-of-­function mutations in ion channel genes predicted to accelerate or slow repolarization. In these cases, channel malfunction creates an arrhythmogenic substrate of re-entry or triggered activity caused by reduced electrical refractoriness or after-depolarization, respectively. Initially, channelopathy-based atrial fibrillation predicted shortening of the action potential duration and proarrhythmogenic reduction in refractory period as mechanisms of arrhythmia [85, 86]. An alternative mechanism for atrial fibrillation, namely increased propensity for prolongation of action potential duration and triggered activity in the human atrium, was identified for a loss-of-function mutation in KCNA5, encoding the voltage-dependent Kv1.5 channel [87]. A possibly equivalent mechanism has been reported in the case of a K_ATP channel mutation conferring risk for adrenergic atrial fibrillation originating from the vein of Marshall [20]. The mutation was identified in a middle-aged patient who, in the absence of identifiable risk factors, presented with long-standing atrial fibrillation precipitated by activity and refractory to medical therapy. In this patient with early-onset atrial fibrillation and an overtly normal heart, adrenergic stress as a possible trigger was investigated using a candidate gene approach and invasive electrophysiologic testing under sympathomimetic challenge [20]. The focal source of rapidly firing electrical activity was mapped to the vein of Marshall, a remnant of the left superior vena cava rich in sympathetic fibers and a recognized source for adrenergic atrial fibrillation. Although this potentially arrhythmogenic veno-atrial interface is present in the population at large, it does not trigger arrhythmia in the majority of individuals despite comparable environmental stress exposure. It was postulated that the patient was vulnerable to adrenergic atrial fibrillation due to an inherent defect in electrical stability [20].

Molecular genetic investigation demonstrated a missense mutation in ABCC9, encoding the regulatory subunit of cardiac K_ATP channels [20]. Identified in exon 38, specific for the cardiac splice variant of SUR2A, this heterozygous c.4640C  >  T transition caused substitution of the threonine residue at amino acid position 1547 with isoleucine (T1547I). Protein alignments revealed that the missense substitution altered the amino acid sequence of the evolutionarily conserved carboxy-terminal tail. Homology modeling mapped the defect adjacent to the signature Walker motifs of the nucleotide binding domain, required for coordination of adenine nucleotides in the nucleotide binding pocket. Removal of the polar threonine (T1547) and replacement with the larger aliphatic and highly hydrophobic isoleucine, as would occur in this patient, predicted compromised nucleotide-dependent K_ATP channel gating [20].

Patch-clamp recording demonstrated that the T1547I substitution compromised adenine nucleotide-dependent induction of K_ATP channel current [20]. Mutant T1547I SUR2A, co-expressed with the KCNJ11-encoded Kir6.2 pore, generated an aberrant channel that retained ATP-induced inhibition of potassium current, but demonstrated a blunted response to ADP. A deficit in nucleotide gating, resulting from the T1547I mutation, would compromise the homeostatic role of the K_ATP channel required for proper readout of cellular distress and maintenance of electrical stability.

The pathogenic link between channel malfunction and adrenergic atrial fibrillation was verified, at the whole organism level, in a murine knockout model deprived of operational K_ATP channels. Compared with the normal atrium, resistant to arrhythmia under adrenergic provocation, vulnerability to atrial fibrillation was recapitulated in the setting of a K_ATP channel deficit [20]. Thus, a lack of intact K_ATP channels, either due to a naturally occurring mutation affecting channel regulation or a targeted ­disruption of the channel complex, is a substrate for atrial electrical instability under stress, and a molecular risk factor for adrenergic atrial fibrillation.

Once the vein of Marshall had been isolated by radiofrequency ablation, atrial fibrillation could no longer be provoked by programmed electrical stimulation and burst pacing with or without isoproterenol infusion [20]. This case demonstrates that vulnerability to arrhythmia can be caused by an inability of mutant K_ATP channels to safeguard against adrenergic stress-induced ectopy. The apparently curative outcome was achieved by disrupting the gene-environment substrate for arrhythmia conferred by the underlying K_ATP channelopathy [19].

While the case underscores heritable channel dysfunction in lone atrial fibrillation, K_ATP channel deficit could play a broader role in the pathogenesis of electrical instability. Gene expression and electrophysiological studies in patients with atrial fibrillation demonstrate altered atrial ion channel mRNA transcription and post-translational activity, including downregulation of the K_ATP channel pore and associated current [88, 89]. Moreover, structural heart disease and/or atrial dilation may compromise metabolic and mechanosensitive gating of K_ATP channels [90–92], precipitating a suboptimal repolarization reserve and providing a substrate for the more common acquired form of atrial fibrillation.

K_ATP channel alteration may also impact predisposition towards ventricular vulnerability to arrhythmia. In this regard, a case of ventricular fibrillation with prominent early repolarization was recently reported in a young patient who was resuscitated following an episode of sudden death. Subsequent, unrelenting ventricular fibrillation was unresponsive to several classes of antiarrhythmics prior to rhythm restoration with quinidine [93]. Myopathic and coronary heart disease were excluded, and a K_ATP channel subunit amino acid substitution, namely the S422L variant of the KCNJ8 gene encoding Kir6.1, identified [93]. The gain-of-function K_ATP channel variant was further linked to the pathogenic substrate of pleiotropic J-wave abnormalities, in single Brugada syndrome and early repolarization syndrome cases [94].

Beyond isolated arrhythmias, K_ATP channelopathy has been implicated in a syndrome of cardiomyopathy with ventricular arrhythmia. The ontological spectrum of cardiomyopathy-­associated mutant gene products has encompassed the fundamental components of excitation-contraction coupling such as contractile, cytoskeletal, and myocellular ion regulatory proteins [95]. Human molecular genetic studies have also linked K_ATP channel defects and aberrant homeostatic stress response in the pathogenesis of dilated cardiomyopathy [19]. These defects, identified in the regulatory K_ATP channel subunit, impair channel-dependent decoding of cellular metabolic state, establishing a previously unrecognized mechanism in human heart failure [18].

The cardiomyopathic-arrhythmia syndrome characterized by the triad of dilated cardiomyopathy, ventricular arrhythmia, and ABCC9 K_ATP channel mutations has been designated CMD1O (OMIM #608569) [21], and salient phenotypic traits were reproduced by K_ATP channel knockout under imposed stress [77]. Clinically, this entity was reported in middle-aged patients with marked left ventricular enlargement, severe systolic dysfunction, and ventricular tachycardia. In these patients, heterozygous mutations were identified in exon 38 of ABCC9, which encodes the C-terminal domain of the SUR2A channel subunit, specific to the cardiac splice variant. DNA sequencing of a mutated allele identified a 3-bp deletion and 4-bp insertion mutation (c.4570-4572delTTAinsAAAT), causing a frameshift at L1524 and introducing four anomalous terminal residues followed by a premature stop codon (fs1524) [21]. Another mutated allele harbored a missense mutation (c.4537G  >  A) causing the amino acid substitution A1513T. The identified frameshift and missense mutations occurred in evolutionarily conserved domains of SUR2A, and neither mutation was present in unrelated control individuals [21].

These mutations were mapped to domains bordering the catalytic ATPase pocket within SUR2A. Structural molecular dynamics simulation showed that residues A1513 and L1524 flank the C-terminal β-strand in close proximity to the signature Walker A motif, required for coordination of nucleotides in the catalytic pocket of ATP-binding cassette proteins [21]. Replacement of A1513 with a sterically larger and more hydrophilic threonine residue or truncation of the C-terminus caused by the fs1524 mutation would disrupt folding of the C-terminal β-strand and, thus, the tertiary organization of the adjacent second nucleotide binding domain (NBD2) pocket in SUR2A. Indeed, ATP-induced K_ATP channel gating was aberrant in channel mutants, suggesting that structural alterations induced by the mutations A1513T and fs1524 of SUR2A distorted ATP-dependent pore regulation [21]. Thus, the mutations A1513T and fs1524 compromise ATP hydrolysis at SUR2A NBD2, generating distinct reaction kinetic defects. Aberrant catalytic properties in the A1513T and fs1524 mutants translated into abnormal interconversion of discrete conformations in the NBD2 ATPase cycle. Alterations in hydrolysis-driven SUR2A conformational probability induced by A1513T and fs1524 perturbed intrinsic catalytic properties of the SUR2A ATPase, compromising proper translation of cellular energetic signals into K_ATP channel-mediated membrane electrical events. Tradi­tionally linked to defects in ligand interaction, subunit trafficking or pore conductance, human cardiac K_ATP channel dysfunction provoked by alterations in the catalytic module of the channel complex establishes a new mechanism for channelopathy.

Susceptibility or resistance to heart failure, despite apparently similar risk load, is attributable to individual variation in homeostatic reserve. Following identification of mutations within a K_ATP channel gene in patients with dilated cardiomyopathy [21], the relationship between the common Kir6.2 E23K polymorphism (rs5219) and subclinical heart disease was investigated [23]. A community-based cross-sectional cohort of 2,031 predominantly Caucasian adults was utilized, for which detailed clinical and prospective echocardiographic data were available. Genotype frequencies were in Hardy–Weinberg equilibrium (EE  =  44 %; EK  =  47 %; KK  =  9 %) and similar to previously reported control populations. In the group at large, there was no significant association between genotypes and measures of cardiac structure/function (left ventricular dimensions, mass, and ejection fraction), electrical instability (atrial and ventricular arrhythmias), or metabolism (fasting glucose, diabetes, and body mass index) at enrollment. However, among individuals with documented hypertension at the time of echocardiography (n  =  1,187), the KK genotype was significantly associated with greater left ventricular dimension and volume in both diastole and systole [23]. A synergistic effect on left ventricular size of KK genotype and left ventricular mass, a marker of chronic cardiac stress load, further validated the impact of Kir6.2 E23K on cardiac structure in hypertension. From a public health perspective, hypertension is the most common risk factor for congestive heart failure, and left ventricular enlargement is an established precursor of symptomatic ventricular dysfunction. The Kir6.2 K23 allele, present in over half the population, is thus implicated as a risk factor for transition from hypertensive stress load to subclinical maladaptive cardiac remodeling [23]. These findings, consistent with previous human and animal studies [19, 76], uncover an interactive K_ATP channel gene-environment substrate that confers cardiac disease risk. Determining the overall impact of Kir6.2 E23K across ethnic groups and on long-term clinical outcome, i.e., progression to left ventricular enlargement and clinical heart failure, will require further study.

The translational significance of the Kir6.2 E23K polymorphism in human cardiac physiology was more recently explored in a cohort of patients with heart failure who underwent comprehensive exercise stress testing [22]. The frequency of the minor K23 allele was found over-represented in the 115 subjects with congestive heart failure compared to the 2,031 community-based controls described above (69 vs. 56 %, P  <  0.001). Moreover, the KK genotype, present in 18 % of heart failure patients, was associated with abnormal cardiopulmonary exercise stress test results [22]. In spite of similar baseline heart rates at rest among genotypic subgroups, subjects with the KK genotype had a significantly reduced heart rate increase at matched workloads. Molecular modeling of the tetrameric Kir6.2 pore structure revealed the E23 residue within the functionally relevant intracellular slide helix region [22]. Substitution of the wild-type E residue with an oppositely charged, bulkier K residue would potentially result in a significant structural rearrangement and disrupted interactions with neighboring Kir6.2 subunits, providing a basis for altered high-fidelity K_ATP channel gating, particularly in the homozygous state. Blunted heart rate response during exercise is a risk factor for mortality in patients with heart failure, establishing the clinical relevance of Kir6.2 E23K as a biomarker for impaired performance under exercise stress underscoring the essential role of K_ATP channels in human cardiac physiology [22].

Experimental evidence has also suggested that K_ATP channels could be involved in the pathogenesis of coronary vasomotor dysfunction and ischemic heart disease [96, 97]. The potential clinical significance of such a premise was documented in a cohort of patients with myocardial infarction at an early age, whereby a rare missense variant V734I in the ABCC9 SUR2A K_ATP channel subunit was found overrepresented [98]. Statistical significance was demonstrated after controlling for multiple established risk factors for coronary artery disease [98].

Deficient cellular energetics set by aberrant K_ATP channel function is increasingly implicated in a spectrum of conditions underlying metabolic imbalance and electrical instability [5]. Indeed, cardiac K_ATP channelopathies are emerging as a recognized disease entity underlying heart failure and arrhythmia [1, 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 [12]. From individual patients to populations, variants in K_ATP channel genes have now been documented in human dilated cardiomyopathy [21], atrial fibrillation [20], and as risk factors for electrical 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/or regulatory sequences in cardioprotective K_ATP channel genes, as well as diagnosing 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 will be increasingly 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 are thus poised to offer new perspectives in the diagnosis and therapy of individuals and populations [103–110].