K ATP channels are amongst the most highly expressed ion channels in striated muscle where they act as critical sensors for metabolism-excitability coupling. Cardiac channel activation, due to elevated workload or metabolic compromise, results in action potential shortening and protects against pathological elevations in cytosolic calcium. Despite their prominence, evidence for a role of myocardial K ATP dysfunction in human disease has remained elusive. Case reports have associated genetic variants in the striated muscle restricted SUR2A subunit splice variant with ventricular arrhythmia and cardiomyopathy, but these associations have never been experimentally tested. Notably, modern clinical databases now indicate that certain cardiac disease-associated variants, which cause similar protein truncating effects, are found in > 1 in 500 people in general populations—which raises the question, if these variants are pathological, how can they be so common? In studies of novel mouse models, we seek to determine the effects of SUR2A-restricted variants on recombinant and native cardiomyocyte K ATP channel function and to test the potential of these variants to drive cardiac pathology. We show that this cluster of SUR2A-restricted variants decrease K ATP channel function and ADP-activation. Genotype dependent decreases native channel function is observed. Unlike pan-SUR2-null mice (in which both the major SUR2A and SUR2B splice variants are ablated), basal cardiac function appears normal in SUR2A-mutants. However, drastic mortality is observed in mutant mice upon adrenergic challenge, which is associated with increased arrhythmic events, fibrosis, and abnormal calcium signaling. These data suggest that SUR2A-restricted loss of function creates a latent cardiac risk, which can develop into lethal arrhythmia and/or heart failure upon secondary stressors. Identification of the circumstances in which pathology arises could lead to “personalized protection” and the avoidance of exacerbating lifestyle risk factors in carriers of these variants.
Nagaraj et al. (Sun,) studied this question.