Physiological remodelling of potassium channels in the heart.

The failing heart undergoes a process of pathological electrical remodelling that is characterized by maladaptive alterations in ion channel expression and function. This shift in phenotype manifests as electrical instability which increases the occurrence of arrhythmic sudden death. Indeed, it is estimated that of the 300 000 annual deaths related to heart failure, up to 50% are the result of sudden cardiac death, most likely from ventricular tachycardia and fibrillation. Thus, a better understanding of the cellular and molecular mechanisms underlying electrical remodelling is vital to developing therapeutic strategies to prevent lethal arrhythmias. Yang et al. describe a thought-provoking series of experiments exploring a signalling pathway underlying adaptive, ‘physiological’ electrical remodelling. The clinical impact of this work is that it provides important clues into ways in which the balance of physiological and pathological signalling can be controlled to prevent sudden cardiac death. The aetiology of pathological electrical remodelling is complex and incompletely understood, partly because of the diverse diseases that lead to heart failure and variations in the severity or duration of disease. Nevertheless, chronic ventricular dysfunction is consistently characterized by inhibition of repolarizing K+ currents and prolongation of action potential duration. Furthermore, delayed repolarization contributes to intracellular Ca2+ dysregulation, development of afterdepolarizations, and increased dispersion of refractoriness, which are important substrates for the genesis of sustained arrhythmias. Recent experimental data indicate that signalling pathways associated with pathological hypertrophy participate in downregulating cardiac K+ channels, particularly those carrying the transient outward current (Ito). In particular, pro-hypertrophic agonists such as angiotensin II or endothelin-1 decrease mRNA and protein abundance of Kv4.x a-subunits (Kv4.3 in human, Kv4.2 and Kv4.3 in rodents) that carry Ito in cardiomyocytes. 5,6 The signalling mechanisms underlying these changes partly involve stress-activated kinases such as apoptosis signal-regulating kinase-1 (ASK1) and its main targets, p38 and c-Jun N-terminal kinase (JNK). Activation of ASK1 is mediated by receptor-stimulated NADPH oxidase and generation of reactive oxygen species, thus implicating oxidative stress as a key participant in remodelling. However, the transcriptional events underlying Kv channel down-regulation are not well defined, although it has been proposed that decreased mRNA stability is involved. A parallel pathway associated with pathological electrical remodelling involves the Ca2+-sensitive phosphatase calcineurin and the transcription factor nuclear factor of activated T-cells (NFATc3). –10 This pathway is activated by sustained elevation in [Ca]i, which stimulates calcineurin to dephosphorylate NFATc3 and promote its translocation to the nucleus. In mice with myocardial infarction or chronic infusion of the b-agonist isoproterenol, down-regulation of several repolarizing K+ currents (Ito, IKslow1, IKslow2) was shown to be prevented by calcineurin inhibition or by genetic knockout of NFATc3. A pivotal role for Ca2+ in Kv channel remodelling is further supported by experiments in canine myocytes where highfrequency activation of Ca2+ i transients by rapid pacing was shown to activate calcineurin and NFATc3, down-regulate Kv4.3 mRNA and protein, and decrease Ito density. 10 In this study, Ito downregulation was also inhibited by blockers of calmodulin kinase II (CaMKII), suggesting that there is cross-talk between CaMKII and calcineurin pathways. Thus, growing evidence indicates that ASK1– p38–JNK and Ca2+–CaMKII–calcineurin–NFATc3 pathways mediate pathological remodelling of K+ currents in the heart. It should be noted, however, that down-regulation of Kv channel expression does not simply parallel the development of hypertrophy. For example, rapid pacing of myocytes down-regulates Kv4.3 channels without significant change in cell morphology. Moreover, experimental models of diabetic cardiomyopathy exhibit characteristic down-regulation of Kv channel mRNA and protein but little evidence of hypertrophy. The present work by Yang et al. features a different form of electrical remodelling that contrasts markedly with that observed with pathological stressors. Specifically, ventricular myocytes from mouse hearts with constitutive activation of the lipid kinase phosphoinositide 3-kinase a (caPI3Ka) have increased current amplitudes and increased cell size (measured by whole-cell capacitance) compared with myocytes from wild-type mice, but K+ current densities between the