A spotlight on electrophysiological remodeling and the molecular biology of ion channels

The present special issue of Cardiovascular Research focuses on two tightly linked and increasingly important areas of cardiovascular electrophysiology. It has become increasingly apparent that the cardiac electrophysiological milieu is highly dynamic. Not only do disease states affect the determinants of cardiac electrical function in profound ways, but we now recognise that cardiac arrhythmias can themselves produce profound changes in the structure and function of the heart, and that these changes can contribute importantly to the initiation and perpetuation of arrhythmias. Disease- and arrhythmia-induced changes in cardiac electrical properties are referred to as electrophysiological remodeling. Our understanding of the mechanisms and significance of these processes has been greatly enhanced by advances in the molecular biology of cardiac ion channels. Knowledge in this field has permitted rapid advances in the understanding of the molecular basis of cardiac electrical activity under normal conditions, under the influence of drugs and genetic abnormalities that affect channel function, and subsequent to remodeling. This spotlight issue includes review articles on rapidly developing areas by experts in each field, as well as original contributions presenting important new information. The review articles begin with an overview by Tomaselli and Marban [1] of electrical remodeling in cardiac hypertrophy and failure, disease entities associated with a particularly high prevalence of sudden cardiac death. A detailed review by Pinto and Boyden [2] of the complex, time-dependent changes in electrophysiology caused by myocardial ischemia and infarction follows. Nattel [3] then discusses recent developments in understanding the electrophysiological remodeling caused by atrial tachycardia, a field receiving a great deal of attention because of its prime importance for understanding the determinants of atrial fibrillation (AF). The final review dealing with remodeling per se is a paper by Saffitz et al. [4] regarding gap junction remodeling in relation to the development of anatomic substrates of arrhythmia. The second series of review papers discuss developments in the molecular biology of ion channels. Roden and Kuperschmidt [5] present an up-to-date review of the increasingly complex picture of the relationships between genes and cardiac ion channels. A paper by Balser [6] reviews the structure and function of Na+ channels that govern cardiac impulse propagation and excitability, and includes some original thoughts about state-dependent block. Bers and Perez-Reyes [7] provide a detailed and timely review of cardiac Ca2+ channel structure and function, an area to which they have made recent contributions of major importance. Sorota [8] discusses cardiac Cl− channels, a family that may respond not only to cell signaling but also to other physiological signals such as changes in cell volume that may be especially important in disease. Snyders [9] completes this section with a detailed review of cardiac K+ channels, a widely diverse group of great relevance to the understanding and treatment of clinical arrhythmias. The first original article by Bryant et al. [10] deals with the important issue of regional variation in electrical remodeling caused by catecholamine-induced hypertrophy, along with the effects of hypertrophy on regional differences in electrical properties. A paper of Aimond et al. [11] follows, and shows decreases in Ca2+ and K+ current density and (in the case of Ca2+ channels) a slowing in inactivation 4–6 months after myocardial infarction induction by left coronary artery ligation in rats. The next original contribution, by Cerbai et al. [12], describes postnatal development in If and advances the concept that If expression in hypertrophied and failing hearts is due to the expression of a fetal gene within the context of a program of fetal gene re-expression. This is followed by a paper by Veldkamp et al. [13] which elegantly demonstrates that the reduction in inward rectifier current that occurs when cardiac myocytes are cultured is due to a decrease in channel number and not in single channel kinetics or conductance. These are followed by five papers on electrical remodeling related to AF, testifying to the intense recent activity in this area. The first two of these relate to changes in L-type ICa, which have recently been shown to be central to the mechanisms by which ‘AF begets AF’. Gaspo et al. [14] show a downregulation in dihydropyridine receptors by atrial tachycardia, suggesting that decreases in Ca2+ channel density contribute to the ICa decreases caused by atrial tachycardia. The following paper by Brundel et al. [15] evaluates in patients with AF the expression of genes involved in cardiac Ca2+ handling, and concludes that persistent AF is associated with decreased expression of genes encoding L-type Ca2+ channels and sarcoplasmic reticulum Ca2+-ATPase. Hara et al. [16] present findings about the dynamic behaviour of action potentials in atria remodeled by AF and present findings consistent with underlying abnormalities in Ca2+ handling. Another clinical paper follows, in which Yu et al. [17] describe the time-dependent reversal of typical atrial electrical remodeling in patients recently cardioverted from longstanding AF. Remarkably, substantial reversal occurred within 4 days in patients whose AF had persisted for an average of 5 years prior to cardioversion, indicating the dynamic nature of this form of remodeling and its reversibility even after very long periods of AF. The final paper on remodeling due to AF, by Courtemanche et al. [18], shows with the use of sophisticated mathematical modeling techniques that the ionic current changes described in atrial myocytes of patients with AF can account for the action potential modifications caused by the arrhythmia, with decreases in ICa being the single most important factor. The actions of specific K+ channel inhibition are analyzed, and found to be importantly affected by atrial electrical remodeling and heterogeneity. The six original papers that follow concern the molecular biology of ion channels. The first three of these deal with the pharmacology of native cardiac wild-type and mutant channels. Chandra et al. [19] study the β-adrenergic regulation of wild-type and ΔKPQ mutant sodium channels that are responsible for the LQT3 variant of the congenital long QT syndrome. Intriguingly, they show that β-adrenergic stimulation increases the persistent Na+ current, believed to cause QT prolongation and ventricular tachyarrhythmias, suggesting a potential pathophysiological mechanism for adrenergic triggering of arrhythmias in LQT3. Their finding that Ca2+/Na+ permeability ratios are not altered by β-adrenergic stimulation raises interesting questions about the mechanism of slip-mode Na+ channel conductance described recently by Santana et al. [20] in Science. Makielski et al. [21] study the well-known cardioselectivity of lidocaine’s Na+ channel blocking action and conclude that this cardioselectivity depends on the intrinsic properties of the pore-containing α-subunit of the cardiac channel, with a less important contribution from the associated β1 subunit. Delpon et al. [22] describe the structural determinants of the blocking and novel ‘agonist’ actions of benzocaine on the current carried by Kv1.5 channels, corresponding to the human atrial ultrarapid delayed rectifier current. The next two papers relate to the congenital long QT syndrome. Deschênes et al. [23] characterize the role of isoleucine and methionine in the IFM cluster in DIII-IV in INa inactivation. Viswanathan et al. [24] use a mathematical model to explore the mechanisms of pause-induced early after-depolarisations in the congenital long QT syndromes that result from K+ or Na+ channel mutations. They conclude that reactivation of L-type ICa plays a central role in pause-induced early after-depolarisations. The final original paper, by Balzer et al. [25], demonstrates that the transient receptor potential (Trp) protein is the molecular basis of oxidant-activated cation channels in vascular endothelial cells. They thus play an important role in the redox sensitivity of vascular endothelium. Like all members of the cardiovascular electrophysiology community, we were very saddened by the news of the untimely death of Dr Edouard Coraboeuf, an extraordinary leader in the area for the past 40 years [26]. He was a pioneer in the field of electrophysiological remodeling, as in many other areas. We are grateful to be able to dedicate this issue presenting exciting recent scientific advances as a small but fitting tribute to his memory.