The real thing.

Fifteen minutes into Tom Stoppard’s The Real Thing, the audience realizes it is seeing a play within a play, the reality of which will be expressed in a dimension yet to unfold. Dramatic license? Of course; and yet it is not far from what we experience in science. Whether because of or despite the fact that the molecular age is upon us, at times we succumb to the temptation to read universal reality (rather than the play within a play imposed by our experimental design) into our results. And there is nothing wrong with this if exercising our imaginations identifies the next set of questions that will reject or substantiate our hypotheses and bring us closer to the truth. Translational Research (formerly Physiology) provides a potent vehicle for associating experimental reality with The Real Thing. Yet all the models we use, whether computers, cells, tissues, or animals, can spew forth data that muddy the distinction between what is real and unreal. One example this statement applies to is mouse physiology. Since the advent of transgenic technology, we have learned a great deal about the mouse, all of it relevant to the mouse, and some of it relevant to other forms of animal life. But what is relevant, where is it relevant, and when? The study by Guo et al1 in this issue of Circulation Research is a case in point. The authors integrate molecular determinism, cellular manifestation, and in vivo expression. The result is an interesting counterpoint, incorporating that which seems absolute and that to which it might relate. The study describes the electrophysiological and electrocardiographic expression of genetically manipulating the fast (Ito,f) and slow (Ito,s) components of the transient outward current, Ito. The major conclusions, that Kv1.4 upregulation is an important determinant of electrical remodeling when Ito,f is eliminated, that both transgenic models are normal with regard to contractile properties and structural integrity, and that cellular electrophysiological and electrocardiographic changes are seen in the absence of Ito,f and Ito,s, are all well and clearly substantiated. In addition, the authors do not attempt to interpret the meaning of their experiments beyond its importance to the biology of repolarization in the mouse. The data raise a number of issues about comparative biology and the roles of specific ion currents within the species studied. It is clear that progressing from the wild-type mouse to the Kv4.2W362F model to the Kv4.2W362F3Kv1.4 model (starting with normal and successively subtracting the repolarizing effects of Ito,f alone and Ito,f1Ito,s), there is a progression from prolongation of the ventricular myocardial action potential to the occurrence of early afterdepolarizations (EADs) that is revealed when cycle length is longest and at low temperature (which itself prolongs action potential duration). The electrocardiographic manifestations of this sequence of changes are only partially consistent with what the molecular and cellular electrophysiological data might predict. In light of the action potential changes, the expectation on ECG is a long QT interval and pause-dependent ventricular tachyarrhythmias, especially torsades de pointes.2,3 Yet only the first of these clearly occurs. Why is this? There likely are a number of contributors. First, the wild-type mouse has a T wave that only another mouse could appreciate; in fact, it resembles the J point and ST segment more than the T wave of the human or canine ECG. Such resemblance is not surprising given the important contribution of Ito to the J point and early ST segment of the canine and, most likely the human, ECG.4,5 However, in the Kv4.2W362F3Kv1.4 model, the murine T wave assumes an appearance that is almost respectable for a dog or human. This information expands our understanding of the determinants of the T wave in the mouse and the extent to which what is measured in mouse is applicable to human physiology. Part of the problem contributing to the T wave difference among species is that Ito, the major repolarizing current in the mouse, is a minor component of repolarization in human and canine ventricles, contributing to the notch of their epicardial and midmyocardial action potentials and having no major expression in endocardium.5 Intervening to abolish or markedly reduce Ito in the dog heart alters the transmural gradient for repolarization and alters T wave configuration,5,6 but does so in a way that would not significantly prolong the QT interval or be anticipated to induce EADs or torsades de pointes. Does torsades de pointes, or indeed any arrhythmia, occur in the Kv4.2W362F3Kv1.4 mouse? Second-degree atrioventricular (AV) block is present (see Figures 7A and 7B in Guo et al1), although there is nothing about the function of the ion channels involved that would lead us to intuit this outcome. In fact, repolarization per se or postrepolarization refractoriness in AV junctional tissues is unlikely to be sufficiently prolonged to account for the magnitude of heart block shown in Figure 7.1 As suggested by the authors, these findings warrant a detailed follow-up study of the AV specialized conducting system. In Figure 7C,1 a period of isorhythmic dissociation accompanies a rhythm arising in the ventricle that is possibly ventricular tachycardia but may alternatively represent an The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Departments of Pharmacology and Pediatrics, Center for Molecular Therapeutics, College of Physicians & Surgeons of Columbia University, New York, NY. Correspondence to Michael R. Rosen, MD, College of Physicians & Surgeons of Columbia University, Department of Pharmacology, 630 W 168 St, PH7W-321, New York, NY 10032. E-mail [email protected] (Circ Res. 2000;87:6-7.) © 2000 American Heart Association, Inc.