Reperfusion arrhythmias and sudden cardiac death: a century of progress toward an understanding of the mechanisms.

The observation that ventricular fibrillation may occur within seconds after restoration of blood flow to myocardium turned ischemic by a period of coronary occlusion (reperfusion) was originally made in the experimental laboratory in the 19th century by Cohnheim and Von Schulthess-Rechberg1 and later confirmed in the early 20th century by Tennant and Wiggers.2 In fact, it was found in subsequent laboratory experiments that ventricular fibrillation may occur more frequently after reperfusion than after coronary artery occlusion.3 It took until the latter part of the 20th century for these early laboratory studies to be translated to clinical medicine. It was noticed that only a minority of those individuals who have been successfully resuscitated from sudden ventricular fibrillation associated with coronary artery disease subsequently developed a myocardial infarction,4,5 suggesting that, if indeed myocardial ischemia caused by coronary occlusion was involved, it was transient. Reperfusion must have occurred. This proposed relationship between transient ischemia, reperfusion, and arrhythmias was corroborated by studies in patients with transient coronary artery spasm in whom ventricular arrhythmias, including ventricular fibrillation, occurred within minutes after the beginning of electrocardiographic signs of myocardial ischemia caused by the spasm6 but also after ST segment changes had returned to normal, when reperfusion had occurred.6–9 What is the mechanism responsible for this occurrence of fibrillation? This is a subject that has been pursued in more than a century of experimentation with slow but continued progress. The most recent advance, now in the 21st century, is the article by Cascio et al10 in this issue of Circulation Research. The initial information on mechanisms of reperfusion arrhythmias came from experiments on in situ hearts of large animals subjected to periods of coronary artery occlusion followed by release of the occlusion that allowed reperfusion. In these experiments, the incidence of reperfusion-induced ventricular fibrillation increased when occlusion periods were lengthened from 5 minutes to 20 or 30 minutes and decreased when reperfusion was delayed beyond 30 to 60 minutes. Also, reperfusion-induced fibrillation tended to occur more often when severe arrhythmias developed during occlusion.11,12 Both these observations suggested that there was a window of time in which the necessary electrophysiological derangements occurred that caused the reperfusion arrhythmias. What are these alterations in electrophysiology? At the beginning of the 21st century, when laboratory studies of arrhythmias are taking advantage of cellular biophysical (patch-clamp studies of ion channel function) and molecular approaches (gene alterations of ion channel function), the successful application of the experimental methods used by Cascio et al10 reminds us that some of the more traditional approaches that originally led to the discovery and clarification of arrhythmogenic mechanisms throughout the 20th century, that is, studies on large tissue preparations and whole hearts, are still important to continue advancing knowledge in this area. Cascio et al10 have used a preparation of rabbit papillary muscle, perfused through a coronary artery, that was developed in 1987 in the laboratory of André Kléber.13,14 The perfused rabbit papillary muscle has the unique advantage of being a preparation that enables coronary artery occlusion and reperfusion to be implemented in a tissue chamber, as it would occur in the in situ heart, while allowing a number of different unique electrophysiological measurements to be made simultaneously rather than individually.14 This in turn enables elucidation of arrhythmogenic mechanisms and mechanisms for alterations in the ECG. In this study, extracellular electrograms and intracellular potential measurements enabled determination of membrane potentials, longitudinal whole-tissue resistance (rt), extracellular resistance (ro), and intracellular resistance (ri). All of these are important determinants of conduction with the latter being an indicator of cellular coupling via gap junctions. Added to these measurements was continuous registration of changes in extracellular potassium (Ko) that has been shown to fluctuate with coronary occlusion and reperfusion and that is also related to alterations in conduction that cause arrhythmias.15 During the period of ischemia in this preparation, Ko increased while Vm decreased, as is known to occur in the in situ heart. There was a simultaneous increase in rt. The increase in rt results from an increase in ro as the microvasculature collapses and an increase in ri that reflects increased gap junctional resistance.14 Eventually nearly complete cellular uncoupling occurred. During this window of ischemia (20 minutes), prior studies with microelectrode transmembrane recordings in the in situ heart have shown marked depression of transmembrane action potentials, and even inexcitability.16 Decreased gap junctional conductance (increased ri) has been linked to the conduction disturbances that The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Pharmacology and Center for Molecular Therapeutics (A.L.W.), College of Physicians and Surgeons of Columbia University, New York, NY, and The University of Amsterdam (M.J.J.), Academic Medical Center, The Netherlands. Correspondence to Andrew L. Wit, PhD, Department of Pharmacology, College of Physicians and Surgeons of Columbia University, 630 W 168th St, New York, NY 10032. E-mail [email protected] (Circ Res. 2001;89:741-743.) © 2001 American Heart Association, Inc.