Eur J Clin Pharmacol (1995) 48:401-402

Crossing the channels Members of the Sicilian Gambit: Antiarrhythmie therapy: a pathophysiologic approach. Armonk, New York: Futura, 1994. 337 pp; (ISBN 0-87993-596-0); Cloth $65.00 P. M. Spooner, A. M. Brown, W. A. Catterall, G. J. Kaczorowski, H. C. Strauss (eds): Ion channels in the cardiovascular system: function and dysfunction. Armonk, New York: Futura, 1994. 580 pp; (ISBN 0-87993-591-X); Cloth $85.00 The cIassification of antiarrhythmic drugs got off to a bad start, from the clinical point of view at any rate. The classification pioneered by Vaughan-WIlliams, and subsequently extended, made pharmacological sense looked at from the point of view of the action potential, but has proved of little clinical reIevance. Other classifcations have added little more. However, now comes a fresh approach to the topic, brought about through increasing understanding of the pathogenesis of cardiac arrhythmias in terms of functional abnormalities of ion channels and pumps and of the actions of antiarrhythmic drugs on those transport systems. A group calling itself the Sicilian Gambit met in Sicily in 1990 to discuss cardiac arrhythmias, and their book, Antiarrhythmic therapy." apathophysiologic approach, is the outcome of a later meeting held in New York in 1993. Both meetings were exceptionally well organized and the book reflects that organization. [In passing, chess players will have noted that there is no such opening as the Sicilian Gambit. There is of course a Sicilian Defence, played by black, but presumably this group of workers want to go on the attack. I think that they have chosen their title well: a gambit involves a sacrifice of a pawn or sometimes a piece, and I suppose that Vaughan-Williams' classification, quite a strong piece in the game, is what they intend to sacrifice.] The traditional method of choosing an appropriate antiarrhythmic drug involves the identification of the arrhythmia followed by the selection of a drug that the clinician thinks may be beneficial, based on criteria such as the known site of action of the drug (e.g. the atria, ventricles, or anomalous pathways), the results of clinical trials in patients with the arrhythmia, and (if the facilities are available) electrophysiological testing (useful for predicting the effects of Vaughan-Williams Class I drugs). Sometimes concern about a possible adverse drug effect or interaction may be taken into account. A therapeutic trial may follow, with clinical followup or Holter monitoring. The Sicilian Gambit takes a more logical approach. First the arrhythmia is diagnosed. Its mechanism is then characterized and its critical components defined. On the basis of this analysis it is decided what structure or function needs to be tackled and the target ion transport system involved. The appropriate drug is then used. The illustrative example given in the text is that of an AV nodal re-entrant tachycardia: the mechanism is nodal re-entry, the critical components are the anatomical atrial pathway and the AV node, the function to be tackled is the AV nodal action potential, and the target system is the L-type calcium channel. The logical choice would be a calcium antagonist. The authors take pains to stress that this approach is no more than an expansion of the traditional method, but it is more than that - - if it were possible to apply this method to all arrhythmias the problem of drug choice in this difficult area would probably be solved, at least within the limitations of the drugs currently available. Of course, the method does not offer a new classification of antiarrhythmic drugs. Rather it offers a way of classifying arrhythmias on the basis of the targets for therapeutic action, in turn predicting what drugs will be therapeutically valuable, a much more useful method of classification. Indeed, it could be argued

© Springer-Verlag 1995

that searching for a method of classifying antiarrhythmic drugs to replace that spawned by Vaughan-Williams is a fruitless pursuit. If the approach of the Sicilian Gambit is to prove useful it will be necessary to define cardiac arrhythmias in terms of the vulnerable abnormalities of structure and function and link them, where possible, to abnormalities of ion transport systems suitable for therapeutic attack. It will also be necessary to develop new drugs that are more selective in their actions on the target systems. These problems are dealt with in detail in individual chapters of this book. It provides a robust introduction to the topic of the drug therapy of cardiac arrhythmias and I look forward to seeing the further outcomes of this approach.

Ion channels in the cardiovascular system: function and dysfunction complements the book by the members of the Sicilian Gambit. It deals in some detail with the ion channels that are to be found in cardiac tissue, the members of related families of complex glycoproteins that mediate the transmembrane transport of sodium, potassium, calcium, or chloride. It only gives a hostage to fortune to say how many of each of these there are, since new ones are being identified all the time. Perhaps it is best to say that there are many. This book deals with some of them. The account starts with CAST, the Cardiac Arrhythmia Suppression Trial, the results of which were published in full in i991 and (CAST-II) 1992, and which set the world of antiarrhythmic drugs back on its heels. Of course, it had been known for some time that all was not rosy in the garden of antiarrhythmic drug therapy, and that proarrhythmic effects were to be expected in some cases, particularly in patients with poor left ventricular function and in those with disturbances of potassium balance. However, the results of the CAST studies came as a surprise. Firstly, encainide and flecainide were shown to have increased the risk of death from dysrhythmias or shock after acute recurrent myocardial infarction in patients who had had ventricular dysrhythmias after a myocardial infarction and in whom the dysrhythmias could be suppressed with those drugs. The relative risk of death or cardiac arrest due to dysrhythmia was 2.64 and due to all causes 2.38. When the results of CAST were published, another 320 patients had been enrolled for treatment with another Class I drug, moricizine, and at that time there was an insignificant trend towards a favourable effect of moricizine on total mortality; the study was therefore continued as a comparison of moricizine with placebo (CAST-II). In CAST-II 1325 patients were studied during the first 14 days after myocardial infarction and 1374 patients during long-term follow-up. CAST-II was stopped prematurely because of excess mortality in the treated group during the first 14 days after myocardial infarction; there was no difference in mortality in the long-term study. That these Class I agents are harmful to this group of asymptomatic patients is not in doubt, and there is evidence that the same is true of other Class I drugs. However, there has since been much debate about the reasons for this and about the proper indications for these drugs. Indeed, CAST was the catalyst for the conference that resulted in this volume, where it is well reviewed and discussed. After chapters on the epidemiology of sudden cardiac death and the role of the autonomic nervous system, the book gets into its stride with chapters on the roles of ion channels in cardiac function. The questions posed here are how heart cells normally function electrically, how firing is regulated, how malfunction occurs, and what can be done about it. Little is taken for granted; for example, the first chapter in this section starts with a picture of a normal action potential and a description of how it is generated. The channels that are covered are the sodium channel, the delayed rectifier and inward rectifier potassium channels, the cAMP-dependent chloride channel, and calcium channels. Later

402 sections deal with modulation of the activity of ion channels, their structure, and their molecular pharmacology. The penultimate section contains four chapters on methods for discovering novel antiarrhythmic drugs, and the book ends with a series of recommendations on the future activities that will be needed in basic and applied science. These two books complement each other. They have been well planned and executed. They are well written and cover extensive

ground. So (as the psychiatrist said at the end of Portnoy's Complaint), now we can perhaps begin. Dr. J. K. Aronson University Department of Clinical Pharmacology Radcliffe Infirmary Woodstock Road Oxford OX2 6HE, UK