ebook img

Myocardial Ischemia and Arrhythmia: Under the auspices of the Society of Cooperation in Medicine and Science (SCMS), Freiburg, Germany PDF

302 Pages·1994·10.34 MB·English
Save to my drive
Quick download
Most books are stored in the elastic cloud where traffic is expensive. For this reason, we have a limit on daily download.

Preview Myocardial Ischemia and Arrhythmia: Under the auspices of the Society of Cooperation in Medicine and Science (SCMS), Freiburg, Germany

Myocardial Ischemia and Arrhythmia M. Zehender, T. Meinertz, H. Just (Editors) Myocardial Ischemia and Arrhythmia Under the auspices of the Society of Cooperation in Medicine and Science (SCMS), Freiburg, Germany .~ Steinkopff Darmstadt ~ Springer New Y ork The Editors: PD Dr. M. Zehender Prof. Dr. T. Meinertz Prof. Dr. H. Just Innere Medizin Medizinische Universitiitsklinik Universitatskrankenhaus Eppendorf Abt. Innere Medizin III MartinistraBe 52 Hugstetter StraBe 55 20246 Hamburg 79106 Freiburg Die Deutsche Bibliothek - CIP-Einheitsaufnahme Myocardial ischemia and arrytbmiajM. Zehender ... (Ed.). Under the auspices of the Society of Coopera tion in Medicine and Science (SCMS), Freiburg, Germany. - Darmstadt: Steinkopff; New York: Springer, 1994 ISBN-13 : 978-3-642-72507-4 (Steinkopff) Gb. e-ISBN-13: 978-3-642-72505-0 DOl: 10.1007/978-3-642-72505-0 NE: Zehender, Manfred [Hrsg.] This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Steinkopff Verlag. Violations are liable for prosecution under the German Copyright Law. Copyright © 1994 by Dr. Dietrich SteinkopffVeriag GmbH & Co. KG, Darmstadt Medical Editor: Sabine Ibkendanz-English Editor: James C. Willis-Production: Heinz J. Scharer Softcover reprint of the hardcover 1st edition 1994 The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Typesetting: Macmillan India Ltd., Bangalore Printed on acid-free paper Preface During recent years, it has become evident that ventricular arrhythmias may arise from myocardial ischemia and that they may be harbingers of sudden cardiac death. On the other hand, ventricular arrhythmias may occur without any prognostic significance and sudden cardiac arrhythmic death may strike without any warning arrhythmia. The role of ischemia in the genesis of ventricular arrhythmias and of sudden cardiac death has been observed beyond doubt. However, the mechanism by which ischemia leads to the appearance of ventricular arrhythmias and/or sudden cardiac death has remained rather poorly understood, inspite of rather remarkable research efforts on the one hand, and the magnitude of the problem on the other hand. We have therefore set out to assemble scientists from around the world in order to define the current state of our knowledge on myocardial ischemia and arrhythmia. Well in line with the tradition of the Gargellen Conferences, we assembled clinicians and basic scientists for the 7th Gargellen Conference. This book presents the proceed ings of the Symposium in the attempt to define the current status of our understand ing of this significant problem. The Symposium was organized by the Society for Cooperation in Medicine and Science (SCMS) and was generously sponsored by Astra Chemicals, Wedel; Bayer AG, Leverkusen; Boehringer-Mannheim; CPI-Lilly, Giessen; Janssen GmbH, Neuss; Minden Pharma, Minden; Rahm Pharma, Weiter stadt; Schering AG, Berlin, and Siemens AG, Erlangen. The publication of this book would not have been possible without the enthusiastic support of the publisher SteinkopffVerlag, in particular Mrs. Sabine Ibkendanz. To her and her associates at Steinkopff, we extend our sincere thanks for expert help and friendly cooperation. M. Zehender T. Meinertz H. Just Introduction Myocardial ischemia is characterized by ionic and biochemical alterations which may lead to malignant ventricular arrhythmias. At the same time, the ischemic myocardium shows both reentry and non-reentrant mechanisms contributing to the initiation and the maintenance of ventricular tachycardias or flutter and fibrillation. The basis may be both anatomical, e.g., scarring, as well as functional through electric inhomogeneity due to various reasons. The complex interaction between reentry and non-reentrant mechanisms may lead to acceleration and the development of mUltiple reentrant circuits, thus setting the stage for ventricular fibrillation and thereby circulatory standstill. The nature of the non-reentrant mechanism remains to be clarified, but may be due to delayed after-depolarizations resulting from altered calcium homoeostasis, as occurs in the ischemic state, as well as with the more chronically occurring phenotype change of the failing human heart. It shall not go unnoticed that alterations of the sympathetic innervation signifi cantly contribute to the lowering of fibrillation threshold and to the initiation of ventricular arrhythmias. The general sequence of events is characterized by rapid decrease in tension development. Within seconds, contractile performance is lost. The ischemic region of the myocardium instead stretches and bulges to the outside under the influence of the intraventricular pressure. Within a few minutes there is a rapid decrease in high energy phosphates, a near complete depletion of creatinine phosphate, whereas AT P declines at a slower rate. The ischemic myocardium turns hypoxic and acidotic. Stagnation of blood flow leads to accumulation of ions and metabolites in the interstitial fluid, which may contribute to the development of lethal arrhyth mias. In addition, the autonomic nervous system and the sympathetic end organs are activated and may both systemically, as well as locally, contribute to arrhyth mogenesis. Let us consider in the following several arrhythmogenic mechanisms which may act either separately or conjointly: Numerous observations have established beyond doubt that myocardial ischemia may precede the appearance of ventricular ectopy and/or of ventricular tachyar rhythmias by minutes or seconds, thereby indicating that acutely occurring changes in the state of ischemia may be responsible for the lethal arrhythmia. VIII Introduction Hypoxia Myocardial ischemia induces a rapid fall of P0 in the ischemic myocardium. As 2 a consequence, electrophysiologic alterations by means of shortening of the action potential are seen together with a decrease in resting membane potential and of z max of phase 0 of depolarization. Voltage clamp studies have shown that the hypoxia induced decrease in repolarization time results from an increase in the time indepen dent potassium current. The slow inward calcium current does not seem to be effective. Hypoxia also augments the internal longitudinal resistence, thereby in fluencing conductive properties. The electrophysiological alterations are exaggerated in the presence of low glucose. The effective hypoxia may be linked to the decreased AT P production via glycolysis. Acidosis Ischemia induces a decrease in both intracellular and extracellular pH. The extra cellular hydrogen ion concentration falls to a plateau between 5.5 and 6.0. Acidosis in itself already leads to a decrease of both z max of phase 0 depolarization and of conduction velocity. At the same time, internal longitudinal resistance increases. Acidosis will also significantly modify the activity of several intercellular enzymes, catabolizing substances known to accumulate in the state of ischemia. Mechanisms leading to premature ventricular contractions and ventricular tachycardia. Early myocardial ischemia is accompanied by premature ventricular contractions and a bout of ventricular tachycardia. In more than 3/4 of the cases these can be linked to intramyocardial reentry. Marked conduction delay of the preceding sinus beat in the subendocardium could lead to reactivation of adjacent subendocardial tissue proximal to the block. The intramural location of the reentrant pathway has been demonstrated repeatedly. Maintenance of ventricular tachycardia often occurs due to intramural reentry, dependent on the continued presence of activation, which is sufficiently delayed in order to permit the adjacent tissue to recover and to become reexcitable upon return of the depolarization wave. The run of ventricular tachy cardia often terminates, even in the presence of continuous marked conduction delay, if there is a significant change in the reentrant pathway and delayed activation of the terminal beat occurring in a region in which excitability has not recovered. Several studies have indicated that ventricular tachycardia can also arise from non-reentrant ~echanisms. A non-reentrant mechanism is one that operates distant from the site of termination of the preceding beat without intervening electrical activity. In terms of the action potential, this rests upon increased velocity of depolarization during phase 4 or is due to delayed early after depolarizations. The non-reentrant excitation arises in almost any part of the myocardium. In chronically overloaded myocardium, especially in the presence of heart failure, Introduction IX myocardial phenotype changes occur which lead to characteristic derangements of calcium homoeostasis. Here the reduced capacity of the sarcoplasmic reticulum calcium ATPase seems to playa major role: with decreased reuptake capacity free cytosolic calcium at the end of systole increases, leading to prolonged contraction and delayed diastolic relaxation. If the condition exists over any longer period of time, then upregulation of the sarcolemmal sodium calcium exchanger may occur. The consequence is a loss of calcium to the outside with subsequent decrease in sarcoplasmic reticulum calcium store and, therefore, a reduction in calcium ions being available at the onset of excitation contraction coupling. At the same time, however, for each calcium ion lost to the outside of the cell, two sodium ions do enter the cytosol. This, of course, may lead to a propensity towards increased after depolarizations and therefore non-reentrant ectopic activity. Since myocardial ischemia quite often occurs on the basis of a chronically overloaded and oftentimes failing myocardium, this condition may playa significant role quite frequently, not withstanding the possibility that other mechanisms may lead to the initiation of ectopic beats and their perpetuation outside the well established reentrant mechanisms. Under conditions of ischemia several authors have observed an increased free cytosolic calcium concentration, which was considered to mediate electrophysiologic alterations characteristic for early ischemia. This observation finds support in the antifibrillatory effect of calcium channel blocking agents. Potassium changes during myocardial ischemia Myocardial ischemia is accompanied by a number of ionic and biochemical alter ations contributing to arrhythmogenesis. Among them, the extracellular potassium increases in the ischemic myocardial zone may be significant: They occur as early as 30 s after coronary occlusion and show a characteristic triphasic response. The initial rise occurs over the first 48 min and is easily reversed. Thereafter follows a plateau phase. The third phase occurs approximately 30 min after the onset of ischemia and consists of an increase of extracellualr potassium, probably arising from cell death in the state of necrosis. Extracellular potassium may reach 50 mmol or more in the central ischemic zone. In the ischemic border zones potassium alterations may be rather inhomogeneous. They can, however, considerably contribute to the potential difference between endocardium and epicardium and thereby to the conditions that increase electrical inhomogeneity. The increase in extracellular potassium appears to correlate directly to the extent of cellular damage. On the other hand, the rise in extracellular potassium cannot be held solely responsible for the profound elec trophysiological alterations characteristic of myocardial ischemia. The mechanisms responsible for the early increase in extracellular potassium in hypoxic cell injury has not been sufficiently clarified. The inhibition of the sodium potassium ATPase may be one mechanism. Enhanced potassium effiux may contribute. It is also possible, that ATP-dependent potassium channels may contribute, especially since gliben clamide, a sulfonyl urea which blocks the AT P-dependent potassium channel, has antiarrhythmic activity during early ischemia and seems to be independent of the x Introduction direct effects of glycolysis. Another possibility is that other concomitant effects of ischemia, such as lysophosphoglycerides or long chain acylcarnitins accumulate in the membranes in ischemic myocardium. It may interact with membrane bound AT P-sensitive potassium channels. However, this awaits clarification. Sympathetic nervous system Ischemia leads to alterations and activations of myocardial sympathetic afferences and thereby induces an increase in afferent sympathetic nerve activity. Reflexly efferent sympathetic nerve activity is increased as well. Asymmetric sympathetic input may occur and can be potentially arrhythmogenic due to inhomogenous alterations of ventricular conduction, rejlOlarization and automaticity. Through the sympathetic nervous systems both reentrant as well as non-reentrant mechanisms may lead to increased ectopic activity and/or ventricular fibrillation. Several observa tions suggest that asymmetric (right-to-Ieft) sympathetic innervation may signifi cantly increase ventricular vulnerability and the incidence of ventricular fibrillation. It has remained unclear if norepinephrine released from intramyocardial nerve terminals within the ischemic zone contributes in any significant way to the appear ance of arrhythmias and/or the propensity to develop ventricular fibrillation. Over all, the release of norepinephrine into the venous effluent of the myocardium during a state of ischemia is not very pronounced. Nevertheless, an enhanced release of norepinephrine almost invariably occurs during ischemia. It is likely that the release of intramyocardial catecholamines occurring during early ischemia may contribute significantly to arrhythmogenesis. Under normal physiologic conditions adrenergic control of the myocardium is mediated through the beta-adrenergic receptors. Intercellular mediation of the sympathetic activity operates through a stimulation of the adenylatecyclase and activation of the CAMP-dependent proteinkinases. This interaction between the beta-adrenergic receptor and the activation of adenylatecyclase is functionally coupled by a guaninnucleotide binding protein (G-protein). Cycling AMP-depending proteinkinase has been shown to phosphorylate sarcolemmal calcium channels. This activates the slow inward current for calcium besides the direct receptor-mediated opening of sarcolemmal calcium channels. Beta-adrenergic receptor stimulation appears to regulate intracellular calcium concentrations through a CAMP-dependent influence upon the calcium channels in addition to the aforementioned mechanism. In the state of myocardial ischemia an increase in sinus rate may increase the extent of conduction delay and functional conduction block. Furthermore, an increase in the slow inward calcium current may lead to an enhancement of the degree of slow conduction and block. Finally, an inhomogeneous reduction in the refractory period between the ischemic and non-ischemic cells may induce electrical inhomogeneity and thereby lower fibrillation threshold. Beta-adrenergic receptor blockade, in turn, has been shown to reduce the occurrence of both ventricular tachycardia and fibrillation in the state of ischemia. The mechanism of action of beta-receptor blockade has not fully been clarified, however. Introduction XI The arrhythmogenic effect of beta-adrenergic stimulation during ischemia may be enhanced by an increase in beta-adrenergic receptors. Such an increase may occur within a few minutes after the onset of ischemia. It is still unclear if the receptor downregulation, as commonly seen in chronic heart failure, has any significant influence upon ventricular vulnerability. It needs to be mentioned, however, that in the chronic failing human myocardium the propensity to develop ventricular fibrilla tion is especially high! Alpha-adrenergic receptor stimulation does not seem to playa significant role in electrical vulnerability. Nevertheless, an increase of the repolarization time and refractory periods and a decrease in automaticity are seen in isolated Purkinje fibres in vitro. These electrophysiological effects, however, could be expected to be antiar rhythmic rather than arrhythmogenic. In contrast, under the conditions of niyocardial ischemia the effects of myo cardial alpha-adrenergic stimulation may be enhanced and may even be arrhyth mogenic. The enhanced alpha I-adrenergic responsiveness of early myocardial ischemia may be mediated by an increase in the density of alpha I-adrenergic receptors and/or the intracellular coupling. Enhanced alpha I-adrenergic respon siveness during ischemia may be related to an increase in number of the recep tors and/or to increased coupling to intracellular signal proteins, such as IP3. Under the conditions of ischemia the fibrillation threshold in response to nore pinephrine concentration seems to be markedly lowered. Alpha I-adrenergic blockade may inhibit the development of delayed after-depolarizations induced by hypoxia. It remains, however, open to further studies if alterations of the alpha-sympathetic tone may contribute to ventricular vulnerability in a clinically significant manner. Electrophysiological alterations of ischemia The aforementioned ionic and metabolic changes lead to characteristic changes in electrophysiologic behavior of the myocardial syncytium: Marked changes are seen within minutes of the onset of ischemia. Transmembrane action potential from the epicardial surface of the ischemic heart demonstrates a marked decrease in resting membrane potential, the action potential amplitude, the rate of upstroke of phase 0, and of action potential duration. Similar observations are seen in the subendocar dium as well. Within 10 min the action potential demonstrates changes in amplitude and duration with subsequent development of inexcitability and conduction block in the central ischemic zone. During longer periods of ischemia excitability begins to return. However, after more than 30 min of ischemia complete inexcitability is seen. Immedi ately after, the onset of ischemia refractory period in the ischemic zone decreases. Action potential lengthens, only to finally exceed the values seen in the non-ischemic control state. This, however, is accompanied by a marked dispersion of the refractory periods between the ischemic and the non-ischemic myocardial zone. The refractory periods in the ischemic zone continue to increase with a development of post repolarization refractoriness. XII Introduction The rapidity and severity of the electro physiologic alterations during the interval after acute ischemia are recognizable in a decrease in amplitude and a variable increase duration of the bipolar electrogram. Activation time is markedly delayed and extracellular electro grams become more asynchronous and fractionated. At times, continuous electrical activity is seen, spanning the interval between a normal sinus beat and the initiation of a ventricular ectopic beat. It has been concluded that continuous reentry can be established under these conditions. Marked slowing of conduction velocity, as seen in early myocardial ischemia, could be due to an increase in extra- and intracellular longitudinal resistance, as well as to a reduction of action potential amplitude and upstroke velocity during phase 0 of depolarization. The most striking observation in myocardial ischemia is the marked degree of electrical inhomogeneity. There is, for one, a considerable variation in the refractory period between the ischemic and non-ischemic zones. This becomes even more pronounced as post repolarization refractoriness develops. There is also spatial dissociation due to cell death and temporal dissociation with development of con duction delay due to the aforementioned electrophysiological abnormalities. Heterogeneity is most evident between the ischemic and the non-ischemic regions in the border zones. Myocardial mapping has demonstrated characteristic spread of the wave fronts over the epicardial and endocardial layers. All the factors mentioned attest to the fact that myocardial ischemia and electrical vulnerability are intimately related. Recent clinical observations during myocardial mapping in the ischemic state, as well as direct observations with Holter-ECG recordings during spontaneously occur ring or induced myocardial ischemic events have demonstrated with increasing clarity that life-threatening ventricular arrhythmias have a tendency to occur prefer entially under the conditions of acute myocardial ischemia. The situation, however, continues to be only incompletely understood. Partial understanding of the electrophysiologic, ionic, and biochemical mechanisms on the one hand, and scanty clinical observations on the other hand calls for further clarification, especially in view of necessary therapeutic consequences. H. Just, Freiburg

This volume presents, in synoptic form, the latest and most comprehensive experimental and multi-faceted clinical findings on the potential arrythmogenic implications of acute myocardial ischemia. Together with a critical discussion of the related diagnostic and therapeutic consequences and outcomes
See more

The list of books you might like

Most books are stored in the elastic cloud where traffic is expensive. For this reason, we have a limit on daily download.