Nitroglycerin 6: Unstable angina pectoris and extracardial indications 9783110846317, 9783110120615

Table of contents :
Contents
Introduction
Pathophysiology and pathological anatomy of unstable angina pectoris
Discussion
Prognosis of unstable angina pectoris
Discussion
Silent ischemia in patients with unstable angina pectoris
Discussion
Experimental findings on nitrate action
Discussion
Clinical pharmacological aspects of nitrate therapy in the treatment of unstable angina pectoris
Discussion
Practical experience and success with nitrate therapy for unstable angina pectoris
Discussion
Management of unstable angina in the era of PTCA, nitrates, calcium antagonists and beta-blockers
Discussion
Indications of surgical therapy for unstable angina pectoris
Discussion
Nitroglycerin as a spasmolytic in the treatment of biliary colics and as premedication for ERPC
Discussion
Studies of the influence on duodenal motility of glyceroltrinitrate, butylscopolaminiumbromide, and a combination of glyceroltrinitrate and butylscopolaminiumbromide
Discussion
On the problem of ureteral spasmolysis by glyceroltrinitrate
Discussion
Award of the 1988 NITROLINGUAL Prize
Studies by Dr. D. Stewart

Citation preview

Nitroglycerin 6

Nitroglycerin 6 Unstable angina pectoris and extracardial indications Sixth Hamburg Symposium

Editor H. Roskamm

w DE

G

Walter de Gruyter Berlin • New York 1990

Library of Congress Cataloging-in-Publication

Data

Hamburger Symposion (6th ; 1988) [Nitroglycerin VI. English] Nitroglycerin 6 ; unstable angina pectoris and extracarial indications / Sixth H a m b u r g Symposium ; editor, H. Roskamm. p. cm. The Sixth H a m b u r g Symposium held in 1988. Translation of: Nitroglycerin VI. ISBN 0-89925-580-9 1. Angina pectoris—Congresses. 2. Nitroglycerin — Congresses. I. Roskamm, H. (Helmut), 1 9 3 3 - . II. Title. III. Title: Nitroglycerin six. [ D N L M : 1. Angina Pectoris—drug therapy—congresses. 2. Glyceryl Trinitrate —therapeutic use —congresses. W G 299 H199n 1988a] RC685.A6H26 1988 616. 1 ' 2 2 0 6 1 - d c 2 0 DNLM/DLC 89-25621 for Library of Congress CIP

CIP-Titelaufnahme

der Deutschen

Bibliothek

Nitroglycerin ... / ... H a m b u r g Symposium. — [Engl. Ausg.]. — Berlin ; New York : de Gruyter. Dt. Ausg. unter demselben Titel NE: Hamburger Nitroglycerin-Symposion [Engl. Ausg.] 6. Unstable angina pectoris and extracardial indications. — 1990 ISBN 3-11-012061-5

© Copyright 1989 by Walter de Gruyter & Co., Berlin 30. All rights reserved, including those of translation into foreign languages. N o p a r t of this book may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system without permission in writing from the publisher. Medical science is constantly developing. Research and clinical experience expand our knowledge, especially with regard to treatment and medication. F o r dosages and applications mentioned in this work, the reader may rely on the authors, editors and publisher having taken great pains to ensure that these indications reflect the standard of knowledge at the time this work was completed. Nevertheless, all users are requested to check the package leaflet of the medicaiton, in order to determine for themselves whether the recommendations given for the dosages or the likely contraindications differ from those given in this book. This is especially true for medication which is seldom used or has recently been put on the market and for medication whose application has been restricted by the G e r m a n Ministry of Health. The quotation of registered names, trade names, trade marks, etc. in this copy does not imply, even in the absence of a specific statement that such names are exempt from laws and regulations protecting trade marks, etc. and therefore free for general use. Typesetting: Arthur Collignon G m b H , Berlin. — Printing: Gerike G m b H , Berlin. — Binding: Dieter Mikolai, Berlin. — Printed in Germany.

Contents These articles were submitted and originally published in German, and appear here in translation. H. Roskamm Introduction

9

W. Rafflenbeul Pathophysiology and pathological anatomy of unstable angina pectoris

13

Discussion

22

H. Tillmanns Prognosis of unstable angina pectoris

25

Discussion

37

Th. v. Arnim Silent ischemia in patients with unstable angina pectoris

41

Discussion

46

E. Bassenge Experimental findings on nitrate action

49

Discussion

60

E. Jähnchen Clinical pharmacological aspects of nitrate therapy in the treatment of unstable angina pectoris

63

Discussion

70

W.-D. Bussmann Practical experience and success with nitrate therapy for unstable angina pectoris

73

Discussion

81

6

Contents

P. G. Hugenholtz, H. Suryapranata, P. W. Serruys, P. J. de Feyter Management of unstable angina in the era of PTCA, nitrates, calcium antagonists and beta-blockers

85

Discussion

103

W. Kupper Indications of surgical therapy for unstable angina pectoris

105

Discussion

112

G. Pott, A. Mameghani Nitroglycerin as a spasmolytic in the treatment of biliary colics and as premedication for ERPC

113

Discussion

121

G. Brunner Studies of the influence of duodenal motility of glyceroltrinitrate, butylscopolaminiumbromide, and a combination of glyceroltrinitrate and butylscopolaminiumbromide

123

Discussion

129

U. Dunzendorfer On the problem of ureteral spasmolysis by glyceroltrinitrate

133

Discussion

155

Award of the 1988 Nitrolingual Prize

157

Studies by D. Stewart

159

Editor Prof. Dr. H. Roskamm

Benedikt-Kreutz-Rehabilitations-Zentrum für Herz- und Kreislaufkranke e.V. Südring 15 7812 Bad Krozingen

List of Contributors Priv. Doz. Dr. Th. von Arnim

Krankenanstalt Rotes Kreuz 1. Medizinische Abteilung Nymphenburger Straße 163 D-8000 München 19

Prof. Dr. E. Bassenge

Institut für Angewandte Physiologie und Balneologie der Albert-Ludwigs-Universität Hermann-Herder-Straße 7 D-7800 Freiburg im Breisgau

Prof. Dr. G. Brunner

Krankenhaus Oststadt Abteilung Gastroenterologie Podbielskistraße 380 D-3000 Hannover

Prof. Dr. W.-D. Bussmann

Klinikum der Johann-Wolfgang-Goethe-Universität Zentrum der Inneren Medizin Abteilung für Kardiologie Theodor-Stern-Kai 7 D-6000 Frankfurt 70

Priv. Doz. Dr. U. Dunzendorfer

Maingau-Krankenhaus Scheffelstraße 2 - 1 6 D-6000 Frankfurt 1

Contributors

8

Prof. Dr. P. G. Hugenholtz

S.O.C.A.R.S.A. 22, Rue Juste-Olivier Ch-1260 Nyon (VD)

Prof. Dr. E. Jähnchen

Benedikt-Kreutz-Rehabilitations-Zentrum für Herz- und Kreislaufkranke e. V. Südring 15 D-7812 Bad Krozingen

Prof. Dr. W. Kupper

Universitätskrankenhaus Eppendorf II. Medizinische Klinik Martinistraße 52 D-2000 Hamburg 20

Prof. Dr. G. Pott

Marienkrankenhaus Nordhorn Innere Abteilung D-4460 Nordhorn

Prof. Dr. W. Rafflenbeul

Medizinische Hochschule Hannover Abteilung Kardiologie Postfach 61 01 80 D-3000 Hannover 61

Prof. Dr. H. Tillmanns

Klinikum der Ruprecht-Karls-Universität Medizinische Klinik Abteilung Innere Medizin III Bergheimer Straße 58 D-6900 Heidelberg

Introduction H. Roskamm

During each of the preceding five Nitroglycerin Symposia in Hamburg a rather general spectrum of recent investigations of nitroglycerin and nitrates have been the basis of discussion. The present Sixth Symposium will for the first time deal with a specific disease, namely unstable angina pectoris, in which of course, nitrate therapy plays an important role. Other aspects of the unstable angina pectoris, such as pathophysiology and prognosis, as well as other therapies for the disease will also be dealt with. In the afternoon we will hear a few lectures on the non-cardial indications of nitrate. I would like to thank the speakers who have taken the time to prepare the lectures and Mr. Bleifeld who is going to moderate the afternoon's session. I should also like to express my appreciation to Pohl-Boskamp for their efforts in preparing this meeting and establishing the necessary framework. Allow me to make a few comments by way of introduction to the main subject of the first section. "Unstable Angina Pectoris". The definition of unstable angina pectoris results as a matter of course from the definition of stable angina pectoris. It can be simplified and divided into three sub-groups: 1. An angina pectoris (initial or De-novo-Angina-pectoris) which has developed within the last four weeks. 2. An angina pectoris which was once stable, where the intensity and/or the frequency of the complaints have recently increased (progressive or Crescendo-Angina-pectoris). 3. An angina pectoris which occurs even with absolute physical rest (spontaneous or at-rest angina pectoris, to which nocturnal angina pectoris or angina decubitus belong). This is a hierarchical order, i. e. patients of groups 1 or 2, who also have an atrest angina pectoris, are placed in group 3. Correspondingly, a primary subdivision in the stress angina and spontaneous or at-rest angina pectoris was suggested, which only really emphasizes group 3. The at-rest angina pectoris, which is either new or has developed from an exercise angina pectoris, is therefore Nitroglycerin 6 © 1989 Walter de Gruyter& Co. • Berlin • New York

10

H. Roskamm

in the foreground of the unstable angina pectoris. The recent change and the angina pectoris now at rest signal the instability. Patients who develop angina pectoris again in the days and weeks following an acute myocardial infarction (so-called early post-infarction angina pectoris) also belong in this sub-group. The continuing instability with remaining or reocurring angina pectoris is more frequent following lysis treatment or infarctions of a strictly intramural nature. The presence of an at-rest angina, which has been known for some time, in conjunction with a stable working angina, does not necessarily signal a dramatic, unstable situation. It is also necessary to view this angina separately from the rare, purely vasospastic or Prinzmetal angina, as long as it is connected with a good exercise tolerance. These definitions of the sub-groups alone indicate that patients with unstable angina pectoris are a very heterogeneous patient group. We are not dealing with one clinical picture, but with many. Furthermore, there is the fact that some patients with myocardial ischemia do not show any signs of angina at rest (silent or asymptomatic myocardial ischemia). There are obviously also patients whose complaints have been incorrectly classified, in whom no myocardial ischemia can be detected. In retrospect it is frequently necessary to assume that the cause of the complaints is extracardial. Some of the patients who were originally classified as having "unstable angina" will be well on the way to myocardial infarction. In such cases one could retrospectively talk about a pre-infarction angina. The original diagnosis is of importance with respect to the management and therapy, however. Even if it is necessary to revise the diagnosis in the case of some patients with the primary diagnosis "unstable angina pectoris" to correspond with the first clinical findings and course of the disease. Patients with a new at-rest angina pectoris should be placed in intensive care. The sub-group De-novo-Angina-pectoris frequently offers difficult management problems. If there is only a single incidence of an angina pectoris attack, the patient often does not visit a doctor. If the patient waits for several days before going to visit the doctor, it is possible that the physician will be tempted to take the angina pectoris incidence less seriously. If on the other hand the physician takes the complaints too seriously it would frequently lead to many unnecessary hospitalizations. It is frequently not possible to make a definite diagnosis on the basis of an anamnesis. Often a compromise is made and the patient is examined by a specialist. It will be difficult for the specialist as well, however, if the at-rest angina attack occurred only a few days

Introduction

11

earlier a stress test will seldom be risked. If the stress test is performed and the results are satisfactory, further care on an out-patient basis is justified. In the case of a very positive stress test result — as in the case of doubt — the decision will probably be made for hospitalization and observation, usually under general care. It is desirable that a functional diagnosis be made and, depending on the results of the functional diagnosis and such factors as age, risk factors for coronary heart disease, concomitant diseases, etc., a coronary angiography be made, too. There are similar management problems in the crescendo angina group. The general practitioner will generally base further procedures on whether causes for an increase in the complaints can be detected. If, for instance, a recently occurred hypertension is determined, or the patient discontinues or reduces the antianginal therapy, a readjustment of the therapy will generally be required. If there is no explanation for increased complaints, hospitalization should be considered. An exercise test is usually performed by the general practitioner or then by the specialist for the purpose of objectively establishing the subjective deterioration. The indication for a cardioangiography is then based on the results of the exercise test. These introductory remarks should remind us again that we are dealing with a very complex clinical picture. Very different sub-groups are contained within it. It is therefore to be expected that the pathophysiology, prognosis and therapy may be different accordingly.

Pathophysiology and pathological anatomy of unstable angina pectoris W. Rafflenbeul

Introduction Diagnosing unstable angina pectoris requires one or more of the following anamnestic bits of information from patients suffering from coronary heart disease: 1. Sudden intensification of an existing, chronically exercise-induced angina pectoris with attacks becoming more frequent, causing more intense pain, and lasting longer. 2. Angina pectoris under conditions of low physical exercise or even at rest. 3. Any new occurrence of angina pectoris which, from the outset, can be initiated by even low physical stress. Frequently, this syndrome is associated with transitory ECG changes, especially differences in the ST-segment or T-waveinversions.

Pathophysiology All these different clinical manifestations are based essentially on one common pathophysiological mechanism. In the area of a pre-existing coronary stenosis there is an abrupt increase in the severity of a stenosis followed by throttling of the coronary blood flow. As the myocardium can meet its oxygen demand only to a very limited extent by more intense oxygen utilization, there is an instantaneous oxygen deficit, i. e., myocardial ischaemia. Such acute throttling of the regional myocardial blood supply initiated focally in an epicardial coronary artery is caused by two mechanisms acting either singly or in combination: 1. Formation of an intracoronary thrombus. 2. Increase in tone of the smooth vascular muscles. Nitroglycerin 6 © 1989 Walter de Gruyter & Co. • Berlin • New York

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W. Rafflenbeul

Intracoronary thrombus formation The primary factor initiating platelet aggregation is a local destruction of the vascular intima in the region of an atheroma ("plaque fissure") [6], This causes the smooth endothelial surface to rupture and the thrombogenic material in the intima below, especially collagen, to contact the passing blood stream. Intima lesions occur preferably in the region of the fibrous cap of atherosclerotic plaque. Frequently, the fibrous cap on atheromatous plaque is thin and will not tolerate high mechanical loads. As a result of this structural weakness, especially at the edges of atherosclerotic plaque, a rupture may be produced by factors such as the increased shear forces at a focal restriction, changes in vasomotor tone, or merely the rhythmic twisting and turning movements of the coronary vessels during cardiac action. This makes the occurrence of such a lesion a purely random phenomenon which may occur at any time in the course of coronary sclerosis, as clinical experience shows. The intima lesions may be small tears, but can also be defects several square centimeters in size or extend deep into the intima. The thrombus forms on top of this intima lesion, producing a typical angiographic picture, the complicated atherosclerotic plaque (Fig. 1). This so-called type II lesion [1], with a narrow base and overhanging serrated edges, as well as an intraluminal filling defect as an expression of a mural, nonocclusive thrombus is found in many patients angiographed immediately after a phase of unstable angina pectoris. Nearly identical pictures have been described in non-transmural infarctions [2], in coronary vessels reopened by lysing therapy, and also angioscopically in patients with unstable angina pectoris [8, 16]. In post mortem studies, the structure of the underlying intima can be reconstructed from serial sections through coronary stenoses [7]. This reconstruction shows that both superficial and deep intima lesions can lead to thrombus formation. Superficial intima lesions are found in those cases where there has only been a loss of endothelium with an exposure of the underlying thrombogenic connective tissue. In contrast to this finding, a deep intima lesion of the type found in 75% of the large intraluminal thrombi shows a deep tear in the intima. This seems to make the formation of an intraluminal thrombus generally dependent on the formation of a highly thrombogenic surface within the very intima lesion. This is formed primarily by the collagen and layers of activated platelets on top of it. An apposition thrombus may attach itself to the mural thrombus consisting mostly of platelets, while the apposition thrombus is made

Pathophysiology and pathological anatomy

15

Fig. 1 Four angiographic examples of "complicated" atherosclerotic plaque (arrows) in the interventricular branch of the left coronary artery (top) and the right coronary artery (bottom). The so-called type II lesion is characterized by its irregular edges and intraluminal filling defect (thrombus).

up chiefly of fibrin and erythrocytes and may extend far into the distal end of the coronary vessel affected (Fig. 2). The sequence of events just described, i. e., intima lesion, mural and intraluminal thrombus formation, is a dynamic process which may be interrupted at any time and may also be reversed.

16

Fig. 2

W. Rafflenbeul

Severe proximal stenosis of the interventricular branch of the left coronary artery with a distal thrombus (arrow) in a patient angiographed 18 hours after the occurrence of unstable angina pectoris.

Increase in vasomotor tone Whether the degree of stenosis is further enhanced by an additional increase in tone of the smooth vascular muscle, in addition to this occlusive thrombotic event, depends mainly on the morphology of the initiating coronary stenosis. In eccentric stenoses, which constituted the majority found in histological serial sections through coronary stenoses [12], part of the vascular circumference is not affected by the atherosclerotic process, and the vascular wall structure is preserved. Above all, the normal wall segment shows a completely intact smooth vascular musculature able to constrict and relax (Fig. 3). This preserved vasomotility of part of the vascular wall within coronary stenoses makes for a clinically important variability in the severity of stenoses (Fig. 4 and 5) [14]. The vasomotor reaction of the smooth vascular musculature in turn depends chiefly on the functional state of the vascular endothelium. Intact vascular endothelia produce vasodilating prostacyclin (PGI 2 ) which, at the same time, suppresses platelet aggregation. In addition, the healthy vascular endothelium stimulated by a number of endogenous substances releases one or more hormonal factors, which cause relaxation of the smooth vascular musculature and are therefore summarized under the term of EDRF (endothelium-derived relaxant factor) (survey in [10]). In man, these substances with vasodilating effects dependent on the endothelium include acetylcholine, ADP, ATP, bradykinin,

17

Pathophysiology and pathological anatomy

Fig. 3 Histological sections through an eccentric (top) and a concentric (bottom) coronary stenosis (for details, see the text).

1.40 m m Fig. 4

D s t e n * 1.96mm

Dilation of a severe eccentric stenosis in the proximal interventricular branch of the left coronary artery. After sublingual administration of 0.8 mg of nitroglycerin and 20 mg of nifedipine, the smallest diameter in the stenosis (Dsten) increases by some 40%.

W. Rafflenbeul

18 Influence on coronary stenoses of 0.8 mg + 20 m g NIF s. I. (n = 50)

Fig. 5

Out of 50 coronary stenoses, whose smallest diameters (Dsten) were measured before (abscissa) and after (ordinate) sublingual administrations of 0.8 mg of nitroglycerin and 20 mg of nifedipine, 31 reacted by developing an average increase in diameter of +49%. Nineteen stenoses showed no change in the smallest diameter.

alpha-adrenergic agonists, ergometrine, substance P, A 23187 (calcium ionophor), and others [5], The direct vasoconstrictive action of some of these substances, such as alphaadrenergic agonists, or of ergometrine and the serotonine released by aggregating platelets, which exists side by side with endothelially mediated vasodilation, thus is weakened by an intact endothelium. Destruction of the endothelium in the area of a "complicated" atherosclerotic plaque largely eradicates this endothelial function directed mainly at vasodilation; now the vasoconstrictive elements dominate (Fig. 6); the loss of prostacyclin produced by the endothelium, like the endothelium-free thrombogenic intima surface, enhances platelet aggregation. The aggregating platelets release 1. thromboxane A 2 , a substance with a strong direct vasoconstrictive effect, and 2. serotonine, and form thrombin by stimulation of the coagulation cascade. Both substances now can unfold their intense vasoconstrictive effects without being counter-acted by an endothelial opposition. As an amplifying effect, the endothelium-dependent vasodilating effect of the substances listed above can no longer be mediated. These processes and others, some of which proceed like vicious circles, lead to the tendency of producing superimposed vasoconstrictions in the regions of

Pathophysiology and pathological anatomy BLOOD

VESSEL

WITH INTACT

Thromboplastin

19

ENDOTHELIUM

Platelets

Prothrombin t Thrombin J

CONTRACTION

Fig. 6

Smooth muscle cells

Schematic diagram showing the importance to vasodilation of an intact endothelium. Top: Intact endothelium prevents platelet aggregation and is stimulated by a number of substances into releasing vasodilating EDRF. Bottom: Destruction of the intact endothelium causes platelet aggregation and direct vasoconstrictive stimulation of the smooth vascular musculature in an atherosclerotic coronary artery. (From: Vanhoutte, P. M., D. S. Houston: Platelets, endothelium and vasospasm. Circ. 72 (1985) 728.)

atherosclerotic plaque complicated by thrombotic appositions, thus further throttling myocardial blood flow. This vasoconstriction can be enhanced even further by stimulation of the sympathetic nervous system, e. g., by angina pectoris pain and the fear associated with it. The catecholamines released activate the alpha-receptors of the smooth vascular musculature, whose cells depolarize in the process. The permeability to calcium ions of the cellular membrane is enhanced and the cytoplasmic calcium concentration rises. This activates the contractile proteins, i. e., the smooth vascular musculature contracts. Coronarography demonstrated a decrease of the diameters of epicardial coronary arteries, especially in coronary stenoses, to be associated with a different type

20

W. Rafflenbeul

of sympathetic nerve stimulation, namely isometric [4] and dynamic [10] exercise. Also after intravenous administration of beta-receptor blockers there is a decrease of the lumen of epicardial coronary arteries and a clear increase in the severity of coronary stenoses as seen in the coronary angiogram, most probably as a result of the absence of the vasodilation induced by beta-receptors to counteract alpha-adrenergic vasoconstriction [15]. This vasoconstrictive effect on epicardial coronary arteries both of dynamic exercise and of beta-receptor blockers can be reversed by nitroglycerin or by nitrates. In addition to these clinically proven vasoconstrictive effects, which can contribute essentially to aggravating unstable angina pectoris conditions, a variety of mechanisms is still being discussed experimentally, which could intensify the tone of the smooth vascular musculature. These include 1. the deposition of cholesterol in the cellular membrane of the smooth vascular musculature, which enhances its sensitivity to sympathetic stimuli [13], 2. the decrease in the number and sensitivity of alpha-adrenergic receptors. In the sense of a disturbed negative feedback mechanism, this increases the release of noradrenalin at the sympathetic nerve end [17]. At the present state of our knowledge, the rupture of a more or less strongly stenosing atherosclerotic plaque in an epicardial coronary artery, which can happen at any time, must be regarded as the predisposing event for acute myocardial ischaemia. The associated loss of protective endothelium promotes platelet aggregation and releases stimuli with strong vasoconstrictive effects. Both mechanisms, probably most often in combination and with different intensities of the individual components, lead to abrupt throttling of the coronary blood flow and cause an acute ischaemic syndrome which can become manifest clinically as unstable angina pectoris, acute myocardial infarction, but also as sudden cardiac death [11].

Literature [1] Ambrose, J. A., S. L. Winters, R. A. Rohit et al.: Angiographic evaluation of coronary artery morphology in unstable angina. J. A. C. C. 7 (1986) 472 — 478. [2] Ambrose, J. A., C. E. Hjemdahl-Monsen, S. Borrico et al.: Angiographic demonstration of a common link between unstable angina pectoris and non-Q-wave acute myocardial infarction. Am. J. Cardiol. 61 (1988) 2 4 4 - 2 4 7 . [3] Brown, B. G.: Coronary vasospasm: observations linking the clinical spectrum of ischemic heart disease to the dynamic pathology of coronary atherosclerosis. Int. Med. 41 (1981) 7 1 6 - 7 2 2 .

Pathophysiology and pathological anatomy

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[4] Brown, G., A. B. Lee, E. L. Bolson et al.: Reflex constriction of significant coronary stenosis as a mechanism contributing to ischemic left ventricular dysfunction during isometric exercise. Circ. 70 (1984) 1 8 - 2 4 . [5] Busse, R., E. Bassenge: Regulation der Gefäßtonus über das Endothel. Z. Kardiol. 74 (Suppl. 7) (1985) 9 9 - 1 0 6 . [6] Davies, M. J., A. C. Thomas: Plaque Assuring: the cause of acute myocardial infarction, sudden ischemic death and crescendo angina. Br. Heart J. 53 (1985) 363 — 373. [7] Davies, M. J.: The pathology of the unstable ischemic syndroms. In: Th. v. Arnim, A. Maseri (eds.): Predisposing conditions for acute ischemic syndromes. SteinkopffVerlag, Darmstadt (1988) (in press). [8] Forrester, J. F., F. Litvak, W. Grundfest et al.: A perspective of coronary disease seen through the arteries of heart in man. Circ. 75 (1987) 505 — 513. [9] Förstermann, U.: Die Bedeutung der Endothelzellen für die Regulation des Tonus der glatten Gefäßmuskulatur — Bildung eines endothelialen, relaxierenden Faktors. Z. Kardiol. 75 (1986) 5 7 7 - 5 8 4 . [10] Gage, J. E., O. M. Hess, T. Murakami et al.: Coronary artery stenosis vasoconstriction during dynamic exercise in patients with classical angina pectoris: reversibility by nitroglycerin. Circ. 73 (1986) 8 6 5 - 8 7 6 . [11] Gorlin, R., V. Fuster, J. A. Ambrose: Anatomic-physiologic link between acute coronary syndromes. Circ. 74 (1986) 6 — 9. [12] Lichtlen, P. R., W. Rafflenbeul, H. Freudenberg: Pathoanatomy and function of coronary obstructions leading to unstable angina pectoris, anatomical and angiographic studies. In: P. G. Hugenholtz, B. S. Goldman (eds): Unstable angina, current concepts and management, p. 81—93. Schattauer-Verlag, Stuttgart (1985). [13] Marx, J. L.: Coronary artery spasms and heart disease. Science 208 (1980) 1127-1130. [14] Rafflenbeul, W., P. R. Lichtlen: Zum Konzept der „dynamischen" Koronarstenose. Z. Kardiol. 71 (1982) 4 3 9 - 4 4 4 . [15] Rafflenbeul, W., C. Berger, S. Jost: Vasoconstriction of epicardial coronary arteries with selective and nonselective ß-blockers. Circ. 77 (Suppl. II), (1988) 11 — 36. [16] Sherman, C. T., F. Litvak, W. Grundfert: Coronary angioscopy in patients with unstable angina pectoris. N. Engl. J. Med. 315 (1986) 9 1 3 - 9 1 9 . [17] Weiss, R. J., C. B. Smith: Altered platelet alpha-2-adrenoceptors in patients with angina pectoris. J. A. C. C. 2 (1983) 6 3 1 - 6 3 7 .

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Discussion

Roskamm: Thank you very much, Mr. Rafflenbeul. We have a few minutes for discussion. I would like to come back once more to the historical development. If we go back in time by five or ten years we see that changes in tone were very much in the foreground of interest at that time. What has been added in the past few years are the morphological changes: plaque fissures and thrombus formation, which also play a major role. What about the reversibility or the dynamics of these morphological changes? Rafflenbeul: The changes emanating from the destruction of the intima, with the formation of a mural thrombus and perhaps also of an appositional thrombus, can stop at any stage of development and behave reversibly. On the other hand, these secondary changes can also progress to prolonged vascular obstruction and on to myocardial infarction. We must consider these morphological changes to be dynamic processes. If we transfer this concept to our clinical practice we see that it is probably the daily varying threshold of angina initiation, which can be found out by painstaking interviews of the patient, that is caused by such dynamic changes within coronary stenoses and less so by external factors, such as changes of the weather, trouble, etc., as is often assumed. In the course of a coronary sclerosis there may again and again be ruptures of atherosclerotic plaque with thrombus apposition. It seems to be a purely random phenomenon in the course of this disease. Hugenholtz: I would like to ask Mr. Rafflenbeul about the rate of mayocardial infarctions after unstable angina pectoris. Rafflenbeul: As a result of the increasing availability of ways and means to detect this syndrome earlier and stabilize patients in time by suitable vasodilating medication and platelet aggregation inhibitors in coronary care, the number of patients actually developing myocardial infarctions has become relatively small. We estimate today that only some 10% of the patients cannot be stabilized, despite the intensive care therapy just indicated, and their disease progresses to myocardial infarction unless acute revascularization measures (balloon dilation, bypass surgery) are elucidated by coronary angiography. Bassenge: Mr. Rafflenbeul, you showed an angiogram of a vascular lumen which had clearly decreased after the administration of beta-receptor blockers, and you explained it as being due to the absence of the beta-stimulating effect while

Pathophysiology and pathological anatomy

23

the alpha-stimulating effect persisted. This is certainly one part of the explanation, albeit only the smaller part, for the main cause is this: The beta-receptor blocker causes the oxygen consumption of the heart to drop sharply, thus reducing coronary blood flow; as a consequence, the stimulating effect of the coronary flow on the release of EDRF and NO, respectively, by its shear forces acting on the endothelium, is lost and this causes pseudoconstriction to occur. This can be demonstrated very well by simply reducing the coronary flow by the proper amount experimentally, which will produce the same constriction without any participation by the beta-receptors. Rafflenbeul: I think we see on this angiogram the combination of several effects, some of them acting in opposite directions. If the decrease of coronary blood flow were the main effect, then the coronary vessels would have to become narrower, for instance, also after nitrates, for the coronary blood flow clearly decreases after nitrates. But just the opposite is true: After nitrates, the coronary vessels dilate. This is obviously a balance effect. Forum: About the mechanism of the random finding that suddenly a complicated lesion may develop. Is it due to the shear forces to which Mr. Bassenge alluded? Rafflenbeul: The shear forces in the region of coronary stenoses certainly play a major role. In addition, the cap covering the atherosclerotic plaque is unable to withstand high mechanical loads and stresses, especially so at the points of transition to the normal vessel. The ruptures described are found frequently at the transition to the normal intima. Also changes in tone of the smooth vascular muscles may have additional deleterious effects, and even the constant twisting and turning movements of the coronary vessels during a cardiac cycle may be a factor causing atherosclerotic plaque to rupture. Which factors play a role in a specific case surely will differ widely. However, as a rule, a combination of various initiators of a rupture of atherosclerotic plaque must be assumed to precede the clinical event.

Prognosis of unstable angina pectoris H. Tillmanns

A. Natural course While the spontaneous course of coronary heart disease in patients with stable angina pectoris symptoms has been the subject of numerous studies, data about the prognosis of unstable angina pectoris have not been available until the past few years. Tables 1 and 2 show the rates of myocardial infarction and of mortality in patients with unstable angina pectoris. It can be seen that most studies report similar courses. For instance, Krauss et al. [17] show the mortality in the first year to be 15%, while Gazes et al. [7] indicate 18%, Watkins et al. [40] state 17% within 14 months, and Plotnick and Conti [29] quote 12.5%. A particularly high mortality rate was reported by Vakil [39] (26% within three months). The occurrence of myocardial infarction (Table 2) was observed by Wood [41] in 22% within the first two months, by Fulton et al. [6] in 16% within three Table 1

Prognosis in unstable angina; natural course, mortality

Vakil (1964) Fulton et al. (1972) (n = 167) Krauss et al. (1972) (n = 100) Watkins et al. (1972) (n = 47) Gazes et al. (1973) (n = 140)

Heng et al. (1976) (n = 158) Plotnick, Conti (1977) (n = 32)

26% within 3 months 3% within 3 months 1% 15% 22% 8% 17% 18% 25% 52%

early (hospital) after 1 year after 20 months early (hospital) within 14 months within the first year after 2 years after 10 years

annual mortality in the first 5 years, 8% 4% early (hospital) annual mortality in the first 6 years, 5% 12.5% after 1 year

Nitroglycerin 6 © 1989 Walter de Gruyter & Co. • Berlin • New York

H. Tillmanns

26 Table 2

Prognosis in unstable angina; natural course, myocardial infarction

Wood (1961) Vakil (1964) Fulton et al. (1972) (n = 167) Krauss et al. (1972) (n = 100) Gazes et al. (1973) (n = 140) Heng et al. (1976) (n = 158) Plotnick, Conti (1977)

22% within 2 months 41% within 3 months 16% within 3 months 7% early (hospital) 22% after 1 year 21% within the first 8 months 13% early (hospital) 17% after 6 years 18% within 36 months

months, by Gazes et al. [7] in 21% of the cases within the first eight months. Over the period of hospitalization, which must be assumed to be on the order of 1 — 2 months, the studies show an average incidence of myocardial infarctions of 7 — 28% and an average death rate of 1 — 32%. It can be seen from the two tables that the data communicated in the literature about the spontaneous course of unstable angina pectoris vary considerably, at least in part because of differences in definition and, consequently, also in the compositions of the groups of patients examined. The course of unstable angina pectoris has been elucidated very much also by the work of the National Cooperative Study Group (NCSG) [38]. That study, which was run in eleven US centers and included a total of 288 patients (147 treated conservatively, 141 surgically), allowed mainly three types of courses to be distinguished: 1. The course leading to sudden cardiac death The incidence of "spontaneous" early deaths in the hospital phase caused by arrhythmia and myocardial infarction, respectively, amounted to 3% in the study. On the whole, the early and late mortality rates (the latter amounting to 7% over an average period of 30 months) were surprisingly low in the study. 2. The course leading to acute myocardial infarction In 8% of the patients with unstable angina pectoris the study of the National Cooperative Study Group indicated the occurrence of acute non-fatal myocardial infarctions still in the hospital phase. In the further course, over a period of 30 months, another 11% of the patients had non-fatal myocardial infarctions (18% with coronary three-vessel diseases, 3% with one-vessel diseases).

Prognosis of unstable angina pectoris

27

3. The course leading to stable angina pectoris By far most of the patients with unstable angina pectoris developed severe stable angina pectoris. In 40% of the patients with coronary two- and three-vessel diseases and in 22% of the patients with coronary one-vessel diseases, severe angina pectoris (New York Heart Association grade III — IV) was observed after discharge from hospital. There is a paucity of data in the literature about the prognoses of the different clinical manifestations of unstable angina pectoris, i. e., recent-onset, crescendo and at-rest angina. According to Bertolasi and co-workers [2] (156 patients), the mortality rate within the first 24 months is 8.5% in patients with recent-onset angina (duration of symptoms ^ 4 — 6 weeks), while it is 7.4% in patients with crescendo angina and 41.6% in patients with angina at rest (the so-called intermediary syndrome). In 34.2% of the patients with recent-onset angina, but in only 7.4% of coronary patients with crescendo angina, and in 37.5% of patients with angina at rest, acute myocardial infarctions occurred within the first 24 months. On the whole, patients with angina at rest showed the highest mortality and myocardial infarction rates. A more recent study by Roberts and co-workers [31] of the prognoses of patients with recent-onset angina (n = 329) as compared to patients with stable "chronic" angina pectoris (n = 1398) pointed in the same direction. Among the patients with angiographically documented coronary heart diseases no significant differences were found in the survival rates of patients with recent-onset angina and those with stable angina pectoris (one-year survival rate of recent-onset angina, 97%; of stable angina pectoris, 98%). On the other hand, cardiac events (non-fatal myocardial infarction or death) were registered in 16% of the patients with recent-onset angina, but in only 7% of the patients with stable angina pectoris [31].

B. Factors influencing the natural course Coronary morphology and left ventricular function In some 10% of unstable angina pectoris cases there is severe (more than 75%) stenosis of the trunk of the left coronary artery [1, 14], For the rest, patients with unstable angina pectoris show the same incidences of one-, two- and threevessel diseases as do patients with stable angina; roughly two thirds of the patients have multiple coronary vessel diseases [19]. In conservative drug therapy, the annual mortality of severe trunk stenoses ( > 75%) of the left coronary artery is 20 — 30% already in stable angina patients [19], and it rises further in the presence of instability symptoms [33].

H. Tillmanns

28

Besides severe trunk stenoses of the left coronary artery, impaired left ventricular function has been found to be another adverse prognostic factor in patients with unstable angina pectoris [29], Plotnick and Conti [29] conducted a 48-month prospective study on 32 patients with unstable angina pectoris, determining haemodynamic and angiographic data as well as the mortality and infarction rates. In patients with impaired left ventricular function (ejection fraction < 50%, n = 11), one-year mortality was 18% as compared to 9.5% in patients with normal left ventricular function (n = 21). After three years, the mortality rate of the patients with impaired left ventricular function had risen to 36% while that of patients with normal ejection fraction remained at a level of 9.5%. Patients with left ventricular ejection fractions < 30% and end diastolic volume indices > 1 2 5 cm3/m2 showed one-year mortality rates of 29% and three-year mortality rates of 57%. Non-fatal myocardial infarctions over the 48 months of observation period occurred in 27% of the patients with impaired left ventricular function, but in only 14% of the patients with normal pumping function. It may be concluded from these data that patients with unstable angina pectoris and still normal left ventricular function, who are under drug treatment, have better prognoses than patients with unstable angina and restricted pumping function.

Transitory myocardial ischaemia (a) Anamnesis and clinical findings

Heng et al. [11] were able to show in a retrospective study of 158 patients with unstable angina pectoris that patients with persistent angina pectoris complaints lasting for more than 24 hours and patients without any indications of earlier ischaemic attacks and myocardial infarctions had worse short-term prognoses during the hospital phase (death or acute myocardial infarction). Arterial hypertension and cigarette smoking had no significant impacts on short-term prognosis. In the same study, data were determined also about the long-term prognosis of unstable angina pectoris. Age > 60 years, increased cardio-thoracic ratio, and the existence of pulmonary congestion were found to be associated with a worse long-term prognosis [11]. (b)

Continuous

EGG

Several studies [9, 10, 13, 23] have shown the occurrence of (mainly silent) ischaemic episodes in patients with unstable angina pectoris (recent-onset, crescendo, and at-rest angina) to be associated with a higher risk of cardiac complications (myocardial infarction, need for revascularization measures) (Table 3). Gottlieb and co-workers [9] reported frequent and prolonged silent ischaemic episodes (continuous ECG, median of twenty minutes per episode) in 37 out of 70 patients admitted as in-patients to intensive care units for angina

29

Prognosis of unstable angina pectoris Table 3

Prognostic significance of continuous ECGs in unstable angina

Johnson (1982) Gottlieb (1986) Nademanee (1987) Gottlieb (1988) (2 yrs.)

With episodes (%)

Myocardial infarctions with vs. without ST (%)

18 53 59

19 16 17 27

vs. vs. vs. vs.

0 3 0 3

at rest and treated with beta-receptor blockers, nitrates, and calcium antagonists. In patients with silent ischaemia documented by continuous ECGs, the rate of cardiac complications (acute myocardial infarction and aorto-coronary emergency bypass surgery, respectively) of 43% after one month was significantly higher than in patients without ischaemic episodes as demonstrated by continuous ECGs (12%). Patients with the longest overall duration of ischaemic episodes were at the highest risk; multivariate analysis determined the ischaemic periods as documented by continuous ECGs to be the most important prognostic factors in one-month short-term prognosis [9]. After two years, patients with documented silent ischaemic periods showed clearly higher rates of myocardial infarction and death (27%) compared to patients without silent ischaemic periods (3%, p < 0.01) [10]. (c)

Radionuclide

studies

If primarily flow-dependent tracers are used, reversible ischaemic myocardial regions can be identified as areas of reduced nuclide density in myocardial scintigrams. In patients with unstable angina pectoris, however, increases in regional krypton-81 m activity were occasionally found in stenosis-dependent myocardial regions after intravenous application of rubidium-81 as indications of severe coronary stenoses [43]. The author's observations indicate that these patients run a greater risk of cardiac complications during the hospital phase.

Microinfarctions A large percentage of patients with unstable angina pectoris have myosin light chains in their serum as an indication of a myocardial infarction. Thus, Katus and co-workers were able to show [15] that 22 out of 42 ( = 52%) patients with angina at rest examined consecutively showed cardiac myosin light chains in the serum during the hospital phase. In 17 of these patients, protracted releases of myosin light chains were observed until the 4th day after hospitalization; in 7 patients the myosin light chains were found only during the first 24 hours. After

30

H. Tillmanns

the loss of membrane integrity, which occurs under ischaemic conditions, first only the free cytoplasmic light chain pool is released into the serum (28% of the unbound light chains) while, under the same conditions, already 68% of cytoplasmic creatine phosphokinase is released. Only after irreversible damage has been caused to the myocardial cell, the structurally bound myosin light chains dissociate from the myosin heavy chains under the influence of proteolytic enzymes and the shift in pH and are released continuously [3, 32], The serum concentrations of the cardiac myosin light chains released in the course of a microinfarction in patients with angina at rest can be determined by means of a radioimmunoassay [16]. In all five patients with angina at rest, who had suffered transmural myocardial infarctions while in hospital, myosin light chains were detected in the serum at least 28 hours before the infarction was diagnosed by ECG and conventional serum enzyme criteria (CPK) [15]. On the other hand, 20 patients without circulating myosin light chains had neither myocardial infarctions nor did they die [15]. Consequently, determination of the myosin light chains in serum enables a subgroup of patients with angina at rest to be identified whose prognosis is inferior.

Disturbed rheological properties of the blood Patients with unstable angina pectoris have higher plasma viscosities and intravascular agglutination than patients with stable angina pectoris [25, 26], To study the prognostic significance of higher plasma viscosity and intravascular agglutination in unstable angina pectoris, a prospective examination was conducted to see whether there was a higher incidence of adverse clinical courses in those cases where, on hospitalization, viscosities r| > 1.38 mPas and time constants for intravascular agglutination (corrected for r|), respectively, of b > 0.5 mPa, were measured. A total of sixty patients with unstable angina pectoris (recent-onset, crescendo, and at-rest angina) were included in the study. In patients with r) > 1.38 and b > 0.5, the occurrence of transmural myocardial infarctions was significantly increased (p < 0.005): Within one month after inclusion in the study, six out of thirteen patients with r| > 1.38, and six out of nineteen patients with b > 0.5 mPa, had myocardial infarctions, while none of the other patients had myocardial infarctions [24], In addition, symptomatic and asymptomatic ischaemic episodes were observed in the continuous ECG (despite complete antianginal medication for twelve hours) significantly more frequently at r| > 1.38 mPas than at r| < 1.38 mPas (p < 0.05). Deaths were encountered only in patients with increased plasma viscosity and elevated intravascular agglutination [24], The findings document the prognostic significance of the haemorheological parameters investigated for the course of unstable angina pectoris.

Prognosis of unstable angina pectoris

31

C. Drug therapy Drug therapy of unstable angina pectoris serves to stop associated complaints and improve the bad prognosis of the spontaneous course of the disease. While pre-1970 studies of patients with unstable angina pectoris indicated a myocardial infarction rate of 21 — 80% and a mortality rate of 1 —60%, more recent studies based on the use of nitrates, beta-receptor blockers and calcium antagonists, indicate infarction rates of 7 — 15% and a mortality rate of 1 — 2%. Table 4 lists the sites of action of the substances used in drug therapy of unstable angina pectoris. Partially occlusive thrombi are treated with platelet aggregation inhibitors and thrombolytic substances; the motility of vascular walls is influenced by nitrates and calcium antagonists (vascular dilation). Myocardial oxygen consumption is reduced by beta-receptor blockers, nitrates and, above all, frequency-decreasing calcium antagonists; the coronary conduction arterioles are dilated by calcium antagonists and nitrates [36, 37]. Table 4

Sites of action of drug therapy of unstable angina

1. Partially occlusive thrombus Platelet aggregation inhibitors; anticoagulants; thrombolytic substances. 2. Vascular wall motility Nitrates; calcium antagonists. 3. Myocardial oxygen consumption Beta-receptor blockers; nitrates; calcium antagonists. 4. Coronary conduction arterioles Calcium antagonists; nitrates.

Nitrates Although clinical experience accumulated over many years has shown that angina pectoris complaints in patients with unstable angina pectoris can be influenced positively by oral or intravenous administrations of nitrates, no influence on prognosis has been documented in any of the major studies.

Beta-receptor blockers In contrast to earlier concerns that beta-receptor blockers could aggravate anginal complaints by increasing the coronary vascular tone, several studies have been able to demonstrate a positive therapeutic effect on patients with unstable angina pectoris, also with respect to prognosis. Thus, the frequencies

32

H. Tillmanns

and durations of symptomatic and silent ischaemic episodes were clearly reduced by the non-selective beta-receptor blocker, propranolol (160 —320 mg/day), which was administered in addition to nitrates and nifedipin [8]. Intravenous administration of a non-selective beta-receptor blocker (propranolol [27]) and a cardioselective beta-receptor blocker (atenolol [42]), respectively, was able in a large percentage of cases to stop the progression from "impending" to "definitive" myocardial infarction: Only 55% of the patients threatened by impending myocardial infarction developed acute transmural infarctions after intravenous administration of propranolol (0.1 mg/kg) (control group: 96%) [27]; after intravenous administration of atenolol (5 mg), only 49% of the patients with impending myocardial infarction suffered transmural infarctions (control group, 66%) [42], After oral administration of metoprolol (twice 100 g), the risk of recurrent ischaemic attacks and acute myocardial infarction was reduced significantly over an 48-hour observation interval [12].

Calcium antagonists Following indications that an increase in tone of the coronary vessels up to spasms was a factor of major pathogenetic significance in the intensification of symptoms in patients with unstable angina pectoris, nitrate and beta-receptor blocker therapy was supplemented by calcium antagonists. However, it was seen that, compared to monotherapy with a beta-receptor blocker (propranolol), diltiazem offered no advantage with respect to the rates of myocardial infarction and death and to the need for aorto-coronary bypass surgery and symptoms [35], while the administration of nifedipine even had adverse effects in respect of cardiac events (myocardial infarction, death) [12]. Better effects on the prognosis of patients with unstable angina pectoris were achieved only with verapamil (320 — 480 mg/d) [21, 28] and with nifedipine used in combination with other anti-anginal substances [4, 12, 22], The additional administration of nifedipine (40 — 80 mg/d) was able to improve the prognosis of patients with unstable angina pectoris only in those cases where nitrates and beta-receptor blockers had been ineffective [12],

Anticoagulants and platelet aggregation inhibitors Despite the absence of an anti-anginal effect, heparin and platelet aggregation inhibitors were able to improve clearly the prognosis of drug therapy in unstable angina pectoris patients. A double-blind randomized placebo-controlled study of patients with angina at rest demonstrated that, after administration of heparin

Prognosis of unstable angina pectoris

33

for one week, only one out of 51 patients ( = 2%) had a transmural myocardial infarction, while 9 out of 54 patients with angina at rest ( = 17%) in the placebo group had myocardial infarctions (p = 0.024) [34], In addition, it was demonstrated in two major studies with platelet aggregation inhibitors (acetylsalicylic acid) that in patients with unstable angina pectoris the risks of acute myocardial infarction or sudden cardiac death can be reduced by 51% for a period of 12 weeks and two years, respectively [5, 18]. The incidence of non-fatal myocardial infarctions was also reduced by 51% in patients who had been treated with acetylsalicylic acid [18]. These favorable prognostic effects were achieved with acetylsalicylic acid dosages of 324 mg/d and four times 325 mg/d, respectively [5, 18]. Whether lower dosages (up to 100 mg/d) have the same favorable effect on prognosis has not yet been proved. Also, no data are available as yet which could document a prognostically favorable effect of thrombolytic therapy on patients with unstable angina.

D. Surgical intervention Several studies were unable to prove any advantage of surgical treatment of unstable angina pectoris over intensive drug therapy [30, 38]. Surprisingly enough, the study by the National Cooperative Study Group [38] even indicated that patients with unstable angina pectoris treated surgically had significantly higher incidences of post-operative non-fatal myocardial infarctions (17%) than the patients undergoing drug therapy (8%) (p < 0.005). Similar results were communicated by Pugh and co-workers [30]. In a multicentric randomized prospective study of 468 patients with unstable angina pectoris, Luchi and co-workers [20] also were unable to show a difference in prognosis between patients treated surgically and patients receiving drugs. The two-year survival rate in both groups did not differ in a statistically significant way. In addition, non-fatal myocardial infarctions occurred in 11.7% of the patients treated surgically and in 12.2% of the patients undergoing drug therapy. If only the patients with compromised left ventricular function were taken into account, however, there was a significant difference (p = 0.03). Patients on whom aorto-coronary bypass surgery had been performed had significantly lower two-year mortality rates than drug-treated patients with unstable angina [20], Thus, these data can only be used to derive a better prognosis after surgery for patients with compromised left ventricular function, not for drug-treated patients with unstable angina pectoris.

34

H. Tillmanns

Literature [1] Alison, H. W., R. O. Russell, J. A. Mantle et al.: Coronary anatomy and arteriography in patients with unstable angina pectoris. Am. J. Cardiol. 41 (1978) 204 — 209. [2] Bertolasi, C. A., J. E. Tronge, C. A. Carreno et al.: Unstable angina — prospective and randomized study of its evolution, with and without surgery. Am. J. Cardiol. 33 (1974) 201-208. [3] Bird, J. W. C., J.H. Carter, R. E. Triemer et al.: Proteinases in cardiac and skeletal muscle. Fed. Proc. 39 (1980) 2 0 - 2 5 . [4] Blaustein, A. S., G.V. Heller, B. S. Kolman: Adjunctive nifedipine therapy in highrisk, medically refractory, unstable angina pectoris. Am. J. Cardiol. 52 (1983) 950-954. [5] Cairns, J. A., M. Gent, J. Singer et al.: Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial. N. Engl. J. Med. 313 (1985) 1369-1375. [6] Fulton, M., B. Duncan, W. Lutz et al.: Natural history of unstable angina. Lancet I (1972) 860-865. [7] Gazes, P.C., E.M. Mobley, Jr., H . M . Faris, Jr. et al.: Preinfarctional (unstable) angina — a prospective study — ten year follow-up. Circulation 48 (1973) 331 —337. [8] Gottlieb, S. O., M. L. Weisfeldt, P. Ouyang et al.: Effect of the addition of propranolol to therapy with nifedipine for unstable angina pectoris: a randomized, double-blind, placebo-controlled trial. Circulation 73 (1986) 331-337. [9] Gottlieb, S.O., M.L. Weisfeldt, P. Ouyang et al.: Silent ischemia as a marker for early unfavorable outcomes in patients with unstable angina. N. Engl. J. Med. 314 (1984) 1214-1219. [10] Gottlieb, S. O., M. L. Weisfeldt, P. Ouyang et al.: Silent ischemia predicts infarction and death during 2 year follow-up of unstable angina pectoris. J. Am. Coll. Cardiol. 10 (1987) 756-760. [11] Heng, M.K., R. M. Norris, B.N. Singh et al.: Prognosis in unstable angina. Br. Heart J. 38 (1976) 921-925. [12] Report of the Holland Interuniversity Nifedipine/Metoprolol Trial (HINT) Research Group: Early treatment of unstable angina in the coronary care unit: a randomised, double blind, placebo controlled comparison of recurrent ischaemia in patients treated with nifedipine or metoprolol or both. Br. Heart J. 56 (1986) 400—413. [13] Johnson, S. M., D. R. Mauritson, M. D. Winniford et al.: Continuous electrocardiographic monitoring in patients with unstable angina pectoris: identification of highrisk subgroup with severe coronary disease, variant angina, and/or impaired early prognosis. Am. Heart J. 103 (1982) 4 - 1 2 . [14] Kasparian, H., L. Wiener, A. Scariato: Coronary arteriography in patients with impending and evolving myocardial infarction. Cardiovasc. Clin. 7 (1975) 143. [15] Katus, H.A., K.W. Diederich, E. Hoberg et al.: Circulating cardiac myosin light chains in patients with angina at rest: Identification of a high risk subgroup. J. Am. Coll. Cardiol. 11 (1988) 487-493.

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35

[16] Katus, H.A., J. Hurrell, G. Matsueda et al.: Increased specificity in human cardiac myosin radioimmunoassays utilizing two monoclonal antibodies in a double sandwich assay. J. Mol. Immunol. 19 (1982) 451-455. [17] Krauss, K.R., A.M. Hutter, Jr. et al: Acute coronary insufficiency: course and follow-up. Circulation 45 - 46 (Suppl. I) (1972) 6 6 - 7 1 . [18] Lewis, H.D., Jr., J. W. Davis, D. G. Archibald et al.: Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N. Engl. J. Med. 309 (1983) 396-403. [19] Lichtlen, P R . : Klinik, Diagnostik und Therapie der unstabilen Angina pectoris. Internist 21 (1980) 636-645. [20] Luchi, R. J., S. M. Scott, R. H. Deupree et al.: Comparison of medical and surgical treatment for unstable angina pectoris. Results of a Veterans Administration Cooperative Study. N. Engl. J. Med. 316 (1987) 977-984. [21] Mehta, J., C.J. Pepine, M. Day et al.: Short-term efficacy of oral verapamil in rest angina: A double-blind placebo controlled trial in CCU patients. Am. J. Med. 71 (1981) 977-982. [22] Muller, J. E., J. Morrison, P. H. Stone et al.: Nifedipine therapy for patients with threatened and acute myocardial infarction: a randomized, double-blind, placebocontrolled comparison. Circulation 69 (1984) 740 — 747. [23] Nademanee, K., V. Intrarachot, P.N. Singh et al.: Prognostic significance of silent myocardial ischemia in patients with unstable angina. J. Am. Coll. Cardiol. 10 (1987) 1-9. [24] Neumann, F. J., E. Hoberg, H. A. Katus et al.: Prognostische Bedeutung von Plasmaviskosität und Erythrozytenaggregation bei instabiler Angina pectoris. Z. Kardiol. (1989, in press). [25] Neumann, F. J., H. Tillmanns, S. Hoffmann-Kuscaty et al.: Hämorheologische Veränderungen bei Patienten mit koronarer Herzkrankheit: Beziehung zu Symptomatik und angiographischem Schweregrad. Z. Kardiol. 75 (Suppl. 1) (1986) 45. [26] Neumann, F. J., H. Tillmanns, P. Roebruck et al.: Hämorheologische Veränderungen bei Patienten mit instabiler Angina pectoris. Z. Kardiol. 77 (Suppl. 1) (1988) 54. [27] Norris, R. M., E. D. Clarke, N. L. Sammel et al.: Protective effect of propranolol in threatened myocardial infarction. Lancet 2 (1978) 907 — 909. [28] Parodi, O., A. Maseri, I. Simonetti: Management of unstable angina at rest by verapamil: A double-blind cross-over study in coronary care unit. Br. Heart J. 41 (1979) 167-174. [29] Plotnick, G. D., C. R. Conti: Unstable angina: Angiography, short- and long-term morbidity, mortality and symptomatic status of medically treated patients. Am. J. Med. 63 (1977) 870-873. [30] Pugh, B., M.R. Platt, L.J. Mills et al.: Unstable angina pectoris: A randomized study of patients treated medically and surgically. Am. J. Cardiol. 41 (1978) 1291-1298. [31] Roberts, K. B., R. M. Califf, F. E. Harrell, Jr. et al.: The prognosis for patients with new-onset angina who have undergone cardiac catheterization. Circulation 68 (1983) 970-978.

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[32] Smitherman, T. C., D. W. Dycus, E. G. Richards: Dissociation of myosin light chains and decreased myosin ATPase activity with acidification of synthetic myosin filaments: possible clues to the fate of myosin in myocardial ischemia and infarction. J. Mol. Cell. Cardiol. 12 (1980) 149-164. [33] Takaro, T., H. N. Hultgren, M. J. Lipton et al.: The Veterans Administration cooperative randomized study of surgery for coronary arterial occlusive disease. II. Subgroups with significant left main lesions. Circulation 54 (1976) III —107. [34] Telford, A. M., C. Wilson: Trial of heparin versus atenolol in prevention of myocardial infarction in intermediate coronary syndrome. Lancet I (1981) 1225—1228. [35] Théroux, P., Y. Taeymans, D. Morissette et al.: A randomized study comparing propranolol and diltiazem in the treatment of unstable angina. J. Am. Coll. Cardiol. 5 (1985) 717-722. [36] Tillmanns, H., F.J. Neumann, N. Parekh et al.: The effect of calcium antagonists (nifedipine, verapamil) on the microcirculation of the normal and ischemic heart. Prog. appl. Microcirc. 14 (1989) 4 0 - 5 1 . [37] Tillmanns, H., M. Steinhausen, H. Leinberger et al.: The effect of coronary vasodilators on the microcirculation of the ventricular myocardium. In: H. Tillmanns, W. Kübler, H. Zebe (eds.): Microcirculation of the heart — theoretical and clinical problems, pp. 305 — 311. Springer, Berlin — Heidelberg — New York 1982. [38] Unstable angina pectoris: National Cooperative Study Group to compare surgical and medical therapy. II. In-Hospital experience and initial follow-up results in patients with one, two and three vessel disease. Am. J. Cardiol. 42 (1978) 839 — 848. [39] Vakil, R. J.: Pre-infarction syndrome — management and follow-up. Am. J. Cardiol. 14 (1964) 5 5 - 6 3 . [40] Watkins, J. C., R. O. Russell, C. E. Rackley: Follow-up of unstable angina in a myocardial infarction research unit. Circulation 46 (Suppl. II) (1972) 11 — 23. [41] Wood, P.: Acute and subacute coronary insufficiency. Br. Med. J. 1 (1961) 1779-1782. [42] Yusuf, S., R. Peto, D. Bennett et al.: Early intravenous atenolol treatment in suspected acute myocardial infarction. Preliminary report of a randomised trial. Lancet II (1980) 273-276. [43] Zimmermann, R., H. Tillmanns, A. Ernst et al.: Noninvasive detection of reduced regional myocardial blood flow at rest in patients with unstable angina: Increased regional Krypton-81m concentration after i. v. injection of Rubidium-81 (in press).

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37

Discussion

Roskamm: Thank you, Mr. Tillmanns. We will discuss this paper except for its last part, the surgical approach, for this topic will be treated at length this afternoon. Before opening the debate I would like to supplement what has been said. As far as management of the third group, with angina at rest, is concerned, especially referral to a coronary care unit etc., there are no major differences of opinion, I think. But what about the situation for the first two groups, de novo angina and crescendo angina? Let me give you an example. Somebody tells me: "Three or four days ago was the first time I had chest pain during physical exertion." Or he says: "My angina pectoris, which I know I have, is becoming clearly worse." What is the general practitioner supposed to do with that patient? Should he put him into a hospital now or is there still time to wait and see? Could you please comment on this aspect? Tillmanns: Let us take for type I, i. e. recent-onset angina, a 35-year old man who had his first attack of typical anginal pain four weeks ago when doing physical work and who now complains of exercise-dependent precordial symptoms which, however, are not getting worse at present. Despite the absence of symptoms, this is a patient whom you must classify as a type I case of unstable angina and whom you should refer to a clinic immediately, if possible to a clinic where he would also be taken care of cardiological^. At this stage, the patient should be treated by an internist and a cardiologist, respectively. While he is in hospital, one should try first to stabilize the patient with drugs. After this socalled cool-off period, invasive cardiological diagnosing should be carried out (coronary angiography). If the patient cannot be stabilized by drug treatment in the initial phase, coronary angiography and coronary angioplasty, respectively, should be performed as soon as possible. I would proceed in the same way with patients suffering from crescendo angina, i. e., first attempt to stabilize with drugs and then perform invasive diagnosis. On the whole, patients with unstable angina pectoris should be treated by internists and cardiologists, respectively, who can decide on the proper time for invasive diagnosing as a function of the response to drug therapy. Of course, there is no need to perform an invasive examination on the very same day on a patient with crescendo angina, but a normal resting ECG; this patient should

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first be supplied with sufficient nitrates, beta-receptor blockers, perhaps also calcium antagonists and platelet aggregation inhibitors. However, if this therapeutic regimen is unable to relieve his complaints on the same day, or if new ECG changes appear while he is resting, such as ST-segment depressions or Tnegativities, invasive approaches should be taken on the same day in an attempt to elucidate the coronary morphology and perhaps, in the same step, do a percutaneous transluminal coronary angioplasty. Roskamm: I would like to come back to the type I unstable angina and to the problem of referral as an inpatient or as an outpatient. There are patients with crescendo angina in whom you, as a general practitioner, are quite able to find reasons for the "crescendo." The patient, for instance, suddenly has high blood pressure, excessively high blood pressure, or there are other reasons; he may not have taken his drugs properly, and the like. Tillmanns: When we see a patient with arterial hypertension, who normally has stable angina pectoris but now presents with much more pronounced symptoms and with very high blood pressure, we do not have to accept him as an inpatient if lowering his blood pressure to the normal range makes his precordial complaints and symptoms disappear and the resting ECG shows no changes. If a clear dependence in time can be established between the occurrences of high blood pressure and precordial complaints, immediate referral to a hospital surely is not necessary. In this case, treatment on an outpatient basis will be sufficient. However, if a dynamic pattern can be discerned in the complaints of the patient which cannot be traced back to any other underlying disease, such as anaemia, fever, increased blood pressure, or hyperthyroidism, we at Heidelberg admit the patient as an inpatient, especially if there are changes in the ST-T-segment of the resting ECG. Forum: My daily work is primarily that of an internist concentrating on gastrointestinal problems. I work together with a partner in a regular 100-bed unit. We quite often see patients with unstable angina pectoris. Do we have to be cardiologists to treat them? Is the general internist allowed to do the initial drug treatment, i. e., attempt stabilization under a drug regimen, and may he decide if and when coronary angiography should be carried out? Tillmanns: Of course, you as an internist, even if you are no cardiologist, can start primary drug therapy and assess whether and when the patient should undergo further invasive diagnosing. Forum: On silent ischaemia. You mentioned that patients with stable angina pectoris have a much worse prognosis, especially with silent ischaemia after a myocardial infarction. Does that also mean that every patient with a silent ischaemia absolutely must undergo angiography? After all, opinions differ in this respect.

Prognosis of unstable angina pectoris

39

Tillmanns: This is a question I would not want to go into in great detail right now, as Mr. von Arnim is going to discuss it in the course of this morning's session. Forum: On the myosin assay. What is it really good for? We are currently introducing it. So far, we have not found anything reasonable in the literature to tell us what it will produce in terms of additional information. Is it worthwhile to introduce the myosin assay in a more generally oriented clinic or also in a cardiological unit? Tillmanns: It is still difficult to assess the value of the assay for myosin light chains in diagnosing unstable angina pectoris. The myosin light chain assay, which is done by Mr. Katus in our case, was published repeatedly between 1986 and 1988 (e. g., J. of American College of Cardiology, 1987; American College of Cardiology, 1988). It is a double sandwich assay with monoclonal antibodies. I think the clinical importance of the myosin light chain assay is going to increase, for especially those patients showed the highest levels of myosin light chains who required emergency PTCA after attempted drug stabilization during their hospital stay. The myosin light chain assay and krypton-81 m scintigraphy supply us with additional parameters which can help us in judging the course of unstable angina pectoris. Roskamm: Are there any further questions? If not, I would very much like to come back to de novo angina pectoris. Again and again, it has been my experience that great uncertainty exists precisely in this field. Let us assume that a patient presents and tells us: "Six days ago, when doing some physical work, I had this retrosternal pressure for the first time." At the beginning, I understood you to say that you would immediately refer that patient to a hospital as an inpatient. Are there also other possibilities? Tillmanns: As I said a few minutes ago, not every patient with de novo angina needs inpatient treatment in a clinic. Yet, I do think that a patient complaining of typical angina pectoris, and whom we suspect of suffering from real ischaemic pain, should be seen by an internist or a cardiologist. On the basis of anamnesis, which of course must be sufficient, a decision will then be made as to whether the patient should be hospitalized or not. In the absence of other predisposing factors, such as anaemia, arterial hypertension, fever, hyperthyroidism, etc., I recommend hospital admission of a patient with de novo angina, just to be on the safe side and also because we do not know whether this patient does not have partial thrombosis of a coronary vessel, which may also soon lead to myocardial infarction. Let me give you a typical example: Recently we saw in our unit a 32-year old man who had had an episode of anginal pain for the first time about two weeks before he was referred to our hospital. He thus met the

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criteria of de novo angina. However, essentially the patient only had exercisedependent pain in his wrists and no other typical anginal complaints. An internist had seen him on an out-patient basis and supplied him with anti-anginal drugs. Ten days later, there was an extended anteroseptal infarction. On the day of the infarction, angiography documented a severe proximal stenosis of the descending branch of the lateral circumflex artery. On the whole, the problem with de novo angina is that we just do not know in what direction symptoms will develop. It appears to be necessary for an experienced colleague to have another look at the patient before one discharges him. Roskamm: Perhaps the prognosis can be summed up by saying that a lot of things can happen, but do not necessarily happen.

Silent ischemia in patients with unstable angina pectoris Th. v. Arnim

Problems of silent myocardial ischemia Silent ischemia defines conditions in which the patient does not complain about angina pectoris or symptoms equivalent to angina pectoris, although by means of objective methods ischemic signs of the myocardium can be detected. In this context the type of method used for detecting the signs of ischemia is irrelevant. In most cases it is the exercise ECG, but scintigraphic or echocardiographic methods may also be applied for detecting silent ischemia. The reason why silent myocardial ischemia has become a particularly interesting phenomenon is that in the 24 hour long-term ECG the incidence of symptomatic episodes during daily life could be proved [1, 2], Various studies have shown meanwhile that there are no essential differences in the characteristics of the ischemia when comparing episodes of silent ischemia with ischemic episodes that are accompanied by anginal symptoms, and that the question whether ischemia is painful or painless is decided by other factors. On the way from the ischemic myocardium via the nerve fibre receptors and the transmission along the spinal cord to the conscious perception of "angina pectoris" various mechanisms may become effective at many different points which prevent the perception of pain. According to studies by Droste [3], the pain inhibiting pathways of the spinal cord, presumably under the effect of endorphines, play a special role. The great importance of silent myocardial ischemia lies in its unfavorable influence on the patient's prognosis. We do not know for sure whether recurrent transient ischemic episodes per se affect the myocardium by causing multiple small necrotic lesions or whether silent ischemia is only a marker for a particularly severe and progressive coronary heart disease the outcome of which, however, is determined by irreversible events occurring at a later stage. In many studies the prognostic value of a pathological exercise ECG could be proved also for asymptomatic patients [4, 5]. In our own study we were able to show in patients with stable angina that, besides the clearly established prognostic influence of persistently positive coronary findings, the detection of transient Nitroglycerin 6 © 1989 Walter de Gruyter & Co. • Berlin • N e w York

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ischemic episodes in the long-term ECG represents an independent predictive factor [6]. The problem of silent myocardial ischemia in totally asymptomatic patients (who really are not patients as yet) is still essentially unsolved. Two groups of patients are involved: A. Patients who are totally asymptomatic B. Patients with a coronary heart disease which has already become manifest in the form of angina pectoris, myocardial infarction or conditions following coronary bypass operation. The first group has a very low prevalence of coronary heart disease and, correspondingly, of silent ischemia; in the second group silent ischemia, as all other manifestations of coronary heart disease, certainly occurs more frequently. It is therefore more worth while to look for silent ischemia in the patients of group B.

Studies of silent ischemia in patients with unstable angina Unstable angina represents a period in the course of a coronary heart disease in which processes occur that are crucial to the patient's outcome. Just as we may say, in a way, that no patient has ever died of stable angina, as important is it to continuously watch and control the patient's symptomatic development and objective findings especially during acute episodes. Decisions for a bypass operation are often made primarily in view of symptoms which persist despite drug therapy. In this context the question arises whether asymptomatic ischemia should not be treated in a similar way. Therefore it is important to find out whether, in addition to anginal pain, patients with unstable angina also have frequent episodes of silent ischemia. In a study comprising 38 consecutive patients with unstable angina admitted to the intensive care unit of our hospital long-term ECGs over a mean period of 2.5 days were made for ST segment analysis. All patients were under full drug therapy, most of them under triple therapy consisting of beta blockers and calcium antagonists and nitrates with additional intravenous heparin. For longterm ECG we used the two-lead Oxford FM recording system and continuous visual analysis. For every episode, ECG recording started a little before onset and showed the beginning, maximum and end of ST segment changes, and only episodes lasting longer than 1 minute with more than 1 mm of ST segment depression were evaluated. According to these criteria, the long-term ECG showed transient ischemic episodes in 16 of the 38 patients (i. e. 42%); 80% of

Silent ischemia with unstable angina pectoris

43

those episodes were not accompanied by symptoms. The percentage share of silent ischemic episodes in the total number of ischemic episodes is higher in this patient group than we found it to be in another study with a group of patients most of whom had stable angina. In the latter group the percentage of silent ischemic episodes was 65%. In a recently published survey Rozanski [7] also found that from the exercise ECG of the out-patient to the long-term ECG of the in-patient an increase in the percentage of silent ischemic episodes can be observed. The cause is unclear but might most probably be seen in the special expectation conditions of the patient under exercise ECG and in the situation of severely ill patients in a hospital environment. Follow-up prognostic examinations of the patients with unstable angina 30 days after admission to the ICU showed that patients still having detectable ischemic

k Admitted to ICU

Fig. 1

Prognostic significance of detecting transient ischemias, most of them silent, in patients with unstable angina. 38 consecutive unstable angina patients at our ICU were monitored for 2.5 days by long-term ECG. Patients with positive findings, i. e. ischemia detected in the long-term ECG, had significantly more cardiac events over a period of 30 days. Such events were: death, myocardial infarction, need for a bypass or PTCA.

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episodes despite intensive drug therapy have an unfavorable prognosis. This result is significant if not only death and myocardial infarction but also the need for a bypass operation or PTCA is considered a cardiac event (Fig. 1). For the cardiac events of death and myocardial infarction only a statistical trend could be obtained. Almost identical results were obtained by teams in Baltimore [8] and Saint Louis [9], Both authors also report on a clearly less favorable outcome in patients whose myocardial ischemia could not be stopped despite intensive drug therapy. As a result, the therapeutic efforts for patients with unstable angina should not aim exclusively at freedom from pain, but, if possible, at freedom from ischemia.

Recent developments of new methods It is true that the documentation of transient ischemic episodes by means of long-term ECG recordings has led to the prognostic findings mentioned above with regard to the significance of silent myocardial ischemia as a marker for unfavorable outcome, but the disadvantage of long-term ECG recordings in clinical use is that an evaluation is not possible until the next day so that such recordings hardly ever supply information for acute therapeutic decisions. Here the recent development of a device with a portable ECG computer (Mortara, Milwaukee, Mich., USA) offers progress because it permits electronic storage of 12-lead ECGs at preset intervals. In monitoring mode the ECG is checked every 20 seconds in all 12 leads for ST segment changes, and if such changes occur an automatic ECG recording is made. These ECG complexes, stored in electronic read-only memories, can be called up any time at the patient's bedside in the ICU, so that during regular rounds a review function of ischemic episodes that may have occurred in the last few hours is being offered. In our own studies we were able to prove high sensitivity and specificity of this type of ECG recordings [10]. With regard to bedside documentation there still is room for improvement. However, such a procedure offers the benefit of identifying ischemias in patients with high sensitivity so that prompt bedside decisions can be made about, e. g., the right time for coronary angiography and possibly interventional therapy.

Silent ischemia with unstable angina pectoris

45

Literature [1] Deanfield, J. E., A. Maseri, A. P. Selwyn et al.: Myocardial ischaemia during daily life in patients with stable angina: its relation to symptoms and heart rate changes. Lancet 1 (1983) 753-759. [2] von Arnim, Th., B. Höfling, M. Schreiber: Characteristics of episodes of ST elevation or ST depression during ambulatory monitoring in patients subsequently undergoing coronary angiography. Brit. Heart J. 54 (1985) 484-488. [3] Droste, C., H. Roskamm: Experimental approach to painful and painless ischemia. In: Th. v. Arnim, A. Maseri (Eds.): Silent Ischemia, S. 31—42: Steinkopff Verlag, Darmstadt, Springer Verlag, New York (1987). [4] Giagnoni, E., M. B. Secchi, S. C. Wu et al.: Prognostic value of exercise ECG testing in asymptomatic normotensive subjects. A prospective matched study. New Engl. J. Med. 309 (1983) 1085-1089. [5] Multiple Risk Factor Intervention Trial Research Group. Exercise electrocardiogram and coronary heart disease mortality in the multiple risk factor intervention trial. Am. J. Cardiol. 55 (1985) 1 6 - 2 4 . [6] v. Arnim, Th., U. Szeimies-Seebach, A. Erath et al.: Transient ischaemic episodes — a marker for future cardiac events in patients with stable angina pectoris. In: Th. v. Arnim, A. Maseri (Eds): Predisposing Conditions for Acute Ischaemic Syndroms, S. 117-122. Steinkopff Verlag, Darmstadt 1989. [7] Rozanski, A., D. S. Berman: Silent myocardial ischemia. I. Pathophysiology, frequency of occurrence and approaches toward detection. Am. Heart J. 114 (1987) 615-626. [8] Gottlieb, S.O., M. L. Weisfeldt, P. Ouyang et al.: Silent myocardial ischemia as a marker for early unfavorable outcomes in patients with unstable angina. New Engl. J. Med. 314 (1986) 1214-1219. [9] Nademanee, K., B.N. Singh, J. Guerrero et al.: Accurate rapid compact analog method for the quantification of frequency and duration of myocardial ischemia by semiautomated analysis of 24-hour Holter ECG recordings. Am. Heart J. 103 (1982) 802.

[10] v. Arnim, Th., E. Reuschel-Janetschek: Continuous bed-side monitoring of the ECG for detection of silent myocardial ischaemia. Eur. Heart J. 9 (Suppl.) (1988, in press).

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Discussion

Roskamm: Thank you, Mr. v. Arnim. Well, silent ischemia in patients with angina pectoris even after stabilisation still, or again, means instability. Forum: Pain perception and silent myocardial ischemia — what about encephalins and endorphins — have you studied them? v. Arnim: No, we haven't. These substances are very difficult to determine, Mr. Droste. In Bad Krotzingen they have just recently equipped a laboratory specifically for this purpose and now offer new data showing that the influence of increased endorphins on pain perception certainly makes an essential contribution to the phenomenon of silent ischemia. It is an interesting observation in this context that certain endogenic opioids are co-localized with catecholamines which means that they are in the same vesicles in the cell, and at the very moment when catecholamines are released in the adrenal cortex endogenic opioids are released too which may contribute to pain suppression. Forum: One of your slides was very interesting in this connection: "Silent ischemia and environmental conditions". Exercise testing, out-patient or in-patient. Is this going in the same direction? v. Arnim: No, this is not the same direction, because what the slide showed was the very fact that patients have less frequently silent ischemias in the exercise ECG. Forty percent of the exercise ECGs had silent ischemias whereas the figure was 80% for the out-patient ECGs. This would speak somewhat against exerciseinduced silent ischemia, but this surely is not the whole truth of either direction. There certainly are many levels at which pain perception can be disturbed. One should not assume that it is one single mechanism which explains silent myocardial ischemia. Roskamm: These probably were not the same patients that were used. v. Arnim: No, these were not the same patients. These were just percentages of silent ischemias taken from large studies. Bleifeld: The patient who had that ST segment depression at 21.50 hs — what do you give him, and in how far does the 12-lead ECG recording device provide more information than other devices? v. Arnim: This depends, of course, on how the ischemia expresses itself and on the other conditions of the patient. If this is a patient, e. g., who is monitored

Silent ischemia with unstable angina pectoris

47

after PTCA, we may return him to the cardiac catheterization laboratory and try to prevent an onsetting acute occlusion, or if there were earlier complications we may take him immediately to the operating theatre. It very much depends on the details of the individual case. The advantage of this method is that you can look at 12-lead ECGs recorded 30 minutes ago when you are at the patient's bedside. In this way you will see a trend, and if the trend is a straight line without any changes you may, according to our studies (and we have checked many thousands of such ECGs), assume that nothing has happened. And if you do see something you can very quickly look at the complete ECG. This possibility has so far not existed — because what ICU would record complete ECGs every two minutes that you would then have to go through? In my time at the ICU I have always been annoyed by the many ECGs, by the piles of paper we had to go through before getting a general idea which is difficult enough even then and is only done at long intervals. Then we had maybe 3 ECGs a day for unstable patients. Now we virtually have continuous monitoring and ECG recordings at the points in time when we want them. I think this is a big step ahead. Forum: What does mental stress mean in connection with the syndrome of unstable angina, time pressure, etc.? v. Arnim: In the New England Journal of Medicine a very interesting article on mental stress was published recently showing that mental stress caused by simulating a public speech on a subject which the patient strongly dislikes was the most powerful factor triggering ischemia. In that test series the same could be shown in a comparison with the exercise ECG in patients with coronary heart disease. Radionuclide ventriculography trials were made which showed clearly that mental stress may trigger intense ischemias. In how far this then leads to the syndrome of unstable angina pectoris is not yet entirely clear. We have made our own study in Munich including angina patients admitted to our clinic after a life event who were examined by a postgraduate student working on his doctor's thesis. So this was a life event study following life events such as loss of job, loss of spouse, severe illness. It turned out that the angina patients in comparison with a control group, which was exactly matched with regard to age, severity of coronary disease, etc., had gone through an increased number of life events in the last three months before being admitted to the clinic. This was an impressive and significant result. Forum: Does this also apply to myocardial infarction? v. Arnim: This equally applies to myocardial infarction, as Mr. Siegrist from Marburg showed. Perach: Another question relating to the 12-lead recording device and the ECG readings. Have you ever checked ECG changes in connection with right ven-

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tricular cardiac catheter measurements in order to find out whether the pressure in wedge position increases during the same period? This would be extremely interesting to know. We checked this and found that ECG changes occur without any change in pressure and vice versa, i. e. pressure rises occur without any ECG changes. This leads me on to a second question. What are you doing if the change in the E C G only amounts to 0.5 or just 1? Will you catheterize the patient again or do you catheterize him the first time? v. Arnim: Your last question first. This is very difficult to decide in a general way, you must always consider the cost and the benefit in each individual case. You cannot generally say that when 0.1 is reached the patient must go back to the catheterization laboratory. This would be too schematic an approach. You must not let yourself be forced into such a rigid pattern. Concerning the changes in comparison to other criteria of ischemia, such as PC pressure increase: It goes without saying that none of the methods available for ischemia diagnosis is 100% sensitive and specific. The ECG is not 100 percent, even if we use the 12 leads we will never see and recognize everything that happens in terms of ischemia, nor is the PC pressure rise. The more methods we can combine the more complete the picture we obtain will be. The question for the consequences of a diagnosis of silent ischemia: You must react in the same way as you react to a patient who says: "Now I am having pain." The ischemia is the same. In the studies we made with larger groups of patients we tried to compare in what respect the symptomatic episodes differ from the unsymptomatic ones. And with regard to the ischemia we did not find any difference, which means that if I see an ST segment change in such a patient this is a signal to me, the same as if he said: "Doctor, I feel a pressure in my chest", and what I'm doing then will go into the same direction, because it is the same disease, it is not a different disease, it is the same heart disease that we have to tackle according to the established rules of treatment.

Experimental findings on nitrate action E. Bassenge

Introduction The favorable effects of nitrate on ischaemic heart diseases are based chiefly on the singular distribution pattern of vascular dilations of varying intensities in various vascular segments. This special activity spectrum influences both coronary conductivity and myocardial preload and afterload in an anti-ischaemic way, thus reducing myocardial oxygen consumption and exerting an extremely favorable therapeutic impact. Some nitro vasodilators in addition inhibit the activation, adhesion, and aggregation of platelets [15, 21, 32].

Different nitrate effects on different vascular segments The special distribution of nitroglycerin-induced vascular reactions in various parts of the circulatory system, which is reponsible for the anti-ischaemic effect, is explained in Fig. 1 [2, 3], The diagram shows the steady-state effects of rising nitroglycerin concentrations on atrial pressure, coronary vascular lumen, peripheral resistance, and coronary-venous saturation as a measure of the dilation of the myocardial resistance vessels. At the lowest concentrations (0.5 ng/kg/ min) only the venous system (atrial pressure) and the coronary vessels are dilated. Only a ten times higher dose (5 ^ig/kg/min) finally also causes the peripheral resistance vessels to be dilated, thus initiating a decrease of afterload. After another fortyfold increase in concentration finally also the myocardial resistance vessels are dilated (with the hazard of a potential steal phenomenon developing). The therapeutic benefit of nitro vasodilators in treating ischaemic heart disease lies in the fact that dilating effects are produced on the low-pressure system, together with a reduction in preload, and on the large coronary vessels even before there is a reduction in peripheral resistance as a consequence of arteriolar dilation, which would result in an undesirable decrease of coronary perfusion pressure. Nitroglycerin 6 © 1989 Walter de Gruyter & Co. • Berlin • N e w York

50

E. Bassenge

A left atrial pressure [mmHg]

A coronary artery diameter

[pm]

Aperipheral resistance

[%]

m

A coronary 5 0 " venous 02-saturation [Ü2-sat-%] o -

0.2

0.5

20

50

200

nitroglycerin [pg/kg/min]

Fig. 1

Cardiovascular effects of increasing steady-state infusions of nitroglycerin in chronically instrumented conscious dogs. Ordinates from top to bottom: Effects on the left atrial pressure (filling pressure), coronary artery diameter, peripheral resistance, and coronary-venous 02-saturation as a measure of coronary arteriolar dilation. Mean values + standard deviation. Hatched sections show significant changes compared to control (p < 0.05). For further details, see text (modified from [2]).

Nitroglycerin and its derivatives thus act by reducing the myocardial preload and wall tension (and thus myocardial oxygen consumption) and by increasing the precollateral coronary perfusion pressure by dilating stenotic segments (improved oxygen transport). Dilation of the large coronary vessels on the whole improves coronary conductivity and appears to be much more important quantitatively than the simultaneous dilation of collaterals [16]. In addition, the reduction in ventricular filling pressure improves perfusion of the relatively under supplied subendocardial ventricular layers at the expense of the much better supplied subepicardial sections, i. e., it achieves the desired favorable redistribution of perfusion.

Experimental findings on nitrate action

51

Similarities in action of nitrovasodilators and endogenous endothelial EDRF (NO) dilator In the metabolism of smooth muscles, nitroglycerin is converted in various steps (as yet unidentified) into NO, which causes stimulation of soluble guanylatecyclase, a key enzyme in vascular dilation. The endogenous endothelium-derived relaxant factor (EDRF) [20] has also been identified chemically as a NO-radical [26]. EDRF is produced and released continuously by the vascular endothelium and influences the adjacent smooth vascular musculature in the sense of dilating it [5]. At the same time, it inhibits the attachment of thrombocytes to the vascular wall and their aggregation, respectively. Also this effect is mediated by a rise in the cGMP level (in this case the intrathrombocytic level). Organic nitrates, such as nitroglycerin, were discovered as vascular dilators by chance more than 100 years ago [11]. Only a few years ago it was demonstrated that they represent the therapeutic equivalent of an endogenous dilating system. In coronary heart disease, with atheromatosis and arteriosclerosis of the large coronary arteries, functional damage is caused to the endothelium, with the consequence of reduced EDRF release [5, 10, 18, 22, 36]. This raises the question how effectively nitroglycerin and its derivatives can be used to substitute the reduced production of EDRF in the affected segments under pathological conditions [6] so as to maintain an adequate state of dilation of the large coronary vessels and compensate for the constrictive agonists, which are more active when the protective endothelial function has been lost (e. g. serotonin and ATP from platelets activated on the vascular wall).

Intensified nitrovasodilator effect in vascular segments with intima lesions Nitroglycerin, a dilator independent of the endothelium, and its derivatives cause dilations of vessels both with intact endothelia and denuded of their endothelia. Surprisingly, dilation is clearly stronger in the segments with defective (denuded) endothelia [13, 28], This finding is shown in Fig. 2 (but applies just as well to a number of other dilator substances, also cAMP-dependent ones, such as PGI 2 or papaverine, though less strongly). It can in fact be stated that as yet uncalcified vascular segments with diminished endothelial function (achieved experimentally by endothelium denuding, pathophysiological^ in atheromatosis and arteriosclerosis) not only are clearly dilated by nitroglycerin, but that the loss of

E. Bassenge

52 Augmented response to GTN after endothelial damage

1800 1

INE E®

D

[p E® 14„„

GTN Fig. 2

4

4

0.1

0.3

4

4

1.0 3.0

uM

Increased sensitivity of vascular segments perfused in vitro with endothelia (E + ) and without endothelia (E~) under the cumulative administration of nitroglycerin (GTN) in the perfusate. D = outside diameter of the segments (NE = noradrenaline 3 x IO - 7 M).

endothelial function even enhances the effect of nitroglycerin. This surprising finding is probably explained by the fact that the presence of defects or functional disorders of the endothelium causes the continuous, permanent release of EDRF and thus the continued basal stimulation of guanylatecyclase to cease. This could well increase the sensitivity of the underlying smooth vascular musculature in the sense of an up-regulation, which could enhance not only the response to cGMP-induced phosphorylation processes with the corresponding dilations, but also the sensitivity of the dilation processes (occurring in parallel as a second relaxation mechanism in most smooth muscles) wholly or partly mediated by cAMP, for instance, after the administration of papaverine [23]. This is why nitroglycerin probably has a particularly strong dilating effect on those sites where, under pathological conditions, the dilation reactions to endogenous agonists are clearly diminished by atheromatous changes of the intima. This improvement in the coronary conductivity especially of diseased coronary segments could be the cause of another aspect of particular therapeutic benefit in the action of nitroglycerin. A clinical finding pointing in this direction was actually demonstrated recently in patients with coronary diseases: In a group of patients with relatively healthy coronary segments, clear coronary dilations were initiated with the endothelium-

Experimental findings on nitrate action

53

dependent stimulator, bradykinin. In the segments with the strongest dilations induced by intracoronary (i. c.) bradykinin, i. c. injections of nitroglycerin surprisingly showed a clearly weaker effect. Conversely, the group of patients with more strongly affected vascular segments — and, for this reason, not very pronounced endothelium-dependent bradykinin dilations — showed particularly strong vascular dilations initiated by i. c. nitroglycerin [30], These findings support the theory that endothelia predamaged by atheromatosis seem to exhibit stronger nitroglycerin-induced dilation also under clinical conditions. They also indicate that coronary conductivity can be improved by nitroglycerin precisely in those segments in which lesions or functional impairment of the endothelium have raised the coronary tone to its peak level and in which conductivity, which is already restricted pathologically, is diminished even further by additional "dynamic" and functional stenoses, respectively. Also more recent clinical findings point in the same direction, indicating that even minimal doses of nitroglycerin (0.025 mg i. v.), which did not cause any measurable venous pooling or reductions in blood pressure, did produce clear anti-ischaemic effects in a placebo-controlled double-blind study with exercise-induced ST-segment depression [33]. The same study showed that this minimal i. v. dose caused significant dilation, detectable by coronary angiography, in stenotic coronary vessels in the region of maximum stenosis, while the adjacent regions did not yet change their lumina [33].

Stimulation of EDRF (NO) release by the blood flow Also mechanical factors, such as the shear forces acting on the endothelium as the blood flow is increased, can enhance the release of NO from endothelial cells. Figure 3 shows that both an enhancement of flow [31] and the onset of highly pulsatile flows with rhythmic dilations of the vascular wall can lead to increased releases of EDRF (as can be seen from a dilation of the detector vessels in the bioassay) [27], The magnitude of the contribution made by hyperpolarization due to shear stress and an increase in K + -conductivity cannot yet be defined [25], This NO released continuously in larger or smaller quantities as a result of mechanical stimuli of varying intensities probably plays an important role in regulation. Under physiological conditions, the abluminally released fraction must maintain adequate dilation, while the luminally released part must maintain adequate anti-aggregation [12, 14]. Consequently, any reduction in this release under pathophysiological conditions is bound to affect both systems. Luminal EDRF release, with its anti-aggregating effect on platelets, is expressed in the fact that coronary perfusion with suspended platelets causes an observable

54

E. Bassenge Flow- and pulsatility-induced release of EDRF basal »

flowt

pulsatile flow

detector force

bioossay of a dilatory factor — redrawing — (Rubonyi et al 1986)

3g flow ml/min

detector 40 pm pulsatile/steady perfusion of the donor

Fig. 3

J - ^ ^ -

4 min

inhibition of the dilatory factor by Hbf-EQRF) —redrawing— (Pohl et al 1986)

Demonstration of EDRF-release and coronary dilation in a bioassay experiment by increasing the intensity of the blood flow and the shear force acting on the endothelium of the donor segment, respectively (upper half, in addition showing the relaxation of the detector coronary vessel ring), and with the onset of pulsatile perfusion with rhythmic dilation of the vascular wall of the donor segment and simultaneous relaxation of the detector segment (lower half)- The EDRF-inactivator, haemoglobin (Hb with arrow), suppresses dilation (modified from [27, 31].

multiple rise in intraplatelet cGMP-content even after only one passage, if the endothelium was stimulated, e. g. with acetylcholine, into releasing more E D R F [29]. This rise in the cGMP-content suppresses the C a + + - s i g n a l in the platelets, which must precede activation, release reaction, and aggregation. Substances spontaneously releasing NO, such as SNP and SIN-1, affect platelet function in the same way as E D R F does. On the other hand, organic nitrates, such as nitroglycerin, ISDN, ISMN, etc., are much less effective with platelets because these substances do not release NO spontaneously but only in a biological process occurring in smooth muscle cells and, to a minor extent, also in plasma [19], but not in platelets. These findings may be able to explain a vicious circle which can be startet by organic or functional stenoses in the coronary system (see Fig. 4): Reduction of the coronary blood flow and of the shear force stops the mechanically stimulated abluminal and luminal releases of E D R F . This further reduces the dilating and anti-aggregating potential in the large and, probably, also in the following smaller coronary vessels. The diminished anti-aggregating capacity results in intensified platelet activation associated with releases of constricting factors, especially if endothelial lesions

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NORMAL V E S S E L FLOW — E O R F - r e l e a s e (-0-) -dilation -antiaggregation FLOW LIMITING STENOSIS • FLOW

:

i EORF

- loss of dilation - loss of antiaggregation

DILATION OF STENOSIS t FLOW —

t EORF

- released from adjacent endothelium

Fig. 4

Potential inductions of a vicious circle with reduction in EDRF-release and resultant increase in coronary vessel tone and platelet aggregation as a result of the occurrence of functional and organic coronary stenoses. Top section: In a normal vessel, stimulation by the blood flow causes a continuous release of E D R F with sufficient dilation and anti-aggregation of the passing platelets. Central section: In the presence of a stenosis both limiting the flow and reducing the shear force, the release of E D R F is diminished and dilation is decreased both in the vicinity of the stenose and in the downstream distal vascular segments, i. e., there is a reduction in coronary conductivity. In addition, the anti-aggregation tendency is much less pronounced, thus facilitating platelet adhesion and thrombus formation. Bottom section: If the coronary flow is increased again by drug-induced or mechanical dilation (with a balloon catheter), this is followed by an intensified EDRF-release with enhanced dilation tendency and increases in the anti-aggregation potential in the coronary vascular system. If the flow is greatly reduced, a vicious circle may build up with increasing tendencies of constriction and thrombus formation. Improved flow can result in higher E D R F and NO-releases, respectively, and raise the potential for dilation and anti-aggregation (modified from [8]).

are present at the same time. Unless this circle is interrupted, it will finally end in infarction. The chain o f events can be interrupted only by mechanical (balloon catheter) or drug-induced c o r o n a r y dilation with a c o n c o m i t a n t increase in flow, in the wall shear force, in luminal and abluminal E D R F releases [4], in the thrombocytic c G M P - c o n t e n t , and in the anti-aggregating and vasodilating potentials.

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No loss of potency (tolerance) of NO (EDRF) produced in the endothelium Continuous permanent administration of nitroglycerin and its derivatives soon suffers from a loss of potency [34, 35], There is no loss of potency in vivo of endogenous NO and EDRF, respectively, released from the endothelium, for instance, during flow-induced dilation [35], This also holds true for NO-bearing dilator substances, such as sodium nitroprusside and SIN-1 [9, 24], which release NO directly, already extracellularly, without there having to be an upstream conversion step in the vascular muscle cell, as with nitroglycerin [17]. Also in vitro, vessels rendered tolerant to nitroglycerin show no loss of potency relative to EDRF (No), sodium nitroprusside, and SIN-1 [24]. The nitroglycerin tolerance evolving under clinically relevant doses therefore obviously is based on a limitation of an intracellular conversion step, not on a desensitization of soluble guanylatecyclase or cGMP-dependent mechanisms. Independently, a more or less pronounced pseudotolerance to nitroglycerin is observed under clinical conditions [1, 7, 34], i. e., a loss of potency due to the onset of counter-regulatory processes. They include the intensified activation of sympathico-adrenergic mechanisms [7, 34], of the renin-angiotensin-aldosterone system [1] with volume retention and presynaptic mechanisms. Appropriate blocker substances or antagonists can reveal these counter-regulatory mechanisms underlying pseudotolerance.

Summary The beneficial therapeutic effects of nitroglycerin and its derivatives are based on these factors: • Effects of different intensities on specific vascular segments. Veins and coronary arteries are much more sensitive than peripheral resistance vessels. In this way, the preload, size of the heart, myocardial wall tension, and oxygen consumption are decreased, while the 0 2 -supply is improved at the same time. • There are similarities with the endogenous, endothelially mediated cGMPdependent EDRF (NO) dilator system. This opens up the possibility of therapeutic substitution by nitro vasodilators. • There is a synergism with other endothelial local hormones (such as PGI 2 ), which can potentiate anti-aggregating effects. • Intensified effects are observed on segments with damaged and denuded endothelia and on atheromatous segments which, however, are still capable

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of expanding and dilating, respectively, i. e., on the very sites where there is an undesirably high tone of the coronary vessels in addition to a thicker intima.

Literature [1] Bacher, S., O. Kraupp, B. Stanek et al.: The effect of repeated intravenous and oral doses of molsidomine (N-carboxy-3-morpholino-sydnonimine-ethylester) on plasma renin activity and plasma catecholamine levels in conscious dogs. Basic Res. Cardiol. 78 (1983) 193-202. [2] Bassenge, E., D. J. Stewart: Effects of nitrates in various vascular sections and regions. Z. Kardiol. 75 (Suppl. 3) (1986) 1 - 7 . [3] Bassenge, E., K. Strein: Dose-dependent effects of isosorbide-5-mononitrate on the venous, arterial and coronary arterial system of conscious dogs. Naunyn-Schmiedebergs Arch. Pharmacol. 334 (1986) 100-104. [4] Bassenge, E., R. Busse, U. Pohl: Abluminal release and asymmetrical response of the rabbit arterial wall to endothelium-derived relaxing factor. Circ. Res. 61 (Suppl. II) (1987) II68-II73. [5] Bassenge, E., R. Busse: Endothelial modulation of coronary tone. Prog. Cardiovasc. Dis. 30 (1988) 349-380. [6] Bassenge, E., H. Gauch: Stellenwert von EDRF als Mediator der Gefaßregulation. Einfluß des Gefäßendothels auf den vaskulären Tonus und die Thrombozytenfunktion. Fortschr. Med. 106 (1988) 4 4 - 4 6 . [7] Bassenge, E., R. Grewe: Bases pharmacologiques de l'échappement thérapeutique. Presse Med. 17 (1988) 985-991. [8] Bassenge, E., D. J. Stewart: Interdependence of pharmacologically-induced and endothelium-mediated coronary vasodilation in antianginal therapy. Cardiovasc. Drugs 2 (1988) 2 7 - 3 4 . [9] Berkenboom, G., J. Fontaine, S. Degre: Persistence of the response to SIN1 on isolated coronary arteries rendered tolerant to nitroglycerin in vitro or in vivo. J. Cardiovasc. Pharmacol. 12 (1988) 345-349. [10] Bossaller, C., H. Yamamoto, P R . Lichtlen et al.: Impaired cholinergic vasodilation in the cholesterol-fed rabbit in vivo. Basic Res. Cardiol. 82 (1987) 396-404. [11] Brunton, T. L.: Amyl nitrite in angina pectoris. Lancet 2 (1867) 97. [12] Busse, R., E. Bassenge: Regulation des Gefaßtonus über das Endothel. Z. Kardiol. 74 (Suppl. 7) (1985) 99-106. [13] Busse, R., U. Pohl, E. Bassenge: Wirkung von Teopranitol auf den Tonus perfundierter Arterien und Venen in vitro. In: F. Bender, E. Gerlach (eds.): Therapie der koronaren Herzkrankheit mit Teopranitol, S. 33 — 43. Steinkopff Verlag Darmstadt 1986. [14] Busse, R., A. Lückhoff, E. Bassenge: Endothelium-derived relaxant factor inhibits platelet activation. Naunyn-Schmiedebergs Arch. Pharmacol. 336 (1987) 566 — 571.

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[15] De Caterina, R., D. Gianessi, W. Bernini et al.: Organic nitrates: direct antiplatelet effects and synergism with prostacyclin. Antiplatet effects of organic nitrates. Thromb. Haemostasis 59 (1988) 207-211. [16] Ertl, G., F. Simm, J. Wichmann et al.: The dependence of coronary collateral blood flow on regional vascular resistance. Studies with glyceryl trinitrate, adenosine and verapamil. Naunyn-Schmiedebergs Arch. Pharmacol. 308 (1979) 265 — 272. [17] Feelisch, M., E. Noak: Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase. Eur. J. Pharmacol. 139 (1987) 19-30. [18] Freimann, P. C., G. G. Mitchell, D. D. Heistad et al.: Atherosclerosis impairs endothelium-dependent vascular relaxation to acetylcholine and thrombin in primates. Circ. Res. 58 (1986) 783-789. [19] Fung, H.L., S. Chong, E. Kowaluk et al.: Mechanisms for the pharmacologic interaction of organic nitrates with thiols. Existence of an extracellular pathway for the reversal of nitrate vascular tolerance by N-acetylcysteine. J. Pharmacol. Exp. Ther. 245 (1988) 524-530. [20] Furchgott, R. F., J.V. Zawadzki: The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288 (1980) 373 — 376. [21] Gerzer, K., B. Karrenbrock, W. Siess et al.: Direct comparison of the effects of nitroprusside SIN 1, and various nitrates on platelet aggregation and soluble guanylate cyclase activity. Thromb. Res. 52 (1988) 1 1 - 2 1 . [22] Heistad, D. D., A. L. Mark, M. L. Marcus et al.: Dietary treatment of atherosclerosis abolishes hyperresponsiveness to serotonin: implications for vasospasm. Circ. Res. 61 (1987) 346-351. [23] Martin, W., R. F. Furchgott, G. M. Villani et al.: Phosphodiesterase inhibitors induce endothelium-dependent relaxation of rat and rabbit aorta by potentiating the effects of spontaneously released endothelium-derived relaxing factor. J. Pharmacol. Exp. Ther. 237 (1986) 539-547. [24] Mulsch, A., R. Busse, E. Bassenge: Desensitization of guanylate cyclase in nitrate tolerance does not impair endothelium-dependent responses. Eur. J. Pharmacol. 158 (1988) 191-198. [25] Olesen, S. P., D. E. Clapham, P. F. Davies: Haemodynamic shear stress activates a K + current in vascular endothelial cells. Nature 331 (1988) 168-170. [26] Palmer, R. M. J., A. G. Ferrige, S. Moncada: Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327 (1987) 524-526. [27] Pohl, U., R. Busse, E. Kuon, E. Bassenge: Pulsatile perfusion stimulates the release of endothelial autacoids. J. Appl. Cardiol. 1 (1986) 215-235. [28] Pohl, U., R. Busse: Endothelium-derived relaxant factor inhibits the effect of nitrocompounds in isolated arteries. Am. J. Physiol. 252 (1987) H307-H313. [29] Pohl, U., R. Busse, E. Bassenge: EDRF-induced augmentation of cGMP levels in platelets passing through the coronary vascular bed. Circulation 78 (Suppl. II) (1988) 11-182. [30] Rafflenbeul, W., E. Bassenge, P. R. Lichtlen: Competition between endothelium- and nitroglycerin-induced coronary vasodilation. Circulation 78 (Suppl. II) (1988) 11-455.

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[31] Rubanyi, G. M., J . C. Romero, P. M. Vanhoutte: Flow-induced release of endothelium-derived relaxing factor. Am. J . Physiol. 250 (1986) H 1 1 4 5 - H 1 1 4 9 . [32] Schröder, H., K. Schrör: Organische Nitrate und Thrombozytenfunktion. Hämostaseologie 8 (1988) 9 0 - 9 9 . [33] Sievert, H., G. Kober, W. Schneider et al.: Antianginöse und koronardilatierende Wirkung von niedrig dosiertem Nitroglycerin. Z. Kardiol. (1989, in press). [34] Stewart, D. J., D. Eisner, O. Sommer et al.: Altered spectrum of nitroglycerin action in longterm treatment: nitroglycerin-specific venous tolerance with maintenance of arterial vasodepressor potency. Circulation 74 (1986) 573 — 582. [35] Stewart, D . J . , J. Holtz, E. Bassenge: Long-term nitroglycerin treatment: effect on direct and endothelium-mediated large coronary artery dilation in conscious dogs. Circulation 75 (1987) 8 4 7 - 8 5 6 . [36] Verbeuren, T. J., F. H. Jordaens, L. L. Zonnekeyn et al.: Effect of hypercholesterolemia on vascular reactivity in the rabbit. I. Endothelium-dependent and endothelium-independent contractions and relaxations in isolated arteries of control and hypercholesterolemic rabbits. Circ. Res. 58 (1986) 552 — 564.

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Discussion

Roskamm: Let us now discuss the paper. I would like to ask you, however, to leave out the tolerance aspect, because I think it will also be covered by Mr. Jahnchen and we may be able to discuss the tolerance problem after his paper. Kukovetz: Mr. Bassenge, you showed this picture of vascular strips or rings with damaged endothelia or no endothelia at all, or what was that? Bassenge: In perfused segments. Kukovetz: Do you achieve much stronger nitroglycerin relaxation in segments denuded of their endothelia than in those still having endothelia? And do you have an explanation? Bassenge: Our finding has been confirmed in the meantime also by Mr. Forstermann and by various other groups who redid the same experiments. The likely explanation is that the basal stimulation by EDRF is absent in these segments and that applying nitroglycerin as a substituent produces a relatively more intensive stimulation of the non-prestimulated system. This has been shown very nicely by Messrs. Pohl and Busse: If a denuded vessel is fed the right amounts of EDRF, the enhanced sensitivity to nitroglycerin disappears again. Roskamm: Mr. Rafflenbeul, is this also in agreement with your findings? Most probably, you measured the dilation capability in stenotic regions as well as in areas of apparently normal vessels. Rafflenbeul: The picture of the coronary angiography findings shown by Mr. Bassenge was about vessels with arteriosclerotic changes, which had no severe stenoses and thus appeared on the angiogram as arteriosclerosis, but not as local or focal constrictions. One does see the different responses to bradykinin of these arteriosclerotic vessels. Bradykinin is a dilator independent of the endothelium which, obviously, is clearly dependent on the state of the endothelium! If one then adds nitro one sees a different reaction, depending on whether the endothelium is still there functionally or not. So, these were no stenoses but, in fact, only coronary vessels changed diffusely, not locally. Bassenge: Nor has it been proved that these sites were in fact denuded of their endothelia or were not intact functionally; that can only be concluded from the bradykinin reactions, which were very clear and very strong in these vascular segments, while they were absent in the other segments, i. e., in the second (control) group.

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Sander, Münster: I was surprised to hear you equate EDRF with the NO-radical, for the group of Rubanyi and Vanhoutte believed they had demonstrated in a certain bioassay experiment that there may be more substances which, in their overall effect, correspond to EDRF. So, let me ask you a question: When you refer to the interaction between nitroglycerin and EDRF, are you saying that the EDRF-production can also be provoked by nitroglycerin or are you only saying that there is an interaction between them? Bassenge: No, you cannot provoke an EDRF-release by nitroglycerin. Nitroglycerin must first be converted into an NO-bearing stimulator substance in a number of intracellular conversion steps, which substance then stimulates guanylatecyclase (a key enzyme of dilation). With certain restrictions, nitroglycerin may be considered to be a substituent. Sander, Münster: Does that mean, only synergistically? Bassenge: Could be; they are very similar in action because they both have NO as the active group. Also the group of Feelisch and Noack was able to show that nitroglycerin (in the presence of cysteine) releases just as much NO as it activates guanylatecyclase. As far as your question about EDRF is concerned: Acetylcholine probably releases one or more other substances, for instance, an endotheliumderived hyperpolarizing factor; however, these details are less important at this point. One can surely say, however, that EDRF is an NO-bearing substance with this NO bound as the active group. It is probably bound to a protein; there are good indications to this being so. This NO is released from 1arginine in endothelial metabolism. The production of NO can be improved, for instance, by administering 1-arginine, but it can also be suppressed by "antagonists" (in which the arginine is replaced by a very similar molecule).

Clinical pharmacological aspects of nitrate therapy in the treatment of unstable angina pectoris E. Jàhnchen

Introduction On account of their antiischemic effect organic nitrates are part of the standard therapy of angina pectoris. In the treatment of hospitalized patients with unstable angina glyceryltrinitrate (GTN) is used in most cases because it is rapidly eliminated and therefore easy to control, thus allowing titration of the hemodynamic effect. Among the galenic forms of GTN available it is especially intravenous infusion and the sublingual route of administration which are of importance. Therefore biopharmaceutical and pharmacokinetic aspects of intravenous and sublingual GTN will be dealt with first, then the question of tolerance to GTN after continuous intravenous supply will be discussed and, finally, some relevant interactions with other drugs will be described.

Biopharmaceutical and pharmacokinetic aspects of intravenous and sublingual GTN In view of the short half life of nitroglycerin (about 2 to 4 minutes) steady-state concentration in the plasma is reached in about 10 to 15 minutes after intravenous infusion with a linear correlation between the rate of infusion and the steadystate plasma concentration [24]. Nitroglycerin elimination occurs as a result of stepwise denitration and conversion to dinitrates (1,2-GDN and 1,3-GDN) and mononitrates (1-GMN and 2-GMN). These metabolites are excreted predominantly as glucuronic acid conjugates or after complete denitration to form glycerin which becomes part of the carbohydrate metabolism [20], The denitration of the metabolites occurs more slowly than the denitration of GTN. This is also reflected by the difference in elimination half life of GTN and metabolites which is about 3 minutes for GTN, about 50 minutes for the dinitrates and 150 minutes for the mononitrates. After intravenous infusion the concentrations of Nitroglycerin 6 © 1989 Walter de Gruyter & Co. • Berlin • New York

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1,2-GDN are about 5 times as high as those of GTN [13], whereas the concentrations of 1,3-GDN are somewhat lower than the GTN concentrations. It has not yet been clarified whether the metabolites contribute to GTN efficacy. On the basis of animal experiments the dinitrates have about 10% of the antihypertensive effect of the parent substance so that after intravenous infusion the metabolites may not have any major contribution to the effect. In GTN intravenous therapy allowance has to be made for the fact that GTN is adsorbed to infusion bottles, infusion tubings, filter membranes and other plastic material. The adsorption depends on the materials used, their surface characteristics and the flow rate [3]. The loss caused by adsorption to infusion tubings made of polyvinylchloride is bigger than the adsorption to materials such as glass or polyethylene. In the case of PVC losses of more than 50% of the dose may occur during the first hour of infusion, especially if low flow rates are used [2], It has so far been assumed that after sublingual administration of GTN the systemic availability is almost 100%. However a systematic trial with 8 healthy subjects has shown that, on an average, bioavailability only amounts to 36%, whereby very big differences between individuals were observed [13]. Some findings also indicate that bioavailability may differ according to galenic preparation [17], Therefore significant inter-individual and intra-individual differences in action are to be expected after sublingual administration.

Induction of tolerance after continuous intravenous infusion There is no doubt today that the hemodynamic effects of long-acting nitrates is attenuated after continous oral therapy [1], As far as nitroglycerin is concerned, this phenomenon became apparent for the first time when transdermal therapeutic systems (nitrate patches) were used and a loss of efficacy was observed already within the first 24 hours after application despite continuous maintenance of plasma concentrations. Whether intravenous supply also leads to a decline in efficacy was unclear for a long time. It was assumed, i. a., that the loss of efficacy would be less pronounced because of the much higher plasma concentrations obtained by this route of administration. Recent studies have shown that both in patients with heart failure [4, 15] and in patients with exerciseinduced angina [18, 24] a decline and, finally, loss of the hemodynamic effects of nitrates,occurs within the first 24 and 48 hours, respectively. In 17 of 24 patients with heart failure, a complete loss of the initial hemodynamic efficacy of GTN was observed after continuous infusion of 6.4 mg/kg/minute

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for 48 hours. In seven patients the hemodynamic efficacy of GTN was attenuated, not completely lost, after 48 hours. If, however, the same therapy was used intermittently (i. e. 12 hours of infusion followed by 12 hours without infusion) no decline in efficacy was observed after 48 hours [15]. The induction of tolerance in those patients was accompanied by an increase in plasma renin activity, heart rate and body weight. Twenty-four hours after termination of infusion responsiveness was restored. Similar results were published by Elkayam et al. [4]. The authors infused rising doses of GTN in patients with ischemia-induced heart failure up to previously determined therapeutic end points (30% reduction in pulmonary capillary pressure). The rate of infusion determined on this basis was then maintained for 24 hours. In this trial 7 of the 15 patients treated showed a loss of efficacy after 12 hours of infusion, whereas in the other 8 patients the effect on the pulmonary capillary pressure was maintained over 24 hours. In patients who had developed complete tolerance a lower mean systemic peripheral resistance was found; all other hemodynamic parameters were not different. Tolerance to nitroglycerin evidently develops not only with regard to its peripheral hemodynamic effects but could also be detected in patients with coronary heart disease as far as its direct coronary vasodilating effect (measured on the basis of the increase in coronary sinus blood flow) was concerned. Thus after a 24 hour infusion of 45 |ag/min. of GTN on an average, the effect of intracoronary bolus doses of nitroglycerin was reduced to about half of the preinfusion value [11]. Tolerance to intravenous GTN was found to develop also to the antianginal effect in patients with stable angina [24], The authors found that the initial increase in exercise tolerance induced by GTN could no longer be detected 8 hours after beginning of infusion. Other hemodynamic effects, however, measured at the same time, were less strongly diminished. Other authors [18] stated an essential loss of the hemodynamic and antiischemic effects (assessed on the basis of ST segment depression) after 24 hours of GTN infusion (50 (ig/minute). These results show that after continuous GTN infusion patients develop a tolerance to the hemodynamic and antianginal action of GTN. Such trials, however, have so far been made in patients with stable angina pectoris and/or heart failure. No results are available with regard to the induction of tolerance in patients with unstable angina. The reason might be that in patients presenting with this syndrome quantitative results are difficult to obtain due to the rapid changes in complaints and the necessity of applying combination therapy. As long as there is no valid conformation of the fact that the therapeutic efficacy of GTN in such patients is caused by other possible effects of organic nitrates

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(such as inhibition of platelet aggregation, stimulation of vasodilative prostaglandins, improvement of blood flow characteristics), a decrease in efficacy must also be expected in the treatment of unstable angina.

Interactions of glyceryltrinitrate with other drugs Long-acting nitrates The problem of cross tolerance to other organic nitrates was judged differently for many years. Most experts held the view that sublingual GTN remains effective despite the decline in efficacy of long-acting nitrates administered orally. Meanwhile cross tolerance between the various organic nitrates has been clearly established in patients with heart failure [15], in patients with stable angina [24] and in studies using healthy subjects [21]. Thus in patients with heart failure who developed a hemodynamic tolerance to intravenous GTN, the effect of orally administered isosorbide dinitrate (40 mg) was also virtually eliminated [15]. In patients with stable angina the attenuated effect of intravenous GTN on exercise tolerance was associated with an essential loss of efficacy of sublingual GTN (0.4 mg) [24], Moreover, subjects taking 30 mg of isosorbide-5-mononitrate every 8 hours showed a complete loss of hemodynamic efficacy of isosorbide-5-mononitrate and of 0.8 mg of sublingual GTN on the fifth day of treatment [21],

N-acetylcysteine In a number of trials N-acetylcysteine was administered with the idea of replenishing the pool of tissue thiols (which is depleted in a state of tolerance) by exogenic supply of SH groups and of reversing tolerance in this way. It was proved convincingly in several studies that high doses of N-acetylcysteine (7 g i. v. or 14 g per os) can partly reverse the tolerance induced by continuous infusion of GTN with regard to its effect on coronary sinus blood flow [11] and the hemodynamic efficacy in patients with heart failure [15]. However, this effect seems to last only for a short period (1 to 2 hours after administering Nacetylcysteine). Besides, N-acetylcysteine potentiates the acute vasodilating effect of GTN both in the peripheral [6] and in the coronary vessels [23]. After administration of methionine, an amino acid which is converted to cysteine in

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the body, a potentiation of the acute GTN effect on arterial blood pressure and pulmonary capillary pressure was also reported [9]. The clinical relevance of a combined therapy of nitroglycerin and N-acetylcysteine was investigated in patients with unstable angina pectoris [6]. In a doubleblind placebo-controlled experimental design 24 patients received an intravenous GTN infusion and, in addition, a short infusion of N-acetylcysteine (5 g every 6 hours for the trial period of 24 hours), and 22 patients received intravenous GTN and a placebo infusion every 6 hours. The GTN infusion started with an initial flow rate of 5 |ig/min. and then gradually doubled according to clinical requirements (persistent severe angina or systolic blood pressure above 140 mm Hg). With regard to the major study end points (number of ischemic episodes and number of increases in rate of infusion) there were no statistically significant differences between the two groups. However, the event rate of acute myocardial infarctions was significantly lower (3/10) and the incidence of symptomatic hypotension higher (7/19) in the group of patients treated with N-acetylcysteine. These results lead to the assumption that in patients with unstable angina the incidence of myocardial infarction is reduced by a combined GTN and Nacetylcysteine therapy, but this effect is accompanied by a higher risk of symptomatic hypotension. The hypotensive events usually occurred 30 to 60 minutes after the short infusion of N-acetylcysteine. In the authors' opinion they might possibly be prevented by a dose reduction or by continuous N-acetylcysteine infusion. This surprising result could be due, on the one hand, to a more effective antiischemic action of this drug combination (potentiation of GTN action and delay in tolerance induction) and on the other hand, to a more effective inhibition of platelet aggregation, N-acetylcysteine was reported to potentiate the inhibiting effect of nitroglycerin on platelet aggregation possibly by forming S-nitroso-Nacetylcysteine [10]. The inhibitory effect of nitroglycerin itself seems to be dependent on the availability of sufficient intracellular reduced SH groups. This availability is diminished by the treatment with GTN and restored by the addition of N-acetylcysteine [19]. It remains to be seen whether trials made on a broader basis will corroborate these encouraging findings.

Acetylsalicylic acid Acetylsalicylic acid is a frequent concomitant medication for patients with unstable angina. There are indications that the vasodilative effect of the nitrates is at least partially due to an increased release of vasodilative prostaglandins [7]. That release can be reduced or blocked by substances which inhibit prostaglandin synthesis. Theoretically, the vasodilative effect of the nitrates could thus be reduced by the simultaneous supply of acetylsalicylic acid. Studies in which an

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analgesically effective dose of acetylsalicylic acid (1 g) and an platelet aggregation inhibiting dose (500 m g every other day) was used rather showed an enhancement of the h e m o d y n a m i c effect of sublingual G T N , especially after giving the high dose of 1 g [22]. T h e reason m a y be the pharmacokinetic interaction with the elimination of G T N leading to an increase of G T N plasma levels and thus to greater efficacy. For the aggregation inhibiting dose, however, this enhancement was only a discrete one and of no therapeutic relevance. In trials with healthy subjects the h e m o d y n a m i c effect of sublingual nitroglycerin was n o t essentially influenced by prior supply o f 650 m g o f acetylsalicylic acid [8].

Heparin Some authors have reported a weakening of the heparin effect by simultaneous intravenous supply of G T N [5], The mechanism of this interaction remaines unclear.

Literature [1] Abrams, J.: Tolerance to organic nitrates. Circulation 74 (1986) 1181 — 1185. [2] Cawello, W., R. Bonn: Bioverfügbarkeitseinflüsse durch die Wahl des Infusionsmaterials bei der Therapie mit Nitroglycerin. Sanol-Schwarz G m b H , Abteilung Pharmakokinetik, Mittelstr. 11 —13, 4019 Monheim. [3] Elliot, G. T., S. L. Quinn: Nitroglycerin intravenous infusion. Drug Intell. clin. Pharm. 16 (1982) 211. [4] Elkayam, U., D. Kulick, N. Mcintosh et al.: Incidence of early tolerance to hemodynamic effects of continuous infusion of nitroglycerin in patients with coronary artery disease and heart failure. Circulation 76 (1987) 577 — 584. [5] Habbab, M. A., J. J. Haft: Heparin resistance induced by intravenous nitroglycerin. Arch. Intern. Med. 147 (1987) 8 5 7 - 8 6 0 . [6] Horowitz, J.D., C. A. Henry, M. L. Syrjanen et al.: Combined use of nitroglycerin and N-acetylcysteine in the management of unstable angina pectoris. Circulation 76 (1988) 7 8 7 - 7 9 4 . [7] Levin, R. I., E. A. Jaffe, B. B. Weksler et al.: Nitroglycerin stimulates synthesis of prostacyclin by cultured human endothelial cells. J. Clin. Invest. 67 (1981) 762 — 769. [8] Levin, R. I., F. Feit: The effect of aspirin on the hemodynamic response to nitroglycerin. Am. Heart. J. 116 (1988) 7 7 - 8 4 . [9] Levy, W. S., R. J. Katz, R. L. Ruffalo et al.: Potentiation of the hemodynamic effects of acutely administered nitroglycerin by methionine. Circulation 78 (1988) 640 — 645. [10] Loscalzo, J.: N-Acetylcysteine potentiates inhibition of platelet aggregation by nitroglycerin. J. Clin. Invest. 76 (1985) 7 0 3 - 7 0 8 .

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[11] May, D.C., J.J. Popma, W.H. Black et al.: In vivo induction and reversal of nitroglycerin tolerance in human coronary arteries. N. Engl. J. Med. 317 (1987) 805-809. [12] Noonan, P. K., L. Z. Benet: Incomplete and delayed bioavailability of sublingual nitroglycerin. Amer. J. Cardiol. 55 (1985) 184-187. [13] Noonan, P. K., L. Z. Benet: Variable glyceryl dinitrate formation as a function of route of nitroglycerin administration. Clin. Pharmacol. Ther. 42 (1987) 273 — 277. [14] Noonan, P. K., R. L. Williams, L. Z. Benet: Dose-dependent pharmacokinetics of nitroglycerin after multiple intravenous infusions in healthy volunteers. J. Pharmacokin. Biopharm. 13 (1985) 143-157. [15] Packer, M., W. H. Lee, P. D. Kessler et al.: Prevention and reversal of nitrate tolerance in patients with congestive heart failure. N. Engl. J. Med. 317 (1987) 799-804. [16] Pizzulli, L., U. Köhler, J. Nitsch et al.: Arzneimittelinteraktion zwischen Glyceroltrinitrat und Heparin. Z. Kardiol. 77 (1988) 83. [17] Sanders, S.W., K. Michaelis, J.M. Maurette et al.: Relative bioavailability of two spray formulations of nitroglycerin. J. Pharm. Sei. 75 (1986) 244 — 246. [18] Schneider, W., U. Kett, M. Kaltenbach: Antiischämische Wirkung einer 24stündigen kontinuierlichen Infusion mit Glyceryltrinitrat bei Patienten mit stabiler Angina pectoris. Dtsch. med. Wschr. 113 (1988) 543-547. [19] Stamler, J., M. Cunningham, J. Loscalzo: Reduced thiols and the effect of intravenous nitroglycerin on platelet aggregation. Am. J. Cardiol. 62 (1988) 377 — 380. [20] Taylor, T., I.W. Taylor, L. F. Chasseaud et al.: Pharmacokinetics and metabolism of organic nitrate vasodilators. In: I. W. Bridges, L. F. Chasseaud, G. G. Gibson (eds.): Progress in Drug Metabolism, Vol. 10, pp. 207 — 336. Taylor & Francis, London, New York, Philadelphia 1987. [21] Wagner, F., F. Siefert, E. Jähnchen: Relationship between plasma concentrations and hemodynamic tolerance to isosorbide-5-mononitrate. Naunyn-Schmiedeberg's Arch. Pharmacol. 335 (Suppl.) (1987) R 105. [22] Weber, S., E. Rey, C. Pipeau et al.: Influence of aspirin on the hemodynamic effects of sublingual nitroglycerin. J. Cardiovasc. Pharmacol. 5 (1983) 874 — 877. [23] Winniford, M. D., P. L. Kennedy, P. J. Wells et al.: Potentiation of NTG-induced coronary dilatation by N-acetylcystein. Circulation 73 (1986) 138 — 142. [24] Zimrin, D., N. Reichek, K.T. Bogin et al.: Antianginal effects of intravenous nitroglycerin over 24 hours. Circulation 77 (1988) 1376-1384.

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Discussion

Roskamm: Thank you very much, Mr. Jahnchen. Axe there any questions? We would like to focus on the tolerance problem now. Kukovetz: Mr. Jahnchen, you already mentioned it: The mechanism of tolerance is, as we believe, still unclear at the molecular level, but I was pleased to hear about the N-acetylcysteine trials you have shown which correspond to those made by Horowitz and to our own findings on isolated low-purity and highpurity enzyme, i. e. that we can induce tolerance in all these models. In connection with the guanylate cyclase this corresponds to a desensitisation of the enzyme as shown by the Murat group. This phenomenon can be avoided by preincubation with N-acetylcysteine. We believe, if I may draw this conclusion, that, in the final analysis, tolerance is essentially due to the inactivation of the guanylate cyclase. Jahnchen: Clinical studies are usually not the proper means for investigating the mechanism of action at the molecular level. The most important question for the clinician is that of therapeutic efficacy. There is no doubt that in the case of organic nitrates the effect is attenuated or completely lost with increasing duration of supply irrespective of the mechanism responsible for this. Klaus: Well, I have difficulties understanding your last remark, Mr. Kukovetz, because Mr. Jahnchen indicated at the end of his presentation that the tolerance phenomenon can be reversed by simply increasing the dose, and how does this agree with your idea that a desensitisation of the guanylate cyclase could do this? How could we then by increasing the nitrate dose still get an effect? One would expect that in the end somehow this would not be effective at all any more. And the basic phenomenon is, in fact, that with all isolated vascular preparations the maximum effect is restored by simply increasing the dose. The dose-effect curve is only shiftet to the right, and the whole system can again be made more sensitive by giving cysteine or other SH group donators. This, however, is only one partial aspect, but the basic phenomenon is that the increase in the nitrate dose causes a relaxation in the completely tolerant vessel. Jahnchen: Clinicians and experimental pharmacologists may define tolerance differently. A shift to the right of the dose-effect curve by a factor of 10 on the isolated vascular preparation would be called an attenuation of action, whereas

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in a clinical situation we speak of complete tolerance. It is difficult to justify that the initial efficacy can be restored by a ten-fold increase in dose. Klaus: I didn't want to comment on the clinical aspect of tolerance, Mr. Jähnchen, but rather on the explanation of the basic mechanism which I simply cannot understand if what Mr. Kukovetz said was true, i. e. that tolerance develops on this basis, when, by simply increasing the dose, you can restore efficacy. Kukovetz: This is quite correct, Mr. Klaus, we do get a clear shift of the doseeffect curve to the right with the same peak. The explanation for this would include the explanation of the molecular basis for induction of tolerance which we don't have. But one possible explanation may be offered by the work of Mr. Böhme who has shown that the enzyme comprises four SH groups that can be activated but whose activation, if continuous, will gradually lead again to enzyme inactivation. What is really going on is unknown. Perach: Let me add a clinical observation. We very often make the observation that small increases in dose, say from 3 to 4 or 5 mg, actually reverse a shift in curve. But there also are those cases, and I have had them — unfortunately, I must admit — three times in succession recently, where, due to wrong perfusor adjustment, as much as 99 mg was infused within 45 minutes without anything happening — neither a decline in pressure nor an increase in heart rate. And this happened 3 times within 5 months. Jähnchen: In a state of complete tolerance even a 50 to lOOfold increase in dose may be without any effect. On the other hand there are, also initially, big interindividual differences in response to nitroglycerin. Thus, for instance, in congestive heart failure with severe peripheral edema efficacy is diminished. And there are healthy persons in whom a dose of 0.8 mg of sublingual nitroglycerin remains completely ineffective. The causes for this are mostly unknown.

Practical experience and success with nitrate therapy for unstable angina pectoris W.-D. Bussmann

Introduction The optimum therapy of unstable angina is based upon the understanding of the underlying pathophysiology. We distinguish between stable angina pectoris which is to be considered invariable and exercise dependent and unstable angina pectoris which is new, also occurs at rest more and more frequently or upon moderate physical exercise, usually lasts for prolonged periods, sometimes for more than 30 minutes.

Course As an example take the case of a 72 year old woman who for four years has had angina pectoris when walking up 3 flights of stairs. Now she has been unstable for 2 days. Angina occurs in the morning already when she washes herself. In addition, every morning around 5 and 7 she suffers two prolonged attacks. She received conservative drug therapy and was stable again 3 days later. Stable means that after 3 days anginal attacks again occurred only after the physical exercise of climbing 3 flights of stairs. Another example is a 67 year old man with a history of coronary heart disease but very few symptoms. He has been unstable for 8 hours. One anginal attack lasted for more than 30 minutes. The ECG shows an ST segment depression. Nitrates, calcium antagonists and acetylsalicylic acid are given, and because of the ST segment depression in the exercise ECG he gets an additional intravenous thrombolysis therapy. Thereafter the patient is stable again. The course of unstable angina is characterized by the following possibilities: Either there is spontaneous stabilisation after 3 to 5 days probably as a result of endogenic lysis which by that time has dissolved the partially occluding Nitroglycerin 6 © 1989 Walter de Gruyter & Co. • Berlin • New York

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thrombus in the coronary vessel, or there is consolidation and remission of complaints. A non-transmural infarction may remain. The third possibility is that instability develops into a definitive myocardial infarction.

Causes When asking for the causes of sudden instability, a number of different answers may be given. There may be a new episode of coronary sclerosis, or the intima breaks in the stenosis itself. Another cause may be a severe coronary spasm with a constrictive effect on an existing stenosis. Often thrombocytes accumulate and form aggregates in the stenotic region and thus narrow the lumen up to the point of mural thrombus formation or intermittent thrombotic occlusion of the vessel.

2. Increased Local a - (or Vasoconstrictor) Receptor Density or Sensitivity 3. Eccentrically Narrowed Lumen With High T:R Ratio

Fig. 1

Cross section of a stenosed coronary artery. On the left there is a large arteriosclerotic plaque, on the right the residual lumen. The increased sympathetic innervation of this short segment of the vessel and the high density of alpha (i. e. vasoconstrictor) receptors are of special importance. Following intima rupture mural thrombi may form which intermittently occlude the whole of the lumen. Due to vasoconstriction the lumen is narrowed even further.

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Figure 1 shows the cross section of the stenotic segment of the vessel. The markedly increased sympathetic innervation of this segment and the density of alpha constrictor receptors are characteristic of a strong tendency towards vasoconstriction. As normal endothelial areas are missing in the stenotic region, a drastic reduction in endothelium-derived ralaxing factors (EDRF) is to be expected. Often a mural thrombus will be found which may rapidly grow in size. It can occlude the whole of the vessel at least intermittently.

Therapeutic concept In analogy to the pathophysiological findings, the therapeutic concept of unstable angina pectoris is therefore characterized by the following three points: 1. Drug-induced dilation of the stenosis 2. Prevention of further thrombocyte aggregates 3. Dissolution of the thrombus. Medication is used accordingly. Nitrates are the most important drug therapy. We give intravenous nitroglycerin for 24 hours followed by oral nitrate therapy of 3 x 20 mg of isosorbide dinitrate or isosorbide-5-mononitrate. Invariably this is combined with a calcium antagonist, be it gallopamil, verapamil or diltiazem. The gallopamil dose is 3 x 50 mg, the verapamil dose 3 x 120mg and the diltiazem dose 3 x 60 mg. Nifedipin is hardly used any more because of its heart rate increasing and strong hypotensive effects. Another important therapeutic component is the administration of acetylsalicylic acid at a dose of 300 to 1000 mg/day. Several recent studies have shown that even low doses of 100 to 300 mg assure adequate protection against recurrent platelet aggregates and thrombus formation in the vessel. If there are signs of ischemia in the ECG, additional lysis therapy can be used either with streptokinase, urokinase or tissue plasminogen activators (TPA).

Nitrate action The mechanism of action of nitrates is seen in a different light today. It is primarily the dilation of the constricted coronary vessel segment that is of importance because this means an immediate improvement of the blood flow to

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the ischemic region. Even very small nitrate doses lead to a dilation of the coronary stenosis and to an improved blood flow (Fig. 2). Dilation of the venous system and reduction of congestion, and thus of left ventricular filling pressure, are only secondary considerations. The dilation of the arterioles and the resulting reduction in blood pressure and peripheral resistance as a relief mechanism for the left ventricle are coming third. This particular mechanism only becomes effective at higher nitrate doses. The change in the sequence of importance of nitrate action is significant in as far as it was thought in the past that the essential mechanism leading to the antiischemic effect of this substance was the reduction in preload and afterload. Antianginal effect of minimum nitroglycerin doses 0.025 mg i.v.

Fig. 2

Double-blind randomized comparison of the effect of 0.025 mg of intravenous nitroglycerin and placebo.

In 1981 already Feldman et al. could prove that a dose of 0.4 —0.8 mg of sublingual nitroglycerin leads to a marked dilation of coronary artery stenosis [2], They especially emphasized the dilation of high-grade stenoses. In this case the cross-sectional area increases by 36% leading to a 100 — 200% blood flow improvement. It can indeed be proved that high-grade stenoses can be considerably dilated by nitroglycerin and that concentric stenoses also respond well to nitroglycerin after sublingual, intravenous or intracoronary administration (Fig. 3). In three vessel disease many stenoses are dilated and, as a result, the clinical situation often

Fig. 3

Eccentric and high-grade stenosis before (upper part) and after (lower part) intracoronary nitroglycerin. Dilation of the stenotic segment also leads to better blood supply to the peripheral vascular region. The picture shows the right coronary artery.

improves dramatically. In previous studies [1, 7] on low-dosage nitroglycerin we were able to show that an injection of 0.025 mg of nitroglycerin regularly causes a reduction of ischemic reactions in the exercise ECG. In a recent double-blind study comprising 40 patients [8] it could be proved that intravenous administration of a minimum nitroglycerin dose of 0.025 mg does not cause dilation of normal coronary vessels, but that a significant increase in the diameter of the stenosis can be observed (Fig. 4). Minimum nitroglycerin doses dilate coronary stenosis. They do not cause changes in blood pressure, heart rate and filling pressure.

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Diameter of stenosis 2

j-pcO.Ol i

• n. s.

SD

mm

1 -

before

Fig. 4

after

before

after

Placebo iv

Nitroglycerin

n = 20

n = 20

0.025 mg iv

Left: No effect on normal vascular segments. Right: Significant dilation of coronary stenosis. Simultaneous changes in blood pressure, heart rate and left ventricular filling pressure do not occur.

Tolerance to nitrates Recently our understanding of the decrease in efficacy or induction of tolerance has improved thanks to a number of studies, and different findings can now be more easily interpreted. Thus, trials with transdermal nitrate have shown that an effect can be observed in the first 8 to 12 hours, but that thereafter antianginal action does no longer exist as a result of consistent plasma levels. This led to the conclusion that nitrates should be given as a discontinuous, not a continuous, therapy. Chronic nitrate therapy can best be described by the consecutive sequence of acute effects. As Schneider et al. were able to show, the antianginal action is also weakened when nitroglycerin is given intravenously for 24 hours

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[5], Whereas initially, i. e. after 90 minutes, a clear reduction of ischemic response was observed, this effect had decreased considerably after 24 hours. Nevertheless, Schneider et al. could prove in another study that also with a daily dose of 3 x 40 mg of isosorbide dinitrate the chronic effect decreases only slightly compared to the acute effect [6]. On the whole, the findings with regard to tolerance to nitrate lead to the conclusion that nitrate treatment of an angina pectoris patient over a period of 24 hours can no longer be considered realistic. Especially in the treatment of unstable angina additional drugs must be used.

Concomitant medication In this context calcium antagonists play an important role as concomitant medication. They too have a clearly spasmolytic effect on the coronary arteries which, although being weaker than the effect of nitrates, still is adequate for providing sufficient antianginal protection at night. The calcium antagonists of the verapamil and diltiazem type are particularly useful in this respect. In Frankfurt we have used verapamil, gallopamil and diltiazem in the last few years. With both substances we reach a 50% reduction in ischemic response. According to studies by Hopf et al., heart rate will increase under nifedipin after physical exercise, whereas calcium antagonists, such as verapamil and gallopamil, cause a marked reduction in heart rate as compared to placebo [4]. Besides, ischemic response is considerably more diminished under gallopamil or verapamil than it is under nifedipin. In patients with vasospastic angina pectoris no differences in efficacy were found in double-blind comparative studies with nifedipin and isosorbide dinitrate, so that a special indication of nifedipin in the management of vasospastic angina does no longer exist [3].

Summary In the treatment of unstable and stable angina pectoris nitrates are to be used as drugs of first choice and basic therapy. Initially a medium dose should be used, increase in dose is effective. By intermittent therapy, i. e. no nitrates at night, a lasting antianginal effect can be obtained. In the nitrate-free interval

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calcium antagonists are required as concomitant medication. The mode of action of nitroglycerin and nitrates primarily consists of coronary dilation in the state of stenosis. Nitrates are useful for all forms of angina pectoris.

Literature [1] Bussmann, W.-D.: Transdermal nitroglycerin: Concluding remarks. In: W.-D. Bussmann, A. Zanchetti (eds.): Transdermal nitroglycerin therapy, pp. 66 — 71. Hans Huber Publishers, Bern - Stuttgart - Toronto 1985. [2] Feldman, R. L., C. J. Pepine, C. R. Conti: Magnitude of dilatation of large and small coronary arteries by nitroglycerin. Circulation 64 (1981) 324 — 333. [3] Hill, J. A., R.L. Feldman, C.J. Pepine et al.: Randomized double-blind comparison of nifedipine and isosorbide dinitrate in patients with coronary arterial spasm. Am. J. Cardiol. 49 (1982) 431 - 4 3 8 . [4] Hopf, R., H. Drews, M. Kaltenbach: Die antianginöse Wirkung von Gallopamil im Vergleich mit einem anderen Calciumantagonisten und Placebo. Z. Kardiol. 73 (1984) 578-585. [5] Schneider, W., U. Kett, M. Kaltenbach: Antiischämische Wirkung einer 24stündigen kontinuierlichen Infusion mit Glyceryltrinitrat bei Patienten mit stabiler Angina pectoris. Dtsch. med. Wschr. 113 (1988) 543-547. [6] Schneider, W., F.-D. Maul, W.-D. Bussmann et al.: Comparison of the antianginal efficacy of isosorbide dinitrate (ISDN) 40 mg and verapamil 120 mg three times daily in the acute trial and following two-week treatment. Europ. Heart. J. 9 (1988) 149-158. [7] Sievert, H., W. Rimili, W. Schneider et al.: Antianginöse Wirksamkeit minimaler Nitroglycerindosen. Z. Kardiol. 74 (1985) (Suppl. 3) 80. [8] Sievert, H., G. Selzer, G. Kober et al.: Nitroglycerin intravenös in extrem niedriger Dosierung bewirkt eine Erweiterung von Koronarstenosen. Z. Kardiol. 76 (1987) Suppl. 1) 272.

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Discussion

Roskamm: Thank you very much, Mr. Bussmann. If I may add one more sentence for clarification. In some of your diagrams you showed that continuous nitroglycerin infusion was interrupted by intervals of 2 hours. But you said that the interval could be prolonged. Must it not be prolonged? Bussmann: It is not enough. The interval must be about 8 to 10 hours. This is probably due to the metabolites, such as dinitrates and various mononitrates. Rafflenbeul: First, I want to congratulate you on the wonderful slides of nitrateinduced dilation of coronary vessels which confirmed what we presented in the morning, although we did not know about each other's material. I only wanted to say a word on the order of importance of the mechanisms of action. Although stenoses can be dilated by nitroglycerin and nitrates, this is not a consistent phenomenon, after all. I had a slide this morning showing that only in 50 to 70% of the stenoses a dilation occurs, and in view of these findings I would not change the order of nitrate action, that is, I would still say that the peripheral relief is clearly in the foreground. In unstable angina coronary dilation is, of course, the most important mode of action, but we are not able to produce it in all stenoses, as has been proved many times. Then a remark on the methodological problem so clearly illustrated by the Braun slide and your own. If you measure stenoses of not more than 1 mm in diameter or less, the errors are getting so big that you can hardly say any more that you are producing a dilation. I have pointed out in particular that, especially in the case of highgrade stenoses, you get dilation only in 36%. Of those 36% you may easily lose 25% on account of methodological errors. This is also reflected by the big standard deviations of the measurements. Bussmann: Yes, of course, it is difficult to accurately measure such narrow coronary vessels, but I think in spite of the methodological objections we may assume that in most patients, let's make this qualification, the crucial event is taking place in the coronary vessel I cannot really understand why in a patient having an anginal attack the whole process of venous pooling must occur first and the blood pressure must decline before the anginal attack will subside. The essential point is the rise in blood flow through the stenosed vessel. This must be borne out further and confirmed by additional trials.

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Bassenge: A very short remark on sequence again: Both approaches are, of course, valid, and we can prove that something is happening, but what we must keep in mind is that, if we improve blood flow in some way or other, the antiaggregation tendency becomes a lot more effective, and we can show that clearly more EDRF is being released and, as a result, less platelet aggregation is taking place. Several groups of authors have shown recently that EDRF is a very strong aggregation inhibitor, maybe it plays a more important role than prostacyclin, and that we can give indometacin without very much happening. But if one removes EDRF alone, a clear aggregation tendency develops. In this respect I think that the NO released directly at the endothelium where then the thrombocytes will attach, is a very important matter. Bussmann: This would mean that thrombocyte aggregates are already sitting in the constricted area. If the stenosis is dilated, the blood flow will increase, and antiaggregation is obtained by the shearing forces, as you say ... a washing effect. Kukovetz: A remark of a more basic nature on your paper, Mr. Bussmann. You said that nitrates imitated what nature is doing, i. e. release EDRF or NO, and here I want to give a little warning. There is no conclusive evidence of the fact that EDRF is actually being released in human coronary arteries. Experiments with acetylcholine made with the purpose of producing this effect have so far always been described to have a negative result. I also believe that the phenomenon exists but is has not yet been convincingly proved in human coronary arteries. Bussmann: In rebuttal to this: Nitroglycerin has existed for a hundred years. It really is the most important drug of the cardiologist. Somehow it must be special, and I believe in what was so well described in Mr. Bassenge's paper, i. e. that NO and EDRF are the important things and that nitroglycerin uses the same system. This would be a logical explanation for everything including my own findings that during an attack something is happening in the coronary artery causing the improvement. Kukovetz: But it has not yet been proved, not yet conclusively and not yet in man. There is no doubt that nitroglycerin acts through NO, activates guanylate cyclase and causes dilation in the muscle, in the vascular muscle, but whether EDRF plays a role here, as does NO, has not yet been proved, and the results obtained so far have all been negative. Tillmanns: Yes, briefly on the last point, i. e. on what Mr. Bussmann said with regard to dilation. I think we must not always look at the stenosis only, at the stenosed region, this may be a big mistake. Ten years ago an article appeared in Circulation which showed that, if you give intravenous nitroglycerin to the

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cat and to the rat, you can dilate arterioles to a maximum of 30 to 100 microns. If you now measure the pressure in the myocardial capillary system of the beating heart delta P is the change in pressure from the larger to the smaller vessels. Conductivity increases. This means that even under these circumstances a dilation of about 20% will occur also in the regions downstream of the stenosis, but not in the very small vessels which are subject to metabolic autoregulation. This is the case for intravenous and also intracoronary administration. This is the factor that is added, that also plays a role here, and not only in the stenosed area itself. Bussmann: Yes, but I still want to insist on the fact that I mean the stenosed region. I was able to show in the double-blind trial comprising 40 patients that after supply of nitroglycerin something changed in the stenosis only — the dose was very low — and nothing in the blood pressure. Nothing had as yet changed in the arterioles, and Mr. Bassenge showed in his first slide that the effect on the arterioles sets in very late at high doses. Hugenholtz: Yes, but dilation is also observed in the other vessels. If you do a lot in the intracoronary region you see that the vessels dilate. Bussmann: If you use a very small dose the coronary arteries will not dilate, only the stenosis. This is the crucial point. The intracoronary dose was only 25 (j.g. In that case no effect can be detected in the large vessels. But if I use the classical dose, i. e. 1 mg, in the coronary artery, everything is dilated.

Management of unstable angina in the era of PTCA, nitrates, calcium antagonists and beta-blockers P. G. Hugenholtz, H. Suryapranata, P. J. de Feyter

P. W. Serruys,

Introduction The interest of the author in this topic goes back at least a decade. Hence it seems appropriate to repeat a few remarks made at a conference on Unstable Angina held 5 years ago in Rotterdam, as they still hold true today. "Any physician intimately involved in the care of patients with coronary disease knows from his own experience that the toughest cases, those who require the most difficult decisions, are found in those patients who are temporarily on the watershed between angina and myocardial infarction. Many therapeutic approaches have been advocated, literally hundreds of articles have been written, many carefully constructed trials have been carried out, and yet the truth concerning the actual cause and the best therapy continues to elude us. This is the principal reason why, after almost 20 years of good clinical investigation and modern research, we are still unclear how to best manage this problem or to optimally direct our therapeutic attack. Yet, unstable angina continues to cause unnecessary death and infarction in too many patients when unexpected, and yet strangely enough not in others when anticipated. Why? Are we not clever enough in our detection and therapy, or does the disease defy our means?" [1]

A major reason for these discrepancies in clinical outcome must be that the disease is multifactorial, and that within the same patient different pathophysiological mechanisms may occur at the same and at different times and in succession. Thus, unstable angina presents itself to us as a continuous spectrum of ischaemic syndromes. Therefore, each physician treating a patient with unstable angina must be aware of the many factors that may be causative at that one particular moment of the disease process, realizing at the same time that the very next moment, a different mechanism may prevail or that spontaneous improvement can occur. Consequently, there will never be one therapy for every Nitroglycerin 6 © 1989 Walter de Gruyter & Co. • Berlin • N e w York

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case of unstable angina, nor will there ever be one best therapy for unstable angina. At best, there can be the optimal therapy for that particular stage of the disease at that particular moment in time for that patient. So, what is in 1988 the significance of the syndrome of unstable angina? It still marks the boundary between the manageable syndrome (by the patient) of exertional angina, and the unmanageable loss of tissue (by the doctor) that ensues once myocardial infarction has taken place. Unfortunately, the boundary is indistinct and blurred in the temporal sense. Also, both conditions can coexist. While it is true that not every case of unstable angina will lead to myocardial infarction or prolonged ischaemia or sudden death, it is not clear how many symptoms or signs of the unstable syndromes have actually preceded sudden death (when by definition we are too late). In fact, we are still woefully short of real understanding of the natural history of unstable angina, within and outside the hospital walls, no matter what some of the reported clinical series would lead one to believe. Yet, it is the uncertainty of outcome in a specific patient that obliges us, urges us and indeed forces us as physicians, to provide maximal treatment to all patients, regardless whether all need that therapy or not. This in turn should result in the prompt (i. e. within 24 hours or less) relief of symptoms with the absence of sequelae, such as subsequent infarction or death. It is my firm belief and aim that any attack of unstable angina, provided it is properly recognized and properly treated, should never result in myocardial infarction or death.

Initial management Fortunately, today patients developing abrupt persistent chest pain without a precipitating cause usually seek help of a physician (the patient's general practitioner or a physician at the mobile coronary care unit, at the emergency room or at the coronary care unit itself). Treatment of such severe chest pain is usually started without a diagnosis being made. The available medications include sublingual or intravenous glyceryl trinitrate, nifedipine, fentanyl, or opiates. After that, whenever an acute cardiac problem remains suspected, the general practitioner, if involved, should always refer the patient to a hospital. If this does not occur the by now ubiquitous emergency systems will take over and do so. Ultimately the patient (or his family) should take that responsibility onto themselves. After arrival in the hospital an early (provisional) diagnosis is made after relief of chest pain if still present. The patient's reaction to pain treatment, the

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interview, and now electrocardiography are the immediate diagnostic tools available to the hospital physician. Each one is indispensable to identify myocardial ischaemia (either reversible or irreversible) as the (presumed) cause of the chest pain. Now, three diagnostic categories become available, each reflecting the physician's perception of the nature of the ischaemia: (1) suspected acute myocardial infarction, i. e. irreversible ischaemia; (2) suspected unstable angina, i. e. reversible ischaemia; (3) probably no angina, i. e. no acute ischaemia. Each diagnostic category has its own therapeutic consequences (Table 1). Prior to the Table 1

Step-up approach in the treatment of unstable angina after hospital admission

In all patients Rest, sedation, correction of hypertension, anaemia, tachycardia, etc. Additional pharmacologic 1 2 3

treatment in subacute cases

Nitrates

Beta blockers

Calcium antagonists

oral sublingual intravenous

oral oral intravenous

— oral sublingual/ intravenous

Further invasive treatment in (persistently) 4

acute cases

Urgent coronary angiography, and depending on its interpretation, angioplasty or surgery, and if necessary intra-aortic balloon pump

enzyme determination which takes a few hours, patients are identified as having sustained acute myocardial infarction: (1) if severe chest pain has persisted for more than 30 minutes (in particular if the response to nitrates is unsatisfactory and opiates are needed to be given to eliminate chest pain); (2) if excessive vegetative symptoms or signs of overt cardiac failure have appeared; or (3) if typical electrocardiography abnormalities aggressively persist or worsen. The task in early management is then: (1) to relieve pain (opiates are rarely used sufficiently these days although i. v. nitrates and, at times, beta-blockers suffice), dyspnoea (a role for i. v. diuretics or ACE inhibitors should not be ignored), and anxiety (how often is this factor not overlooked?); (2) to provide continuous monitoring and prompt treatment of life-threatening arrhythmias, if they should occur (fortunately whether ischaemia or reperfusion induced, various pharmacological agents and the defibrillator have put an end to this unnecessary form of death); (3) to salvage as much of the jeopardized myocardium as possible if infarction is suspected; and (4) to threat left heart failure, if present. As myocardial infarction is usually caused by complete occlusion of a (major branch of a) coronary artery, thrombolytic treatment now has become the first

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therapeutic option if the occlusion is thought to have occurred within the last four to six hours. There is now substantial evidence that treatment with streptokinase (intravenously but especially intracoronary) may be very useful, if not decisive. Treatment with recombinant tissue-type plasminogen activator is even more effective, and reductions in death rates by 50% are now possible. In addition, there is strong evidence that early beta blockage reduces early mortality in patients with uncomplicated myocardial infarction, it probably is the best adjuvant therapy together with aspirin. On the other hand, in patients identified as still having unstable angina (1) when chest pain did not last for more than 30 minutes and had ceased spontaneously or could rapidly be relieved by glyceryl trinitrate; and (2) where the electrocardiogram shows signs of reversible myocardial ischaemia, management is conservative. Without objective evidence for myocardial ischaemia patients with severe but as yet unexplained disappearing chest pain are usually kept in the hospital for further observation while therapeutic measures are deferred either until symptoms reappear or until exercise testing or angiography is performed as a provocative or elective procedure. Appropriate measures are taken when the chest pain can be attributed to a non-cardiac cause (e. g. peptic ulcer, oesophagitis, or gall stones) or to a noncoronary cardiac cause (e. g. aortic stenosis).

Pharmacological therapy In the so called "medical" treatment of angina pectoris a distinction must be made between the treatment to eliminate acute chest pain and maintenance treatment to prevent subsequent episodes of angina pectoris and ischaemia or to diminish their frequency. Treatment of acute chest pain begins with limitation of those factors and conditions which initiated the attack, aided in some patients by sedation. If chest pain persists, it can be relieved by the sublingual use of nitrates (glyceryl trinitrate or isosorbide dinitrate) or by a capsule of nifedipine. Opiates are usually needed to relieve the pain associated with more severe ischaemia, suspected to be caused by actual myocardial infarction. Episodes of anginal pain may also be prevented by readjustment of the factors determining oxygen consumption and oxygen supply. Nitrates, beta blockers, and calcium antagonists, either alone or in combination, are advocated as being useful in this context. Their influences on oxygen consumption and oxygen supply of the heart muscle are summarized in Table 1. The clinician has to select on an individual basis which combination he prefers to begin his therapy with.

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It should be remembered however that desired drug effects may "overshoot". Nitrates increase the venous capacitance, causing pooling of blood in the peripheral veins. Myocardial oxygen demand is attenuated by the ensuing reduction in left ventricular end diastolic volume (preload) and systemic blood pressure (afterload). Nitrates may also diminish coronary vasomotor tone, all of which improves coronary perfusion and increases oxygen supply. The most important side effects therefore are orthostatic hypotension often manifested by severe headaches, or palpitations, while reflextachycardia and nausea may also occur. Sublingual glyceryl trinitrate is rapidly absorbed from the sublingual mucosa. Its onset of action occurs within minutes, with maximal effects at three to 15 minutes, while little residual activity remains at 20 to 30 minutes. Thus, patients with stable angina might have used the drug prophylactically prior to an activity that is known to precipitate angina pectoris. Recently, glyceryl trinitrate in ointments and in transdermal therapeutic systems (plasters) for topical applications have become an important addition to the available anti-anginal agents for some patients, yet for unstable angina these do not suffice if only because of tolerance. Intravenous glyceryl trinitrate is now frequently, or nearly always, used in coronary care units to eliminate the acute unstable episode or recurrent episodes of ischaemia, as problems with absorption delay the assessment of the diagnostic value of nitrate therapy. While long-lasting anti-anginal effects may also be obtained from oral slow release preparations of nitrate esters, such as isosorbide dinitrate, high oral doses have to be given to overcome the rather extensive first pass liver metabolism. Isosorbide mononitrate, a metabolite of isosorbide dinitrate, is characterized by more favourable pharmacokinetic properties. Furthermore, continuous long-term use of nitrates, in particular of glyceryl trinitrate, may cause tolerance, which offsets anti-anginal effects in certain patients. Thus long acting preparations have their rational use only after the first attacks have subsided and additional time is being sought for. Beta blocking agents antagonize the actions of catecholamines on the beta receptors by competitive inhibition. Beta blockade therefore reduces the oxygen demand by reducing heart rate and blood pressure and depressing contractility. To be really effective a resting heart rate of 55 — 60 beats min must be achieved. Consequently, beta blockers are contra-indicated in patients with signs of cardiac failure, obstructive lung dysfunction, bradycardia, or conduction disorders all of which may coexist with the unstable angina state. Cardioselective beta blockers carry a smaller risk for bronchoconstriction than nonselective beta blockers. A systematic comparison of the efficacy of the numerous beta blockers currently available in the management of unstable angina has not been performed, but propranolol, atenolol and metoprolol are most often mentioned in research and clinical reports. Side effects of beta blockers include cold distal limbs, impotence,

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and occasionally intermittent claudication. Gastro-intestinal dysfunction, hallucinations, coronary artery spasm, Raynaud's syndrome, and congestive cardiac failure, are less frequent but even more undesired side effects. Calcium antagonists represent a heterogeneous group of vasodilating drugs which share the ability to inhibit the transmembrane influx of calcium in all types of muscle cells. The most popular are nifedipine, verapamil, and diltiazem. Although the three drugs share the same principle, they vary in their potency to affect the different components of the cardiovascular system. Their direct action on the smooth muscle of certain arteries depends on the specific compound. Usually, all inhibit or relieve coronary spasm and produce dilation of coronary arteries including both large and small arteries as well as collateral vessels, thereby causing an increased cardiac blood supply. Furthermore, dilation of the peripheral arteriolar bed will reduce vascular resistance and systemic blood pressure and thus the afterload to the heart. Calcium antagonists may also decrease contractility. In contrast to nifedipine, which may cause an increase in heart rate, verapamil and diltiazem usually lead to a reduction in heart rate. When considered at a cellular level, it can be argued that all calcium antagonists will confer protection to the myocardium against the deleterious effect of ischaemia by slowing excessive calcium influx, by blocking early catecholamine release, by avoidance of high-energy phosphate breakdown with suppression of attendant loss of purine derivates. However, it was recently stressed that cardioprotective effects of calcium antagonists were only observed in animal preparations when the drugs were given before the ischaemic condition had been established, and that, as a logical consequence, similar effects may only be expected in clinical practice under similar circumstances [2], This means in particular that fewer or no benefits should be expected when calcium antagonists are given after onset of ischaemia. A recent report on nisoldipine, the most powerful dihydropyridine thus far released, suggests that such protective effects may be expected up to 90 minutes after onset of occlusion [9]. Adverse effects are those of all peripheral vasodilators: flushing, headache, pretibial oedema, while aggravation of angina can occur in some patients, an effect possibly related to arterial hypotension in combination with reflex tachycardia or to coronary "steal".

Further management of patients with unstable angina After initial pain relief, the aims of early treatment in patients identified as having untable angina at hospital admission are the prevention of recurrent ischaemia or progression to myocardial infarction and the restoration of a stable

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clinical condition. As electrocardiography and the severity of chest pain have limited sensitivity for (ir)reversibility of myocardial injury, chest pain initially impressing as unstable angina may in fact still originate from evolving myocardial infarction, for which the subsequent analysis of enzyme levels such as HDL, aHBDH, CPK-MB, provide the best evidence after the first 12 hours. Assuming that no evidence for actual necrosis exists, the role of antiaggregatory agents such as aspirin or of anticoagulant therapy such as heparin has become much clearer since recent studies[4 —6]. In fact, they now provide overwhelming, albeit indirect, evidence that aspirin is a must. While the first two of the cited references began therapy well after the triggering unstable angina event and thus cannot be construed as proof of efficacy in the acute episode, the ISIS 2 study has included many patients who by conventional standards had no "proven" infarcts, but rather patients in the precursor state. Even though poorly described in that study (normal, or slightly abnormal ECG's with the clinical conviction of a heart attack) they must belong to the large category of patients suspected of having an acute infarction. The ISIS 2 data show that aspirin alone (and even more so the combination of streptokinase with aspirin) can reduce the eventual outcome in a highly significant way by reducing acute mortality by some 25% (and nearly 50% by their combination). Thus aspirin, while never having been assessed in terms of efficacy prospectively in patients with unstable angina as defined earlier, would currently appear to be indicated in all patients in whom no contraindications exist.

Management of patients with refractory symptoms It is generally agreed upon that when symptoms, in spite of such intensive pharmacologic treatment persist, a state of refractory angina has occurred. This forms an indication for urgent coronary angiography. That decision must be taken within 12 — 24 hours lest there is no salvageable cardiac tissue left. If the angiographic appearance suggests that a thrombus is present at the symptom related segment, thrombolysis may be attempted as indicated earlier. If the symptom related lesion appears suitable for angioplasty or bypass grafting, that interventin is usually performed as soon as possible. If the intervention cannot be performed at short notice, the intra-aortic balloon pump can be used for temporary stabilization of patients awaiting further interventions. As the inoperable refractory patient has a grave prognosis, the physician, while in addition to continuing and optimizing the medical treatment in that situation, can only offer support and symptomatic relief with analgesics as needed. He must acknowledge that infarction is inevitable and death possible.

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The role of PTCA in acute unstable angina Percutaneous Transluminal Coronary Angioplasty is therefore now the preferred manner of therapy when optimal step-up pharmacological therapy has failed. In a study from our unit involving 200 patients out of 2,887 admitted to the coronary care unit between January 1983 and 1985 at the Thoraxcentrum in Rotterdam, in whom despite such step-up pharmacological symptoms persisted beyond the first 24 hours, (aged 30 to 74, average 56 years, 164 men and 36 women), PTCA was carried out. Single vessel coronary disease was present in 135 patients, and multivessel disease in 65. The mean global left ventricular ejection fraction was 0.59 + 0.10 indicating a still normal ventricular function. The extent of coronary artery disease and the details of the actual management of these patients are shown in Tables 3 to 7. The characteristics of the undilated segments of the 65 patients with multivessel disease and balloon dilation of only the culprit lesion are shown in Table 2. Table 2

Characteristics of non-dilated coronary stenoses in 65 patients with multivessel disease and PTCA of the culprit lesion only Undilated lesions per patient

Number of undilated lesions Technically suitable for CABG Technically suitable for PTCA Non-dilated LAD Non-dilated RCA/CX Stenosis to infarcted myocardium PTCA CABG LAD RCA CX

: = = = =

1 lesion (44 patients)

2 lesions (21 patients)

44 41 22 6 38 15

42 36 18 2 40 6

percutaneous transluminal coronary angioplasty; coronary aorta bypass grafting; left anterior descending coronary artery; right coronary artery; left circumflex artery.

Patients were categorized into three groups according to their history: (1) recent onset unstable angina, defined as chest pain for the first time within 1 month before coronary angioplasty: (2) worsening angina, defined as chronic stable angina that had progressed to chest pain at rest, and (3) early postinfarction unstable angina, defined as occurrence of a myocardial infarction within 1 month before coronary angioplasty.

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The documented ECG ST-T segment changes associated with chest pain at rest were classified, in ranking order of severity, as follows: (1) transient ST segment elevation ( > 0 . 1 mV) during pain, with return to (nearly) normal or to the ST level that existed before the onset of chest pain at rest; (2) transient ST segment depression ( > 0 . 1 mV) during pain, with return to (nearly) normal or to the level that existed before the onset of chest pain at rest; (3) development of permanent negative T waves ( > 0 . 1 mV) during or after disappearance of chest pain at rest, without documented ST segment elevation or depression ( > 0.1 mV); and (4) transient minimal ST-T changes: ST elevation or depression ( < 0 . 1 mV), minimal T wave inversion ( < 0 . 1 mV), pseudonormalization of a negative T wave and T wave amplitude increase or decrease during pain. Coronary angiograms were obtained in multiple views, including hemiaxial projections. A consensus of two angiographers was used to evaluate the coronary angiograms. The degree of coronary obstruction was assessed with the use of a caliper system and was given in percent of luminal diameter. The length of the lesion was measured in relation to the length of the inserted balloon. A lesion was considered long if it was > 1 cm. Lesions were categorized into concentric lesions (symmetric, hourglass coronary narrowing) and eccentric lesions (asymmetric narrowing). Collateral vessels were considered present when they were angiographically visible. For this study, only the presence of collateral circulation to the ischaemia-related vessel was noted. An intracoronary thrombus was defined as (1) contrast medium staining at the site of an abrupt occlusion of the vessel, or (2) the presence of an intracoronary filling defect.

Coronary angioplasty This was performed with a steerable dilation system. A 7F pacing electrode catheter was positioned in the right atrium. At the beginning of the procedure, heparin (100 mg) and aspirin (250 mg) were administered intravenously and low molecular weight dextran was infused slowly. The electrocardiogram and blood pressure were continuously monitored. To prevent coronary spasm, intracoronary nifedipine or isosorbide dinitrate was given. Initial balloon inflation pressure was 2.0 atm, with subsequent inflations ranging to 12 atm. Inflation was maintained according to the ECG changes, degree of decrease in blood pressure or induced pain. Balloon inflations were repeated until there was a significant reduction in the transstenotic pressure gradient and a reduction in the severity of the obstruction as judged from repeat angiograms obtained immediately after the dilation. Coronary angioplasty was considered to be successful if a reduction in the severity of the obstruction of < 50% luminal diameter narrowing was obtained or if the transstenotic gradient index was reduced to < 0.30 (according to the equation mean proximal pressure minus mean distal pressure divided by

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