Nitroglycerin 8: Basics, Standard and Elective Applications. Eighth Hamburg Symposium [Reprint 2020 ed.] 9783110821284, 9783110149784

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Nitroglycerin 8

Nitroglycerin 8 Basics, standard and elective applications Eighth Hamburg Symposium

Editor H. C. Mehmel

w DE

G

Walter de Gruyter Berlin • New York 1996

This book contains 37 figures and 16 tables.

Die Deutsche Bibliothek — Cataloging-in-Publication

Data

Nitroglycerin 8 : basics, standard and elective applications / Eighth Hamburg Symposium. Ed. H. C. Mehmel. - Berlin ; New York : de Gruyter, 1996 Dt. Ausg. u.d.T.: Nitroglycerin VIII ISBN 3-11-014978-8 NE: Mehmel, Helmuth C. [Hrsg.]; Hamburger NitroglycerinSymposion

© Copyright 1995 by Walter de Gruyter & Co., D-10785 Berlin All rights reserved, including those of translation into foreign languages. No part 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. For 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 medication, in order to determine for themselves whether the recommentations 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 German 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: Premedia, Berlin. - Printing: Gerike GmbH, Berlin. - Binding: Liideritz & Bauer, Berlin. - Printed in Germany.

Editor Prof. Dr. H. C. Mehmel

II. Medizinische Klinik Städt. Klinikum Moltkestr. 14 D-76133 Karlsruhe Deutschland

List of Contributors Prof. Dr. J. Abrams

Department of Medicine The University of New Mexico 211 Lomas Boulevard Albuquerque New Mexico 87131-5271 USA

Dr. W. Auch-Schwelk

Deutsches Herzzentrum Berlin Augustenburger Platz 1 D-13353 Berlin Deutschland

Prof. Dr. W.-D. Bussmann

Abteilung für Kardiologie Klinikum der Johann-Wolfgang-GoetheUniversität Theodor-Stern-Kai 7 D-60596 Frankfurt Deutschland

Prof. Dr. U. Elkayam

USC School of Medicine Division of Cardiology 2025 Zonal Avenue GH Room 7621 Los Angeles California 90033 USA

6

Prof. Dr. E. Fleck

Dr. M. Gräfe

Prof. Dr. K.-E. Karlberg

Prof. Dr. G. Klein

Prof. Dr. Th. F. Lüscher

Dr. R. Schiele

Prof. Dr. J. Scholze

Dr. A. Shotan

Contributors

Deutsches Herzzentrum Berlin Augustenburger Platz 1 D-13353 Berlin Deutschland Deutsches Herzzentrum Berlin Augustenburger Platz 1 D-13353 Berlin Deutschland Department of Medicine Huddinge Hospital S-14183 Huddinge Sweden Klinik Höhenried D-82347 Bernried/Obb. Deutschland Kardiologische Abteilung Medizinische Universitätsklinik Inselspital CH-3010 Bern Schweiz Medizinische Klinik B Klinikum der Stadt Ludwigshafen Bremserstraße 799 D-67063 Ludwigshafen Deutschland Universitäts-Poliklinik Charité Luisen Straße 13 D-10098 Berlin Deutschland Heart Institute Sheba Médical Center Tel Hashomer 52621 Israel

Contents

H. C. Mehmet Introduction M. Gräfe, W. Auch-Schwelk, G. Steinheider, E. Fleck

9 D. Terbeek, H. Hertel, K. Graf,

The role of the endothelium in the development of atherosclerosis . . .

11

W. Auch-Schwelk, M. acute Gräfe,ischemic E. Flecksyndromes in coronary artery The development of disease

25

E. Fleck, J. Hug Invasive cardial diagnostic procedures

37

Th. F. Lüscher, M. R. Tschudi Nitric oxide - an endothelium-derived local vascular nitrovasodilator system

55

U. Elkayam Organic nitrates - mechanisms of action and potential limitations

. . .

K.-E. Karlberg Nitroglycerin attenuates platelet aggregation beyond the effect of acetylsalicyclic acid in man J. Scholze The spectrum of extracardial, clinical indications for nitroglycerin and nitrates

75

89

97

R. Schiele, J. Senges The prehospital phase of acute myocardial infarction

115

W.-D. Bussmann Therapy of acute myocardial infarction with nitroglycerin in the intensive care unit

129

8

Contents

A. Shotan Hibernating myocardium - identification, including pharmacological intervention, therapeutic implication and prognostic significance

139

J. Abrams Remodeling

145

G. Klein, J. Gehring Heart attack - what happens next?

169

Awarding of the 1994 Nitrolingual Prize

183

A n n o u n c e m e n t "1998 Nitrolingual-Prize"

187

Introduction The history of nitrates in medicine is almost 130 years of age. It began with the correct observation that nitrates have an antianginal effect and an incorrect explanation of the mechanism of action: reduction of arterial pressure (Brunton 1867). The concept of direct coronary effect was developed in the 1930s (Lewis 1933). 30 years later, the peripheral effect returned to the spotlight with the explanation of the venous pooling (Gorlin 1959). With the knowledge that most coronary arterial stenoses are excentric in nature, i.e. they have a respondent wall segment in the stenosis, the concept of the central effect of nitrates enjoyed a renaissance (Freudenberg and Lichtlen 1981). Independent of the question about the nitrate's point of attack, hypotheses about the nitrate's molecular mechanism of action were developed. Analogous to atomic physics, in which the existance of certain elementary particles are first postulated and then proven, the existance of an EDRF (endothelial derived relaxing factor) was first of all postulated by Furchgott from experimental observations. Only later was NO proven to be at least a working principle of the EDRF (Moncada). Using this approach, a number of recent scientific postulates, about which we will hear something today, have been derived. This volume of the Nitroglycerin Forum Series - as is traditional - will not be strictly limited to nitrates or nitroglycerin. By way of introduction we will hear some ideas about the pathogenesis of arteriosclerosis and restenosis, about the development of the ischemic syndrome, the shift between acute myocardial infarction and stable angina pectoris as well as new diagnostic procedures which may eventually replace traditional, invasive coronary angiography. These will be followed by discussions on the molecular mechanism of action and clinical applications of nitroglycerin. Five contributions are dedicated to acute myocardial infarction before, during and after clinical treatment. This volume is based on lectures presented at the VIII. Hamburger Nitroglycerin Symposium. I should like to take this opportunity to express my appreciation to the sponsor of this event, the Pohl-Boskamp Company, for the cordial invitation and the extraordinary preparations. Furthermore, I would like to thank them for the chance to meet with the many researchers, clinicians and practicing physicians who have a special interest in cardiovascular diseases, and especially for the role of nitrates, that have been able to come, sometimes travelling great distances, to Hamburg to exchange ideas and experiences in a friendly atmosphere. H. C. Mehmel

The role of the endothelium in the development of atherosclerosis M. Gräfe, W. Auch-Schwelk, G. Steinheider, E. Fleck

D. Terbeek,

H. Hertel,

K.

Graf,

Introduction Epidemicological studies have led to the identification of risk factors which advance the appearance and progression of atherosclerotic lesions [22, 39]. As a result of intensive research, many mechanisms that lead to atherosclerosis are understood more completely. The "Response to Injury" theory, developed in the seventies, states that an endothelial defect can result from mechanic or toxic stimuli. Thus platelets adhere to the exposed subendothelial structures and thus release thrombogenic substances (ADP, thrombin, platelet factor III) as well as growth factors for smooth muscle cells (plateled derived growth factor = PDGF) which lead to an increased proliferation of smooth muscle cells and an increase in connective tissue [42]. In the course of time, this - in its beginning phase - rather mechanical theory, has been modified a number of times and changed to a complicated cellular and humural interactions model. The following comments are limited to a number of aspects of the importance of endothelial cells in the development of atherosclerosis.

Classification of atherosclerotic lesions The initial stage of atherosclerosis is the fatty streak. It is the circumscript fat infiltration of the vessel wall. Seen histologically, one finds monocytes in these regions that phagocytize the fat infiltration. One also finds foam cells with lipid vacuoles that develop from the monocytes. One already discovers these fatty streaks or uncomplicated lesions at an early age. They are completely reversible [23, 32], After further development it becomes an advanced lesion. More leukocytes, organized in multiple layers, migrate into the subendothelial space. One can simulta-

12

M. Gräfe, W. Auch-Schwelk, D. Terbeek, H. Hertel, K. Graf, G. Steinheider, E. Fleck

neously observe individual smooth muscle cells in the intima. These wander from the media, but never reach the number of the leukocytes which wander into the subendothelial space [31]. The number of the smooth muscle cells is only greater than that of the leukocytes in the stage of atherosclerotic plaque. In combination with the increase of the smooth muscle cells within the intima, there ist also an increased formation of extracellular matrix and thus a stenosis of the vessel diameter [42], In addition to the cellular elements and lipids, oxidized lipoproteins [26], cytokines - i. e. tumor necrosis factor (TNF) [1], and growth factors such as PDGF [21] were proven to exist in the region of atherosclerotic plaques.

Endothelial injury Endothelial injury is of central importance for the pathogenesis of atherosclerosis. Injury does not necessarily mean that a morphological endothelium defect occurs and subendothelial structures are exposed to blood, but rather that there is an altered function of endothelial cells. Endothelial cells show a whole range of functions that affect the production of vasoactive substances, matrix remodeling, the clotting system, and the secretion of growth factors (Tab. 1). The importance of lipids, especially oxidized LDL (ox-LDL) was recognized for endothelial injurely in the last few years. It appears as though the oxidized part of the LDL is, above all, responsible for the atherogenic potential of the lipoproteins [8, 50]. ox-LDL was found in high concentrations in the atherosclerotic lesions [51]. An oxidation can result from endothelial cells, macrophages, and smooth muscle cells. All of these cells can generate free radicals that change the content of lipoproteins on oxidized fatty acids and lead to a fragmentation of the apolipoprotein B 100. In this process, the characteristics of LDL ar changed so that they are no longer recognized by the normal LDL-receptor but rather by a "Scavenger Receptor" which, in contrast to the LDL-receptor, demonstrates no saturation kinetics [51]. Through a number of experiments, it has been proven that ox-LDL modulates endothelial functions. They lead to an increased secretion of endothelial growth factors [40], to a decrease of t-PA secretion, and to an increase in PAI-1 and cellular procoagulant activity [20, 25, 47] (Fig. 1). Leukocytes attach to a greater degree on endothelial cells incubated with ox-LDL, both in vitro [9, 15] as well as in vivo [26] (see below). In addition, effects on the release of EDRF and thus on tonus regulation [17, 45] and on the migration of endothelial cells [35] have been described. An altered function of endothelial cells can be proven in vivo in animal experiments as well [6], The macrophages that had migrated into the subendothelial space, which also have a scavenger receptor, are overloaded with

The role of the endothelium

13

cholesterol through the o x i d i z e d lipoproteins and turn into f o a m cells. T h e s e c e l l s then in turn release c y t o k i n e s and growth factors w h i c h o n their part alter the function o f the endothelial c e l l s further (Tab. 2). Table 1

Endothelial substances that are important in the pathogenesis of atherosclerosis (modified according to Gerritsen et al. [19])

Gen product Matrix

building/remodeling PAI-1 t-PA, u-PA

collagenase tissue factor Leukocytes/endothelial interaction E-, P-selectin ICAM-1, VCAM MHC-I, II Interleukin-1, -6, -8 MCP-1 Vessel tone Cyclooxigenase NO-synthase endothelin Growth

factors GM-CSF, M-CSF

PDGF FGF TGF-ß

Function

Inhibitor or u-PA and t-PA activate plasminogen to plasmin matrix reduction activation of TGF-P matrix reduction cofactor for extrensic clotting mechanisms adhesion molecules of the selectin group adhesion molecules of the immunoglobulin group histocompatibility antigens, present target structure to cytotoxic T-lymphocytes cytokines chemotactic factor for monocytes synthesis of PGI2 and PGE2, TXA2 synthesis of NO (EDRF) vasoconstrictor induce the formation of monocyte colonies from precursor cells, modulate monocyte functions mitogen for smooth muscle cells mitogen for many cell lines growth stimulant and inhibitor

Abbreviations: PAI-1 = plasminogen activator inhibitor-1, t-PA = tissue-plasminogen activator, u-PA = urokinase-plasminogen activator, ICAM-1 = intercellular adhesion molecule-1, VCAM = vascular adhesion molecule, MCP-1 = monocyte chemotactic protein-1, GM-CSF = granulocyte macrophage colony stimulating factor, M-CSF = macrophage colony stimulating factor, PDGF = platelet derived growth factor, FGF = fibroblast growth factor, TGF-P = transforming growth factor-P, EDRF = endothelial relaxing factor, TXA2 = thromboxan

14

M. Gräfe, W. Auch-Schwelk, D. Terbeek, H. Hertel, K. Graf, G. Steinheider, E. Fleck 80 n p < 0.05 70605040< Q- 302010-

0-

Control

n-LDL ox-LDL (100 ng/ml) (100 fig/ml)

50-, p o "" cd "ocd ccd uT3 3 2 a s 2

ü

ob E

E. Fleck, J. Hug

46

Fig. 7

Three-dimensional reconstruction of a vascular tree of a left coronary artery from biplane projections.

of a better spatial representation, this also allows a more exact evaluation by the investigator.

Function tests For a small number of patients with chest pain and angiographically documented normal coronary vessels, vasospastic constrictions of the coronary vessels may be present as a triggering cause. This is - probably - due to a localized disease of the smooth musculature of the vessel, which appears on both recog-

Invasive cardial diagnostic procedures

47

nizably arteriosclerotic and non-arteriosclerotic coronary segments and can at present only be verified by function tests with angiographic monitoring [10, 26]. Empirically tested pharmacological tests are available and the use of alkaloids of ergonovin type are accepted [4, 13]. Tab. 2 shows the prevalence of positive ergovonin tests in large trial series. It can be seen that, through a strict selection of patients with clinically typical spontaneous angina pectoris, the share of exclusionary diagnostic procedures can be significantly reduced and that in such patient populations, the prevalence of positive ergonovin tests is significantly higher. The consequence of a diagnosis of vasospastic angina pectoris is an improved prognosis for the disease through an effective therapy with calcium antagonists and nitrates [ 1 , 2 ]

Table 2

Prevalence of positive ergonovine tests in large studies (GHCB = German Heart Center Berlin, CHD = coronary heart disease)

Author

Bertrand 1979-80

Bory 1977-86

Harding 1980-89

GHCB 1986-92

< 99 %

< 50 %

< 50 %

< 50 %

17,327

7,089

3,447 127 4

8 538 819 281 34

Inclusion criteria: Stenosis Angiographies total (n) Angiographies due to suspected CHD (n)

1,330 886

Patients with exclusionary CHD % n Ergonovine test (n) Positive (n) % of the tests Portion of the % with suspected CHD

46 405 886 131 15 15

1,200 127 11

4

48

E. Fleck, J. Hug

Supplemental diagnostic procedures Selective coronary angiography is considered the "gold standard" for diagnosing stenotic lesions of the coronary vessels. With a few contrast medium injections, the entire coronary artery system can be evaluated and relevant stenoses can be displayed in a precise fashion. The limitations of coronary angiography are, on the one hand, that only an outline of the vessel lumen is displayed with the image and, on the other, that a three dimensional structure is displayed in a two-dimensional image [14], Plaque ruptions, arterial thromboses or dissections can either not be portrayed or only insufficiently portrayed angiographically, an evaluation of the vessel wall is not possible [3, 20]. These limitations can be partially compensated for in new supplementary diagnostic procedures either already in clinical use or still in the stage of scientific testing. These include angioscopy, intravasal ultrasound and Doppler flow velocity measurements in the coronary vessels.

Angioscopy In contrast to conventional angiography, angioscopy shows a three-dimensional perspective of the intracoronary surface morphology in color. The color discrimination available in angioscopic pictures makes it possible to differentiate between thromboses, dissections or spasms and allows statements to be made about plaque morphology. This knowledge can play a decisive role in choosing a therapy and thus influence the prognosis. In angioscopic studies, a high incidence of thrombosis was detected in patients with instable angina pectoris, while this finding can only be insufficiently documented with conventional angiography [22, 24]. The reason why angiography has until now only been successfull in scientific applications, despite its higher sensitivity regard to coronary pathology, lies in existing technical difficulties in the instruments now available to date. An important consideration will be whether or not the additional angioscopic information will lead to an improvement in intervention results.

Intravasal ultrasound New electronic and acoustic technologies have made possible the development of miniaturized intravasal ultrasound, which have the capability to produce

Invasive cardial diagnostic procedures

49

tomographic image of coronary arteries in real time. Two alternative procedures are available as image-producing systems, mechanically rotating instruments and electronic tools with circularly arranged crystals. The advantage of the intravasal ultrasound lies in its ability to create a representation of the vessel lumen cross-section area independent of angiographic projections. This makes possible precise quantitative measurements of the vessel diameter, even if very eccentric stenoses or significant vessel wall changes are present, such as after interventions [12, 23], Another great advantage lies in its ability to obtain information on the composition of the vessel wall and the morphology of arteriosclerotic plaques. Even in patients with angiographically normal vessel sections, arteriosclerotic wall changes are often noted with intravasal ultrasound. The disadvantage of intravasal ultrasound is that to perform a quantitative analysis of the lumen cross-section area orthograde cuts are necessary. If the transducer lies at an angle in the vessel, on oversized elliptical lumen area appears. The current models also have a shallow depth of acoustic penetration, which leads to problems in optimal picture acquisitation. The presence of calcium deposits lead to a dissipation of the sound waves, so that layers under these deposits cannot be identified. Another consideration is that differentiation can only be made between echo-rich and echo-poor structures with intravasal ultrasound. A histological characterization of the morphology of vessel walls or plaques is not possible at present. The safety of the use of intravasal ultrasound has been demonstrated in several studies. It is expected that intravasal ultrasound will be a sensitive technology for the recognition of coronary heart disease through the representation of plaque morphology, that it will produce knowledge about progression and regression and that it will aid the investigator in making decisions in interventions with complex morphology.

Doppler flow velocity measurement The development of angioplasty-guide wires with a Doppler crystal on the tip made it possible to investigate the coronary blood flow velocity profile both proximally and distally of a coronary obstruction. This enabled insight into the physiological effects of various mechanical and pharmacological changes before and during interventions, which had previously only been possible in animal experiments. In anatomically normal epicardial coronary arteries and normal myocardium in the supply area, the administration of a potential vasodilator like papaverin or adenosine leads to approcimately a triplin of the coronary blood flow [8], In the presence of a flow-limiting stenosis, this ability to raise coronary blood flow is limited [21]. Through this mechanism, the func-

50

E. Fleck, J. Hug

tional degree of severity of stenoses can be measured with Doppler flow velocity measurement, which can significantly influence the therapy decision, especially in a stenosis beween 40 and 70 % occlusion [7], In addition, Doppler flow velocity measurements can be used for the immediate evaluation of an intervention's success, whereby in this case it is less the increase in the coronary flow reserve than the increase in the distal flow velocity that is useful. The limitations to Doppler flow velocity measurements are that the measurements are not only dependent on the degree of severity of the stenosis, but are also influenced by other factors such as the blood supply of the myocardium (infarction, hypertension), pre-load (blood pressure, heart rate) and other Theological conditions (anemia, blood viscosity). At this time clinical studies are being conducted to investigate the usefulness of Doppler flow velocity measurement during interventions and to determine the relationsship of the various measurable flow parameters to the clinical result.

Summary Recent developments have shown that the current status of digital technology in the catheter laboratory permits safer and simpler interventions, thereby reducing the burden on the patient and investigator. There is still the hope, however, for more image creating capability, perhaps through fast high-resolution MRT and more information from functional diagnostic procedures. Experience has shown how slowly and difficultly this development has progressed. Independent of this, more attention must be paid to a stronger rational use of invasive diagnostic procedures. Conducting examinations for purely diagnostic purposes without consecutive measures in no longer adequate today.

References [1]

[2]

[3] [4]

Bertrand, M., J. Lablanche, P. Tilmant et al.: Frequency of procoked coronary arterial spasm in 1089 consecutive patients undergoing coronary arteriography. Circulation ( 1 9 8 2 ) 1 2 9 9 - 1 3 0 6 . Bertrand, M., J. Lablanche, P. Tilmant et al.: The provocation of coronary arterial spasm in patients with recent transmural myocardial infarction. Eur. Heart J. 4 (1983) 532-535. Block, P., R. Myler, S. Sterzer et al.: Morphology after transluminal angioplasty in human beings. N. Engl. J. Med. 305 (1981) 3 8 2 - 3 8 5 . Bory, M., P. Joly, J. Bonnet et al.: Methergin (R) testing with angiographically normal coronary arteries. Am. J. Cardiol. 61 ( 1 9 9 5 ) 2 9 8 - 3 0 2 .

Invasive cardial diagnostic procedures

51

[5] Bruckenberger, E.: Situation der Herzchirurgie 1993. Bericht des Krankenhausausschusses 1994. [6] Collins, S., D. Skorton, D. Harrison et al.: Qantitaive computerbased videodensitometry and the physiological significance of a coronary stenosis. Comp, in Cardiol. (1982) 222-229. [7] Donohue, T., M. Kern, F. Aguirre et al.: Determination of the hemodynamic significance of angiographically intermediate coronary stenoses by intracoronary Doppler flow velocity. J. Am. Coll. Cardiol. 19 (1992) 242A. [8] Doucette, J., P. Corl, H. Payne et al.: Validation of a Doppler guidewire for intravascular measurement of coronary artery flow velocity. Circulation 85 (1992) 1899-1911. [9] Erbel, R., U. Sommerfeld, M. Ashry et al.: Qualitätsmanagment im Herzkatheterlabor. Z. Kardiol. 83 (1994) 4 3 - 5 5 . [10] Fleck, E., W. Auch-Schwelk, E. Frantz et al.: Diagnostik der dynamischen Läsion. Z. Kardiol. 82 (1993) 2 3 - 3 2 . [11] Gould, K. et al.: Quantification of coronary artery stenosis in vivo. Circ. Resarch 57 (1985) 341-353. [12] Gurley, J., S. Nissen, C. Grines et al.: Comparision of intravascular ultrasound and angiography following percutaneous transluminal angioplasty. Circulation 82 (1990) 111-72 (Abstract). [13] Harding, M., M. Leithe, D. Mark et al.: Ergonovine maleate testing during cardiac catherization: a 10-year perspective in 3447 patients without significant coronary artery disease or Prinzmetal's variant angina. J. Am. Coll. Cardiol. 20 (1992) 107-111. [14] Katritsis, D., M. Webb-Peploe. Limitations of coronary angiography: an underestimated problem. Clin. Cardiol. 14 (1991) 20-24. [15] Kemp, H. G., R. A. Kronmal, R. E. Vliestra et al.: Seven years survival of patients with normal or near normal coronary arteriograms: a CASS registry study. J. Am. Coll. Cardiol. 7 (1986) 479^183. [16] Killip, T.: The coronary artery surgery study (CASS) - a randomized trial and a registry. Z. Kardiol. 74 (Suppl. 6) (1982) 7 9 - 8 5 . [17] Logan, S. et al.: On the fluid mechanics of human coronary artery stenosis. IEEE Trans, on Biom. Eng. (1975) 327-344. [18] Markus, M., D. Skorton, S. Collins et al.: Visual estimates of percent diameter coronary stenosis: "a battered gold standard". J. Am. Coll. Cardiol. (1988) 882-885. [19] Meier, B., A. Gruentzig, R. Pyle: Assessment of stenoses in coronary angioplasty, inter- and intraobserver variability. Int. J. Cardiol. (1983) 159-169. [20] Mizuno, K., A. Kurita, N. Imazeki: Pathological findings after percutaneous transluminal coronary angioplasty. Br. Heart J. 52 (1984) 588-590. [21] Ofili, E., A. Labovitz, J. St. Vrain et al.: Analysis of coronary blood flow dynamics in angiographically normal and stenosed arteries before and after endoluminal enlargement by angioplasty. J. Am. Coll. Cardiol. 21 (1993) 308-316. [22] Sherman, C., F. Litvack, W. Grundfest et al.: Coronary angioscopy in patients with unstable angina pectoris. N. Engl. J. Med. 315 (1986) 913-919. [23] Tobis, J., J. Mallery, D. Mahon et al.: Intravascular ultrasound imaging of human coronary arteries in vivo. Analysis of tissue charcterizations with comparison to in vitro histological specimens. Circulation 83 (1991) 913-926.

52

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[24] White, C., S. Collins, C. Ramee et al. (eds.): Advances in quantitative coronary arteriography. ??? (1993). [25] White, C., C. Wright, D. Doty et al.: D o e s visual interpretation of the coronary arteriogram predict the physiologic importance of coronary stenosis? N. Engl. J. Med. 310 ( 1 9 8 4 ) 8 1 9 - 8 2 4 . [26] Yasue, H., A. Takizawa, M. Nagao et al.: Long-term prognosis for patients with variant angina and influential factors. Circulation 78 ( 1 9 8 8 ) 1 - 9 . [27] Zir, L. M., S. W. Miller, R. Dinsmore et al.: Interobserver variabity in coronary angiography. Circulation 53 ( 1 9 7 6 ) 6 2 7 - 6 3 2 .

Discussion Fleck: I would like to stress that we have to be able to correctly interpret the complaint symptoms and not just have them in our heads. We have to actually use the supplementary investigations which are required. Becker: I would just like to add another aspect, not so much the indication for angiography. The more frequently coronary angiography is performed in a department, the greater the distance between clinical symptoms and morphology. And one has to stop the morphologists who want to dilate every stenosis. It would be patient-friendly, if diagnostic and therapeutic procedures were combined in one session. But this means that if I want to be on the safe side, I have to have a lung function, the blood group and carotid-doppler investigations for all patients in advance, because the patients need to be potentially eligible for surgery. And this would totally exceed my budget. In addition, this effort is simply not to be achieved on diagnostic investigations in 24 hours. Fleck: The logistics have improved such that the important non-invasive findings are available within a short period of time. Besides, we can now supply blood within 20 minutes if necessary. One has to plan the logistics for the extreme case, so that if complications arise - which is seldom the case - the necessary steps can be taken quickly. For this reason, one had to know where one should invest one's money beforehand. Mr. Becker is absolutely right in saying that there are a few additional investigations which need to have been completed beforehand and which, I believe, can be achieved, even with the shortest hospital stays. For us, this is two and a half days. Forum: Is high-speed MRI already available in Germany? As far as I know, two of these devices have already been installed in Austria. These devices would also be of great significance in other medical fields, for example in liver diagnosis.

Invasive cardial diagnostic procedures

53

Fleck: What you are referring to is a Cine-CT, which has been installed in Graz. And Mr. Riedmiiller, who was previously in Grosshadern, is using it quite extensively. I believe that CT investigations are not as interesting in this connections as the MRI investigations, because they require a greater cost and above all a large amount of contrast medium, which is not well-suited to representing the coronary vessels. Cine-CT is suitiable for anatomy, but I don't see this for coronary angiography at the moment, because one can expect better results from MRI with different contrast media. These Cine-CTs are experimental devices, which still cannot be practically used anywhere in the cardiac area.

Nitric oxide an endothelium-derived local vascular nitrovasodilator system Th. F. Liischer, M. R. Tschudi

Introduction Ever since Thomas Lauder-Brunton first introduced amylnitrate into clinical medicine [1], nitrovasodilators of different classes have been extensively used in the medical treatment of angina pectoris, myocardial infarction and heart failure [2, 4], In recent years, the understanding of the mechanisms of action of nitrates has been greatly increased, particularly since the discovery of endothelium-dependent relaxation and its mediatior, the endogenous nitrovasodilator, NO (Fig. 1; [5, 6], This review summarizes curent knowledge of the endothelial L-arginine/NO pathway in the human circulation and updates previous articles [7],

Endothelium-dependent vasodilation In isolated blood vessels, as well as in the intact organism, endothelium-dependent relaxation or vasodilatation respectively occurs in response to physical, chemical and hormonal stimuli [6, 8-12], Indeed, acetylcholine relaxes or dilates conduit arteries (Fig. 2) and increases local blood flow when infused intra-arterially [13, 14], In the human forearm circulation, intraarterial infusion of acetylcholine causes a pronounced increase in blood flow, unaffected by acetylsalicylic acid (which inhibits the formation of prostacyclin) or by phentolamine (which excludes a contribution by the prejunctional inhibitory effects of the muscarinic agonist on adrenergic neurotransmission; [14]). Similarly, in sympathectomized animals, the vasodilator response to intra-arterial acetylcholine is maintained [15]. However, infusion of the inhibitor of NO production, L-N G -monomethylarginine (L-NMMA), inhibits the response to acetylcholine both in isolated arteries as well as in the human forearm circulation (Fig. 3). Thus, the vasodilator effects of acetylcholine are mediated by endothelium-derived NO [5].

Th. F. Liischer, M. R. Tschudi

56

Platelets cGMP

R-O-NO2

R-0-N=0

L -Arginine:

SIN

R-SH (Cysteine)

R - S - N =0 (Nitrosothiol)

Endothelium Nitric

Oxide

cGMP

|relaxat¡on| Vascular smooth muscle cell

Fig. 1

The L-arginine/NO pathway. The endogenous nitrovasodilator, NO, is formed from L-arginine within endothelial cells and released both luminally and abluminally. In vascular smooth muscle cells, N O activates soluble guanylyl cyclase (sGC) and in turn leads to the formation of cyclic GMP, the second messenger mediating relaxation. In platelets, increased levels of cyclic GMP are associated with a decreased adhesion and aggregation of cells. Therapeutic nitrates such as organic nitrates ( R - 0 - N 0 2 ) or sydnonimines (SIN-1; the active metabolite of molsidomine) directly activate sGC by releasing NO from their molecules. In contrast to SIN-1, organic nitrates have to undergo a biotransformation requiring thiol groups (reproduced with permission [5]).

Endothelium-derived N O

c o 'i o (0 ** c o o a> a> c £ a. a> a> a. o ^ a> a> Q. 8 ra 0) en

57

0 1 L-NMMA plus Indomethacin

20-

n=5 L-NMMA n=4

40 -

60-

80-

J

T

J IIIndomethacin IL 6

- f — J — J — g Control n=8

100-J

Acetylcholine (-logM) Fig. 2

Endothelium-dependent relaxation of acetylcholine in the human internal mammary artery. Under control conditions, acetylcholine causes full relaxation. The inhibitor of N O formation L-N G -monomethyl arginine ( L - N M M A ; 10 4 M ) markedly reduces the response. Under these conditions, inhibition of prostaglandin formation has a weak addtitional inhibitory effect (reproduced with permission

[18]).

Formation of endothelium-derived NO NO is formed from the amino acid L-arginine (Fig. 1; [16, 17]). Cultured endothelial cells deprived of L-arginine lose their ability to release NO, while administration of L-arginine restores this response [16]. In arteries obtained from experimental animals and humans, endothelium-dependent relaxation by acetylcholine is inhibited by the analogue of the amino acid L-N G -monomethyl arginine (L-NMMA) and restored by the addition of L-arginine [18, 19]. LNMMA, but not its enantiomer D-NMMA, induces endothelium-dependent contractions in intramyocardial coronary arteries [19] and markedly increases

58

Th. F. Lüscher, M. R. Tschudi

Diameter (%)

Flow ( % ) 200 p