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JACC Vol. 5, No.6 175B June 1985:175B-184B

Role of and in Coronary Atherosclerotic Disease and Sudden Death

VALENTIN FUSTER, MD, FACC, PETER M. STEELE, MB, JAMES H. CHESEBRO, MD, FACC New York, New York and Rochester, Minnesota

During the last decade, significant advances have been sion during the acute coronary syndromes, post­ made in the understanding of the pathogenesis of coro­ mortem coronary arteriography, and methods for serial nary atherosclerotic disease. Two facts are important: histopathologic and histochemical studies, have brought 1) the early and some of the advanced coronary athero­ to light the clinical importance of the processes of plaque sclerotic lesionsprogress very slowly,probably by means rupture, dissecting hemorrhage and, most important, of a complex stepwise biologic process with one of the thrombosis. These complicated processes appear to be steps being an interaction between platelets and the ar­ of paramount importance in the Pllthogenesis of some terial Wall; the process can be favored by the so-called of the acute coronary syndromes including unstable an­ risk factors of atherosclerotic disease, and 2) some of the gina, myocardial and sudden coronary death. advanced coronary atherosclerotic lesions progress very Antithrombotic and inhibitor therapy is under rapidly, probably by means of complicating anatomic investigation and appears promising in some of these events, one of whichis related to a thrombogenic process. patient subsets. From a clinical point of view, technologic improve­ (J Am Coil CardioI1985;5:175B-184B) ments, such as serial coronary arteriography, reperfu-

Natural Evolution of Atherosclerotic Lesions to clinically relevant advanced atherosclerotic lesions (such The International Project 0), which in­ as fibrous plaques) frequently occurs in those persons with volved 14 countries with 19 different racial groups, had the the so-called risk factors of atherosclerotic disease; 2) the objective of describing the incidence and natural history of early and some of the advanced atherosclerotic lesions pro­ atherosclerotic lesions found in coronary or the aorta gress very slowly, probably by means of a complex stepwise at autopsy in these different populations. In the study, 23,000 biologic process in which one of the steps is related to sets of and aortas were evaluated. The interaction between platelets and the arterial wall; and 3) findings demonstrated that raised fatty streaks are a universal some of the advanced atherosclerotic lesions progress very phenomenon in young persons in all geographic and racial rapidly, probably by means of complicating anatomic events, groups; however, their evolution into clinically relevant fi­ one of which is related to a thrombogenic process. brous plaques and complicated lesions varies in incidence and extent among different geographic and racial groups Pathogenesis of Early Atherosclerotic Lesions and also among the various arterial systems, being predom­ inant in the coronary artery system (2). The major critical events in the development of the early atherosclerotic lesions (Table 1, Fig. 1) (3) are: 1) hemo­ In the natural history of the atherosclerotic lesion (Fig. dynamic turbulence, endothelial injury and 1 and 2), three facts are important: 1) the progression of early coronary atherosclerotic lesions (raised fatty streaks) cell proliferation; 2) interaction between platelets and the arterial wall; 3) proliferation of fibrous tissue; and 4) ac­ cumulation of lipoproteins. From the Division of Cardiology, Mount Sinai MedicalCenter, New Hemodynamic tpfbulence, endothelial injury and York, New York and the Divisionof Cardiovascular Diseaseand Internal smooth muscle cell ppoliferation. Arterial branch points Medicine,MayoClinicand MayoFoundation,Rochester,Minnesota. This study was supportedin part by researchGrants HL 17430, HL 21533and and other areas where atherosclerotic plaques usually de­ HL 23550 from the National Heart, Lung, and Institute, National velop have been shown to be sites of endothelial injury (4), Institutesof Health, Bethesda, Marylandand Grant CRC-RR585 fromthe There is some evidence that hemodynamic factors are in­ United States Public Health Service, Bethesda, Maryland. Addressfor reprints: ValentinFuster, MD, MountSinai MedicalCen­ volved in causing such focal and chronic or continuous ter, One Gustave L. Levy Place, New York, New York 10029. minimal endothelial injury. From experiments in which hy-

©1985 by the American ColIege of Cardiology 0735-1097/85/$3.30 176B FUSTER ET AL. JACC Vol. 5. No.6 CORONARY ATHEROSCLEROTIC DISEASE June 1985:1758-184B

Coronary Atherosclerotic Disease

Complicated lesion (Thrombosis) IPathology I

Early Figure 1. Scheme of evolution of coronary artery Norma l lesion atherosclerosis . The progression of early lesions to clinically relevant advanced lesions tends to occur in those persons with the so-called risk factors of atherosclerotic disease. The early and some of the • clinically relevant advanced lesions can progress to total occlusion of an artery either through slow pro­ gression or rapidly by formation with sub­ sequent fibrotic organization. Icr ical l Ulstable Angina Asymptomatic Sudden Death Sudden death

I I i 10 50 60 Age (years)

draulic models of various flow patterns were used, it was (9) was very superficial, the possibility arises that the mi­ possible to predict from the site of maximal turbulence the gration and proliferation of smooth muscle cells are related areas of predilection for occurrence of atherosclerosis within to an interaction between blood components and the injured the human aorta (5); similarly, the localization of athero­ surface of the arterial wall. sclerotic plaques in the coronary artery tree appears to cor­ Interaction between platelets and the arterial wall. relate with sites of hemodynamic turbulence (2,6,7). There Evidence that platelets and other formed elements of the is increasing evidence that some of the so-called risk factors blood can interact with the minimally injured vascular en­ of atherosclerotic disease may contribute to this chronic dothelium in regions of blood turbulence has been obtained process of endothelial injury (8). in a number of studies . Formed elements, mainly platelets, The concept that atherosclerosis is a local response to have been detected on the endothelial surface of arteries chronic or continuous minimal endothelial injury has also from rabbits, pigs and young human subjects who died received further support (9). Experimental endothelial injury suddenly; these elements occurred near those sites where reproduces the full spectrum of early atherosclerotic lesions. atherosclerosis develops (10). In such experiments, as in spontaneous atherosclerosis, one Thus far, it appears that the observed attachment of plate­ of the first structural changes is an intimal proliferation of lets to damaged endothelial surfaces, and particularly their smooth muscle cells that presumably derive from the media activation, depends mainly on a complex molecule related of the artery. Because the arterial injury in these experiments to factor VIII (II). This molecule, called the Willebrand

Figure 2. Progression of coronary ar­ tery atherosclerosis. Slow progres­ sion: A, normal artery; B, A with fibrosis; C, advanced fibrous plaque. Rapid progression: D, occlu­ sion by thrombus formation over su­ perficial plaque damage; E, thrombus in process of fibrotic organization. (Reproduced from Fuster V [3], with permission .) JACC Vol. 5. No.6 FUSTER ET AL. 1778 June 1985:1758-1848 CORONARY ATHEROSCLEROTIC DISEASE

Table 1. Simplified Unified Concept of Probable Sequential erties (16). It is conceivable that, during the platelet-arterial Events in Coronary Atherosclerotic Disease: Role of Platelets wall interaction, platelet factor 4 and platelet-derived growth and Thrombosis* factor penetrate the vessel wall; then platelet factor 4 may Early lesions-asymptomatic stage attract the smooth muscle cells from the media toward the Hemodynamic factors-endothelial damage intima, and platelet-derived growth factor, together with Platelet deposition other growth factors, may playa role in the proliferation of Smooth muscle cell migration and proliferation Connective tissue synthesis intimal smooth muscle cells. Lipid transformation and deposition Insight into the contribution ofplatelets to the initiation Growing lesions-angina pectoris of atherosclerosis has also been gained by investigating Progression of above (slow process) whether inhibition of platelet function occurs in experi­ Organization of thrombi (rapid processi' mental animals resistant to the development of atheroscle­ Clinical complications Unstable angina rosis. For several years, a breeding colony of pigs with Plaque rupture. thrombosis' severely impaired platelet function in the form of homo­ Myocardial infarction zygous von Willebrand's disease has been maintained in Plaque rupture. thrombotic occlusion' Rochester, Minnesota. Fuster et al. (17,18) showed that Sudden death such pigs have a marked impairment in platelet attachment Chronic myocardial fibrosis to the vascular wall, and they are resistant to the initiation Myocardial infarction} . T MyocardiiaI'ISChemierma thrombosis and progression of both spontaneous atherosclerosis (17) ? Microemboli and atherosclerosis induced by a diet mildly high in cho­

*Italic type indicates steps in which platelets and thrombosis play a lesterol (18). However, pigs with heterozygous von Wil­ role; "events that may be prevented or diminished by use of platelet­ lebrand's disease and, thus, less severely impaired platelet inhibiting drugs. function are not resistant to atherosclerosis. This is con­ sistent with the idea that the presence of normal or nearly normal platelet function may be important in the initial factor, is normally present in the circulating plasma and stages of atherosclerosis. platelets as well as in the endothelial and subendothelial Fibrous tissue formation. The formation of fibrous tis­ regions (probably attached to collagen fibrils), and there is sue contributes significantly to the initiation of the athero­ increasing evidence that it favors the platelet-arterial wall sclerotic plaque and, most importantly, to its progression, interaction and platelet activation in such regions of endo­ as discussed later. The elements making up this fibrous thelial damage. tissue are collagen, proteoglycans, elastin and glycopro­ The possibility has been raised that when attached to the teins, and all of them appear to be synthesized by the smooth mildly injured arterial wall, these platelets are one of the muscle cells of the artery (19-23). principal factors that stimulate the smooth muscle cell pro­ Collagen formation is the major contributor to the growth liferation that occurs at the initial stages of atherosclerosis. ofthe atherosclerotic plaque. The glycosaminoglycans and In experimental atherosclerosis induced by endothelial in­ elastin fibers appear to be important in the binding of lipid jury, one of the first morphologic events is the appearance into the arterial wall. In addition, elastin fibers contribute of platelets undergoing intracytoplasmic degranulation and significantly to the process of calcification of the athero­ adhering to the endothelial surface and subendothelial de­ sclerotic plaque. appear to be important in nuded areas. This precedes the migration and proliferation certain interactions of collagen and elastin fibers. of smooth muscle cells (9). An important finding by Ross This concept offibrous tissue synthesis assumes that the et al. (12) was that a substance derived from platelets­ endothelial injury and platelet deposition not only lead to platelet-derived growth factor-was necessary for the pro­ the migration and proliferation of the smooth muscle cells, liferation of smooth muscle cells and fibroblasts in culture, but also stimulate them to produce the synthesis components and it has been assumed that this substance is one of the of fibrous tissue. In addition, it appears that the chronic main factors responsible for smooth muscle cell proliferation pulsatile distension of the arteries also favors the synthesis in the early atherosclerotic lesions. This growth factor is a of collagen by the smooth muscle cells and, thus, the slow low molecular weight, heat-stable protein that has been pu­ progression of the atherosclerotic plaque (24). rified (13). Platelet-derived growth factor, platelet factor 4, Lipoprotein entry into and accumulation by the ar­ which is an antiheparin factor, and beta-thromboglobulin terial wall. The major class of lipids accumulating in the are all released from the platelet alpha-granules during plate­ arterial wall during atherogenesis is esters. The let activation (14). The observation that platelet factor 4 can cholesterol is derived from plasma lipoproteins. Biochem­ penetrate the vessel wall intima during the process of plate­ ical studies of atherosclerotic vessels at various stages of let-arterial wall interaction (15) is of interest, particularly development have shown that whereas plasma and the nor­ in view of the recent observation of its chemotactic prop- mal arterial wall contain cholesterol linoleate, the devel- 178B FUSTER ET AL. JACC Vol. 5, No.6 CORONARY ATHEROSCLEROTIC DISEASE June 1985:175B-184B

opment of atherosclerotic plaques is characterized by the complicating anatomic events, one of them related to a accumulation of cholesterol oleate within cells (25,26). This thrombogenic process. Indeed, atherosclerotic plaques, par­ is also the case for most types of experimentally induced ticularly those of an already moderate or significant degree, atherosclerosis. As plaques become more advanced, free may progress very rapidly by means of superimposed plate­ cholesterol and cholesterol linoleate from trapped plasma let and thrombi (Fig. 2D), which then tend to undergo also accumulate bound to extracellular connective tissue and phagocytosis and fibrotic atherogenic transformation (Fig. particularly in macrophages or cells derived from circulating 2E) (32,33). It is likely that this fibrotic organization of monocytes (26). thrombi is also dependant on the activation of the smooth The possible ultrastructural and biochemical roles of muscle cells, not only by the platelet-derived growth factor, lipids in atherosclerotic plaque formation have been sum­ but also probably by the fibrin itself as well as by the throm­ marized (8) in the following way: 1) It appears that a high bin and generated in the thrombus media (14). serum concentration of low density lipoprotein contributes An important question to be answered is why does throm­ to the process of endothelial injury (27). 2) Studies with bus formation tend to occur over atherosclerotic plaques? smooth muscle cell cultures (27,28) suggest that lipoproteins In this context there are at least three important aspects to may be mitogenic, probably by contributing to cell mem­ consider: 1) hemodynamic factors; 2) arterial damage, plaque brane formation. 3) The space occupying intracellular and rupture and thrombogenicity; and 3) hypercoagulable state. extracellular accumulations of also may contribute to the Hemodynamic factors. In regions of focal arterial nar­ growth of the atherosclerotic plaque (26). 4) It has been rowing, there is a significant wall shear stress (force parallel suggested that factors that impair removal of cholesterol to surface and independent of turbulence) with wide from the arterial wall may favor its accumulation and, there­ variations in the direction of these forces (34). These ob­ fore, the progression ofthe disease. Conversely, recent stud­ servations are of particular significance in view of the cal­ ies (29,30) have established a consistent correlation between culations that forces at or exceeding the yield stress of the high concentrations of high density lipoproteins in plasma arterial surface lining may explain in part the superficial and a decreased incidence and progression of atherosclerotic damage to the arterial wall and, most important, the plaque disease. Because high density lipoprotein molecules traverse rupture that is characteristic of the complicated atheroscle­ the arterial wall easily and are able to transport cholesterol rotic lesions. Other additional hemodynamic factors leading out of aortic smooth muscle cells in culture, it has been to superficial arterial damage and plaque rupture may be suggested that the observed protection against atheroscle­ variations in (35,36), changes in the vascular rosis is related to this removal of cholesterol from the arterial tone (37) and even the normal bending and twisting of the wall. 5) There is evidence that lipoproteins enhance platelet arteries which occur at every heart contraction (38). reactivity (31); as discussed later in regard to the patho­ Arterial damage, plaque rupture and thrombogen­ genesis of advanced atherosclerotic lesions, this enhance­ icity. There are two different types of arterial damage that ment of platelet reactivity may explain the increased throm­ probably lead to thrombus formation over the atherosclerotic bogenicity of an ulcerated atherosclerotic plaque in which plaques: 1) superficial damage mainly involving the endo­ the arterial wall fat may come in contact with circulating thelial and subendothelial layers, and 2) deeper damage platelets. mainly involving rupture, break, tear or ulceration of the atherosclerotic plaque. Pathogenesis of the Advanced and 1) Superficial damage. This superficial damage is likely related to the hemodynamic factors described earlier. It is Complicating Atherosclerotic Plaques now evident experimentally that in such damaged areas there Early coronary artery atherosclerotic lesions, particularly is a significant tendency for platelet aggregation and throm­ in the form of fatty streaks, are a universal phenomenon in bus formation (39,40). Contrary to the minimal endothelial young persons; however, the evolution into clinically rel­ injury of the early atherosclerotic lesions, which appears to evant lesions frequently occurs in those with the so-called lead only to platelet adhesion, this type of superficial arterial risk factors of atherosclerotic disease (Fig. 1, Table 1). We damage in regions of arterial narrowing appears to be some­ now have experimental, pathologic and clinical evidence what deeper, affecting the endothelial and subendothelial that the early atherosclerotic lesions can progress to the layers and leading to platelet aggregation and thrombogen­ advanced and clinically relevant atherosclerotic plaques by icity (Fig. 2D). That is, in these constricted arterial regions, at least two completely different pathogenetic processes. platelets easily become attached to the damaged surfaces as One is related to a continuation of the process responsible a result of the same factors described for the endothelial for the development of the early atherosclerotic lesions as injury of the early atherosclerotic plaques (that is, Wille­ described previously-a chronic phenomenon leading to a brand factor and collagen fibrils), and in this type of deeper slow progression of the atherosclerotic plaque over a period damage, the thrombogenicity is also favored by the absence of decades (Fig. 2A, B and C) (8). The second involves of two natural antithrombotic systems usually present in the JACC Vol. 5, No.6 FUSTER ET AL. 179B June 1985:1758-1848 CORONARY ATHEROSCLEROTIC DISEASE

intact endothelial and subendothelial arterial layer: the fi­ With such a fragile atherosclerotic plaque, it is not surprising brinolytic system (41) and the system (par­ that addition of the hemodynamic factors may lead to plaque ticularly or prostaglandin Iz) (42), rupture, tearing or ulceration. In these stenotic regions of superficial arterial damage, Stepwise histologic sectioning ofthe coronary artery sys­ the clotting mechanism is activated during the processes of tem, including 100 to 1,000 sections of each segment with platelet adhesion and aggregation and is generated, complicating thrombosis, has revealed the following infor­ further promoting the aggregation of platelets and, most mation. Rupture, cracking or ulceration of atherosclerotic important, leading to the formation and polymerization of plaques is a common autopsy finding in patients with coro­ fibrin, which maintains the stability and fixation of the ar­ nary atherosclerotic disease (35,36,38,46,47), In more than terial thrombus (14), Such secondary superimposed depo­ half of the ruptured atherosclerotic plaques, the predominant sition of thrombus (mural thrombus) may undergo athero­ feature is hemorrhage from the lumen through the break genesis with plaque growth (Fig, 2E) (32,33). In addition, (dissecting hemorrhage); this type of rupture tends to occur the thrombus may totally occlude the artery (occlusive in plaques causing of 50 to 85% of the coronary thrombus). However, in contrast to the regions of plaque lumen (38), and usually the hemorrhage does not cause any rupture described later, in these stenotic regions of super­ further compromise of the coronary lumen. Nearly half of ficial arterial damage the thrombus is less fixed and may be the ruptured atherosclerotic plaques reveal hemorrhage and carried away by the high velocity flow and dissolved by the associated mural or occlusive thrombi; such ruptures com­ intrinsic blood lytic system, Indeed, there is now increasing plicated by thrombi tend to occur in plaques causing stenosis evidence that in these atherosclerotic damaged regions where of more than 85% of the coronary artery lumen and the thrombus tends to form there is a continuous dynamic for­ thrombi cause further compromise of the lumen (4,38), Con­ mation and disappearance of platelet thrombi (40) as well versely, and most important, the majority of the compli­ as fluctuating vasotonicity (40,43). Both of these intermit­ cating coronary artery thrombi (80 to 100%) are anchored tent phenomena may explain some of the intermittent coro­ in cracks or ruptured atherosclerotic plaques; the part of the nary artery syndromes, thrombus directly overlying the fissure is predominantly 2) Deep damage or plaque rupture: the complicating platelet-related (35,38). lesions. Arteries that have advanced atherosclerotic lesions Thus, with meticulous histologic sectioning, a frequent (Fig. 3) often have an alteration and fragmentation of their finding at autopsy in cases of acute myocardial infarction elastic elements (44,45) as well as softening related to the is an acute ruptured and hemorrhagic atherosclerotic plaque fatty "gruel," particularlyat the margin of the plaque (35,46). at the site of the complicating occlusive thrombus that pre-

Figure 3. A, Thrombus over a fissure of the capsule of a fibrous plaque. The ma­ terial in the lower half of the field is the collagen of the atheroscleroticarterial wall. The thrombus (the mass in the upper field) is anchored in the break of the underlying capsule. The part of the throm­ bus directly overlying the fissure is rich in "white" components (leukocytes, platelets and fibrin). B, Thrombus mixed with gruel over a wide tear in the collagen of a fibrous coronary plaque. C, Throm­ bus over a wide gap in the capsule of an atheroma, The thrombus (the reticular material in the upper field) has developed over the exposed gruel (the material with the cholesterol clefts in the lower field). The broken end of the atheroma capsule can be seen just to the right of center and the original arterial wall is at the extreme left. D, Occlusive thrombus over a crack at left lower margin of an atheroma at the junction of the atheroma capsule with the original coronary artery wall. Some has occurred through the fissure into the lower part of the atheroma. (Re­ produced from Constantinides P [35] with permission. ) 1808 FUSTER ET AL. lACC Vol. 5, No.6 CORONARY ATHEROSCLEROTIC DISEASE June 1985:175B-184B

sumably contributed to the infarction (48,49). In addition, segment. This may imply complicating or rapidly progres­ and probably more commonly than in the regions of su­ sive lesions as the cause of the syndrome. perficial damage previously described, in these ruptured Indeed, our recent data identify a specific configuration, plaques the complicating thrombi may stabilize and be par­ on routine coronary , in the majority of patients tially occlusive or mural, leading to atherogenesis and plaque with unstable angina presenting as either new onset or cre­ growth (32,33). scendo angina. An asymmetric eccentric lesion with a nar­ In the genesis of thrombi as a of ruptured row neck or irregular borders, or both, was found in 73% atherosclerotic plaques, in addition to the thrombogenic of "angina-producing" coronary vessels in patients with factors when the damage is superficial, as discussed earlier unstable angina, but in only 16% in patients with stable (that is, collagen fibrils and absence of fibrinolytic system angina (59). It has been suggested by postmortem angiog­ and prostaglandin Iz), there are three other important factors raphy and pathologic analysis that such eccentric angio­ to be considered: I) when the atherosclerotic plaque ruptures graphic lesions represent ruptured atherosclerotic plaques and hemorrhage enters the plaque, adenosine diphosphate with or without associated thrombi (60). released from erythrocytes probably contributes to the pro­ In fact, 6 to 45% ofpatients with unstable angina have cess of platelet aggregation (50); 2) in the advanced ath­ some angiographic evidence ofocclusive thrombi (61-64). erosclerotic plaque the accumulated fat is usually underneath In this context it is important to appreciate that more than but, when the plaque ruptures, such fat can come in contact 10% of patients with unstable angina develop myocardial with the circulating blood and activate platelets and promote infarction or die suddenly within 12 weeks of its onset (65). thrombogenicity (31,51); and 3) the acutely damaged site Furthermore, there is increasing evidence that a substantial of the vascular wall can generate tissue thromboplastin which percent of such events may be prevented by antithrombotic also promotes thrombosis (52). therapy in the form of platelet inhibition (66) or heparin Hypercoagulable state. Focal thrombosis can lead to a (67). Finally, intermittent thrombosis or spasm over a su­ secondary hypercoagulable or thrombotic state which may perficially damaged or ruptured plaque may explain some favor progression or recurrence of thrombi (14). However, of the cases of unstable angina that manifest as intermittent it is not entirely clear whether a primary hypercoagulable resting angina (40,43). or thrombotic state that can favor focal thrombosis and ath­ Myocardial infarction. Until recently, most of our erosclerosis really exists. Platelet aggregation and the sub­ knowledge about the lesions associated with transmural in­ sequent generation of thrombin may be activated by cir­ farction had been derived from autopsy studies. Although culating catecholamines (53). This interrelation may be of helpful, these studies represent a highly selected sample of major importance because it may be a link between con­ the population. In addition, the autopsy may have been ditions of stress and the development of arterial thrombosis performed in patients who died suddenly (less than 6 hours (54). Of no less importance is the increasing evidence of after the onset of symptoms) or who died days to weeks an enhanced platelet reactivity in cigarette smokers (55), in after the infarction. Morphologic confirmation of infarction patients with a strong family history of coronary artery dis­ is rarely possible within 6 hours of the onset of symptoms, ease (55), in patients with hyperlipidemia (31) and those and the meaning of pathologic findings observed days to with diabetes mellitus (56). However, it is conceivable that weeks after infarction may be obscured by antemortem re­ in such high risk conditions for atherosclerotic and throm­ canalization of the thrombus or by postmortem botic disease, the enhanced platelet reactivity and coagu­ and thrombus retraction from the arterial wall (32,68,69). lability may be a secondary phenomenon rather than a pri­ In addition, there are important differences in the methods mary conditioner of the disease. used to examine the coronary arteries. This variability in groups studied and methods used in autopsy series is re­ Thrombosis and the Coronary Syndromes flected in the reported incidence of thrombosis associated with transmural infarction; this rate has ranged from about Including Sudden Death 20 to about 95% (70). Unstable angina pectoris. Analysis of coronary artery DeWood et al. (71) were the first to use coronary arte­ anatomy has revealed that the distribution of lesions, the riography systematically to define the prevalence of total number of diseased vessels and the percent stenosis in pa­ coronary artery occlusion in the early hours after transmural tients with unstable angina is similar to that in patients with myocardial infarction. Total coronary occlusion was ob­ stable angina (57). However, because these studies did not served in 87% of patients who were evaluated within 4 hours identify the coronary anatomy before the onset of unstable after the onset of symptoms; this proportion decreased to angina, their significance is unclear. Recently, Moise et al. 65% when patients were studied 6 to 24 hours after the onset (58) found progression of coronary artery disease in 76% of symptoms. Among patients with angiographic features of patients with stable angina restudied after an episode of of coronary artery thrombosis, the thrombus was retrieved crescendo angina and progression in a previously healthy by Fogarty in 88%. Thus, total coronary artery JACC Vol. 5, No.6 FUSTER ET AL. 1818 June 1985:1758-1848 CORONARY ATHEROSCLEROTIC DISEASE

occlusion is frequent during the early hours of transmural transient myocardial and sudden ventricular fi­ infarction and decreases in frequency during the initial 24 brillation. Clinical assessment of the frequency of such em­ hours, suggesting that coronary spasm or thrombus for­ boli is impossible because they are so small and, unlike the mation with subsequent recanalization or both may be im­ retina, the myocardium cannot be visualized in life. Some portant in the evolution of infarction. previous pathologic studies of sudden death have found Recent early postinfarction angiographic studies (72) of morphologic evidence of intramyocardial platelet emboli the efficacy of thrombolytic therapy to restore perfusion of within small vessels (77,78). However, the frequency was the infarct-related coronary artery have indicated that throm­ not much higher than that in control patients. botic coronary artery occlusion probably plays a role in It can be concluded that, in a high proportion of cases about 60 to 90% of transmural myocardial infarcts and in of sudden coronary death, the pathologic process probably a lesser number of subendocardial myocardial infarcts (the involves a rapidly evolving coronary artery lesion in which importance of rupture of a significantly stenotic atheroscle­ plaque fissure and resultant thrombus formation lead to an rotic plaque in the genesis of the thrombus was discussed ischemic and fatal electrical instability of the heart. Whether earlier in this paper). In addition, spontaneous lysis of the intramyocardial platelet emboli play a role in some cases thrombus and recurrence of the occlusion are frequent phe­ of sudden coronary death is debatable and difficult to prove. nomena; such processes appear to be favored by the use or nonuse of anticoagulation in the postinfarction period, respectively. The Role of Platelet-Inhibiting Drugs Sudden death due to coronary disease. In most cases Because of the evolving importance of platelets in the of sudden unexpected death, there is little doubt that the pathogenesis of atherosclerotic disease and its complica­ terminal event is some form of electrical instability of the tions, a brief statement on the role of platelet inhibitors is heart (73). Considered from a numerical standpoint, the pertinent. This discussion will focus on the two different majority of such sudden deaths occur in persons with ex­ mechanisms of atherosclerotic plaque progression: slow pro­ tensive coronary artery disease (73,74). The electrocardio­ gression of the early atherosclerotic lesions toward the ad­ graphic diagnosis of acute myocardial infarction or ischemia vanced atherosclerotic plaques and rapid thrombogenic pro­ in resuscitated survivors provides a more accurate estimate gression and complications of the advanced atherosclerotic of the incidence of acute myocardial involvement in sudden plaques. coronary death than does standard histologic examination, The slow process of atherosclerotic progression. which may give unremarkable results at this early stage There is evidence that platelet-arterial wall interaction is an (32,68,69). Electrocardiographic evidence of acute myo­ important step in the pathogenesis of the early atheroscle­ cardial infarction and, more commonly, ischemia, has been rotic lesions and of the slow progression of advanced ath­ noted in nearly three-quarters of these patients (74,75). This erosclerotic plaques. Indeed, it appears that the minimal may indicate a decrease in coronary blood supply as a result endothelial injury caused by chronic hemodynamic turbu­ of an acute coronary artery lesion. Indeed, acute compli­ lence and by some of the so-called risk factors of athero­ cated coronary artery lesions were found at autopsy in nearly sclerotic disease may lead to intermittent platelet-arterial three-quarters of the patients (75,76), and the majority were wall interaction and the slow development of atherosclerotic consistent with plaque rupture and resultant thrombus for­ lesions. We have been able to reproduce such minimal endo­ mation as described earlier. In the remaining quarter of the thelial injury in the experimental pig (without desquamation patients, sudden coronary death appeared to be associated of the endothelial cells from the subendothelial layer) (79); with a fibrotic myocardium (previous myocardial infarction) a single layer of platelets interacting with the damaged en­ or other alterations (74,75). dothelium appears to be sufficient to induce the intimal On the basis ofthe previous information, it is not unrea­ smooth muscle cell proliferation compatible with the ath­ sonable to consider thrombus formation in the coronary erosclerotic lesion. The important point is that currently arteries as a frequent factor precipitating sudden death. there is no platelet-inhibitor drug available that can totally The question is whether the terminal electrical instability of prevent adherence of this single layer of platelets. Therefore, the heart is an ischemic response to the complicated coronary we think that the use of platelet-inhibiting drugs will not obstruction or to intramyocardial thromboemboli that orig­ prevent the slow atherosclerotic process. inate from the coronary lesion and lodge within small ves­ If a new platelet-inhibiting drug that can totally prevent sels. The importance of the intramyocardial thromboemboli platelet adhesion to the vessel wall becomes available in in contributing to death is more conjectural. By analogy the future. then a new risk will emerge: the risk ofbleeding. with thrombi in the carotid artery and transient cerebral Pigs with homozygous von Willebrand's disease have a ischemic attacks, the coronary thrombi could be a source marked impairment in platelet attachment to the vascular of emboli consisting predominantly of platelets that are car­ wall (79) and are resistant to the initiation and progression ried into the myocardium. Such emboli could give rise to of atherosclerotic disease (17,18), but they have a severe 182B FUSTER ET AL. JACC Vol. 5, No.6 CORONARY ATHEROSCLEROTIC DISEASE June 1985:1758-1848

bleeding tendency. On the other hand, pigs that have less turbulence in hemic systems and in the distribution of the atheroscle­ severely impaired platelet-arterial wall interaction, that is, rotic lesion. 1965;57:155-61. have heterozygous von Willebrand's disease, develop ath­ 6. Halon DA, Sapoznikow D, Lewis BS, et al. Localization of lesions in the coronary circulation. Am J Cardiol 1983;52:921-6. erosclerosis but are free of significant bleeding (80). Also, 7. Saltissi S, Webb-Peploe MM, Coltart OJ. Effect of variation in coro­ Friedman et al. (81) produced marked nary artery anatomy on distribution of stenotic lesions. Br Heart J 3 (platelet count < 7,OOO/mm ) in rabbits by administering 1979;42:186-91. antiplatelet antiserum. Injury of the in these 8. Fuster V. Pathogenesis of Atherosclerosis. In: Spittell JA Jr, ed. Clin­ rabbits with a polyethylene catheter was not followed by ical Medicine. Vol 6. 1-22. the development of atherosclerotic lesions, but the animals 9. Spaet TH, Stemerman MB, Veith FJ, et al. Intimal injury and regrowth in the rabbit aorta: medial smooth muscle cells as a source of neoin­ had a significant bleeding tendency; however, rabbits with tima. Circ Res 1975;36:58-70. less severe thrombocytopenia were not protected from 10. Jorgensen L, Packham MA, Roswell HC, et al. Deposition of formed atherosclerosis. elements of blood on the intima and signs of intimal injury in the aorta These findings emphasize that prevention of the initiation of rabbit, pig, and man. Lab Invest 1972;27:341-50. and progression of the slow atherosclerotic process in the II. Meyer D, Baumgartner HR. Annotation: role of arteries might be accomplished only if platelet function and in platelet adhesion to the subendothelium. Br J Haematol 1983;54:1-9. platelet count decreased to the point of causing significant 12. Ross R, Glomset J, Kariya B, et al. A platelet-dependent serum factor that stimulates the proliferation of arterial serum factor that stimulates bleeding. Therefore, it is not unreasonable to think that only the proliferation of arterial smooth muscle cells in vitro. Proc Natl those platelet-inhibiting agents that cause severe platelet Acad Sci USA 1974;71:1207-10. dysfunction and bleeding might be of benefit in preventing 13. Antoniades HN, HunkapiIIer MW. Human platelet-derived growth the progression of the slow atherosclerotic process. Such factor (PDFG): amino-terminal amino acid sequence. Science 1983;20:963-5. agents are not yet available, and we think are undesirable. 14. Fuster V, Chesebro JH. Current concepts of thrombogenesis. Role of In practical terms, for the slow progression of atheroscle­ platelets. Mayo Clin Proc 1981;56:102-12. rosis, which tends to occur in a period of decades, preven­ IS. Goldberg JD, Stemerman MB, Handin RI. 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