Pathophysiology
of Acute Coronary Syndromes
Prediman K. Shah,
MD,
The natural history of coronary artery dii is punctuated by clinical manifestations of unstable angina, acute myocardiil infarction, and ischemit sudden death. These acute coronary syndromes share common pathophysiologic mechanisms that include fissuring of a plaque followed by varying degrees of dynamic coronary obstruction, which is due to vasoconstriction and coronary thrombosis. The response to plaque fissure is likely to be modulated by local and/or systemic procoagulant and antiiagulant-fibrinolytic actiii. The key role of coronary thrombosis in acute coronary syndromes has substantial implications for prevention and treatment of complications of coronary atherosclerosis.
and James S. Forrester,
MD
I
n the past few years, intensive investigations have focused on the pathophysiologic events leading to conversion of stable manifestations of atherosclerotic coronary artery disease (CAD) to its more acute and sinister manifestations: unstable angina, acute myocardial infarction (MI), and ischemic sudden death (acute coronary syndromes). Unstable angina, characterized by recurrent episodes of prolonged myocardial ischemia triggered predominantly by episodic reductions in coronary blood flow, is an important model for understanding the basic pathophysiologic events that lead to all acute ischemic syndromes. Acute coronary syndromes are the first clinical expression of CAD in about 30% of patients with CAD. CORONARY ATHEROSCLEROTIC UNSTABLE ANGINA
From the Division of Cardiology and the Department of Medicine, Cedars-Sinai Medical Center and University of California School of Medicine, Los Angeles, California. Address for reprints: Prediman K. Shah, MD, Division of Cardiology, Room 5314, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048.
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PLAQUE IN
The traditional angiographic indices of the severity of CAD (number of vessels with significant stenosis, percent diameter stenosis, minimal diameter, length of stenosis, and the presence or absence of collaterals) cannot accurately differentiate patients with stable CAD from those with unstable angina (Figure 1).14 A detailed examination of the morphology of coronary stenosis in culprit arteries, using antemortem as well as postmortem angiography, shows that in at least 7040% of patients with unstable angina, the stenosis is eccentric, with overhanging or irregular margins and intraluminal haziness or radiolucent filling defects-features rarely observed in the coronary arteries of patients with stable angina.4’5 Meticulous and detailed postmortem examination of atherosclerotic plaques in the culprit coronary arteries of unstable angina patients shows them to be complex, with fissures or cracks in the fibrous cap of the plaque (Figure 2). These fissures or ruptures usually occur either at the margins of the plaque in the area where the eccentric plaquebearing segment joins the non-plaque-bearing segment of the arterial wall or in the center of the plaque.6 Fissures average about 300-400 pm in length and vary in width from narrow slits to large gaps or ulcerations of the plaque surface.’ Areas of hemorrhage are commonly observed and may be NOVEMBER 4, 1991
secondary to plaque fissure.7 Coronary angioscopy has confirmed the presence of complex and fissured plaques in the culprit coronary arteries of patients with unstable angina undergoing coronary artery bypass surgery (Figure 3).’ POTENTIAL MECHANISMS
OF PLAQUE FISSURE
The precise events leading to plaque fissure remain unclear. Fissures occur more frequently in plaques that are rich in extracellular and eccentric pools of lipid. However, they are not unique to severely occlusive atherosclerotic plaques, but also frequently occur in mildly occlusive plaques.g-ll Pathologic studies show that often the plaque fissure develops at the margin of the atheroma, where the atheroma joins the normal arterial wall and plaque-fissure shows a predilection for thin acellular, lipid-rich, soft, or highly vascularized atheromatous plaques.6,7s9 Richardson et al6 demonstrated by means of in vitro computer models of arteries, that circumferential stress is greatest at the endothelial surface of the arterial wall, stress is concentrated at the junction of the fibrous cap with the more compliant normal arterial wall, and softer plaques tend to develop a higher shear stressI These findings suggest that hemodynamic or mechanical stress associated with heartbeat, bending and twisting of an artery, or increases in blood pressure (exercise, diurnal changes, sudden change in coronary tone) may contribute to fissuring of certain types of vulnerable plaque.13 Experimental studies in mammalian atherosclerotic arteries show that a sudden surge of blood pressure in synergy with endothelial damage can produce plaque fissures.7 Fissures may also occur when activated, subintimal, lipid-laden macrophages and other inflammatory cells release
100
75
Percent Area Stenosis
50 A A
25
0
I
I
SA
UA
I MI involved vessel
Figure l. Comparatlve severity of coronary stenosis In the coronary arteries of patlents wlth stable aNIna @A), unstable angina (UA), and acute myocardlal Infarction (Ml) following thrombolysls. Note the overlap In the severity of steno& In the arteries of patknts wlth SA and those of the culprit arteries of patlents wtth UA and acute MI. (Adapted from Circuration.“)
humoral mediators, such as proteases and tumor necrosis factor, which erode the plaque from within.13,14 Cinematographic studies of cleared human hearts and microsphere studies show that extensive neovascularization of atherosclerotic plaques is associated with a fivefold increase in medial flow compared to normal arterial wall with blood flow directed from adventitia towards the intima.15,16 This increased vascular@ of the atherosclerotic plaque from proliferation of vasa vasora may play a role in plaque fissure by providing a source of bleeding into the plaque and/or by bringing cellular and/or humoral mediators into the plaque, which may contribute to fissuring.15”6This point of view, however, has been challenged by Constan-
Flgure 2. Hlstopathology of a coronary arterial stenosls showing an atherosclerotk plaque (P) wlth a fissure (arrow). An intramural and intralumlnal thrombus (7) Is attached at the slte of the plaque flssure. (Adapted from Davles MJ, ed. Color Atlas of Cardlovascular Pathology. Dxford Unlverslty Press, 1987.)
A SYMPOSIUM:
MECHANISMS
OF UNSTABLE
ANGINA
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Flgure 3. lntraoperathre angloscopk appearance uf smooth atheroma in a patlent wfth stable anglna (A); fissued plaque In a patlent wlth unstable angina (B); and partially occlusive ltiracoronary thrombus In patient with unstable anglna (C). (Adapted from N EngIll Med.B)
tinides on the basis of pathologic findings.17 Several recent studies suggest that plaques considered noncritical or angiographically insignificant ( < 50% diameter stenosis) may become the sites of subsequent plaque fissures with superimposed coronary thrombosis.“1’,1s3’9 Although the precise causes of plaque fissure remain unclear, a variety of factors may render a plaque vulnerable to rupture by damaging the endothelial lining or weakening the fibrous cap or the smooth muscle cells that produce the collagen for the fibrous cap. These factors include chemical or metabolic insults such as prolonged hyperlipidemia, high angiotensin levels, elevated acetoacetic acid levels (i.e., diabetes), nicotine, circulating immune complexes, inflammatory cells and their isC
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 68
humoral products, and increased fragility of collagen from increased cross-linking or contraction.17
CONSEQUENCES OF PLAQUE FISSURE Plaque fissure may abruptly change the geometry of a coronary stenosis, leading to a sudden increase in coronary luminal obstruction. In addition and perhaps more importantly, plaque fissure may trigger more dynamic mechanisms of coronary obstruction (i.e., abnormal vasomotor tone, platelet aggregation, and platelet-fibrin thrombus formation) (Table I), These dynamic factors are implicated in the intermittent coronary artery occlusion that leads to episodic coronary flow reduction and precipitation of unstable angina. NOVEMBER 4, 1991
activation and platelet- or leukocyte-mediated vasoconstriction.3sFurthermore, endothelial dysfunc1. Fixed Coronary Stenosis tion with local thrombin formation may contribute Fissured plaque and to vasoconstriction. Even normal changes in vaso2. Dynamic coronary obstruction motor tone may significantly reduce blood flow in a Vasoconstriction severely stenotic coronary’ artery. Clinical observaPlatelet aggregation Platelet-fibrin thrombus tions that endothelium-independent vasodilators *The interaction is between 1 and 2. such as nitrates and calcium antagonists reduce the number of ischemic episodes in unstable angina patients suggestsome role for coronaryvasomotion DYNAMIC FACTORS COmIBUTING TO in the pathogenesis of ischemia in unstable angina. EPISODIC CORONARY ARTERY OBSTRUCTION However, the limited effect of these agents in IN UNSTABLE ANGINA Abnormal vasomotion: Atherosclerotic arter- reducing the risk of acute MI argues that mechaies have an exaggerated response to certain vaso- nisms other than vasoconstriction are more imporconstrictor stimuli or a paradoxical vasoconstrictor tant. Platelet aggregation: In experimental models response to stimuli that dilate normal blood vessels (Figure 4).20-27 These abnormal or anomalous vaso- of partial coronary artery stenosis and endothelial motor responses of atherosclerotic arteries have injury, Folts et aP6initially reported that spontanebeen observed in experimental models, human ous intermittent coronary occlusion and cyclical arteries studied in vitro as well as in vivo, and variations in coronary blood flow distal to the resemble those of normal arterial strips from which stenosis result from intermittent platelet aggregaendothelial lining has been deliberately removed.28,2gtion. These cyclical flow variations are abolished or Thus, atherosclerosis appears to impair the normal reduced by agents that inhibit platelet aggregation and/or inhibit the effects of platelet-derived thromvasodilator effects of the endothelium.22,30 boxane and serotonin, such as aspirin, thromboxIn normal endothelium, vasodilation appears to be mediated through the release of substances ane synthetaseinhibitors, thromboxane and serotosuch as endothelium-derived relaxation factor nin receptor antagonists, and certain a-adrenergic (EDRF), which may be either nitric oxide or a antagonists. Cyclical variations are exaggerated by nitrosothiol compound synthesizedby the endothe- platelet aggregatory agents such as ADP, plateletlium from arginine.29,31 Stimuli that produce vasodi- activating factor, (Y agonists, nicotine, thrombin, lation in the presence of normal endothelium and exercise (Figure 5).37-45 Evidence of platelet activation in humans with include acetylcholine, histamine, bradykinin, serotonin, substance P, adenosine diphosphate (ADP), unstable angina includes elevatedcirculating and/or adenosine triphosphate (ATP), calcium ionophore urinary levels of products of platelet activation A23187, platelet-activating factor, thrombin, platelets, increased shear stress, increased blood flow, ATHEROSCLEROTIC NORMAL CORONARY ARTERY CORCNJARY ARTERY and exercise (endothelium-dependent vasodilators).32,33 When the endothelium is damaged, such as occurs in atherosclerosis or hypercholesterol150emia, the vasomotor response to endotheliump 2 125dependent vasodilators is blunted or converted to E vasoconstriction. A recent study shows that endoce ioothelial cells in culture produce a potent vasocon- E I 7=strictor peptide labeled endothelin.34 Thus, endoa thelium may modulate vascular tone by releasing d2 50both vasodilator and vasoconstrictor substances. Y 25 The hyperreactivity of the vascular smooth muscle OL ’ ’ ’ ’ ’ 1 ’ ’ ’ ’ ’ ’ cell may reflect atherosclerotic-induced endothe- I Cl C2 A&,,, C3 TNG Cl C2 A&,.. ‘23 TNG I lial dysfunction leading to deficient release of Figure 4. Vasomotor responss of the athsrosckMk and EDRF and/or excessiverelease of endothelin. It is normal coronary atierles to acetykhollns. Note that athstill unclear whether an intrinsic abnormality of the erosderotksegmentsreactwlthatranslentdecraasaIn lumlnal dlamater, whereas the normal arteries react wlth vascular smooth muscle cell also plays a role. a slight Increase In lumlnal diameter. C=contrd; Ash= Plaque fissure may contribute to vasomotor awtykhoflne; lNG=nltroglycarln. (Adapted from N Eng/l hyperreactivity by triggering platelet or leukocyte Me&=) TABLE I Pathophysiology
of Unstable Angina*
A SYMPOSIUM:
MECHANISMS
OF UNSTABLE
ANGINA
%%
such as P-thromboglobulin, platelet factor IV, and thromboxane metabolites46-48; pathologic evidence of platelet microemboli in myocardial microvasculature downstream from the culprit coronary stenosis49;and finally, a strong protective effect of aspirin against development of MI in patients with unstable angina.50-52 Careful autopsy studies by Falk4’ show that platelet microemboli are seen in about 50% of patients who die soon after the onset of ischemic symptoms.53These emboli are almost exclusively seen in arterioles and in small arteries downstream from the artery with a fissured plaque and may be associated with scattered foci of myocardial necrosis. Platelet aggregates on a fissured plaque may reduce coronary blood flow by direct occlusion or through the release of humoral mediators such as serotonin and/or thromboxane. In the absence of normal endothelial function, these mediators produce vasoconstriction. In addition, platelet emboli may produce ischemia or infarction and, conceivably, trigger fatal disturbances of rhythm and conduction.
Mean Aortic Pressure (mm Hg)
150 r 1: ,I
-c
-
Coronary thrombosii: Intraluminal coronary thrombosis appears to play an important role in the pathogenesisof unstable angina.Angiographic studies show intraluminal filling defects and lucencies, indicating a thrombus at the site of a complex coronary stenosis in 1% to 85% of patients with unstable angina.5”61 The inconsistencies in the reported angiographic incidence of intracoronary thrombus may be related to several factors, including variability in the timing of angiography in relation to the symptoms and less than optimal sensitivity of the angiographic criteria for the detection of thrombus. A relatively low incidence of thrombus has been reported in studies where angiography was performed several days to weeks after the last episode of angina.54S5,57-59 In contrast, a higher incidence (50-85%) has b een reported when angiography was performed soon after the last episode of unstable angina.56,60,6* Gotoh et a161observed evidence of intracoronary thrombus in 57% of patients with unstable angina when angiography was
1 min 4
Left Ventricular Pressure (mm Hg)
dP/dt
Mean Left Atrial Pressure (mm t-b)
20 i-m 10 7 0 L
Mean Circumflex Blood Flow (mllmin)
Electrocardiogram
Figure 5. Platelet-mediated spontaneous cyclical coronary flow varlatlon In the canine coronary steno& od from I Am CONcardiof,) l554$i 1417.
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NOVEMBER 4, 1991
model. (Adapt-
performed during episodes of ischemia. Their study used both morphologic features and response to intracoronary thrombolytic therapy as the criteria for thrombus. More importantly, they documented the dynamic and evanescent nature of the intracoronary thrombus in unstable angina. Intraoperative angioscopic observations also show a high prevalence of visible intraluminal thrombus in the culprit arteries of patients with unstable angina undergoing bypass surgery (Figure 3).8 The presence of ongoing thrombosis in unstable angina is further supported by indirect evidence, such as elevated levels of circulating fibrin and urinary markers of thrombin-mediated fibrin formation, such as fibrinopeptide A and other fibrinrelated antigens.62Histopathologic studies confirm the high prevalence of intraluminal and intraintima1 thrombus at the site of a fissured atherosclerotic plaque in patients with unstable angina and other acute coronary syndromes.7,9,10,49,63,64 The frequent development of acute MI, a complication that is now considered to be the consequence of prolonged coronary artery occlusion due to an intraluminal thrombus, is further evidence of the important pathophysiologic role of intracoronary thrombus in unstable angina. Finally, the beneficial effects of anticoagulants (and in some cases thrombolytic therapy) in reducing ischemia and the frequency of infarction argue strongly that coronary thrombosis plays an important role in unstable angina.52S65 FACTORS CONTRIBUTING TO PLATELET AGGREGATION AND CORONARY THROMBOSIS IN UNSTABLE ANGINA Plaque fissure appears to be the initial event that creates a milieu for platelet adhesion, aggregation, and subsequent fibrin-platelet thrombus formation. After fissuring occurs, the contents of the plaque are exposed to circulating platelets. They in turn adhere to the exposed fibrillar collagen (type I) and elastin matrix of the plaque through the interaction of von Willebrand factor and adhesive glycoprotein platelet receptors (Ib and possibly Ia). The high shear rate in the vicinity of a severe coronary stenosis contributes to platelet adhesion and aggregation by a cyclooxygenase independent mechanism. Deep arterial wall injury is associated with a more intense and prolonged platelet deposition against the arterial wall at high as well as low shear rates. This is in contrast to more superficial endothelial injury where platelet deposition is higher at high shear rates, with maximum deposition occurring within lo-20 minutes and dislodge-
ment of platelets caused by the blood flo~.~~ The model of superficial injury and high shear rate simulates a coronary stenosis with mild ulceration of the plaque; the deep injury model simulates an area of arterial stenosis with a deep plaque fissure.13 Following platelet adhesion, exposure of another type of platelet glycoprotein receptor (IIB/ IIIA), binding fibrinogen, von Willebrand factor, and possibly fibronectin bridge activated platelets, leading to platelet aggregation. Platelet-derived procoagulants, as well as the procoagulant effect of the “tissue factor” expressed by the plaque and released from the plaque, activate the clotting cascade, leading to thrombin formation. Thrombin in turn leads to fibrin formation, further platelet aggregation contributing to fibrin-platelet thrombus formation, and vasoconstriction. ROLE OF HYPERCOAGUlABll.llY In addition to the severity of the plaque fissure, the intensity and the duration of the thrombotic response may be further modulated by the balance between systemic or local procoagulant and fibrinolytic state as well as the aggregability of platelets. Hypercoagulable states associated with elevated fibrinogen levels, increased triglyceride and lipoprotein(a) levels, chronic smoking, elevated factor VII activity levels, and depressed fibrinolytic state due to high levels of plasminogen activator inhibitor type 1 may particularly predispose certain individuals to thrombosis, whereas an efficient fibrinolytic system and a hypocoagulable state may protect others from thrombotic consequences of plaque fissure. Autopsy studies in patients who die from the complications of unstable angina frequently show that coronary thrombi of varying ages are seen at the site of a fissured plaque, suggesting ongoing waves of thrombosis and its dynamic nature in the acute coronary syndromes.49 Incorporation and organization of thrombi into the plaque may contribute to accelerated progression of CAD. This has been angiographically demonstrated in up to 70% of patients with unstable angina who were serially studied during progression from a stable to an unstable state.“,67 A UNIMNG MECHANISM TO EXPLAIN THE PATHOPHYSIOLOGY OF ACUTE CORONARY SYNDROMES The acute coronary syndromes of unstable angina, acute MI, and ischemic sudden death appear to share a common pathophysiologic basis, with plaque fissure in the coronary artery as the pathoA SYMPOSIUM: MECHANISMS OF UNSTABLE ANGINA
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Corormry Ftxed
Stenosis
Obstruction
Plaque Fiewre 1
Varieblo
$ Dynamic Obrtruction
Degree
V48omotion pf4telet &grog Thrombo4i4 Pt4tefet embofi
/
I Stenoria
Progre8rion ’ Thrombur
Incorporation
I
into Plaque
logic hallmark (Figure 6).‘,” In addition to the plaque fissure, varying amounts of intraluminal and intramural platelet-fibrin thrombus constitute the acute intimal lesion observed in the vast majority of patients who die of acute coronary syndromes?,l’ When plaque fissure is associated with brief periods of coronary occlusion (due to platelet aggregation, vasoconstriction, or evanescentplatelet-fibrin thrombosis), the result is unstable angina; when the coronary occlusion is more prolonged, the result is acute MI. Subendocardial infarction is more likely to develop when spontaneous reperfusion occurs, before occlusion-induced necrosis has spread transmurally, or when the transmural spread of necrosis from a permanent coronary occlusion is halted by well-developed epicardial collaterals. Sudden cardiac death is likely to occur when a large area of myocardium is rendered ischemic, leading to a fatal disturbance in cardiac rhythm or conduction. This may develop during brief or prolonged periods of coronary occlusion or perhaps when platelet aggregates embolize downstream from the acute coronary lesion. ACKNOWLEDGMENT: The authors gratefully acknowledge the editorial assistance of Beverly Yoshioka in the preparation of this manuscript.
3. Wilson RF, Holida MD, White CW. Quantitative angiographicmorphologyof coronary stenosisleading to myocardial infarction or unstableangina.Cimhtion 1986;73:286. A Ambrose .I& Winters SL, Stem A, Eng A, Teichholz LE, Gorlin R, Fuster V. Angiographicmorphologyand the pathogenesisof unstableanginapectoris.JAm Cd C&l 1985;5:60%16. 5. L&n DC, Fallon JT. Signiice of angiographicmorphology of localized coronary stenosis.Histopathological correlates.&&f&x 1982;66:316. 6. RichardsonPD, Da& MJ, Born GVR. Influence of plaque configuration and stressdistriiution on fissuringof coronary atheroscleroticplaques.Lancet 1989;k 941-944. 7. ConstantinidesP. Plaquefissuresin human coronary thrombosis.JAthemscZer Res 1966;6:1-17. 8. ShermanCT, Litvack F, Gnmdfest W, Lee M, Hickey A, Chaux A, Kass R, Blanche C, Matloff .I, Morgenstem L, Ganz W. Coronary angioscopyin patients with unstableanginapectoris.NEnd JMed 1986;315:913-919. 9. Davies MJ, Thomas AC, ShahPK, Pichler M, Berman DS, Singh BN, Swan HJC. Plaque fissuring-the cause of acute myocardial infarction, sudden ischaemicdeath, and crescendoangina.Br Heart J 1985;53:363-373. l6. Davies MJ, Thomas AC. Thrombosis and acute coronary artery lesions in suddenischemiccardiac death.N Engl J Med 19&1;310:1137-1140. il. Ambrose JA, Winters SL, Arora RR, Eng A, Riccio A, Gorlin R, Faster V. Angiographic evolution of coronq artery morphology in unstableangina.JAm CoU Cardioll986;7:472.
l2.Keeny SM, Richardson PD. Stress analysis of atherosclerotic arteries. IEEE/Ninth Annual Conference of Engineering in Medicine and Biology Society,1987. 13. Faster V, Badimon L, Cohen M, Ambrose JA, Badimon JJ, Chesebro J. Insightsinto the pathogenesisof acute ischemicsyndromes.Ctiu&io~ 198877: 121~1220. 14. Davies MJ. The role of macrophagesin human coronzuyartery thrombosis. In: Fuster V, ed. Proceedingsof Coronary Artery DiseasesConference.SanJuan, Puerto Rico: Smith-Kline Laboratories, 1988:30. l5. Barger AC, Beeuwkes Reiner III, Lainey LL, Silverman KJ. Hypothesis: Vasavasoram and neovascularizationof human coronary arteries: a possiblerole in the pathophysiologyof atherosclerosis.N Engf JMed 1984,310:175-177. Is. Barger CA, BeeuwkesR. Rupture of coronary vasavasormn as a trigger of acutemyocardialinfarction&n J Cam!iol1990,66:41~3. 17. ConstantinidesP. Cause of thrombwii in human atherosclerotic coronary arteries&n
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Coronary artery thrombosisin patientswith unstableangina.BrHeati J 1981;45:411. responses.JClin Invest1989;84:1373-1378. 33. Gordon JB, Ganz P, Nabel EG, Fish DR, Zebede J, Mudge GH, Alexander 56. Vetrovec GW, Leinbach RC, Gold HK, Rowley MJ. Intracoronary thrombolRW, SelwynAP. Atherosclerosisinfluencesthe vasomotorresponseof epicardial ysisin syndromesof unstableischemia:angiographicand clinical resultsAm Heart J 1982;104:946. coronary arteries to exercise.J C&zInvest1989;83:194f%1952. 57. Mandelkom JB, Wolf NM, Singh S, ShechterJA, Kersh RI, Rodgers DM, 34. YanagisawaM, Kurihara H, Kinmra S, Tomobe Y, Kob+yashiM, Mitsui Y, Yazaki Y; Goto K, Masaki T. A novel potent vasoconstrictorpeptideproducedby Workman MB, Bentivogllo LG, LaPorte SM, Meister SG. Intracoronary thrombusin nontransmuralmyocardialinfarction and in unstableanginapectoris.AmJ vascularendothelial cells.Nnfure 1988;332:411-415. 35. Lam JYT, Chesebro JH, Steele PM, Badimon L, Fuster V. 1svasospasm Cardid 1983;52:1. 58. Zack PM, IschingerT, Aker UT, Dincer B, Kennedy HL. The occurrenceof related to platelet deposition? Relationship in a porcine preparation of arterial injury in viva. C&d&on 1987;75:2113-248. angiographically detected intracoronary thrombus in patients with unstable 36. Felts JD, Rowe GG. Cyclical reductions in coronary blood flow in coronary [email protected];108:1408. arterieswith iixed partial obstruction and their inhibition with aspirin (abstr).Fed 69. Bresnahan DR, Davis JL, Holmes DR Jr, Smith HC. Angiographic occurProc 1974;33:413. rence and clinical correlates of intraluminal coronary artery thrombus: role of 37. Folts JD, GaUagherK, Rowe GG. Blood flow reductionsin stenosedcanine unstableangina.JAm Co11Cardiol1985;6:285. coronary arteries: vasospasmor platelet aggregation?Ctiulafion 1982;65:248- 60. Capone G, Wolf NM; Meyer B, Meister SG. Frequency of intracoronary 255. filling defects by angiographyin unstable angina pectoris at rest. Am J Cardiol 38. Felts JD, Bonebrake FC. The effects of cigarette smoke and nicotine on 1985;56:403. platelet thrombus formation in stenoseddog coronary arteries: inhibition with 6l. Gotoh K, Minamino T, Katoh 0, Hamano Y, Fukui S,Hori M, Kusuoka H, phentolamine.Circrclarion1982;65:46&465. Mishima M, Inoue M, KamadaT. The role of intracoronary thrombusin unstable 39. Bush LR, Campbell WB, Tilton GD, Buja LM, Willerson JT Effects of the angina:angiographicassessmentand thrombolytic therapy during ongoing anpiselective thromboxane synthetase inhibitor, dazoxiben, on variations in cyclic nal attacks.Cirntfation 1988;77:52f+534. blood flow in stenosedcaninecoronary arteries.CirnJatzi~n1984,69:1161-1170. 62. Krnskal JB, Commerford PJ, Franks JJ, Kirsch RE. Fibrin and fibrinogen40. BushLR, CampbellWB, Kern g Tilton GD, Apprill P, Ashton J, SchmitzJ, related antigensin patients with stable and unstable coronary artery disease.N Buja LM, Willerson JT. The effects of alphq-adrenergic and serotonergic EnglJMed 1987;317:1361-1370. receptor antagonistson cyclic blood flow alterations in stenosedcanine coronary 63.Friedman M, Van den Bavenkamp GJ. The pathogenesisof coronary arteries.ChicRes 1984,55:642652. thrombus.AmJPathol1966;4831%44. 41. Ashton JH, Ogletree ML, Taylor AL, Fitzgerald C, Rabeja S,CampbellWB, 64. Falk E. Plaque rupture with severe pre-existing stenosisprecipitating coroBuja LM, Willerson JT. A thromboxanereceptor antagonist,SQ 29,548,abolishes nary thrombosis:characteristicsof coronary atherosclerotic plaques underlying or attenuatescyclic flow variations in severelynarrowed canine coronary arteries fatal occlusivethrombi. BrHearfJ 1983;50:127-134. (abstr). Circulation 1985;72(suppIII):III-69. 65. DeZwaan C. Thrombolytic therapy in unstable angina. CardiovascRev Rep 42. Ashton JH, Benedict CR Fitzgerald C, Raheja S, Taylor A, Campbell WB, 1989;1:15-22. Buja LM, Willerson JT. Serotonin is a mediator of cyclic flow variations in 66. Badimon L, Badimon JJ, Galvez A, Chesebro JH, Fuster V. Influence of stenosedcaninecoronary arteries. Circulation 1986;73:572-578. arterial damageandwall shearrate on platelet deposition:exvivo studyin a swine 43. Ashton JH, Taylor AL, Ogletree ML, Raheja S, Buja LM, Schmitz J, model.Atikosckrosis 1986;6:312-320. Campbell WB, Wierson JT. Serotonin (5HT,) and thromboxane A,/PGH, 67. Moise A, ThCrouxP, TaeymansY, DescoingsB, Lesp&ance J, Waters DD, mechanismsare both important in mediating cyclic flow variations in severely Pelletier GB, Bourassa MG. Unstable angina and progression of coronary narrowed canine coron;uy arteries (abstr). Clti Res 1986;34:707A. atherosclerosis.NEnglJMed 1983;309:685689. tion 1%5;72:128-734.
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ANGINA
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of Acute Coronary Syndromes
Prediman K. Shah,
MD,
The natural history of coronary artery dii is punctuated by clinical manifestations of unstable angina, acute myocardiil infarction, and ischemit sudden death. These acute coronary syndromes share common pathophysiologic mechanisms that include fissuring of a plaque followed by varying degrees of dynamic coronary obstruction, which is due to vasoconstriction and coronary thrombosis. The response to plaque fissure is likely to be modulated by local and/or systemic procoagulant and antiiagulant-fibrinolytic actiii. The key role of coronary thrombosis in acute coronary syndromes has substantial implications for prevention and treatment of complications of coronary atherosclerosis.
and James S. Forrester,
MD
I
n the past few years, intensive investigations have focused on the pathophysiologic events leading to conversion of stable manifestations of atherosclerotic coronary artery disease (CAD) to its more acute and sinister manifestations: unstable angina, acute myocardial infarction (MI), and ischemic sudden death (acute coronary syndromes). Unstable angina, characterized by recurrent episodes of prolonged myocardial ischemia triggered predominantly by episodic reductions in coronary blood flow, is an important model for understanding the basic pathophysiologic events that lead to all acute ischemic syndromes. Acute coronary syndromes are the first clinical expression of CAD in about 30% of patients with CAD. CORONARY ATHEROSCLEROTIC UNSTABLE ANGINA
From the Division of Cardiology and the Department of Medicine, Cedars-Sinai Medical Center and University of California School of Medicine, Los Angeles, California. Address for reprints: Prediman K. Shah, MD, Division of Cardiology, Room 5314, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048.
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PLAQUE IN
The traditional angiographic indices of the severity of CAD (number of vessels with significant stenosis, percent diameter stenosis, minimal diameter, length of stenosis, and the presence or absence of collaterals) cannot accurately differentiate patients with stable CAD from those with unstable angina (Figure 1).14 A detailed examination of the morphology of coronary stenosis in culprit arteries, using antemortem as well as postmortem angiography, shows that in at least 7040% of patients with unstable angina, the stenosis is eccentric, with overhanging or irregular margins and intraluminal haziness or radiolucent filling defects-features rarely observed in the coronary arteries of patients with stable angina.4’5 Meticulous and detailed postmortem examination of atherosclerotic plaques in the culprit coronary arteries of unstable angina patients shows them to be complex, with fissures or cracks in the fibrous cap of the plaque (Figure 2). These fissures or ruptures usually occur either at the margins of the plaque in the area where the eccentric plaquebearing segment joins the non-plaque-bearing segment of the arterial wall or in the center of the plaque.6 Fissures average about 300-400 pm in length and vary in width from narrow slits to large gaps or ulcerations of the plaque surface.’ Areas of hemorrhage are commonly observed and may be NOVEMBER 4, 1991
secondary to plaque fissure.7 Coronary angioscopy has confirmed the presence of complex and fissured plaques in the culprit coronary arteries of patients with unstable angina undergoing coronary artery bypass surgery (Figure 3).’ POTENTIAL MECHANISMS
OF PLAQUE FISSURE
The precise events leading to plaque fissure remain unclear. Fissures occur more frequently in plaques that are rich in extracellular and eccentric pools of lipid. However, they are not unique to severely occlusive atherosclerotic plaques, but also frequently occur in mildly occlusive plaques.g-ll Pathologic studies show that often the plaque fissure develops at the margin of the atheroma, where the atheroma joins the normal arterial wall and plaque-fissure shows a predilection for thin acellular, lipid-rich, soft, or highly vascularized atheromatous plaques.6,7s9 Richardson et al6 demonstrated by means of in vitro computer models of arteries, that circumferential stress is greatest at the endothelial surface of the arterial wall, stress is concentrated at the junction of the fibrous cap with the more compliant normal arterial wall, and softer plaques tend to develop a higher shear stressI These findings suggest that hemodynamic or mechanical stress associated with heartbeat, bending and twisting of an artery, or increases in blood pressure (exercise, diurnal changes, sudden change in coronary tone) may contribute to fissuring of certain types of vulnerable plaque.13 Experimental studies in mammalian atherosclerotic arteries show that a sudden surge of blood pressure in synergy with endothelial damage can produce plaque fissures.7 Fissures may also occur when activated, subintimal, lipid-laden macrophages and other inflammatory cells release
100
75
Percent Area Stenosis
50 A A
25
0
I
I
SA
UA
I MI involved vessel
Figure l. Comparatlve severity of coronary stenosis In the coronary arteries of patlents wlth stable aNIna @A), unstable angina (UA), and acute myocardlal Infarction (Ml) following thrombolysls. Note the overlap In the severity of steno& In the arteries of patknts wlth SA and those of the culprit arteries of patlents wtth UA and acute MI. (Adapted from Circuration.“)
humoral mediators, such as proteases and tumor necrosis factor, which erode the plaque from within.13,14 Cinematographic studies of cleared human hearts and microsphere studies show that extensive neovascularization of atherosclerotic plaques is associated with a fivefold increase in medial flow compared to normal arterial wall with blood flow directed from adventitia towards the intima.15,16 This increased vascular@ of the atherosclerotic plaque from proliferation of vasa vasora may play a role in plaque fissure by providing a source of bleeding into the plaque and/or by bringing cellular and/or humoral mediators into the plaque, which may contribute to fissuring.15”6This point of view, however, has been challenged by Constan-
Flgure 2. Hlstopathology of a coronary arterial stenosls showing an atherosclerotk plaque (P) wlth a fissure (arrow). An intramural and intralumlnal thrombus (7) Is attached at the slte of the plaque flssure. (Adapted from Davles MJ, ed. Color Atlas of Cardlovascular Pathology. Dxford Unlverslty Press, 1987.)
A SYMPOSIUM:
MECHANISMS
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ANGINA
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Flgure 3. lntraoperathre angloscopk appearance uf smooth atheroma in a patlent wfth stable anglna (A); fissued plaque In a patlent wlth unstable angina (B); and partially occlusive ltiracoronary thrombus In patient with unstable anglna (C). (Adapted from N EngIll Med.B)
tinides on the basis of pathologic findings.17 Several recent studies suggest that plaques considered noncritical or angiographically insignificant ( < 50% diameter stenosis) may become the sites of subsequent plaque fissures with superimposed coronary thrombosis.“1’,1s3’9 Although the precise causes of plaque fissure remain unclear, a variety of factors may render a plaque vulnerable to rupture by damaging the endothelial lining or weakening the fibrous cap or the smooth muscle cells that produce the collagen for the fibrous cap. These factors include chemical or metabolic insults such as prolonged hyperlipidemia, high angiotensin levels, elevated acetoacetic acid levels (i.e., diabetes), nicotine, circulating immune complexes, inflammatory cells and their isC
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humoral products, and increased fragility of collagen from increased cross-linking or contraction.17
CONSEQUENCES OF PLAQUE FISSURE Plaque fissure may abruptly change the geometry of a coronary stenosis, leading to a sudden increase in coronary luminal obstruction. In addition and perhaps more importantly, plaque fissure may trigger more dynamic mechanisms of coronary obstruction (i.e., abnormal vasomotor tone, platelet aggregation, and platelet-fibrin thrombus formation) (Table I), These dynamic factors are implicated in the intermittent coronary artery occlusion that leads to episodic coronary flow reduction and precipitation of unstable angina. NOVEMBER 4, 1991
activation and platelet- or leukocyte-mediated vasoconstriction.3sFurthermore, endothelial dysfunc1. Fixed Coronary Stenosis tion with local thrombin formation may contribute Fissured plaque and to vasoconstriction. Even normal changes in vaso2. Dynamic coronary obstruction motor tone may significantly reduce blood flow in a Vasoconstriction severely stenotic coronary’ artery. Clinical observaPlatelet aggregation Platelet-fibrin thrombus tions that endothelium-independent vasodilators *The interaction is between 1 and 2. such as nitrates and calcium antagonists reduce the number of ischemic episodes in unstable angina patients suggestsome role for coronaryvasomotion DYNAMIC FACTORS COmIBUTING TO in the pathogenesis of ischemia in unstable angina. EPISODIC CORONARY ARTERY OBSTRUCTION However, the limited effect of these agents in IN UNSTABLE ANGINA Abnormal vasomotion: Atherosclerotic arter- reducing the risk of acute MI argues that mechaies have an exaggerated response to certain vaso- nisms other than vasoconstriction are more imporconstrictor stimuli or a paradoxical vasoconstrictor tant. Platelet aggregation: In experimental models response to stimuli that dilate normal blood vessels (Figure 4).20-27 These abnormal or anomalous vaso- of partial coronary artery stenosis and endothelial motor responses of atherosclerotic arteries have injury, Folts et aP6initially reported that spontanebeen observed in experimental models, human ous intermittent coronary occlusion and cyclical arteries studied in vitro as well as in vivo, and variations in coronary blood flow distal to the resemble those of normal arterial strips from which stenosis result from intermittent platelet aggregaendothelial lining has been deliberately removed.28,2gtion. These cyclical flow variations are abolished or Thus, atherosclerosis appears to impair the normal reduced by agents that inhibit platelet aggregation and/or inhibit the effects of platelet-derived thromvasodilator effects of the endothelium.22,30 boxane and serotonin, such as aspirin, thromboxIn normal endothelium, vasodilation appears to be mediated through the release of substances ane synthetaseinhibitors, thromboxane and serotosuch as endothelium-derived relaxation factor nin receptor antagonists, and certain a-adrenergic (EDRF), which may be either nitric oxide or a antagonists. Cyclical variations are exaggerated by nitrosothiol compound synthesizedby the endothe- platelet aggregatory agents such as ADP, plateletlium from arginine.29,31 Stimuli that produce vasodi- activating factor, (Y agonists, nicotine, thrombin, lation in the presence of normal endothelium and exercise (Figure 5).37-45 Evidence of platelet activation in humans with include acetylcholine, histamine, bradykinin, serotonin, substance P, adenosine diphosphate (ADP), unstable angina includes elevatedcirculating and/or adenosine triphosphate (ATP), calcium ionophore urinary levels of products of platelet activation A23187, platelet-activating factor, thrombin, platelets, increased shear stress, increased blood flow, ATHEROSCLEROTIC NORMAL CORONARY ARTERY CORCNJARY ARTERY and exercise (endothelium-dependent vasodilators).32,33 When the endothelium is damaged, such as occurs in atherosclerosis or hypercholesterol150emia, the vasomotor response to endotheliump 2 125dependent vasodilators is blunted or converted to E vasoconstriction. A recent study shows that endoce ioothelial cells in culture produce a potent vasocon- E I 7=strictor peptide labeled endothelin.34 Thus, endoa thelium may modulate vascular tone by releasing d2 50both vasodilator and vasoconstrictor substances. Y 25 The hyperreactivity of the vascular smooth muscle OL ’ ’ ’ ’ ’ 1 ’ ’ ’ ’ ’ ’ cell may reflect atherosclerotic-induced endothe- I Cl C2 A&,,, C3 TNG Cl C2 A&,.. ‘23 TNG I lial dysfunction leading to deficient release of Figure 4. Vasomotor responss of the athsrosckMk and EDRF and/or excessiverelease of endothelin. It is normal coronary atierles to acetykhollns. Note that athstill unclear whether an intrinsic abnormality of the erosderotksegmentsreactwlthatranslentdecraasaIn lumlnal dlamater, whereas the normal arteries react wlth vascular smooth muscle cell also plays a role. a slight Increase In lumlnal diameter. C=contrd; Ash= Plaque fissure may contribute to vasomotor awtykhoflne; lNG=nltroglycarln. (Adapted from N Eng/l hyperreactivity by triggering platelet or leukocyte Me&=) TABLE I Pathophysiology
of Unstable Angina*
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MECHANISMS
OF UNSTABLE
ANGINA
%%
such as P-thromboglobulin, platelet factor IV, and thromboxane metabolites46-48; pathologic evidence of platelet microemboli in myocardial microvasculature downstream from the culprit coronary stenosis49;and finally, a strong protective effect of aspirin against development of MI in patients with unstable angina.50-52 Careful autopsy studies by Falk4’ show that platelet microemboli are seen in about 50% of patients who die soon after the onset of ischemic symptoms.53These emboli are almost exclusively seen in arterioles and in small arteries downstream from the artery with a fissured plaque and may be associated with scattered foci of myocardial necrosis. Platelet aggregates on a fissured plaque may reduce coronary blood flow by direct occlusion or through the release of humoral mediators such as serotonin and/or thromboxane. In the absence of normal endothelial function, these mediators produce vasoconstriction. In addition, platelet emboli may produce ischemia or infarction and, conceivably, trigger fatal disturbances of rhythm and conduction.
Mean Aortic Pressure (mm Hg)
150 r 1: ,I
-c
-
Coronary thrombosii: Intraluminal coronary thrombosis appears to play an important role in the pathogenesisof unstable angina.Angiographic studies show intraluminal filling defects and lucencies, indicating a thrombus at the site of a complex coronary stenosis in 1% to 85% of patients with unstable angina.5”61 The inconsistencies in the reported angiographic incidence of intracoronary thrombus may be related to several factors, including variability in the timing of angiography in relation to the symptoms and less than optimal sensitivity of the angiographic criteria for the detection of thrombus. A relatively low incidence of thrombus has been reported in studies where angiography was performed several days to weeks after the last episode of angina.54S5,57-59 In contrast, a higher incidence (50-85%) has b een reported when angiography was performed soon after the last episode of unstable angina.56,60,6* Gotoh et a161observed evidence of intracoronary thrombus in 57% of patients with unstable angina when angiography was
1 min 4
Left Ventricular Pressure (mm Hg)
dP/dt
Mean Left Atrial Pressure (mm t-b)
20 i-m 10 7 0 L
Mean Circumflex Blood Flow (mllmin)
Electrocardiogram
Figure 5. Platelet-mediated spontaneous cyclical coronary flow varlatlon In the canine coronary steno& od from I Am CONcardiof,) l554$i 1417.
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NOVEMBER 4, 1991
model. (Adapt-
performed during episodes of ischemia. Their study used both morphologic features and response to intracoronary thrombolytic therapy as the criteria for thrombus. More importantly, they documented the dynamic and evanescent nature of the intracoronary thrombus in unstable angina. Intraoperative angioscopic observations also show a high prevalence of visible intraluminal thrombus in the culprit arteries of patients with unstable angina undergoing bypass surgery (Figure 3).8 The presence of ongoing thrombosis in unstable angina is further supported by indirect evidence, such as elevated levels of circulating fibrin and urinary markers of thrombin-mediated fibrin formation, such as fibrinopeptide A and other fibrinrelated antigens.62Histopathologic studies confirm the high prevalence of intraluminal and intraintima1 thrombus at the site of a fissured atherosclerotic plaque in patients with unstable angina and other acute coronary syndromes.7,9,10,49,63,64 The frequent development of acute MI, a complication that is now considered to be the consequence of prolonged coronary artery occlusion due to an intraluminal thrombus, is further evidence of the important pathophysiologic role of intracoronary thrombus in unstable angina. Finally, the beneficial effects of anticoagulants (and in some cases thrombolytic therapy) in reducing ischemia and the frequency of infarction argue strongly that coronary thrombosis plays an important role in unstable angina.52S65 FACTORS CONTRIBUTING TO PLATELET AGGREGATION AND CORONARY THROMBOSIS IN UNSTABLE ANGINA Plaque fissure appears to be the initial event that creates a milieu for platelet adhesion, aggregation, and subsequent fibrin-platelet thrombus formation. After fissuring occurs, the contents of the plaque are exposed to circulating platelets. They in turn adhere to the exposed fibrillar collagen (type I) and elastin matrix of the plaque through the interaction of von Willebrand factor and adhesive glycoprotein platelet receptors (Ib and possibly Ia). The high shear rate in the vicinity of a severe coronary stenosis contributes to platelet adhesion and aggregation by a cyclooxygenase independent mechanism. Deep arterial wall injury is associated with a more intense and prolonged platelet deposition against the arterial wall at high as well as low shear rates. This is in contrast to more superficial endothelial injury where platelet deposition is higher at high shear rates, with maximum deposition occurring within lo-20 minutes and dislodge-
ment of platelets caused by the blood flo~.~~ The model of superficial injury and high shear rate simulates a coronary stenosis with mild ulceration of the plaque; the deep injury model simulates an area of arterial stenosis with a deep plaque fissure.13 Following platelet adhesion, exposure of another type of platelet glycoprotein receptor (IIB/ IIIA), binding fibrinogen, von Willebrand factor, and possibly fibronectin bridge activated platelets, leading to platelet aggregation. Platelet-derived procoagulants, as well as the procoagulant effect of the “tissue factor” expressed by the plaque and released from the plaque, activate the clotting cascade, leading to thrombin formation. Thrombin in turn leads to fibrin formation, further platelet aggregation contributing to fibrin-platelet thrombus formation, and vasoconstriction. ROLE OF HYPERCOAGUlABll.llY In addition to the severity of the plaque fissure, the intensity and the duration of the thrombotic response may be further modulated by the balance between systemic or local procoagulant and fibrinolytic state as well as the aggregability of platelets. Hypercoagulable states associated with elevated fibrinogen levels, increased triglyceride and lipoprotein(a) levels, chronic smoking, elevated factor VII activity levels, and depressed fibrinolytic state due to high levels of plasminogen activator inhibitor type 1 may particularly predispose certain individuals to thrombosis, whereas an efficient fibrinolytic system and a hypocoagulable state may protect others from thrombotic consequences of plaque fissure. Autopsy studies in patients who die from the complications of unstable angina frequently show that coronary thrombi of varying ages are seen at the site of a fissured plaque, suggesting ongoing waves of thrombosis and its dynamic nature in the acute coronary syndromes.49 Incorporation and organization of thrombi into the plaque may contribute to accelerated progression of CAD. This has been angiographically demonstrated in up to 70% of patients with unstable angina who were serially studied during progression from a stable to an unstable state.“,67 A UNIMNG MECHANISM TO EXPLAIN THE PATHOPHYSIOLOGY OF ACUTE CORONARY SYNDROMES The acute coronary syndromes of unstable angina, acute MI, and ischemic sudden death appear to share a common pathophysiologic basis, with plaque fissure in the coronary artery as the pathoA SYMPOSIUM: MECHANISMS OF UNSTABLE ANGINA
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Corormry Ftxed
Stenosis
Obstruction
Plaque Fiewre 1
Varieblo
$ Dynamic Obrtruction
Degree
V48omotion pf4telet &grog Thrombo4i4 Pt4tefet embofi
/
I Stenoria
Progre8rion ’ Thrombur
Incorporation
I
into Plaque
logic hallmark (Figure 6).‘,” In addition to the plaque fissure, varying amounts of intraluminal and intramural platelet-fibrin thrombus constitute the acute intimal lesion observed in the vast majority of patients who die of acute coronary syndromes?,l’ When plaque fissure is associated with brief periods of coronary occlusion (due to platelet aggregation, vasoconstriction, or evanescentplatelet-fibrin thrombosis), the result is unstable angina; when the coronary occlusion is more prolonged, the result is acute MI. Subendocardial infarction is more likely to develop when spontaneous reperfusion occurs, before occlusion-induced necrosis has spread transmurally, or when the transmural spread of necrosis from a permanent coronary occlusion is halted by well-developed epicardial collaterals. Sudden cardiac death is likely to occur when a large area of myocardium is rendered ischemic, leading to a fatal disturbance in cardiac rhythm or conduction. This may develop during brief or prolonged periods of coronary occlusion or perhaps when platelet aggregates embolize downstream from the acute coronary lesion. ACKNOWLEDGMENT: The authors gratefully acknowledge the editorial assistance of Beverly Yoshioka in the preparation of this manuscript.
3. Wilson RF, Holida MD, White CW. Quantitative angiographicmorphologyof coronary stenosisleading to myocardial infarction or unstableangina.Cimhtion 1986;73:286. A Ambrose .I& Winters SL, Stem A, Eng A, Teichholz LE, Gorlin R, Fuster V. Angiographicmorphologyand the pathogenesisof unstableanginapectoris.JAm Cd C&l 1985;5:60%16. 5. L&n DC, Fallon JT. Signiice of angiographicmorphology of localized coronary stenosis.Histopathological correlates.&&f&x 1982;66:316. 6. RichardsonPD, Da& MJ, Born GVR. Influence of plaque configuration and stressdistriiution on fissuringof coronary atheroscleroticplaques.Lancet 1989;k 941-944. 7. ConstantinidesP. Plaquefissuresin human coronary thrombosis.JAthemscZer Res 1966;6:1-17. 8. ShermanCT, Litvack F, Gnmdfest W, Lee M, Hickey A, Chaux A, Kass R, Blanche C, Matloff .I, Morgenstem L, Ganz W. Coronary angioscopyin patients with unstableanginapectoris.NEnd JMed 1986;315:913-919. 9. Davies MJ, Thomas AC, ShahPK, Pichler M, Berman DS, Singh BN, Swan HJC. Plaque fissuring-the cause of acute myocardial infarction, sudden ischaemicdeath, and crescendoangina.Br Heart J 1985;53:363-373. l6. Davies MJ, Thomas AC. Thrombosis and acute coronary artery lesions in suddenischemiccardiac death.N Engl J Med 19&1;310:1137-1140. il. Ambrose JA, Winters SL, Arora RR, Eng A, Riccio A, Gorlin R, Faster V. Angiographic evolution of coronq artery morphology in unstableangina.JAm CoU Cardioll986;7:472.
l2.Keeny SM, Richardson PD. Stress analysis of atherosclerotic arteries. IEEE/Ninth Annual Conference of Engineering in Medicine and Biology Society,1987. 13. Faster V, Badimon L, Cohen M, Ambrose JA, Badimon JJ, Chesebro J. Insightsinto the pathogenesisof acute ischemicsyndromes.Ctiu&io~ 198877: 121~1220. 14. Davies MJ. The role of macrophagesin human coronzuyartery thrombosis. In: Fuster V, ed. Proceedingsof Coronary Artery DiseasesConference.SanJuan, Puerto Rico: Smith-Kline Laboratories, 1988:30. l5. Barger AC, Beeuwkes Reiner III, Lainey LL, Silverman KJ. Hypothesis: Vasavasoram and neovascularizationof human coronary arteries: a possiblerole in the pathophysiologyof atherosclerosis.N Engf JMed 1984,310:175-177. Is. Barger CA, BeeuwkesR. Rupture of coronary vasavasormn as a trigger of acutemyocardialinfarction&n J Cam!iol1990,66:41~3. 17. ConstantinidesP. Cause of thrombwii in human atherosclerotic coronary arteries&n
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[email protected] pathophysiologyofacutecoronarysyndromes of unstable anglna, acute my+ cardlal infarctlon (AM), and sudden cardiac death. CAD=coronary artery dkmase.
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A SYMPOSIUM:
MECHANISMS
OF UNSTABLE
ANGINA
23C
