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provided by Elsevier - Publisher Connector JACC Vol. 9. No.6 1397 June 1987:1397-402 EDITORIALS

Arteriographic Anatomy and Mechanisms of Myocardial Ischemia in Unstable Angina

JOHN A. AMBROSE, MD, FACC , CRAIG E. HJEMDAHL-MONSEN, MD New York, New York

Over the past 20 years, there has been considerable research stable angina; and 3) all ischemic rest pain without evidence into the pathogenesis of myocardial ischemia in unstable of myocardial infarction. angina. Early data (1-3) suggested that transient increases These catagories are not mutually exclusive . The cate­ in myocardial oxygen demand explained episodes of rest gory of rest pain would include some patients with previ­ pain in patients with unstable angina and severe coronary ously mild angina and a marked increase in symptoms (cres­ artery disease. In the 1970s this view changed and the con­ cendo angina) and also patients with previously severe angina cept of vasospasm became the most favored mechanism to and a slight increase in symptoms. Other proposed classi­ explain episodes of myocardial ischemia and rest pain, thus fications for unstable angina include the categories of sub­ changing the emphasis from the demand side to the supply endocardial infarction and postinfarction angina. The natural side of coronary dynamics (4,5). More recently, serial an­ history of patients with these conditions may be different giographic studies (6,7) have demonstrated that progression from that of patients classified in the preceding categories of coronary artery disease is extremely common in patients (14). More complex classifications have been proposed based with stable angina who are restudied after an episode of on clinical or angiographic criteria , or both (15,16). For the unstable angina . Angiographic, angioscopic and pathologic remainder of this discussion, we will classify unstable an­ data (8-13) have also incriminated thrombus in the patho­ gina as we did in the preceding paragraph . genesis of this condition. In this review we explore the relation between the coronary arteriographic anatomy in unstable angina and mechanisms of myocardial ischemia. Coronary Arteriographic Anatomy in Unstable Angina Definition of Unstable Angina Atherosclerotic disease. Eighty-five to 90 percent of patients with unstable angina have significant coronary ar­ A major difficulty in unraveling the cause of any con­ tery disease but in about 10 to 15% of patients, normal or dition occurs when that condition is not precisely defined. nonobstructed coronary arteries are found (17,18). Thus , Such is the case with unstable angina, which is a descriptive some patients with normal or nonobstructed coronary ar­ term for a spectrum of acute myocardial syndromes that teries have dynamic obstruction and myocardial ischemia clinically lie between stable angina and myocardial infarc­ related to coronary artery spasm or some other mechanism; tion. It generally includes the following categories: I) New other patients have a chest pain syndrome that is noncardiac onset of angina (1 to 2 months' duration) occurring at low in origin. work loads or at rest; 2) crescendo angina defined as a The majority ofpatients with unstable angina have mul­ marked increase in the frequency or severity of previously tivessel coronary artery disease. However, if one looks at only those patients with recent onset unstable angina, there *Editorials published in Journal ofthe American College ofCardiol ogy is a high incidence of one vessel disease (25 to 50%) (19,20) . rellect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. Significant obstruction of the left main coronary artery is From the Department of Medicine. Division of Cardiology. The Mount more common in unstable than in stable angina and occurs Sinai School of Medicine and The Mount Sinai Medical Center. New in up to 25% of patients with rest and exertional chest pain York, New York 10029. This work is supported by the New York Cardiac Center, Englewood Cliffs, New Jersey. and a previous history of stable angina (21). Manuscript received September 29. 1986; revised manuscript received Ischemia-producing artery. In patients with unstable December 10, 1986, accepted January 7. 1987. angina and single vessel disease, it can be assumed that the Address for reprints: John A. Ambrose, MD, Division of Cardiology . The Mount Sinai Medical Center, One Gustave L. Levy Place, New York. ischemia-producing artery is that vessel with the significant New York 10029. obstruction . In rare instances, however, ergonovine testing

©1987 by the American College of Cardiology 0735-1097/87/$3.50 1398 AMBROSE AND HJEMDAHL-MONSEN JACC Vol. 9, No.6 EDITORIAL June 1987:1397-402

has indicated spasm (with reproducibility of clinical symp­ toms) of a normal-appearing artery in the presence of sig­ nificant obstruction in other vessels (22). Whereas multi­ vessel disease is common in unstable angina, it is often possible to identify an ischemia-producing artery. By a care­ ful assessment of both the distribution of lesions within the coronary arteries and segmental wall motion analysis as well as electrocardiographic (ECG) changes during pain, we (8) were able to localize the presumed artery responsible for symptoms in about 40% of patients with either stable or unstable angina and multivessel coronary artery disease. The presence of an "acute" coronary lesion as determined by analysis of coronary morphology will increase the likelihood of localizing the ischemia-producing artery in unstable an­ gina and multivessel disease (see later). Figure 1. Left coronary artery angiogram intheleftanterior oblique Progression of coronary artery disease. In previously projection showing a type II eccentric lesion in the left anterior catheterized patients with a history of stable angina pectoris, descending artery (arrow). progression of coronary artery disease is seen in approxi­ mately 75% who are recatheterized after an episode of un­ stable angina (6,7). On the other hand, only about 33% of farction in comparison with patients with one vessel disease patients recatheterized with little or no increase in symptoms and unstable angina. The lack of more quantitative data show such progression. This progression can be seen to makes it difficult to assess the role of the degree of stenosis, occur in lesions that at the time of the first angiogram were the minimal diameter or the cross-sectional area of the coro­ either significant (>50% diameter obstruction) or "non­ nary lesion in the ischemia-producing artery as a sole de­ obstructive" «50% diameter obstruction) (6,7). We found terminant of the particular clinical syndrome. Therefore, (7) that in unstable angina, progression in the ischemia­ more quantitative data are required to compare unstable producing artery usually originated from a previously in­ angina with other acute coronary syndromes. significant lesion or even from a normal-appearing artery. Qualitative analysis of coronary lesions in unstable This pattern of progression from previously insignificant angina. In either acute presentations of unstable angina (8), disease was seen less commonly in the study of Moise et recent non-Q wave infarction (26), acute infarction with ST al. (6). Although quantitative techniques for analyzing coro­ segment elevation or recent Q wave myocardial infarction nary stenoses were not utilized in these studies of coronary (27), a characteristic coronary lesion is found in the majority disease progression, approximately 25% of patients in both of cases in which an ischemia-producing artery < 100% studies did not appear to have any progression of disease occluded is identified. An eccentric stenosis in the form of despite the symptomatic progression to unstable angina. a convex intraluminal obstruction with a narrow neck due Quantitative analysis of coronary lesions in unstable to one or more overhanging edges, or borders that are scal­ angina. There are ample data, (18,23) suggesting that the loped (type II eccentric lesion) is found in approximately extent and location of coronary artery disease are similar two-thirds of such patients (Fig. 1). This type II eccentric for patients with stable and unstable angina except for the lesion is also common in coronary artery disease progres­ higher incidence of left main coronary involvement in un­ sion. It is rarely found in patients with stable angina. In the stable angina. However, there are few data that quantita­ remaining one-third of ischemia-producing arteries in these tively analyze the degree of stenosis or the minimal diameter acute syndromes, other types of morphology can be seen. of the ischemia-producing lesion in unstable angina versus Symmetricand smooth (concentric)or asymmetric and smooth other acute coronary syndromes. Although visual analysis (type I eccentric) narrowings are the most common lesions of the degree of coronary stenosis has been shown to be in those ischemia-producing arteries that contain non-type similar in the acute coronary syndromes (23), this method II eccentric lesions. is inaccurate for precise comparison. Raffenbeul et al. (24) Other angiographic studies have assessed the importance found similar degrees of stenosis in patients with either of intracoronary filling defects in unstable angina (9,10). unstable angina or stable angina when lesions were quan­ Filling defects located either within or distal to a lesion have titatively measured with a vernier caliper. Utilizing previ­ been described in about one-third of patients with unstable ously developed quantitative techniques, McMahon et al. angina and probably represent intracoronary thrombi. In (25) found more significant stenosis (both a higher percent patients with an episode of rest pain within 24 hours before stenosis and a smaller minimal diameter) in a small number angiography, the incidence of intracoronary filling defects of patients with one vessel disease and subendocardial in- is even higher. Bresnahan et al. (9) found that about two- JACC Vol. 9, No.6 AMBROSE AND HJEMDAHL-MONSEN 1399 June 1987:1397--402 EDITORIAL

thirds of filling defects were located distal to the lesion. The the onset of changes in rate-pressure product during an isch­ recognition of filling defect location is important because emic episode; they concluded that, in patients with rest the pathogenesis of proximal and distal defects might differ. angina, a primary reduction in myocardial perfusion, rather A filling defect located within a lesion probably represents than an increase in demand, was the cause of ischemia. thrombus forming ar a disruption of the atherosclerotic plaque Any proposed mechanism for ischemia in unstable angina whereas a filling defect distal to a lesion probably represents must explain the variable threshold that exists for the oc­ thrombus formation due to altered flow patterns in a region currence of ischemic pain. Patients with unstable angina of diminished or turbulent blood flow. may be exercised or their heart artificially paced to a higher Pathologic-arteriographic correlations. Postmortem heart rate and blood pressure without pain than during spon­ angiographic analysis (12) of patients dying after myocardial taneous episodes of pain (32,33). Furthermore, the activity infarction or after coronary bypass surgery has indicated required to elicit pain may vary during the day. These ob­ that the "complicated lesions" exhibited plaque disruption servations also suggest that decreases in supply rather than with partially occlusive or totally occlusive thrombus. These increases indemand are primarily responsible for ischemic complicated lesions were usually eccentric with irregular symptoms in patients with unstable angina. Although the borders. Careful histopathologic sectioning of the coronary visual assessment of the severity of coronary disease has arteries in patients dying suddenly after an episode of un­ been found to be similar in patients with stable and unstable stable angina (13) has shown that thrombi are commonly angina (23), transient decreases in coronary artery diameter present which are anchored to a disruption of the athero­ related to vasospasm or intermittent thrombosis occurring sclerotic plaque. Furthermore, these thrombi are usually at the time of an ischemic episode can account for the layered, indicating that such events are not necessarily acute. unstable angina. Almost all plaque disruptions occur at the proximal side of Fluid dynamics of coronary stenoses. Dynamic changes the atherosclerotic lesion, suggesting the importance of in coronary diameter can explain episodes of ischemia in rheologic factors in its formation (Davies M, personal com­ unstable angina. To understand how small changes in coro­ munication, 1986). Calculations based on an arterial model nary stenoses affect myocardial blood supply, we must con­ indicate that this is the point ofmaximal shear forces (28). sider the fluid dynamics of blood flow through a coronary It is likely that the type II eccentric lesion represents a stenosis. Pressure loss in terms of flow through a coronary disrupted plaque or a partially occlusive thrombus. or both. stenosis is mathematically represented by the following Undoubtedly, this lesion is similar in appearance to that equation (neglecting inertial losses) (34): described by other groups as intracoronary filling defects at 81T~L pk 2 the site of an angiographic stenosis. Angioscopic exami­ dP = -2-) Q + -(I - - - I) Q2, ( As 2 As An nation of the coronary arteries at the time of coronary bypass surgery has also emphasized the importance of these lesions where ilP is the pressure loss across the lesion, p. is the in unstable angina. Preliminary data with this technique (11) blood viscosity, L is the stenosis length, As is the cross­ have shown that plaque rupture and thrombus are even more sectional area of the stenosis, An is the cross-sectional area frequent than suggested by angiography. of the normal segment, p is the blood density, k is a constant related to the shape of the distal portion of the stenosis and Q is blood flow. The first term in the equation represents Mechanisms of Ischemia in Unstable Angina pressure lost through viscous or frictional effects whereas Supply versus demand. In establishing the origin of the second term represents pressure lost as blood flow exits ischemia in unstable angina, it is important to ascertain a lesion by flow separation and turbulence. If one expresses whether myocardial ischemia is due to an increase in oxygen area of the stenotic segment in terms of diameter, then demand relative; to supply or to a reduction in supply relative changes in pressure vary as the fourth power of diameter. to demand. Roughgarden (1) determined that in cases of There are several important consequences to the fluid spontaneous angina, increases in blood pressure or heart dynamic equation. Viscous losses are dependent on the blood rate, or both (rate-pressure product), preceded the occur­ viscosity, stenosis length and minimal cross-sectional area rence of pain. Other investigators (2,3,29) also noted in­ of the stenosis. Turbulent losses are also dependent on the creases in rate-pressure product before the onset of subjec­ area of the stenosis, as well as the area of the normal seg­ tive pain sensation. This associationmight lead one to conclude ment. The relation between pressure loss and flow is not that changes in oxygen demand are the cause of myocardial linear. As flow increases, turbulent losses increase as the ischemia. However, this is not necessarily the case because square of the flow. Except for extremely long lesions, the chest pain may be delayed by minutes after the onset of first term in the equation has little impact on the pressure myocardial ischemia as determined by 5T segment changes gradient due to a stenosis. The percent stenosis, which is (5). Several investigators (5,30,31) studied patients with still widely used to assess the severity of a coronary lesion, rest angina and found that ECG changes occurred before does not appear in the equation. Rather, the minimal cross- 1400 AMBROSE AND HJEMDAHL·MONSEN JACCVol. 9, No.6 EDITORIAL June 1987:1397-402

sectional area of the stenosis is the primary geometric factor giographically, thus accounting in some instances for the that determines the hemodynamic significance of a lesion. apparent lack of progression of disease reported in some In a study by McMahon et al. (25), patients with unstable patients with unstable angina. angina had a minimal area of stenosis of 0.63 mrrr'. At this In concentrically narrowed canine coronary arteries, cyclic range, changes in stenosis severity of as little as 0.1 mm reductions in coronary flow have been demonstrated (40,41) in diameter can greatly increase the pressure loss across the distal to the stenosis and appear related to platelet aggre­ lesion, and account for an ischemic episode. This small gation alternating with dislodgment of thrombus and em­ change can be related, as mentioned, to vasospasm or a bolization. Thromboxane and serotonin inhibitors are usu­ small intraluminal thrombus. ally effective in abolishing these cyclical variations in flow Causes of altered supply. There are several possible (42,43); in these studies alpha-2-adrenergic antagonists par­ causes for a change in stenosis severity that can account for tially reduced these cyclical flow reductions whereas alpha­ rest ischemia in unstable angina. 1- and beta-antagonists did not. An eccentrically narrowed Active vasomotion. Coronary arteriesare subjectto changes experimental model does not exist although most human in smooth muscle tone that are under the control of various coronary lesions are asymmetric. In such patients platelet­ humoral and autonomic factors. Variation in these factors mediated release of these vasoactive prostanoid and non­ can result in changes in caliber of the coronary vessels. This prostanoid substances at the site of a disrupted plaque can active vasomotion or spasm has been proposed by Maseri cause active constriction of the ring of normal tissue that et al. (35) as an explanation for rest ischemia in patients partially surrounds the eccentric stenosis (44,45). In addi­ with unstable angina. Increases in sympathetic or parasym­ tion, it has been observed (46) that concentric lesions in pathetic activity can also alter the stimulation of alpha­ fresh segments of coronary arteries from heart transplant adrenergic receptors in the coronary arteries causing vaso­ recipients are just as capable of contraction in response to constriction or dilation. Among the humoral factors that vasomotor stimuli as are eccentric lesions. cause active coronary vasoconstriction are angiotensin, se­ When flow is reduced during an episode of myocardial rotonin and acetylcholine. The role of some of these and ischemia and rest pain, conditions are further enhanced for other platelet-related factors are considered later. It also is extension of this platelet-rich thrombus at the site of a dis­ possible that normal daily variation in the level of these rupted plaque with formation of a red thrombus that may factors causing mild constriction of the epicardial vessel further occlude the lumen. A vicious cycle can result with adjacent to an atheroma can alter coronary hemodynamics platelet-induced vasospasm and thrombus formation leading and account for spontaneous episodes of myocardial isch­ to further platelet aggregation and thrombus formation and emia (36) . ultimately to myocardial infarction . Counteracting this ten­ Passive vasomotion. Changes in coronary artery perfu­ dency to clotting and vasoconstriction are various platelet, sion pressure can alter the geometry of a coronary stenosis endothelial and humoral factors that cause dilation of the as a result of passive changes in intraluminal distending lumen through relaxation of smooth muscle and endogenous pressure. Thus, passive vasomotion can also cause increased thrombolysis. Platelet aggregates forming on the athero­ coronary stenosis resistance and episodes of ischemia in sclerotic plaque may subsequently dislodge and embolize unstable angina. to the distal coronary bed. This latter view is supported by Role of platelets. Platelet attachment changes the ge­ pathologic studies of Falk (13) in which platelet-rich thrombi ometry of the stenosis and alters coronary flow in several were seen distal to a disrupted plaque in patients dying with ways. Platelets release vasoactive substances , including a history of unstable angina. Antiplatelet drugs, which can thromboxane , serotonin and platelet-derived growth factor, prevent platelet aggregation , do not prevent the attachment which are known to be powerful vasoconstrictors (37,38) . of the single layer of platelets (39) to the damaged endo­ These substances are released when platelets attach to in­ thelium of a disrupted atherosclerotic plaque . Therefore, jured vascular endothelium and become activated. In an these drugs may not be protective against episodes of chest experimental pig model (39), the degree of vasospasm of a pain, although they might protect against thrombotic occlu­ normal carotid artery after endothelial injury was propor­ sion. In a recent clinical trial using aspirin for unstable tional to the degree of platelet deposition at the site of injury. angina (47), myocardial infarction and death were reduced Also, platelet aggregates might plug the coronary stenosis by aspirin therapy, but the frequency of anginal attacks was and lead to further reduction in stenosis diameter during the not reduced . Experimentally (39), pretreatment with aspirin episodes of myocardial ischemia . decreases but does not eliminate arterial vasospasm after In some cases, these changes in luminal caliber needed balloon dilation of the carotid artery. This is related to to significantly affect coronary flow might be small enough decreased platelet deposition with aspirin at the site of endo­ to be beyond the resolving power of cineangiographic sys­ thelial injury and might partially explain the inability of tems used for cardiac catheterization. It may, therefore, be aspirin to decrease the incidence of anginal pain in unstable difficult to identify these changes in coronary stenoses an- angina. JACC Vol. 9, No.6 AMBROSE AND HJEMDAHL-MONSEN 1401 June 1987:1397-402 EDITORIAL

Anatomic and Pathophysiologic Correlates Observations before and during spontaneous episodes of Incorporating the arteriographic, pathologic and angio­ myocardial ischemia and chest pain may be necessary to scopic anatomy with the potential mechanisms of myo­ resolve certain questions concerning the causes of ischemia cardial ischemia in unstable angina, one can suggest hy­ in unstable angina. Analysis of patients before stabilization potheses that begin to explain the pathophysiology of this with medication may be necessary. Many important issues syndrome (48). need to be resolved. The exact role of platelets and humoral In patients with unstable angina, plaque disruption with mediators in the genesis of ischemia needs to be precisely resultant platelet deposition or thrombus formation, or both determined. The influence, if any, of the autonomic nervous appears to be the initial event in most patients presenting system on spontaneous changes in vasomotor tone needs to with this acute syndrome. The formation of this "compli­ be evaluated. The importance of thrombus and plaque dis­ cated plaque" may significantly reduce the lumen of the ruption in eccentric and concentric lesions as well as quan­ coronary artery to a critical point. Angiographically, this titative analysis of the ischemia-producing coronary lesions stage appears to be represented by the eccentric and irregular during episodes of spontaneous ischemia should also be lesions seen in most patients with unstable angina (7). It is studied. A randomized, placebo-controlled trial of throm­ unclear how much of this progression is due to thrombus bolytic agents appears warranted. formation within or distal to the lesion. However, angio­ These and other areas will have to be examined to link scopic data (11) suggest that it may be a ubiquitous finding. anatomy to ischemia in unstable angina. It is likely that Pathologic examination of eccentric atherosclerotic plaques there is more than one mechanism for ischemia in unstable (44,45) demonstrates a ring of relatively normal vessel wall angina. Given the varied presentation and coronary anat­ that is capable of responding to changes in arterial tone omy, multiple mechanisms are probably responsible. A bet­ mediated by vasoactive substances or changes in autonomic ter understanding of myocardial ischemia in unstable angina tone. Vasomotion in this arc of normal wall or lysis of should result in more effective therapy, platelet aggregates may be all that is necessary to produce We thank Richard Gorlin, MD, and Valentin Fuster, MD, for continued small changes in coronary artery diameter. Thus, sponta­ support and helpful suggestions in reviewing this manuscript. neous occurrences of myocardial ischemia are usually fol­ lowed by spontaneous resolution of the ischemia and re­ establishment of flow through the coronary artery. Whether these same mechanisms are operative in concentric stenoses References is unknown although, as mentioned, concentric lesions re­ I. Roughgarden JW. Circulatory changes associated with spontaneous spond to vasomotor stimuli in similar fashion as do eccentric angina pectoris. Am J Med 1966;41:947-61. lesions. 2. Cannon OS, Harrison DC, Schroeder JS. Hemodynamic observations In patients in whom there is no obvious angiographic in patients with unstable angina pectoris. Am J Cardiol 1974;33:17-22. progression ofcoronary disease despite the new appearance 3. Scheidt S, Wolk M, Killip J. 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