Coronary Artery Embolism and Myocardial Infarction A Clinicopathologic Study of 55 Patients KATE ROTHKO PRIZEL, M.D.; Baltimore,
B.S.; GROVER M. HUTCHINS,
M.D.; and BERNADINE H. BULKLEY,
Maryland
Although coronary artery embolism is a recognized entity, there is little morphologic information indicating it is a cause of myocardial infarction. We studied patients with coronary artery embolic infarcts, which comprised 1 3 % of our autopsy-studied infarcts. Underlying diseases predisposing to coronary emboli included valvular heart disease ( 4 0 % ) , myocardiopathy ( 2 9 % ) , coronary atherosclerosis ( 1 6 % ) , and chronic atrial fibrillation ( 2 4 % ) . Mural thrombi were present in 18 ( 3 3 % ) . Myocardial infarction, clinically diagnosed in 15 ( 2 7 % ) patients, caused death in 11 ( 2 0 % ) . Most emboli involved the left coronary artery and lodged distally, causing infarcts that were usually transmural. Because of their distal location and recanalization, coronary emboli may be a cause of infarcts with angiographically normal coronaries. Thus, coronary emboli are not rare, may produce signs and symptoms indistinguishable from atherosclerotic coronary disease, and by lodging distally in coronary arteries that are usually previously normal, they most often cause small but transmural myocardial infarction.
technique makes it easier to detect coronary artery embolism at autopsy. Using such a methodology, we have identified 55 autopsied patients who had embolism associated with myocardial infarction, including 15 patients in whom clinically apparent acute myocardial infarction developed as a consequence of the acute arterial occlusions. This study suggests that coronary arterial embolism with infarction is not a rare event, is most often not fatal, and produces a characteristic pattern of infarction that may present clinically with signs and symptoms indistinguishable from ischemic heart disease due to atherosclerosis. Materials and Methods P A T I E N T SELECTION
Of the 5000 autopsied patients at The Johns Hopkins Hospital since 1967, the hearts of 1050 were selected for postmortem coronary arteriogram because of a known or suspected history of cardiovascular or pulmonary disease. Among this group of patients there were 55 who had autopsy evidence of myocardial infarction caused by coronary artery emboli. These patients form the basis of this report.
M Y O C A R D I A L INFARCTION is most often due to athero-
sclerosis (1). Although recognized, coronary artery embolism is generally viewed as a rare cause of coronary artery occlusion. Most information about coronary embolism is derived from a handful of case reports that have appeared in the literature during the past 20 or 30 years, and much of the information from these studies is contradictory (2-31). Some maintain that coronary embolism is invariably fatal (5, 15), whereas others indicate that it is not an infrequent autopsy finding, but is usually of no clinical consequence and only rarely leads to acute myocardial infarction (6, 7). Some studies also suggest that coronary embolism usually occurs in young men in their 20s and 30s and that it is most often related to infective endocarditis (16). This variation in findings is partially explained because coronary embolism is a difficult diagnosis to make clinically or at autopsy, as emboli frequently lodge in the most distal portion of the coronary artery tree. In our laboratory, all hearts are studied with postmortem angiography with radiographs taken in multiple views; this • From the Cardiovascular Division, Department of Medicine, and the Department of Pathology, The Johns Hopkins Medical Institutions; Baltimore, Maryland.
METHODS
The clinical and pathologic features of the 55 patients with coronary embolism were reviewed. In each instance, the hearts were studied after postmortem coronary angiography using a barium-gel-pigment injection mass with subsequent fixation in formalin in a distended state before sectioning. Stereoscopic radiographs were prepared in at least two planes, the coronaries sectioned were at 2-to-3-mm intervals, and any occlusive lesions were removed en bloc for serial sectioning and histologic study. The myocardium was inspected for gross evidence of remote or recent myocardial infarction and suspicious areas taken for histologic section. In addition, routine sections of myocardium from mid-left and mid-right ventricle were taken. For the purpose of this study, only areas of myocardial necrosis or fibrosis that were at least 3 cm in size in one dimension were deemed significant infarcts and included in this review. A coronary lesion was considered to be embolic if at autopsy a source was apparent (that is, valve vegetations, intracardiac thrombus), and the artery occluded showed no evidence of mural disease including arteritis or significant atherosclerosis (Figures 1-3) with an essentially normal intima at the site of the occlusive mass. The few patients (5) in whom no source for embolism was present at autopsy were included because a thromboembolus was present in a coronary artery that was otherwise entirely normal. Finally, the clinical history of each patient in the embolic group was re-reviewed to ascertain which of the myocardial lesions were associated with clinical signs or symptoms of infarction.
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were lodged in the proximal or mid portion of the artery. In eight patients (15%) multiple coronary artery emboli were evident. In five they involved more than two coronary arteries (left anterior descending and circumflex in two, left anterior descending and right in three). In three embolic lesions occurred in multiple branches of a single coronary artery but the infarcts were histologically of different ages. In two patients with multiple coronary emboli, at least one event was associated with clinically recognized myocardial infarct. Death was related to the coronary embolic event per se in 11 (20%) patients. CLINICALLY RECOGNIZED VERSUS SILENT EMBOLI
Figure 1 . Fresh thromboembolus occluding a normal coronary artery. (Hematoxylin and eosin stain; original magnification, x 4 0 . )
Results CLINICAL AND PATHOLOGIC DATA
Among 419 patients with myocardial infarction who met the criteria for this study, 55 patients (13%) had evidence of embolic infarction. The findings in these patients are summarized in Table 1. The patients ranged in age from 19 to 88 years (average, 59 years), and 3 5 % were women. Underlying disease states that may have predisposed to coronary artery embolism were present in the majority of patients. Valvular abnormalities were associated with coronary emboli in 22 (40%) patients and included prosthetic valves in eight patients, noninfected abnormal valves in eight (luetic in four, rheumatic in four), infective endocarditis in three, and nonbacterial thrombotic endocarditis in three. Other predisposing conditions included coronary artery disease in nine (16%) and myocardiopathy in 16 (29%). In addition, 13 patients (24%) had atrial fibrillation as a chronic rhythm. Cardiac catheterization with coronary angiography was associated with coronary embolism in two patients (4%), and four had collagen vascular disease and were on steroid therapy but had no underlying heart disease. In the 55 patients there were 64 embolic infarcts, as seven patients had two embolic infarcts and one patient had three. Coronary artery emboli occurred in the distribution of the left coronary artery in 46 instances (72%) and of the right coronary artery in 18 (28%). The left anterior descending coronary artery and its branches were the most frequent site of embolism, being involved in 33 (52%) of the 64 infarcts. In 53 (83%) of the 64 embolic events the emboli were located in the most distal portion of the epicardial coronary artery. Myocardial infarction was associated with each embolic episode, but varied in size and extent. Although 48 (75%) of the infarcts were transmural, the majority of them were small, with 8 4 % involving less than 15% of the left ventricular circumference. In all 10 infarcts that exceeded 2 0 % of left ventricular circumference, the coronary artery emboli 156
Among the 55 patients with coronary arterial embolism, myocardial infarction was clinically recognized in 15 (27%). In nine (60%) patients chest pain was present, and in four patients new onset congestive heart failure developed, which was thought to be related to the myocardial insults. In all 15 patients, the electrocardiographic changes were diagnostic of ischemia or infarction. Of the 15 clinically recognized myocardial infarctions, emboli were suspected as the cause in five (33%) patients: in one, the diagnosis was readily made at the time of cardiac catheterization; in two patients with atrial fibrillation, coronary artery embolism was suspected as the cause of an unexpected acute myocardial infarction; and in two other patients, who were drug addicts and developed their myocardial infarcts at ages 23 and 37, respectively, the clinical impression was coronary embolism related to a bacterial endocarditis. The remainder of the acute coronary events were attributed clinically to atherosclerotic coronary artery disease. When the patients who developed clinically significant coronary arterial embolism with myocardial infarction were compared with those who did not (Table 1), there were few differences between the groups. Predisposing conditions were similar in both groups but valve disease was almost twice as common in those with silent lesions. In both groups the left coronary artery was the most frequent site for embolism and the distal portions of the coronary arteries were mostly involved. Although in both groups the myocardial infarcts were mostly transmural, the infarcts tended to be larger in the group with clinically recognized coronary occlusive events. This difference in size of infarction between the two groups paralleled the greater prevalence of proximal or mid coronary occlusions in the clinically recognized group. TIME COURSE OF EMBOLIC EVENTS
Dividing the embolic episodes in the 55 patients by age, there were five embolic episodes that were only hours old. Atherosclerotic coronary disease was present in one of these patients who had generalized coronary artery disease, two previous infarcts, and mural thrombi overlying the infarcts. Mural thrombi within the heart were the source of emboli in two other patients, and in two others, emboli came from the catheter tip at the time of catheterization. Four of the myocardial infarctions were transmural, one was subendocardial, and two of the five events were clinically diagnosed.
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Figure 2. A thromboembolus occluding the distal left anterior descending coronary artery has produced a small but transmural myocardial infarct. Rupture of the infarcted myocardium occurred during resuscitation. A. Postmortem coronary arteriogram. Note obstruction to filling (arrow) of the distal left anterior descending coronary artery (LAD), but otherwise normal vessels. B. Transverse section of the coronary artery obstructed by thromboembolus showing formation of channels of recanalization between embolus and vessel wall (Hematoxylin and eosin stain; original magnification, x 120.) C. Transverse section through right (RV) and left ventricle (LV) near the apex of the heart showing the myocardial infarct in the interventricular septum (IVS).
Five patients had coronary artery emboli that were between two and 14 days old at autopsy. Two myocardial infarcts were subendocardial and three were transmural. In each, embolic material was present in coronary arteries that were otherwise histologically normal. Endocarditis was present in three patients and a prosthetic aortic valve in one. One of these patients with marantic endocarditis had two separate embolic infarcts in the left distribution, one, 7 to 10 days old and one, 3 weeks old. In the fifth patient, who had chronic heart failure and longstanding hypertension, small amounts of thromboembolic material were present within the distal epicardial and proximal intramural coronary arteries without an obvious source. Four patients had coronary artery emboli that occurred within 2 to 8 weeks of death and had not been clinically recognized. Three caused transmural infarcts and one subendocardial infarct; in none was there associated coronary artery disease. The source of embolization at autopsy included nonbacterial thrombotic endocarditis in one patient, infective endocarditis in one, and intracardiac mural thrombus related to chronic heart failure in
one. The fourth patient had systemic lupus erythematosus, with a widely patent foramen ovale, and had an occlusive thromboembolus lodged in an otherwise normal distal left anterior descending coronary artery, which was presumably a paradoxical embolus. In eight patients coronary artery emboli occurred between 2 and 12 months of death. In six patients atherosclerotic coronary artery disease was negligible. The sources were identified in six patients: an aortic valvular prosthesis in one, atrial thrombus associated with atrial fibrillation in one, mural left ventricular thrombus associated with myocardiopathy in two, and mural thrombus overlying a previous myocardial infarction in two. Both of these latter patients had focal occlusive coronary artery disease, but not in the arteries occluded by emboli. The seventh patient was a heroin addict; healed infective endocarditis or paradoxical embolus through a probe patent foramen ovale may have been the cause. The eighth patient had no apparent source or reason for embolism. In three of these eight patients there were multiple coronary emboli. In one they involved two different arteries and were of approximately the same age; in two patients Prize/eta/.
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vessel distributing to the region of old infarction was occluded by material showing channels of recanalization and by webs or bands within the coronary lumen. EXTRACARDIAC EMBOLIZATION
Evidence of extracardiac embolization was found at autopsy in 22 (40%) patients. In seven patients, the extracardiac emboli were the cause of death: three due to cerebrovascular events, two due to peripheral arterial emboli with gangrene and sepsis, and two due to bowel infarction. Of the 15 patients with clinically recognized embolic myocardial infarction, four had extracardiac embolic lesions at autopsy, and two died of these extracardiac events.
Discussion
Although coronary artery embolism is reported to be an infrequent cause of acute coronary artery occlusion, with less than 150 cases reported in the literature since Virchow's original description in 1856 (2), we have studied 55 patients at autopsy with myocardial infarction due to coronary embolism. Viewing these patients as a whole, certain patterns emerge with regard to clinical presentation and morphologic findings. PREDISPOSING CONDITIONS
Figure 3. An organized recanalized thromboembolus has occluded a coronary artery and produced transmural infarct in its distribution. A. Transverse section of coronary artery with multiple channels of recanalization filled with black staining injection mass (Hematoxylin and eosin stain; original magnification x 30.) B. Transmural myocardial infarct in the distribution of the occluded artery shown in A. There is extensive organizing mural thrombus on the left (Hematoxylin and eosin stain; original magnification, x 11.)
they involved branches of the same vessel and one of the two infarcts was years old. The remaining 33 patients with embolic infarcts had lesions that were histologically older than 1 year of age. Sources of embolic material in these patients at autopsy included atrial thrombus in 14 (nine of whom had longstanding atrial fibrillation), left ventricular mural thrombus in 10 patients, prosthetic valve prosthesis in four patients, and endocarditis in three. In the two others the source of embolization was not identified, but in each the coronary arteries were normal and evidence of systemic embolization was present. In these 33 patients the healed infarcts related to a distal epicardial coronary branch artery and its intramural branches, which contained organized embolic material. In each instance, the coronary 158
In our study conditions predisposing to coronary embolism were varied. Previous studies have suggested that three quarters of cases of coronary emboli in the setting of infective endocarditis occur in young patients (4, 6-9, 11-16). In our 55 patients, however, the mean age was 59 years, and valve disease was an underlying condition in only 4 2 % of patients; in only 5 % was the valve infected. Furthermore, compared with infective endocarditis, noninfected prosthetic valves were three times more frequent, and nonbacterial thrombotic endocarditis was as frequent, as conditions predisposing to coronary emboli. Thus, although the cardiac valves continue to be a major source of coronary emboli, infective endocarditis appears to no longer be the major source of these lesions. Coronary emboli frequently occurred in association with intracavitary thrombi, particularly in patients with chronic atrial fibrillation (19, 21), idiopathic myocardiopathy, and previous myocardial infarction. In our study all coronary emboli developing in patients with atherosclerotic coronary disease resulted from intracardiac mural thrombus rather than from atheromatous embolization. More recently it has been recognized that coronary embolism may occur in association with coronary arteriography (27, 28); in two of our 55 patients coronary emboli were of this origin. Of the 55 patients, five (9%) had no apparent predisposing conditions or source of emboli. It is possible that in these cases the coronary occlusions may have arisen as thromboses in normal coronary arteries. It is of note, that three of the five patients had collagen vascular disease and two were on high doses of steroids, which appear to predispose to thrombosis (31).
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Table 1. Coronary Arterial Embolism: Data in 55 Patients
Patients, no. Age range (mean), yrs. Sex, no. female (%) Predisposing conditions Valve disease Infective endocarditis Nonbacterial thrombotic endocarditis Prosthetic valve Abnormal valve, not infected Coronary disease Myocardiopathy Atrial Fibrillation Cardiac Catheterization Unknown Signs of coronary embolism Chest pain Electrocardiogram changes (ischemia/infarction) Total embolic infarcts, no. Patients with multiple coronary emboli, no. Artery involved Left coronary artery Left anterior descending Left circumflex Right coronary artery Distal artery Infarction Transmural infarct Patients with infarct > 2 0 % left ventricle Mural thrombus Cause of death
Clinically Recognized
Not Clinically Recognized
Total
15 23 to 84 (55) 7 (47%)
40 19 to 88 (60) 12 (30%)
55 19 to 88 (59) 19 (35%)
19 (48%) 2 3 7 7 6(15%) 12(30%) 8 (20%) 1 (3%) 2 (5%)
22 (40%) 3 3 8 8 9 (16%) 16(29%) 13(24%) 2 (4%) 5 (9%)
9 (60%) 15(100%) 19 4 (27%)
45* 4 (10%)
64 8 (15%)
14 (74%) 12 2 5 (26%) 15 (79%)
32(71%) 21 11 13(29%) 39 (87%)
46 (72%)
16(84%) 4 (27%) 4 (27%) 4 (27%)
32(71%) 6(15%) 14 (35%) 7 (18%)
48 10 18 11
CLINICAL PRESENTATION OF EMBOLIC INFARCTS
Although we have found coronary emboli as the cause of infarction in approximately one in 10 patients autopsied with myocardial infarction, for the most part these embolic infarcts were clinically unrecognized. Of particular interest, however, were the 15 patients who sustained clinically apparent acute myocardial infarction as a consequence of arterial embolism. These 15 patients were diagnosed as having acute myocardial infarctions on the basis of symptoms and electrocardiogram, and two-thirds of them were thought to have atherosclerotic coronary disease. There were few differences between the patients with clinically recognized and unrecognized infarcts. Silent embolic infarcts were more common among patients who had abnormal valves, either due to chronic disease or prosthetic replacement. Patients with clinically apparent embolic infarcts had a higher frequency of multiple coronary emboli and larger infarcts, which may have contributed to infarct recognition. Overall, the differences were not great, and the high rate of silence of embolic infarcts may reflect primarily the underlying diseases that may have obscured the myocardial injury when it occurred. CHARACTERISTIC MORPHOLOGY OF EMBOLIC INFARCTS
A curious feature of coronary artery embolism that has been long recognized (15, 16), and that was most evident in our patients, was the tendency for emboli to involve the left coronary artery three to four times more often
3 1 0 1 1 3 4 5 1 3
(20%)
(20%) (27%) (33%) (7%) (20%)
18 (28%) 53 (83%) (75%) (18%) (33%) (20%)
than the right, and the left anterior descending coronary artery more often than the left circumflex. It has been suggested that the take-off and downward course of the left anterior descending coronary artery is more favorable for embolization than that of the right and left circumflex coronary arteries, which run at a 90° angle from their parent trunks. Coronary artery dissection is also more apt to involve the left coronary artery (33). Whatever the special features may be, these two causes of acute coronary occlusions in what are usually previously normal vessels (33) have a predilection for the same coronary artery. A consistently recognized morphologic feature of coronary emboli is that they most frequently lodge in the distal portions of the coronary tree. It is commonly believed (8, 15, 17) that coronary embolism more often leads to sudden death than coronary thrombosis in patients with atherosclerosis. Although it is true that patients without pre-existing ischemic heart disease have poorly developed collaterals so that an occlusion of a major coronary artery branch might be more disastrous, the distal lodging of the emboli probably accounts for the relatively small number of deaths (20%) due to embolization in our series. The distal location of the majority of emboli in our series accounts for two other of our morphologic observations: [1] 7 5 % of the infarcts were transmural (this is most likely due to poor development of collaterals in humans without pre-existing coronary occlusive disease), and [2] only 14% of the infarcts were large (that is, involved > 2 0 % of left ventricular circumPrizel et al. • Coronary Artery Embolism
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curring in only eight of our patients. As only 2 0 % of the coronary emboli were a cause of death, death does not appear to offer the explanation for the lack of recurrent coronary emboli. CORONARY EMBOLISM AS A NOT-SO-RARE CAUSE OF INFARCTION WITH NORMAL CORONARIES
Figure 4. Diagram contrasting myocardial infarcts produced by atherosclerotic coronary artery disease and those produced by coronary artery emboli. Occlusions on atheromas tend to be more proximal and in major epicardial coronary arteries. The infarct involves a greater surface extent of the heart, but because of the vascular disease elsewhere collateral channels tend to be developed and the infarct is subendocardial. In contrast emboli tend to be found in hearts with normal arteries. The embolus lodges in a distal epicardial branch. Because the collaterals are underdeveloped the embolic occlusion produces a small but transmural infarct. PA = pulmonary artery.
ference). In fact, and not surprisingly, the size of the infarct correlated directly with the location of the embolic occlusion. In all 10 patients in whom a large infarct was present, the embolus lodged in the proximal or mid coronary artery, and they represented 10 of the 11 cases in which the embolus was in this more proximal location. Small infarct size is probably the major factor accounting for patient survival. The discrepancy from previous reports may be due to a tendency to detect and report only the more dramatic cases. Coronary artery emboli are only infrequent relative to atherosclerotic disease of the coronary artery and to arterial emboli elsewhere in the body. Cardiac disorders predisposing to embolization, such as endocarditis, cardiac mural thrombosis, or atrial fibrillation, are more apt to result in emboli to the brain or spleen than to the myocardium. Swift current flow around the coronary ostia, or caliber differences between the aorta and the coronary arteries, and the acute angle at which the coronary arteries exit the aorta may account for this (5, 13). The position of the coronary ostia behind the valve cusp during systole may also keep the coronary arteries out of the central stream of systolic blood flow. Not only are the coronary arteries relatively protected from emboli, compared with other organs, but the frequency of multiple emboli to the heart also appears to be relatively low, oc160
The fact that we have studied 55 patients, autopsied at a single institution, with coronary arterial emboli associated with myocardial infarction, most of whom had previously normal coronary arteries, is particularly noteworthy. Furthermore, these patients represent 1 3 % of a consecutive series of patients autopsied with myocardial infarcts from a single institution. Embolism may be becoming more frequent because of advances such as cardiac catheterization and surgery, but the fact that only a handful of our patients (4%) had emboli related to these procedures makes this an insufficient explanation for the frequency of embolic infarcts in our institution. It is more likely that coronary emboli are under-diagnosed, for reasons including a failure to distinguish embolism from thrombosis, failure to report only the most dramatic cases, or a failure to make a systematic search for small emboli in the distal and intramural branches of coronary arteries (7, 19). We believe that the method of postmortem angiography with serial histologic sectioning of the coronary lesions provides a particularly sensitive technique for the detection of small and peripheral emboli that might otherwise be overlooked. It should be stressed, however, that the prevalence of embolic infarct detected at autopsy does not necessarily represent the frequency of embolic infarction in a general population. Angina and myocardial infarction with normal coronary arteries has been the source of great interest and speculation, with anywhere from 4 % to 2 0 % of patients with a history of probable or definite angina or acute myocardial infarction having angiographically normal coronary arteries (34-37). Coronary arterial spasm is one recognized cause of angina pectoris and even of infarction with normal coronaries (38-41). The patients studied here clearly show that coronary emboli may also be a cause. Angiography after an infarct may fail to show a coronary embolus because of its distal location or its recanalization. Coronary emboli also may occur in patients with mild heart failure, or silent or inactive valvular lesions, so that the clinical suspicion of embolism might be low. Possible clues to coronary emboli as a cause of infarction with normal coronary arteries are that such events occur in the distribution of the left coronary artery in three quarters of cases, and that they cause small but transmural myocardial infarctions (Figure 4). This predilection for the left coronary artery is in contrast to coronary artery spasm that appears at selective coronary angiography to most often involve the proximal right coronary artery (39). Also, unlike spasm and atherosclerotic coronary disease, embolic infarcts are not apt to be recurrent or associated with postinfarct symptoms of ischemic heart disease. Perhaps a thorough search for the risk factors for coronary emboli should be made in all patients
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who carry the diagnosis of infarction with normal coronary arteries. ACKNOWLEDGMENTS: Grant support: by Grant P50-HL-17655-03 from the National Institutes of Health, Public Health Service, Department of Health, Education, and Welfare; and the Stetler Research Fund for Women Physicians. Received 16 June 1977; revision accepted 27 September 1977.
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the coronary artery. Report of 10 cases and review of literature. Am J Cardiol 11:228-237, 1963 22. RIVERA R, TALLON R: Coronary embolism in mitral stenosis. / Cardiovasc Surg 5:382-385, 1964 23. LANKIN EH, O E H L E R C, BALSLEY MD: Coronary embolism with myocardial infarction. Late complication in a patient with a Starr-Edwards mitral-valve prosthesis. JAMA 194:1019-1020, 1965 24. C O R D E I R O A, P I M E N T E L C, L A G I N H A F, R I B E I R O C, COSTA H: Coro-
• Requests for reprints should be addressed to Bernadine H. Bulkley, M.D.; Department of Pathology, The Johns Hopkins Hospital; Baltimore, M D 21205.
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B.S.; GROVER M. HUTCHINS,
M.D.; and BERNADINE H. BULKLEY,
Maryland
Although coronary artery embolism is a recognized entity, there is little morphologic information indicating it is a cause of myocardial infarction. We studied patients with coronary artery embolic infarcts, which comprised 1 3 % of our autopsy-studied infarcts. Underlying diseases predisposing to coronary emboli included valvular heart disease ( 4 0 % ) , myocardiopathy ( 2 9 % ) , coronary atherosclerosis ( 1 6 % ) , and chronic atrial fibrillation ( 2 4 % ) . Mural thrombi were present in 18 ( 3 3 % ) . Myocardial infarction, clinically diagnosed in 15 ( 2 7 % ) patients, caused death in 11 ( 2 0 % ) . Most emboli involved the left coronary artery and lodged distally, causing infarcts that were usually transmural. Because of their distal location and recanalization, coronary emboli may be a cause of infarcts with angiographically normal coronaries. Thus, coronary emboli are not rare, may produce signs and symptoms indistinguishable from atherosclerotic coronary disease, and by lodging distally in coronary arteries that are usually previously normal, they most often cause small but transmural myocardial infarction.
technique makes it easier to detect coronary artery embolism at autopsy. Using such a methodology, we have identified 55 autopsied patients who had embolism associated with myocardial infarction, including 15 patients in whom clinically apparent acute myocardial infarction developed as a consequence of the acute arterial occlusions. This study suggests that coronary arterial embolism with infarction is not a rare event, is most often not fatal, and produces a characteristic pattern of infarction that may present clinically with signs and symptoms indistinguishable from ischemic heart disease due to atherosclerosis. Materials and Methods P A T I E N T SELECTION
Of the 5000 autopsied patients at The Johns Hopkins Hospital since 1967, the hearts of 1050 were selected for postmortem coronary arteriogram because of a known or suspected history of cardiovascular or pulmonary disease. Among this group of patients there were 55 who had autopsy evidence of myocardial infarction caused by coronary artery emboli. These patients form the basis of this report.
M Y O C A R D I A L INFARCTION is most often due to athero-
sclerosis (1). Although recognized, coronary artery embolism is generally viewed as a rare cause of coronary artery occlusion. Most information about coronary embolism is derived from a handful of case reports that have appeared in the literature during the past 20 or 30 years, and much of the information from these studies is contradictory (2-31). Some maintain that coronary embolism is invariably fatal (5, 15), whereas others indicate that it is not an infrequent autopsy finding, but is usually of no clinical consequence and only rarely leads to acute myocardial infarction (6, 7). Some studies also suggest that coronary embolism usually occurs in young men in their 20s and 30s and that it is most often related to infective endocarditis (16). This variation in findings is partially explained because coronary embolism is a difficult diagnosis to make clinically or at autopsy, as emboli frequently lodge in the most distal portion of the coronary artery tree. In our laboratory, all hearts are studied with postmortem angiography with radiographs taken in multiple views; this • From the Cardiovascular Division, Department of Medicine, and the Department of Pathology, The Johns Hopkins Medical Institutions; Baltimore, Maryland.
METHODS
The clinical and pathologic features of the 55 patients with coronary embolism were reviewed. In each instance, the hearts were studied after postmortem coronary angiography using a barium-gel-pigment injection mass with subsequent fixation in formalin in a distended state before sectioning. Stereoscopic radiographs were prepared in at least two planes, the coronaries sectioned were at 2-to-3-mm intervals, and any occlusive lesions were removed en bloc for serial sectioning and histologic study. The myocardium was inspected for gross evidence of remote or recent myocardial infarction and suspicious areas taken for histologic section. In addition, routine sections of myocardium from mid-left and mid-right ventricle were taken. For the purpose of this study, only areas of myocardial necrosis or fibrosis that were at least 3 cm in size in one dimension were deemed significant infarcts and included in this review. A coronary lesion was considered to be embolic if at autopsy a source was apparent (that is, valve vegetations, intracardiac thrombus), and the artery occluded showed no evidence of mural disease including arteritis or significant atherosclerosis (Figures 1-3) with an essentially normal intima at the site of the occlusive mass. The few patients (5) in whom no source for embolism was present at autopsy were included because a thromboembolus was present in a coronary artery that was otherwise entirely normal. Finally, the clinical history of each patient in the embolic group was re-reviewed to ascertain which of the myocardial lesions were associated with clinical signs or symptoms of infarction.
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were lodged in the proximal or mid portion of the artery. In eight patients (15%) multiple coronary artery emboli were evident. In five they involved more than two coronary arteries (left anterior descending and circumflex in two, left anterior descending and right in three). In three embolic lesions occurred in multiple branches of a single coronary artery but the infarcts were histologically of different ages. In two patients with multiple coronary emboli, at least one event was associated with clinically recognized myocardial infarct. Death was related to the coronary embolic event per se in 11 (20%) patients. CLINICALLY RECOGNIZED VERSUS SILENT EMBOLI
Figure 1 . Fresh thromboembolus occluding a normal coronary artery. (Hematoxylin and eosin stain; original magnification, x 4 0 . )
Results CLINICAL AND PATHOLOGIC DATA
Among 419 patients with myocardial infarction who met the criteria for this study, 55 patients (13%) had evidence of embolic infarction. The findings in these patients are summarized in Table 1. The patients ranged in age from 19 to 88 years (average, 59 years), and 3 5 % were women. Underlying disease states that may have predisposed to coronary artery embolism were present in the majority of patients. Valvular abnormalities were associated with coronary emboli in 22 (40%) patients and included prosthetic valves in eight patients, noninfected abnormal valves in eight (luetic in four, rheumatic in four), infective endocarditis in three, and nonbacterial thrombotic endocarditis in three. Other predisposing conditions included coronary artery disease in nine (16%) and myocardiopathy in 16 (29%). In addition, 13 patients (24%) had atrial fibrillation as a chronic rhythm. Cardiac catheterization with coronary angiography was associated with coronary embolism in two patients (4%), and four had collagen vascular disease and were on steroid therapy but had no underlying heart disease. In the 55 patients there were 64 embolic infarcts, as seven patients had two embolic infarcts and one patient had three. Coronary artery emboli occurred in the distribution of the left coronary artery in 46 instances (72%) and of the right coronary artery in 18 (28%). The left anterior descending coronary artery and its branches were the most frequent site of embolism, being involved in 33 (52%) of the 64 infarcts. In 53 (83%) of the 64 embolic events the emboli were located in the most distal portion of the epicardial coronary artery. Myocardial infarction was associated with each embolic episode, but varied in size and extent. Although 48 (75%) of the infarcts were transmural, the majority of them were small, with 8 4 % involving less than 15% of the left ventricular circumference. In all 10 infarcts that exceeded 2 0 % of left ventricular circumference, the coronary artery emboli 156
Among the 55 patients with coronary arterial embolism, myocardial infarction was clinically recognized in 15 (27%). In nine (60%) patients chest pain was present, and in four patients new onset congestive heart failure developed, which was thought to be related to the myocardial insults. In all 15 patients, the electrocardiographic changes were diagnostic of ischemia or infarction. Of the 15 clinically recognized myocardial infarctions, emboli were suspected as the cause in five (33%) patients: in one, the diagnosis was readily made at the time of cardiac catheterization; in two patients with atrial fibrillation, coronary artery embolism was suspected as the cause of an unexpected acute myocardial infarction; and in two other patients, who were drug addicts and developed their myocardial infarcts at ages 23 and 37, respectively, the clinical impression was coronary embolism related to a bacterial endocarditis. The remainder of the acute coronary events were attributed clinically to atherosclerotic coronary artery disease. When the patients who developed clinically significant coronary arterial embolism with myocardial infarction were compared with those who did not (Table 1), there were few differences between the groups. Predisposing conditions were similar in both groups but valve disease was almost twice as common in those with silent lesions. In both groups the left coronary artery was the most frequent site for embolism and the distal portions of the coronary arteries were mostly involved. Although in both groups the myocardial infarcts were mostly transmural, the infarcts tended to be larger in the group with clinically recognized coronary occlusive events. This difference in size of infarction between the two groups paralleled the greater prevalence of proximal or mid coronary occlusions in the clinically recognized group. TIME COURSE OF EMBOLIC EVENTS
Dividing the embolic episodes in the 55 patients by age, there were five embolic episodes that were only hours old. Atherosclerotic coronary disease was present in one of these patients who had generalized coronary artery disease, two previous infarcts, and mural thrombi overlying the infarcts. Mural thrombi within the heart were the source of emboli in two other patients, and in two others, emboli came from the catheter tip at the time of catheterization. Four of the myocardial infarctions were transmural, one was subendocardial, and two of the five events were clinically diagnosed.
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Figure 2. A thromboembolus occluding the distal left anterior descending coronary artery has produced a small but transmural myocardial infarct. Rupture of the infarcted myocardium occurred during resuscitation. A. Postmortem coronary arteriogram. Note obstruction to filling (arrow) of the distal left anterior descending coronary artery (LAD), but otherwise normal vessels. B. Transverse section of the coronary artery obstructed by thromboembolus showing formation of channels of recanalization between embolus and vessel wall (Hematoxylin and eosin stain; original magnification, x 120.) C. Transverse section through right (RV) and left ventricle (LV) near the apex of the heart showing the myocardial infarct in the interventricular septum (IVS).
Five patients had coronary artery emboli that were between two and 14 days old at autopsy. Two myocardial infarcts were subendocardial and three were transmural. In each, embolic material was present in coronary arteries that were otherwise histologically normal. Endocarditis was present in three patients and a prosthetic aortic valve in one. One of these patients with marantic endocarditis had two separate embolic infarcts in the left distribution, one, 7 to 10 days old and one, 3 weeks old. In the fifth patient, who had chronic heart failure and longstanding hypertension, small amounts of thromboembolic material were present within the distal epicardial and proximal intramural coronary arteries without an obvious source. Four patients had coronary artery emboli that occurred within 2 to 8 weeks of death and had not been clinically recognized. Three caused transmural infarcts and one subendocardial infarct; in none was there associated coronary artery disease. The source of embolization at autopsy included nonbacterial thrombotic endocarditis in one patient, infective endocarditis in one, and intracardiac mural thrombus related to chronic heart failure in
one. The fourth patient had systemic lupus erythematosus, with a widely patent foramen ovale, and had an occlusive thromboembolus lodged in an otherwise normal distal left anterior descending coronary artery, which was presumably a paradoxical embolus. In eight patients coronary artery emboli occurred between 2 and 12 months of death. In six patients atherosclerotic coronary artery disease was negligible. The sources were identified in six patients: an aortic valvular prosthesis in one, atrial thrombus associated with atrial fibrillation in one, mural left ventricular thrombus associated with myocardiopathy in two, and mural thrombus overlying a previous myocardial infarction in two. Both of these latter patients had focal occlusive coronary artery disease, but not in the arteries occluded by emboli. The seventh patient was a heroin addict; healed infective endocarditis or paradoxical embolus through a probe patent foramen ovale may have been the cause. The eighth patient had no apparent source or reason for embolism. In three of these eight patients there were multiple coronary emboli. In one they involved two different arteries and were of approximately the same age; in two patients Prize/eta/.
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vessel distributing to the region of old infarction was occluded by material showing channels of recanalization and by webs or bands within the coronary lumen. EXTRACARDIAC EMBOLIZATION
Evidence of extracardiac embolization was found at autopsy in 22 (40%) patients. In seven patients, the extracardiac emboli were the cause of death: three due to cerebrovascular events, two due to peripheral arterial emboli with gangrene and sepsis, and two due to bowel infarction. Of the 15 patients with clinically recognized embolic myocardial infarction, four had extracardiac embolic lesions at autopsy, and two died of these extracardiac events.
Discussion
Although coronary artery embolism is reported to be an infrequent cause of acute coronary artery occlusion, with less than 150 cases reported in the literature since Virchow's original description in 1856 (2), we have studied 55 patients at autopsy with myocardial infarction due to coronary embolism. Viewing these patients as a whole, certain patterns emerge with regard to clinical presentation and morphologic findings. PREDISPOSING CONDITIONS
Figure 3. An organized recanalized thromboembolus has occluded a coronary artery and produced transmural infarct in its distribution. A. Transverse section of coronary artery with multiple channels of recanalization filled with black staining injection mass (Hematoxylin and eosin stain; original magnification x 30.) B. Transmural myocardial infarct in the distribution of the occluded artery shown in A. There is extensive organizing mural thrombus on the left (Hematoxylin and eosin stain; original magnification, x 11.)
they involved branches of the same vessel and one of the two infarcts was years old. The remaining 33 patients with embolic infarcts had lesions that were histologically older than 1 year of age. Sources of embolic material in these patients at autopsy included atrial thrombus in 14 (nine of whom had longstanding atrial fibrillation), left ventricular mural thrombus in 10 patients, prosthetic valve prosthesis in four patients, and endocarditis in three. In the two others the source of embolization was not identified, but in each the coronary arteries were normal and evidence of systemic embolization was present. In these 33 patients the healed infarcts related to a distal epicardial coronary branch artery and its intramural branches, which contained organized embolic material. In each instance, the coronary 158
In our study conditions predisposing to coronary embolism were varied. Previous studies have suggested that three quarters of cases of coronary emboli in the setting of infective endocarditis occur in young patients (4, 6-9, 11-16). In our 55 patients, however, the mean age was 59 years, and valve disease was an underlying condition in only 4 2 % of patients; in only 5 % was the valve infected. Furthermore, compared with infective endocarditis, noninfected prosthetic valves were three times more frequent, and nonbacterial thrombotic endocarditis was as frequent, as conditions predisposing to coronary emboli. Thus, although the cardiac valves continue to be a major source of coronary emboli, infective endocarditis appears to no longer be the major source of these lesions. Coronary emboli frequently occurred in association with intracavitary thrombi, particularly in patients with chronic atrial fibrillation (19, 21), idiopathic myocardiopathy, and previous myocardial infarction. In our study all coronary emboli developing in patients with atherosclerotic coronary disease resulted from intracardiac mural thrombus rather than from atheromatous embolization. More recently it has been recognized that coronary embolism may occur in association with coronary arteriography (27, 28); in two of our 55 patients coronary emboli were of this origin. Of the 55 patients, five (9%) had no apparent predisposing conditions or source of emboli. It is possible that in these cases the coronary occlusions may have arisen as thromboses in normal coronary arteries. It is of note, that three of the five patients had collagen vascular disease and two were on high doses of steroids, which appear to predispose to thrombosis (31).
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Table 1. Coronary Arterial Embolism: Data in 55 Patients
Patients, no. Age range (mean), yrs. Sex, no. female (%) Predisposing conditions Valve disease Infective endocarditis Nonbacterial thrombotic endocarditis Prosthetic valve Abnormal valve, not infected Coronary disease Myocardiopathy Atrial Fibrillation Cardiac Catheterization Unknown Signs of coronary embolism Chest pain Electrocardiogram changes (ischemia/infarction) Total embolic infarcts, no. Patients with multiple coronary emboli, no. Artery involved Left coronary artery Left anterior descending Left circumflex Right coronary artery Distal artery Infarction Transmural infarct Patients with infarct > 2 0 % left ventricle Mural thrombus Cause of death
Clinically Recognized
Not Clinically Recognized
Total
15 23 to 84 (55) 7 (47%)
40 19 to 88 (60) 12 (30%)
55 19 to 88 (59) 19 (35%)
19 (48%) 2 3 7 7 6(15%) 12(30%) 8 (20%) 1 (3%) 2 (5%)
22 (40%) 3 3 8 8 9 (16%) 16(29%) 13(24%) 2 (4%) 5 (9%)
9 (60%) 15(100%) 19 4 (27%)
45* 4 (10%)
64 8 (15%)
14 (74%) 12 2 5 (26%) 15 (79%)
32(71%) 21 11 13(29%) 39 (87%)
46 (72%)
16(84%) 4 (27%) 4 (27%) 4 (27%)
32(71%) 6(15%) 14 (35%) 7 (18%)
48 10 18 11
CLINICAL PRESENTATION OF EMBOLIC INFARCTS
Although we have found coronary emboli as the cause of infarction in approximately one in 10 patients autopsied with myocardial infarction, for the most part these embolic infarcts were clinically unrecognized. Of particular interest, however, were the 15 patients who sustained clinically apparent acute myocardial infarction as a consequence of arterial embolism. These 15 patients were diagnosed as having acute myocardial infarctions on the basis of symptoms and electrocardiogram, and two-thirds of them were thought to have atherosclerotic coronary disease. There were few differences between the patients with clinically recognized and unrecognized infarcts. Silent embolic infarcts were more common among patients who had abnormal valves, either due to chronic disease or prosthetic replacement. Patients with clinically apparent embolic infarcts had a higher frequency of multiple coronary emboli and larger infarcts, which may have contributed to infarct recognition. Overall, the differences were not great, and the high rate of silence of embolic infarcts may reflect primarily the underlying diseases that may have obscured the myocardial injury when it occurred. CHARACTERISTIC MORPHOLOGY OF EMBOLIC INFARCTS
A curious feature of coronary artery embolism that has been long recognized (15, 16), and that was most evident in our patients, was the tendency for emboli to involve the left coronary artery three to four times more often
3 1 0 1 1 3 4 5 1 3
(20%)
(20%) (27%) (33%) (7%) (20%)
18 (28%) 53 (83%) (75%) (18%) (33%) (20%)
than the right, and the left anterior descending coronary artery more often than the left circumflex. It has been suggested that the take-off and downward course of the left anterior descending coronary artery is more favorable for embolization than that of the right and left circumflex coronary arteries, which run at a 90° angle from their parent trunks. Coronary artery dissection is also more apt to involve the left coronary artery (33). Whatever the special features may be, these two causes of acute coronary occlusions in what are usually previously normal vessels (33) have a predilection for the same coronary artery. A consistently recognized morphologic feature of coronary emboli is that they most frequently lodge in the distal portions of the coronary tree. It is commonly believed (8, 15, 17) that coronary embolism more often leads to sudden death than coronary thrombosis in patients with atherosclerosis. Although it is true that patients without pre-existing ischemic heart disease have poorly developed collaterals so that an occlusion of a major coronary artery branch might be more disastrous, the distal lodging of the emboli probably accounts for the relatively small number of deaths (20%) due to embolization in our series. The distal location of the majority of emboli in our series accounts for two other of our morphologic observations: [1] 7 5 % of the infarcts were transmural (this is most likely due to poor development of collaterals in humans without pre-existing coronary occlusive disease), and [2] only 14% of the infarcts were large (that is, involved > 2 0 % of left ventricular circumPrizel et al. • Coronary Artery Embolism
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curring in only eight of our patients. As only 2 0 % of the coronary emboli were a cause of death, death does not appear to offer the explanation for the lack of recurrent coronary emboli. CORONARY EMBOLISM AS A NOT-SO-RARE CAUSE OF INFARCTION WITH NORMAL CORONARIES
Figure 4. Diagram contrasting myocardial infarcts produced by atherosclerotic coronary artery disease and those produced by coronary artery emboli. Occlusions on atheromas tend to be more proximal and in major epicardial coronary arteries. The infarct involves a greater surface extent of the heart, but because of the vascular disease elsewhere collateral channels tend to be developed and the infarct is subendocardial. In contrast emboli tend to be found in hearts with normal arteries. The embolus lodges in a distal epicardial branch. Because the collaterals are underdeveloped the embolic occlusion produces a small but transmural infarct. PA = pulmonary artery.
ference). In fact, and not surprisingly, the size of the infarct correlated directly with the location of the embolic occlusion. In all 10 patients in whom a large infarct was present, the embolus lodged in the proximal or mid coronary artery, and they represented 10 of the 11 cases in which the embolus was in this more proximal location. Small infarct size is probably the major factor accounting for patient survival. The discrepancy from previous reports may be due to a tendency to detect and report only the more dramatic cases. Coronary artery emboli are only infrequent relative to atherosclerotic disease of the coronary artery and to arterial emboli elsewhere in the body. Cardiac disorders predisposing to embolization, such as endocarditis, cardiac mural thrombosis, or atrial fibrillation, are more apt to result in emboli to the brain or spleen than to the myocardium. Swift current flow around the coronary ostia, or caliber differences between the aorta and the coronary arteries, and the acute angle at which the coronary arteries exit the aorta may account for this (5, 13). The position of the coronary ostia behind the valve cusp during systole may also keep the coronary arteries out of the central stream of systolic blood flow. Not only are the coronary arteries relatively protected from emboli, compared with other organs, but the frequency of multiple emboli to the heart also appears to be relatively low, oc160
The fact that we have studied 55 patients, autopsied at a single institution, with coronary arterial emboli associated with myocardial infarction, most of whom had previously normal coronary arteries, is particularly noteworthy. Furthermore, these patients represent 1 3 % of a consecutive series of patients autopsied with myocardial infarcts from a single institution. Embolism may be becoming more frequent because of advances such as cardiac catheterization and surgery, but the fact that only a handful of our patients (4%) had emboli related to these procedures makes this an insufficient explanation for the frequency of embolic infarcts in our institution. It is more likely that coronary emboli are under-diagnosed, for reasons including a failure to distinguish embolism from thrombosis, failure to report only the most dramatic cases, or a failure to make a systematic search for small emboli in the distal and intramural branches of coronary arteries (7, 19). We believe that the method of postmortem angiography with serial histologic sectioning of the coronary lesions provides a particularly sensitive technique for the detection of small and peripheral emboli that might otherwise be overlooked. It should be stressed, however, that the prevalence of embolic infarct detected at autopsy does not necessarily represent the frequency of embolic infarction in a general population. Angina and myocardial infarction with normal coronary arteries has been the source of great interest and speculation, with anywhere from 4 % to 2 0 % of patients with a history of probable or definite angina or acute myocardial infarction having angiographically normal coronary arteries (34-37). Coronary arterial spasm is one recognized cause of angina pectoris and even of infarction with normal coronaries (38-41). The patients studied here clearly show that coronary emboli may also be a cause. Angiography after an infarct may fail to show a coronary embolus because of its distal location or its recanalization. Coronary emboli also may occur in patients with mild heart failure, or silent or inactive valvular lesions, so that the clinical suspicion of embolism might be low. Possible clues to coronary emboli as a cause of infarction with normal coronary arteries are that such events occur in the distribution of the left coronary artery in three quarters of cases, and that they cause small but transmural myocardial infarctions (Figure 4). This predilection for the left coronary artery is in contrast to coronary artery spasm that appears at selective coronary angiography to most often involve the proximal right coronary artery (39). Also, unlike spasm and atherosclerotic coronary disease, embolic infarcts are not apt to be recurrent or associated with postinfarct symptoms of ischemic heart disease. Perhaps a thorough search for the risk factors for coronary emboli should be made in all patients
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who carry the diagnosis of infarction with normal coronary arteries. ACKNOWLEDGMENTS: Grant support: by Grant P50-HL-17655-03 from the National Institutes of Health, Public Health Service, Department of Health, Education, and Welfare; and the Stetler Research Fund for Women Physicians. Received 16 June 1977; revision accepted 27 September 1977.
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the coronary artery. Report of 10 cases and review of literature. Am J Cardiol 11:228-237, 1963 22. RIVERA R, TALLON R: Coronary embolism in mitral stenosis. / Cardiovasc Surg 5:382-385, 1964 23. LANKIN EH, O E H L E R C, BALSLEY MD: Coronary embolism with myocardial infarction. Late complication in a patient with a Starr-Edwards mitral-valve prosthesis. JAMA 194:1019-1020, 1965 24. C O R D E I R O A, P I M E N T E L C, L A G I N H A F, R I B E I R O C, COSTA H: Coro-
• Requests for reprints should be addressed to Bernadine H. Bulkley, M.D.; Department of Pathology, The Johns Hopkins Hospital; Baltimore, M D 21205.
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