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- Received February 8, 1996
- Revision received May 6, 1996
- Accepted May 8, 1996
- Published online October 1, 1996.
- GROVER M HUTCHINS*
- ↵*Address for correspondence: Dr. Grover M. Hutchins, Department of Pathology, The Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, Maryland 21287.
Objectives. We sought to determine whether myocardial lesions develop in association with unstable angina pectoris.
Background. We observed a patient with unstable angina
pectoris who developed foci of ischemic necroses in the distribution of a single coronary artery. The artery had an atherosclerotic plaque that had undergone ulceration of its fibrous cap. This case prompted us to study the occurrence of focal myocardial ischemic necroses in other patients with unstable angina pectoris.
Methods. Focal ischemic injuries of an age consistent with the duration of the episode of unstable angina pectoris were observed in 6 of 21 patients who died after hospital admission. The 21 patients had not undergone any invasive coronary procedures or thrombolysis, and the heart had been examined after postmortem arteriography and fixation in distension.
Results. Of the six patients with focal ischemic lesions, three had foci of contraction band necrosis and three had focal areas of ischemic necrosis in a state of early repair. Three had a recent myocardial infarct of an age less than the duration of unstable angina pectoris. In each of the six patients, the histologic age of the focal myocardial lesions correlated with the time frame of unstable angina.
Conclusions. We conclude that the focal ischemic injuries observed in the myocardium were due to ischemic episodes that also produced the clinical manifestations of unstable angina pectoris.
Clinically, unstable angina pectoris is defined as pain at rest or new onset or accelerating angina. It is currently thought [1–5]that thrombus formation and coronary vasoconstriction secondary to plaque rupture play a major and frequent role in the development of this acute coronary syndrome. In unstable angina, the thrombus is labile, and there is variable persistence of the thrombus and associated vasospasm.
Many patients with unstable angina later have a myocardial infarction, whereas others may have a period of stable angina. Studies of the heart in patients with unstable angina [6–8]have concentrated on descriptions of the associated coronary artery disease. We have found no information on the occurrence of myocardial injuries associated with unstable angina pectoris. It seems possible that the coronary occlusion, myocardial ischemia and reperfusion in unstable angina may result in ischemic injury to the myocardium.
In a patient with unstable angina pectoris, we found focal ischemic myocardial lesions of varying ages in the distribution of a coronary artery containing an atherosclerotic plaque undergoing ulceration. This case prompted us to review the frequency of myocardial ischemic lesions that correlate with the clinical period of unstable angina pectoris in other patients.
Background. A 42-year old white man was admitted to the hospital with bilateral hemothorax/pneumothorax secondary to multiple stab wounds. There was a past history of obesity, heavy cigarette smoking and poorly controlled hypertension. He was treated with bilateral chest tubes, but later had respiratory insufficiency requiring ventilator support for 1 week. His recovery was otherwise unremarkable, and he was discharged after a 2-week hospital stay.
Three weeks before death, he was seen in outpatient follow-up. At that time, his chest radiograph was satisfactory, but he described anterior upper chest discomfort. This symptom was thought to be secondary to his previous injuries, but an electrocardiogram (ECG) was not obtained.
During the next 3 weeks, the patient continued to report intermittent chest discomfort, as well as shortness of breath with exertion. On the day of his death, a prolonged episode of severe chest pain led to ventricular fibrillation from which he could not be resuscitated.
At autopsy the heart weighed 430 g. The coronary arteries had severe atherosclerosis involving all three major branches. The left anterior descending coronary artery had 80% to 90% obstruction of the lumen. The left circumflex and right coronary arteries also had severe obstructive atherosclerosis, and the right coronary artery had an atherosclerotic plaque that had undergone ulceration of its fibrous cap and had an organizing thrombus on the exposed atheromatous material of the plaque (Fig. 1). The organizing thrombus was ∼2 weeks old and did not occlude the lumen of the coronary artery.
The myocardium showed foci of ischemic injury that were of three distinct ages. All lesions occurred in the same area of the inferior wall of the left ventricle and were in the epicardial half of the myocardium. The oldest lesions were subepicardial mature replacement fibrosis and many months to years of age. A second group of ischemic foci consisted of areas of coagulation necrosis 2 to 3 weeks old, as demonstrated by the incomplete resolution of the necrotic myocytes within the center of one of the foci. These lesions were associated with several small emboli of admixed atheromatous debris and thrombus within intramyocardial arteries (Fig. 2). The third group of ischemic lesions within this area of myocardium were foci of contraction band necrosis with associated polymorphonuclear leukocytes and macrophages (Fig. 3). These lesions were 2 to 3 days old. The remainder of the myocardium and the specialized conduction system of the heart showed no significant abnormality. The lungs showed severe congestion, hemorrhage and edema typical of the changes found in sudden cardiac death.
The clinical and pathologic findings in this case are interpreted as follows. A remote episode of transient ischemia in the distribution of the right coronary artery led to subepicardial foci of replacement fibrosis. No clinical events had been noted that correlated with these lesions. Two to three weeks before death, ulceration of the fibrous cap of an atherosclerotic plaque in the right coronary artery produced embolization of atheromatous debris, nonocclusive thrombosis on the ulcerated plaque and development of focal ischemic subepicardial necroses in the distribution of the artery. About 2 to 3 days before death, focal contraction band necrosis, attributed to coronary artery spasm, developed in the same subepicardial distribution. Death was probably due to another episode of arterial spasm at the site of the plaque that caused a prolonged episode of severe chest pain and precipitated a lethal arrhythmia. The rapidity of death would not allow time for the development of pathologically detectable changes, and none were found.
Study patients. We reviewed the data of all autopsy patients at The Johns Hopkins Hospital who had a clinical history of unstable angina pectoris and whose heart had been examined after postmortem coronary arteriography and fixation in distension . Only those 21 patients who had not undergone coronary artery bypass graft surgery, angioplasty or thrombolysis were included in this study.
The clinical records were reviewed and age, race, gender, time course of unstable angina, risk factors for coronary artery disease and cause of death were determined. Information was sought on ECG changes and serum enzyme levels during the period of the patient's unstable angina.
The autopsy report, heart, postmortem coronary arteriograms, photographs and available histologic slides were reviewed. Additional histologic slides were prepared for this study, if necessary, to ensure examination of the anterior, lateral, posterior and septal wall of the left ventricle and any area of grossly identifiable ischemic injury in each heart.
The severity of coronary occlusions was determined by reviewing postmortem coronary artery angiograms and histologic findings. The type and degree of myocardial necrosis were determined from review of the heart and the histologic slides.
A myocardial infarct was defined as an ischemic injury >3 cm in one dimension. Lesions <3 cm in one dimension were considered to be focal ischemic lesions. Two types of ischemic myocardial necrosis may be recognized: coagulation necrosis and contraction band necrosis. Coagulation necrosis is commonly associated with fixed obstruction to blood flow as occurs in myocardial infarcts. Contraction band necrosis is commonly caused by reperfusion of ischemic myocardium and is most commonly a focal lesion. When the repair process has led to removal of the necrotic myocytes it cannot be determined which type of necrosis had been present. All lesions were assigned an approximate age corresponding to their histologic features, as previously described [10–13]. Foci of contraction band necrosis that could be attributed to resuscitation efforts were not included as lesions associated with unstable angina pectoris.
Clinical features. Among the 21 patients meeting the criteria for inclusion in this study, 6 showed myocardial lesions of an age that correlated with their course of unstable angina. Their clinical features are summarized in Table 1; they ranged in age from 46 to 60 years. The six were examined at autopsy between 1979 and 1993; five were male and all were white. The onset of unstable angina pectoris occurred ∼4 weeks to <1 week before death. Three of the six patients had hypertension; hyperlipidemia was known to be present in two. One patient had adult onset diabetes mellitus; another had had diabetes mellitus type II for 5 years, although it was not present at the time of her death. Four patients had other chronic illnesses in addition to their heart disease, but death was caused by a complication of ischemic heart disease in all six. The three patients who did not show an acute myocardial infarct at autopsy may have died before histologic change became evident.
Review of the clinical information showed that transient ECG changes commonly occurred during the period of unstable angina. However, no serum enzyme changes were found that could be correlated with the focal ischemic lesions.
Pathologic features. Pathologic information was obtained on heart weight and coronary artery disease severity (Table 2). All six hearts were hypertrophied, ranging in weight from 486 to 800 g. Postmortem coronary arteriograms and histologic study demonstrated ≥95% stenosis of the right coronary artery in all six hearts. In five hearts, the left anterior descending coronary artery had ≥50% stenosis. The left circumflex coronary artery was totally occluded in one heart and had <50% stenosis in the remaining five.
Myocardial lesions of varying age and size were found in all six hearts (Table 2). Three of the six patients had myocardial infarcts <2 weeks of age. Five had infarcts that antedated the period of unstable angina pectoris and one had no infarct. In addition, there were focal ischemic lesions of contraction band necrosis in three hearts (Fig. 4) and similar sized foci of myocardial necroses undergoing resolution in the three other hearts in which the nature of the original necrotic lesion could not be identified (Fig. 5). No focal ischemic lesions of coagulation necrosis were identified; however, coagulation necrosis was present in the myocardial infarcts.
Twenty-one patients who died after admission to the hospital with unstable angina pectoris were studied. None had undergone an invasive procedure. Fifteen (72%) had no focal ischemic necroses detected in the myocardium of an age that correlated with the onset of unstable angina. Six patients (29%) had focal myocardial ischemic injuries of an age contemporaneous with the unstable angina pectoris. In three of these six patients, a myocardial infarct developed after the onset of unstable angina. All six hearts had focal areas of contraction band necrosis or resolving necrosis where the type of necrosis could not be determined. Focal coagulation necrosis was not seen. These six patients had severe obstructive coronary artery atherosclerosis.
Review of the clinical information on these six patients showed that although transient ECG changes were commonly found during this period of unstable angina, there were no serum enzyme changes that could be correlated with the focal ischemic lesions. This finding is most likely due to the timing of enzyme determinations relative to the transient release of enzymes from the damaged myocardial cells, or to the relatively small amount of necrotic myocardium observed in the focal ischemic necroses.
The symptoms of unstable angina pectoris are thought to develop as a result of a sudden decrease in coronary blood flow due to some combination of plaque rupture with superimposed platelet aggregation, labile intracoronary thrombosis and vasoconstriction [1–5]. There may be variable persistence of the thrombosis and vasospasm. If the ischemic period is sufficiently prolonged, myocardial infarction or smaller areas of coagulation necrosis may occur. Focal areas of coagulation necrosis can also occur as a result of atheromatous embolization. When thrombosis and vasospasm resolve, reflow of blood occurs, and contraction band necrosis may develop in the ischemic myocardium. Of the 21 hearts observed, 6 showed new necrotic lesions of varying ages. It is hypothesized that the other 15 hearts may have had ischemic periods of shorter duration and consequently areas of necrosis did not develop.
Summary. Unstable angina pectoris is currently thought to be due to an abrupt decrease in coronary blood flow due to some combination of plaque disruption, thrombus formation and vasospasm [1, 5]. This study has demonstrated that this condition may be associated with focal myocardial ischemic necroses. That the lesions show contraction band necrosis indicate that they are due to reperfusion after resolution of the process of transient coronary artery obstruction. Such focal necroses may serve as a histologic marker for the pathophysiologic changes of unstable angina pectoris.
- Received February 8, 1996.
- Revision received May 6, 1996.
- Accepted May 8, 1996.
- THE AMERICAN COLLEGE OF CARDIOLOGY
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