ANNUAL REVIEWS
Annu. Rev. Med. 1991. 42:35-45 Copyrighl © 1991 by Annual Reviews Inc. All righls reserved
Further
Quick links to online content
INITIATING EVENTS OF ACUTE
Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
CORONARY ARTERIAL OCCLUSION James S. Forrester, M.D., Frank Litvack, Warren Grund/est, M.D.
M.D.,
and
Department of Cardiology, Cedars-Sinai Medical Center, Los Angeles, California 90048 KEY WORDS:
coronary thrombosis, myocardial infarction, unstable angina, angioscopy
ABSTRACT Acute myocardial infarction is caused by coronary thrombosis on an ulcerated atheroma. We now believe that the predominant cause of this intimal disruption is the rupture of the atheroma through the intimal surface, caused by enzymes released by activated macrophages. The sub sequent clinical course following atheroma disruption is determined by the rate and size of thrombus formation. Partially occlusive thrombi produce unstable angina; completely occlusive thrombi produce myocardial infarc tion; clot embolization can produce sudden death. The localized thrombus lyses within days. The healing process, however, is frequently accompanied by rapid local progression of th e size of the atheroma at the site of intimal disruption. With healing of the intimal surface, the patient's clinical status stabilizes. Thus coronary disease is a cyclical phenomenon driven by cellu lar events within the atheroma and by the interaction of the atheroma with circulating blood elements. INTRODUCTION
The factors that precipitate myocardial infarction in an apparently healthy person, or unstable angina in a patient with stable coronary disease, have 35 0066-4219/91/0401-0035$02.00
Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
36
FORRESTER,
LITVACK
& GRUNDFEST
been a source of conjecture for most of this century (I). The development of fiberoptic angioscopy, which provides detailed information about the coronary intimal surface at the time when the patient is symptomatic, has clarified the cause of these unstable coronary chest pain syndromes. In this review, we integrate the angioscopic observations with clinical, angio graphic, and postmortem data to describe how the spectrum of acute coronary symptoms results from previously unobserved events on the coronary intimal surface. Figure I displays these relationships. Coronary artery disease begins as a fatty streak on the blood vessel surface. Over time the streak enlarges to become a plaque. If the plaque is quite large, it can partially obstruct the vessel and cause stable angina; if it is not obstructive, the disease is symptomatically silent. Some of the plaques ulcerate and platelets aggre gate at the site immediately. The platelet aggregates release powerful coronary vascoconstrictors capable of producing accelerated angina. The
Ir / l
St STABLE ANGINA
l\. J �
/�
Healing INCREASED ST ENOSIS
.
Ulceration
------. Emboli
ACC ELERAT ED ANGNA
Parti al Thrombus UNSTABLE REST ANGINA
!
Complete
MYOCARDIAL
Figure 1
The ulceration-thrombosis cycle of coronary disease.
CORONARY ARTERIAL OCCLUSION
37
platelets periodically attach and are dislodged by the flowing blood. If the downstream emboli are sufficiently large, they can cause sudden ischemic cardiac death. Alternatively, the platelet aggregates can evolve into a thrombus. If the thrombus mass is large enough to partially obstruct the vessel, the patient develops unstable rest angina. If the thrombus becomes
Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
completely obstructive it causes myocardial infarction. Approximately
90% of patients survive these acute events. Intimal disruption heals within a few weeks and the thrombus is lysed, often within a week. During healing fibrous tissue proliferates and the residual thrombus is incorporated into the blood vessel wall. Since both these processes increase the magnitude of stenosis, healing is often a ccompanied by rapid local progression in atheroma size. The stable plaque may subsequently rupture again, and the cycle is repeated. Thus, the conundrum of sudden onset of unstable angina,
myocardial infarction, or sudden death becomes understandable when examined at the level of the intimal surface (1). STABLE ATHEROMA AND STABLE ANGINA Figure
2a shows a smooth, crescent-shaped, light-colored atheroma pro stable angina. Smooth
truding into the coronary lumen in a patient with
Figure 2a
A stable atheroma in the left anterior descending coronary artery of a patient
with stable angina pectoris.
Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
38
FORRESTER, LITVACK & GRUNDFEST
Figure 2b
Histologic image or an atheroma (see text) (courtesy, Dr. Meyer Friedman).
atheromas of varying size and morphology were seen throughout the length of the vessel. Figure 2b shows the histologic counterpart of this angioscopic image. There is a large mature atheroma with an intact intimal surface and a heavy fibrous cap. At the base of the atheroma is an area of necrosis. Although most of the necrotic core was lost in preparation, macrophages still lined its wall. In patients with stable angina we see many smooth atheromas in a single blood vessel. The smallest lesions are oblong protrusions. As the lesions enlarge they appear to lose their regular shape; the great majority are localized and eccentric. Histologic study shows that these atheromas pass through stages that correspond to those seen by angioscopy. The small nonocclusive fatty streaks are composed predominantly of lipid-laden macrophages. As the atheroma enlarges, smooth muscle cells migrate into the subendothelium in the area of the lipid-laden macrophages. The smooth muscle cells change from being contractile to being synthetic; they produce fibrous tissue that encircles the lipid and creates an atheroma core. Over this core, there is a fibrous cap of varying thickness. Integrating our clinical, angioscopic, angiographic, and histologic information, we conclude that stable angina is caused by a partial obstruction of coronary blood flow created by smooth-surfaced atheroma.
CORONARY ARTERIAL OCCLUSION
39
INTIMAL DISRUPTION AND ACCELERATED
Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
ANGINA
The appearance of the blood vessel surface changes dramatically in unstable chest pain syndromes. The first step in this clinical continuum is accelerated angina, which is defined as angina of increasing frequency and duration, without rest pain. Figure 3 shows the coronary vascular surface in such a patient. The intimal surface is disrupted and there is subintimal hemorrhage. There is no thrombus. When examined by histology, this type of lesion shows progressive thinning of the fibrous cap at the point of rupture. Intimal disruption is the feature seen by angioscopy that distinguishes acute and stable coronary disease. There are probably two underlying causes for intimal disruption (2, 3). The first is rupture of the atheroma through the intimal surface. This erosion from within is thought to be due to enzymes (collagenase, elastase, etc) released by activated macrophages that have ingested lipid in the vessel wall. The second cause of intimal disruption is the superficial fissures in the atheroma. These may arise
Figure 3
An intimal ulceration in the left anterior descending coronary artery of a patient
with accelerated angina.
40
FORRESTER,
LITVACK
& GRUNDFEST
from repetitive bending during cardiac contraction. Although the specific mechanism by which intimal disruption causes accelerated angina is not yet well established, platelet aggregation at the site with subsequent release of vasoconstrictive compounds is thought to play a major role. PARTIALLY OCCLUSIVE THROMBUS AND
Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
UNSTABLE ANGINA
Accelerated angina frequently evolves to become unstable rest angina. We differentiate the two conditions by the additional symptom of chest pain at rest. Figure 4a shows an angioscopic image from a patient with unstable rest angina. There is a partially occlusive thrombus just distal to the stenosis. The thrombus surface undulated during infusion of the clear viewing solution but was not dislodged. All but one of our 12 unstable rest patients has had thrombus, compared with none in our stable angina group. Figure 4b shows the histologic appearance of this type of lesion. The fibrous cap that covered an atheroma cavity has ruptured and a
Figure 4a
A fresh, partially occlusive coronary thrombosis in a patient with unstable rest
angina pectoris.
Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
CORONARY ARTERIAL OCCLUSION
Figure 4b
41
A partially occlusive coronary thrombosis attached to an intimal ulceration
(courtesy, Dr. Meyer Friedman).
thrombus formed at the point of rupture. Beneath the point of rupture lies an atheroma. Cholesterol crystals from the replaced atheroma were trapped in the base of the thrombus. Careful pathologic studies found that over 90% of coronary thrombi are attached to a disrupted intimal surface (4). Unstable rest angina frequently becomes stable after several days of supportive medical therapy. These clinical data, which suggest endogenous thrombolysis, are supported by angiographic data from the myocardial infarction literature. The prevalence of thrombus is 80-90% in the first 4 hours after infarction, yet only 33% at 14 days after infarction (5). Thus based on clinical, angioscopic, and angiographic data we conclude that partially occlusive thrombosis causes unstable rest angina. The thrombus typically resolves in a few days by endogenous thrombolysis or by therapy. About 20% of unstable rest angina patients, however, progress to acute myocardial infarction (6). This evolution can occur over days or even weeks, which suggests that the rate of thrombus formation is highly vari able and that it can even be episodic. The concept of episodic progression of thrombus is supported by autopsy identification of two or more layers
42
FORRESTER, LlTVACK
& GRUNDFEST
in 81 % of the thrombi from unstable angina patients (3). In fact, clinical studies suggest that about a third of patients with acute myocardial infarc tion have an unstable prodrome of days to several weeks immediately preceding the infarction. Thus we can also conclude that partially occlusive coronary thrombi may progress episodically to occlusion, which in turn causes myocardial infarction. THROMBOTIC OCCLUSION AND MYOCARDIAL Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
INFARCTION
Myocardial infarction more typically begins, however, with sudden onset of chest pain. In these cases the development of total thrombotic occlusion is presumed to be rapid, following the rupture of the necrotic atheromatous debris into the flowing blood stream. Figure 5a shows an angioscopic image from a patient with a developing myocardial infarction. At the site of angiographic occlusion, there is a coronary thrombus obstructing the
Figure 5a
A completely occlusive coronary thrombosis in the lell anterior descending
coronary artery.
Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
CORONARY ARTERIAL OCCLUSION
Figure 5b
43
A coronary thrombosis containing fragments of the endothelial surface and
cholesterol clefts in a patient who died soon after the onset of an acute myocardial infarction (reprinted with permission, Friedman, M., et al. 1966. Am. J. Pathol. 48: 19).
lumen. The histology of this type of lesion is shown in Figure 5b. A large atheroma cavity has ruptured into the lumen. Cholesterol clefts are embedded in the thrombus, which occludes the lumen. When an atheroma ruptures into a flowing blood stream, two competing forces determine whether or not the evolving thrombus becomes com pletely occlusive. The first factor is the magnitude of coronary obstruction before rupture; the second is the efficiency of endogenous thrombolysis. Thus, Falk found that complete thrombotic occlusion was common when the obstruction compromised more than 75% of the original lumen (7). Conversely, when the pre-existing stenosis obstructed less than 75% of the original lumen, complete obstruction occurred in only 3% of cases. The data suggest that an extensive intimal disruption can heal if the pre-existing stenosis is not severe. The fate of a developing coronary thrombosis is determined by the magnitude of stenosis when the atheroma ruptures through the intimal surface.
44
FORRESTER, LITVACK
& GRUNDFEST
Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
THERAPEUTIC IMPLICATIONS
From our understanding of the pathogenesis of coronary syndromes, we can speculate that there are four categories of therapy that could interrupt the repeating cycle of ulceration, thrombosis, and healing. The therapies are those that prevent ulceration, inhibit platelet aggregation, lyse thrombi, or promote healing of the intimal surface. The mechanism of intimal disruption is undefined and there are as yet no treatments that prevent it. Platelet inhibitors are effective in patients with syndromes due to intimal disruption. Such treatment both reduces platelet emboli and impedes thrombus formation. In the Veterans Administration trial of buffered aspirin, Lewis (8) randomized 1266 men with unstable angina to treatment or placebo. There was a 51% lower cardiac event rate at three months in the aspirin-treated group. Com parable results have been reported from a Canadian multicenter trial by Cairns et al (9). Thus we believe that in the absence of contraindication, all unstable angina and acute infarction patients should be placed on a platelet antagonist after hospitalization. Streptokinase, urokinase, and tissue plasminogen activator effectively lyse thrombi. The available data are thus far inconclusive for therapy of unstable angina. At present, we use heparin for systemic anticoagulation in all our patients, but we do not routinely use lytic agents in unstable rest angina unless the patient is unresponsive to other therapies and has an angiographically documented thrombus. In summary, acute coronary diseasc is caused by a cycle of evcnts at the intimal surface. A stable atheroma ruptures, platelets aggregate, thrombus forms, and the lesion heals. Each step in this cycle causes a specific clinical syndrome, and each can benefit from specific therapy. ACKNOWLEDGMENTS
This work was supported in part by funds from the Specialized Center of Research in Ischemic Heart Disease (grant HL-17651) from the National Institutes of Health in Bethesda, Maryland. The authors wish to acknowl edge the invaluable work of Drs. Myles E. Lee, Aurelio Chaux, Carlos Blanche, Robert Kass, Jack Matloff, C. Todd Sherman, and Anne Hickey, who gathered much of the angioscopic data, and of Ms. Dwana Williams for her word processing assistance. We are indebted to Dr. Meyer Fried man for retrieving his landmark histologic work from the 1960s and allowing us to republish four of his illustrations. We are also deeply appreciative of the continuing support of Mr. Steven Mcadow, Mr. Zev Lapin, the Grand Foundation and the Medallions Foundation.
CORONARY ARTERIAL OCCLUSION
45
Literature Cited
I. Forrester, J. S., Litvack, F., Grundfest,
2.
Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
3.
4.
5.
W. S. 1987. A perspective of coronary disease seen through the arteries of living man. Circulation 75(3): 505-13 Willerson, J. T., Hillis, D., Winniford, M., Buja, M. 1986. Speculation regarding mechanisms responsible for acute heart disease syndromes. J. Am. Col!. Cardiol. 8: 245 Falk, E. 1985. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embol ization culminating in total vascular occlusion. Circulation 71: 699 Friedman, M., Van den Bovenkamp, G. J. 1966. Role of thrombus in plaque for mation in the human diseased coronary artery. Br. J. Exp. Pathol. 47: 550 Rentrop, P., Blanke, H., Karsch, K. R., Kaiser, H., Kostering, H., Leitz, K. 1981.
6.
7.
8. 9.
Elective intracoronary thrombolysis in acute myocardial infarction and unstable angina pectoris. Circulation 63: 307 Duncan, B., Fulton, M., Morrison, S. L., Lutz, W., Donald, K. W., et al. 1976. Prognosis of new and worsening angina pectoris. Br. Med. J. 1: 981 Falk, E. 1983. Plaque rupture with severe pre-existing stenosis precipitating cor onary thrombosis: characteristics of cor onary atherosclerotic plaques underlying fatal occlusive thrombi. Br. Heart J. 50: 127 Lewis, D. A. 1984. Endogenous anti inflammatory factors. Biochem. Phar macal. 1: 33(11): 1705 Cairns, J. A., Gent, M., Singer, J., et al. 1985. Aspirin, su1finpyrazone, or both in unstable angina: results of a Canadian multicenter trial. N. Engl. J. Med. 313: 1369
Annu. Rev. Med. 1991. 42:35-45 Copyrighl © 1991 by Annual Reviews Inc. All righls reserved
Further
Quick links to online content
INITIATING EVENTS OF ACUTE
Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
CORONARY ARTERIAL OCCLUSION James S. Forrester, M.D., Frank Litvack, Warren Grund/est, M.D.
M.D.,
and
Department of Cardiology, Cedars-Sinai Medical Center, Los Angeles, California 90048 KEY WORDS:
coronary thrombosis, myocardial infarction, unstable angina, angioscopy
ABSTRACT Acute myocardial infarction is caused by coronary thrombosis on an ulcerated atheroma. We now believe that the predominant cause of this intimal disruption is the rupture of the atheroma through the intimal surface, caused by enzymes released by activated macrophages. The sub sequent clinical course following atheroma disruption is determined by the rate and size of thrombus formation. Partially occlusive thrombi produce unstable angina; completely occlusive thrombi produce myocardial infarc tion; clot embolization can produce sudden death. The localized thrombus lyses within days. The healing process, however, is frequently accompanied by rapid local progression of th e size of the atheroma at the site of intimal disruption. With healing of the intimal surface, the patient's clinical status stabilizes. Thus coronary disease is a cyclical phenomenon driven by cellu lar events within the atheroma and by the interaction of the atheroma with circulating blood elements. INTRODUCTION
The factors that precipitate myocardial infarction in an apparently healthy person, or unstable angina in a patient with stable coronary disease, have 35 0066-4219/91/0401-0035$02.00
Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
36
FORRESTER,
LITVACK
& GRUNDFEST
been a source of conjecture for most of this century (I). The development of fiberoptic angioscopy, which provides detailed information about the coronary intimal surface at the time when the patient is symptomatic, has clarified the cause of these unstable coronary chest pain syndromes. In this review, we integrate the angioscopic observations with clinical, angio graphic, and postmortem data to describe how the spectrum of acute coronary symptoms results from previously unobserved events on the coronary intimal surface. Figure I displays these relationships. Coronary artery disease begins as a fatty streak on the blood vessel surface. Over time the streak enlarges to become a plaque. If the plaque is quite large, it can partially obstruct the vessel and cause stable angina; if it is not obstructive, the disease is symptomatically silent. Some of the plaques ulcerate and platelets aggre gate at the site immediately. The platelet aggregates release powerful coronary vascoconstrictors capable of producing accelerated angina. The
Ir / l
St STABLE ANGINA
l\. J �
/�
Healing INCREASED ST ENOSIS
.
Ulceration
------. Emboli
ACC ELERAT ED ANGNA
Parti al Thrombus UNSTABLE REST ANGINA
!
Complete
MYOCARDIAL
Figure 1
The ulceration-thrombosis cycle of coronary disease.
CORONARY ARTERIAL OCCLUSION
37
platelets periodically attach and are dislodged by the flowing blood. If the downstream emboli are sufficiently large, they can cause sudden ischemic cardiac death. Alternatively, the platelet aggregates can evolve into a thrombus. If the thrombus mass is large enough to partially obstruct the vessel, the patient develops unstable rest angina. If the thrombus becomes
Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
completely obstructive it causes myocardial infarction. Approximately
90% of patients survive these acute events. Intimal disruption heals within a few weeks and the thrombus is lysed, often within a week. During healing fibrous tissue proliferates and the residual thrombus is incorporated into the blood vessel wall. Since both these processes increase the magnitude of stenosis, healing is often a ccompanied by rapid local progression in atheroma size. The stable plaque may subsequently rupture again, and the cycle is repeated. Thus, the conundrum of sudden onset of unstable angina,
myocardial infarction, or sudden death becomes understandable when examined at the level of the intimal surface (1). STABLE ATHEROMA AND STABLE ANGINA Figure
2a shows a smooth, crescent-shaped, light-colored atheroma pro stable angina. Smooth
truding into the coronary lumen in a patient with
Figure 2a
A stable atheroma in the left anterior descending coronary artery of a patient
with stable angina pectoris.
Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
38
FORRESTER, LITVACK & GRUNDFEST
Figure 2b
Histologic image or an atheroma (see text) (courtesy, Dr. Meyer Friedman).
atheromas of varying size and morphology were seen throughout the length of the vessel. Figure 2b shows the histologic counterpart of this angioscopic image. There is a large mature atheroma with an intact intimal surface and a heavy fibrous cap. At the base of the atheroma is an area of necrosis. Although most of the necrotic core was lost in preparation, macrophages still lined its wall. In patients with stable angina we see many smooth atheromas in a single blood vessel. The smallest lesions are oblong protrusions. As the lesions enlarge they appear to lose their regular shape; the great majority are localized and eccentric. Histologic study shows that these atheromas pass through stages that correspond to those seen by angioscopy. The small nonocclusive fatty streaks are composed predominantly of lipid-laden macrophages. As the atheroma enlarges, smooth muscle cells migrate into the subendothelium in the area of the lipid-laden macrophages. The smooth muscle cells change from being contractile to being synthetic; they produce fibrous tissue that encircles the lipid and creates an atheroma core. Over this core, there is a fibrous cap of varying thickness. Integrating our clinical, angioscopic, angiographic, and histologic information, we conclude that stable angina is caused by a partial obstruction of coronary blood flow created by smooth-surfaced atheroma.
CORONARY ARTERIAL OCCLUSION
39
INTIMAL DISRUPTION AND ACCELERATED
Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
ANGINA
The appearance of the blood vessel surface changes dramatically in unstable chest pain syndromes. The first step in this clinical continuum is accelerated angina, which is defined as angina of increasing frequency and duration, without rest pain. Figure 3 shows the coronary vascular surface in such a patient. The intimal surface is disrupted and there is subintimal hemorrhage. There is no thrombus. When examined by histology, this type of lesion shows progressive thinning of the fibrous cap at the point of rupture. Intimal disruption is the feature seen by angioscopy that distinguishes acute and stable coronary disease. There are probably two underlying causes for intimal disruption (2, 3). The first is rupture of the atheroma through the intimal surface. This erosion from within is thought to be due to enzymes (collagenase, elastase, etc) released by activated macrophages that have ingested lipid in the vessel wall. The second cause of intimal disruption is the superficial fissures in the atheroma. These may arise
Figure 3
An intimal ulceration in the left anterior descending coronary artery of a patient
with accelerated angina.
40
FORRESTER,
LITVACK
& GRUNDFEST
from repetitive bending during cardiac contraction. Although the specific mechanism by which intimal disruption causes accelerated angina is not yet well established, platelet aggregation at the site with subsequent release of vasoconstrictive compounds is thought to play a major role. PARTIALLY OCCLUSIVE THROMBUS AND
Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
UNSTABLE ANGINA
Accelerated angina frequently evolves to become unstable rest angina. We differentiate the two conditions by the additional symptom of chest pain at rest. Figure 4a shows an angioscopic image from a patient with unstable rest angina. There is a partially occlusive thrombus just distal to the stenosis. The thrombus surface undulated during infusion of the clear viewing solution but was not dislodged. All but one of our 12 unstable rest patients has had thrombus, compared with none in our stable angina group. Figure 4b shows the histologic appearance of this type of lesion. The fibrous cap that covered an atheroma cavity has ruptured and a
Figure 4a
A fresh, partially occlusive coronary thrombosis in a patient with unstable rest
angina pectoris.
Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
CORONARY ARTERIAL OCCLUSION
Figure 4b
41
A partially occlusive coronary thrombosis attached to an intimal ulceration
(courtesy, Dr. Meyer Friedman).
thrombus formed at the point of rupture. Beneath the point of rupture lies an atheroma. Cholesterol crystals from the replaced atheroma were trapped in the base of the thrombus. Careful pathologic studies found that over 90% of coronary thrombi are attached to a disrupted intimal surface (4). Unstable rest angina frequently becomes stable after several days of supportive medical therapy. These clinical data, which suggest endogenous thrombolysis, are supported by angiographic data from the myocardial infarction literature. The prevalence of thrombus is 80-90% in the first 4 hours after infarction, yet only 33% at 14 days after infarction (5). Thus based on clinical, angioscopic, and angiographic data we conclude that partially occlusive thrombosis causes unstable rest angina. The thrombus typically resolves in a few days by endogenous thrombolysis or by therapy. About 20% of unstable rest angina patients, however, progress to acute myocardial infarction (6). This evolution can occur over days or even weeks, which suggests that the rate of thrombus formation is highly vari able and that it can even be episodic. The concept of episodic progression of thrombus is supported by autopsy identification of two or more layers
42
FORRESTER, LlTVACK
& GRUNDFEST
in 81 % of the thrombi from unstable angina patients (3). In fact, clinical studies suggest that about a third of patients with acute myocardial infarc tion have an unstable prodrome of days to several weeks immediately preceding the infarction. Thus we can also conclude that partially occlusive coronary thrombi may progress episodically to occlusion, which in turn causes myocardial infarction. THROMBOTIC OCCLUSION AND MYOCARDIAL Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
INFARCTION
Myocardial infarction more typically begins, however, with sudden onset of chest pain. In these cases the development of total thrombotic occlusion is presumed to be rapid, following the rupture of the necrotic atheromatous debris into the flowing blood stream. Figure 5a shows an angioscopic image from a patient with a developing myocardial infarction. At the site of angiographic occlusion, there is a coronary thrombus obstructing the
Figure 5a
A completely occlusive coronary thrombosis in the lell anterior descending
coronary artery.
Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
CORONARY ARTERIAL OCCLUSION
Figure 5b
43
A coronary thrombosis containing fragments of the endothelial surface and
cholesterol clefts in a patient who died soon after the onset of an acute myocardial infarction (reprinted with permission, Friedman, M., et al. 1966. Am. J. Pathol. 48: 19).
lumen. The histology of this type of lesion is shown in Figure 5b. A large atheroma cavity has ruptured into the lumen. Cholesterol clefts are embedded in the thrombus, which occludes the lumen. When an atheroma ruptures into a flowing blood stream, two competing forces determine whether or not the evolving thrombus becomes com pletely occlusive. The first factor is the magnitude of coronary obstruction before rupture; the second is the efficiency of endogenous thrombolysis. Thus, Falk found that complete thrombotic occlusion was common when the obstruction compromised more than 75% of the original lumen (7). Conversely, when the pre-existing stenosis obstructed less than 75% of the original lumen, complete obstruction occurred in only 3% of cases. The data suggest that an extensive intimal disruption can heal if the pre-existing stenosis is not severe. The fate of a developing coronary thrombosis is determined by the magnitude of stenosis when the atheroma ruptures through the intimal surface.
44
FORRESTER, LITVACK
& GRUNDFEST
Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
THERAPEUTIC IMPLICATIONS
From our understanding of the pathogenesis of coronary syndromes, we can speculate that there are four categories of therapy that could interrupt the repeating cycle of ulceration, thrombosis, and healing. The therapies are those that prevent ulceration, inhibit platelet aggregation, lyse thrombi, or promote healing of the intimal surface. The mechanism of intimal disruption is undefined and there are as yet no treatments that prevent it. Platelet inhibitors are effective in patients with syndromes due to intimal disruption. Such treatment both reduces platelet emboli and impedes thrombus formation. In the Veterans Administration trial of buffered aspirin, Lewis (8) randomized 1266 men with unstable angina to treatment or placebo. There was a 51% lower cardiac event rate at three months in the aspirin-treated group. Com parable results have been reported from a Canadian multicenter trial by Cairns et al (9). Thus we believe that in the absence of contraindication, all unstable angina and acute infarction patients should be placed on a platelet antagonist after hospitalization. Streptokinase, urokinase, and tissue plasminogen activator effectively lyse thrombi. The available data are thus far inconclusive for therapy of unstable angina. At present, we use heparin for systemic anticoagulation in all our patients, but we do not routinely use lytic agents in unstable rest angina unless the patient is unresponsive to other therapies and has an angiographically documented thrombus. In summary, acute coronary diseasc is caused by a cycle of evcnts at the intimal surface. A stable atheroma ruptures, platelets aggregate, thrombus forms, and the lesion heals. Each step in this cycle causes a specific clinical syndrome, and each can benefit from specific therapy. ACKNOWLEDGMENTS
This work was supported in part by funds from the Specialized Center of Research in Ischemic Heart Disease (grant HL-17651) from the National Institutes of Health in Bethesda, Maryland. The authors wish to acknowl edge the invaluable work of Drs. Myles E. Lee, Aurelio Chaux, Carlos Blanche, Robert Kass, Jack Matloff, C. Todd Sherman, and Anne Hickey, who gathered much of the angioscopic data, and of Ms. Dwana Williams for her word processing assistance. We are indebted to Dr. Meyer Fried man for retrieving his landmark histologic work from the 1960s and allowing us to republish four of his illustrations. We are also deeply appreciative of the continuing support of Mr. Steven Mcadow, Mr. Zev Lapin, the Grand Foundation and the Medallions Foundation.
CORONARY ARTERIAL OCCLUSION
45
Literature Cited
I. Forrester, J. S., Litvack, F., Grundfest,
2.
Annu. Rev. Med. 1991.42:35-45. Downloaded from www.annualreviews.org Access provided by University of Toronto Library on 11/22/14. For personal use only.
3.
4.
5.
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