Angiography John A. Ambrose,
in Unstable AngMna MD,
and Douglas H. Israel,
Wdhin the last decade, it has been appreciated that the acute coronary syndromes of unstable angina, non-Q-wave, and Q-wave myocardial infarctiin often share a common pathogenesis based on plaque disruption and thrombosis. Such “acute” lesions frequently have a characteristic angiographii appearance wtth sharp overhanging edges, irregular borders, and intraluminal lucencye This review focuses on the benefits and limitations of qualiiie assessment of coronary lesion morphology, with respect to the sensitiitty, specificity, and prognostk significance of complex lesions and intracoronary thrombi. Angiographic findings following thrombolysis for unstable angina are dii, as well as the possible role for thrombolytii therapy as an adjunct to angioplasty in unstable angina. (Am J Cardiil199136&78B44B)
MD
he clinical syndrome of unstable angina has held the fascination of cardiologists for > 30 years. Much has been written about it or one of its pseudonyms, e.g., coronary insufficiency, preinfarction angina, intermediate coronary syndrome, and various mechanismshave been suggested for its development. Early studies suggested that rest angina was related to a transient imbalance between myocardial oxygen supply and demand similar to that in stable angina. In the 1970sthe concept of vasospasmwas implicated not only to explain the pathogenesis of Ptinzmetal’s angina, but also that of rest angina with ST depression or T-wave inversions. Within the last 5 years, there have been convincing data suggestinga different pathogenetic mechanism for unstable angina and the other acute coronary syndromes of non-Q- and Q-wave myocardial infarction. All syndromes appear to share a common pathogenesiswith plaque disruption and thrombus formation as the underlying substrate in a majority of patients.
T
COMPLEX LESIONS AND INlRACOHONAHY THHOMBI Angiographic features of compjicated lesions and thrombi in unstable angina: Unstable
From the Cardiac Catheterization Laboratory, Mount Sinai Hospital, New York, New York. Address for reprints: John A. Ambrose, MD, Cardiac Catherization Laboratory, Mount Sinai Hospital, 1 Gustave Levy Place, New York, New York 10029. 78B
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
68
angina may be defined as ischemic cardiac pain occurring at rest or at minimal workloads. In some cases, the syndrome occurs de novo, and in many others it represents an abrupt acceleration of a previously stable angina1pattern. Sequential studies in patients undergoing angiography before and after the development of unstable angina have, in fact, shown that the transition to the unstable state is associated with progression of coronary stenosis in about 75% of cases1and that these new unstable lesions have a specific coronary morphology. In fact, although stable and unstable angina do not differ in the usual angiographic variables of the number of diseased vesselsor the percent stenosis in the involved vessels,2’3the 2 syndromes may be reliably differentiated in most cases by the angiographic morphology of the lesion. Coronary morphology refers to the qualitative assessment of coronary lesions at angiography, with special attenSEPTEMBER
3, 1991
tion to the symmetry of the lesion and whether or not its borders are regular or irregular. Morphology should be determined in orthogonal views in projections that avoid foreshortening of the lesion or overlap of vessels. Since morphology is a qualitative assessment, it is best evaluated by a consensus of angiographers similar to that of subjective analysis of percent coronary narrowing. The classic angiographic features of lesions associated with the acute coronary syndromes, including irregular ragged borders and intraluminal lucency, were first demonstrated by Levin and Fallon using postmortem angiography in patients dying following myocardial infarction or coronary bypass surgery. In our studies, we have found that coronary lesion morphology determined at angiography was predictive of unstable angina.5-8Unstable angina-producing lesions were eccentric, with a narrow neck, overhanging edges or irregular borders. Lesions with some or all of these features were found in 71% of patients with unstable angina. These eccentric and irregular stenoses, which we have called type II eccentric lesions, occur in only lo-20% of patients with stable angina.6 These qualitative observations have been confirmed by other investigators who have described lesions with similar angiographic characteristics as “T” lesions,g intracoronary thrombi,” or lesions with complex morphology.” Our original classification of coronary lesions is illustrated in Figure 1. A modification of this classification is also included (Figure 2), which illustrates the most common coronary lesion geometries found at angiography. Since on occasion concentric or symmetrical lesions may be highly irregular and occur in ischemia- or infarct-related arteries in unstable angina or myocardial infarctionI we now favor the term “complicated” or “complex” lesions, as opposed to type II eccentric lesions, to describe these angiographic findings in the acute syndrome. It is also important to note that in some cases unstable angina may develop with ischemia-producing lesions on angiography that are smooth or symmetrical. These are the usual characteristics of coronary lesions in stable angina. In this situation, arteriography may have been performed some time after the acute event, with remodeling of the lesion by the time of angiography. In yet other cases, the development of unstable symptoms may occur due to transient increases in myocardial oxygen demand or other supply-related variables, such as coronary spasm or the development of anemia. In these latter situations, the presence of a complex plaque also may not be necessary.
CONCENTRIC LESIONS
ECCENTRIC LESIONS
Type’~~~ ~ ;’..:; ...: :,:... j MULTIPLE
IRREGULARITIES
FIGURE l. 9~hmatk drawlngs of the dtffsrsnt ConflFiWratkns of coronary stenotk kskns. Concsntrk kskns were synunetrkal and usually smooth. Typs I eccentric leskns were asymmetrical and smooth and most wars of the type dspkted at ths r&M. Typs II accwmc kskns were eRher smooth with a narrow nsck due to overhanging sdges (feffj, or had lrmgular borders (ffg/W Multiple Irrsgularltles lm&ulsd vessels with serial kslons or severe dlffusedlseass.
Recently, quantitative techniques have been applied to the assessment of coronary morphology. Using a complex computer algorithm, Kalbfleisch et all3 verified the predictive value of lesion irregularity for identifying patients with unstable symptoms. Although analysis of arterial borders with automated edge detection may allow for a more objective assessment of lesion irregularity or roughness, such techniques do not incorporate an assessment of translucency or filling defects within the borders of the lesion. Angiographic evidence of thrombus formation in unstable angina: The incidence of intracoronary thrombi at angiography in unstable angina varies widely according to the study quoted. This incidence ranges between 1% and 52%.14 Two recent publications noted an incidence of 45% and A SYMPOSIUM:
MANAGEMENT
OF UNSTABLE
ANGINA
798
C.M. OF DISCRETE LESIONS Simple
Complex
Because a patent ischemia-related artery is the rule rather than the exception in unstable angina, this would apply to approximately SS-90% of patients with this syndrome. We have defined an intracoronary thrombus as a filling defect located proximal or distal to a significant stenosis (Figure 3) surrounded by contrast on at least 3 sides and visible in multiple projections, or as a lesion irregularity that resolves following thrombolytic therapy (Figure 2). Otherwise, we characterize a filling defect within a stenosis as a complex lesion.17 Despite these caveats,the distinction between a complex lesion and an intracoronary thrombus is by no means absolute. Pathologic studies in patients succumbing to acute ischemic syndromes have shown that the causativemajor plaque disruptions, including plaque fissures, ulcers, and frank atheromatous rupture, are complicated by thromDirect angioscopic observabosis in most cases.18-20 tions have also confirmed that complex plaques in patients with unstable angina usually contain thrombotic material, but that such thrombi are often angiographically inapparent or indefinite.21 Even though it is likely that most complex plaques contain thrombi, it has been our anecdotal experience that only proximal or distal thrombi, but not a complex lesion alone, increase the risk of acute vessel closure during angioplasty. Therefore, the location or volume of thrombus in these lesions may have clinical relevance when angioplasty is considered. Prognostic significance
FIGURE 2. New schema of dlscrete simple versus complex lesions showing the most frequent lesion geometries noted.
41%.15J6Angiographic detection of thrombus is related to a number of factors,’ including whether or not the patient was on heparin prior to catheterization and the timing of angiography in relation to the onset of unstable angina or the last episode of rest pain. Given the marked variability in the reported incidence of coronary thrombus, it is likely that some of these differences may be spurious. Not only is the definition of unstable angina variable among these studies, but, importantly, there is also no standardized angiographic definition of intracoronary thrombus, especially when the ischemia-related vessel is < 100% occluded. SOB
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 68
of coronary morphol-
ogy: Recent data suggest that angiographic lesion morphology may be predictive of the risk of adverse coronary events. In a case-control study using angiographic data from the Coronary Artery Surgery Study registry, Ellis et al” studied morphologic features of the left anterior descending artery in 118 medically treated patients with a subsequent anterior myocardial infarction during a 3-year follow-up, compared with 141 medically treated patients with no infarction during follow-up. By multivariate analysis,lesion “roughness” and length strongly predicted risk for infarction. Eccentricity, ulceration, and thrombus also predicted increased risk, but their incidence was low in this clinically stable population. In a prospective study, Freeman et all6 randomized nearly 80 patients with new onset unstable angina to coronary angiography within 24 hours of hospital admission, or later angiography within 1 week of hospitalization. Patients with ongoing chest pain crossed over to late urgent angiography. Coronary lesions were analyzed for complex morSEPTEMBER 3, 1991
FlGURE 3. Lslrge fllllng defect distal to a stenotk leslon In the right coronary artery from a patient wlth unstable anglna. large arrow lndkates leslon and small arrows hlghllght distal thrombus.
Acute management of unstable angina: The role of thrombolytic therapy in the acute management of unstable angina has been evaluated in a number of small studies. Except for patients with totally occluded ischemia-producing vessels, the angiographic benefits of thrombolytic therapy have not been overwhelming (Table I). In fact, most of the studies that have assessed the angiographic response to thrombolytic therapy in culprit arteries not totally occluded have shown that decreases in percent coronary stenosis are relatively minor, when they occur at all. In studies utilizing quantitative analysis of coronary anatomy after thrombolysis in unstable angina, the studies of Ambrose et alz3and Top01 et al” showed no consistent angiographic improvement, whereas the study of DeZwaan et al” showed improvement in a subset of patients with subtotally occluded arteries as well as patients with total coronary occlusion. In this latter study, 33% of patients with arteries >90% and < 100% stenosed demonstrated small improvements, and 3 other patients demonstrated improved distal flow after thrombolysis while the lesions remained > 90% stenotic. This is consistent ANGlOGRAPHIC FINDINGS FOLLOWING with the concept that significant improvements in THROMDOLYSIS IN UNSTABLE ANGINA blood flow may accompany minimal improvements Thrombolytic therapy in the management of in arterial patency, since the pressure gradient acute myocardial infarction is of proven efficacy. across a stenosis is inversely related to the fourth The role of thrombolytic therapy in unstable an- power of the lumen diameter.25 This may also help gina is presently under evaluation. Thrombolysis in explain why Top01 et al” were able to demonstrate unstable angina has been utilized in two situations: an increase in the pacing threshold to ischemia the acute management of unstable angina, and as following thrombolytic therapy in unstable angina adjunctive therapy to angioplasty in patients with despite a lack of definite angiographic improveor without acute closure complicating the proce- ment. In studies analyzing angiographic responses dure. to thrombolysis in unstable angina without the use phology defined as irregularity and overhanging edges, or thrombus defined as filling defect or luminal staining. Thrombus was detected in 43% of the early angiography group, 75% of the late urgent group, and 21% of the late elective group. Complex morphology occurred in about 40% of each group of patients. The risk of an adverse cardiac outcome (infarction, death or need for revascularization) was greatest in the patients with intracoronary thrombus, followed by those with multivessel disease. The pathogenic and prognostic significance of thrombus is underscored by its high frequency of detection and the high cardiac event rate in the patients with late urgent angiography. Similarly, angiographic resolution of thrombi in the late elective group, whose symptoms stabilized, is paralleled by a low cardiac event rate. This study emphasizes the dynamic nature of coronary thrombi in unstable angina, the importance of the timing of angiography for the detection of such thrombi, and may help to explain why thrombolytic therapy is of less certain benefit in unstable angina than in acute myocardial infarction (see later).
A SYMPOSIUM:
MANAGEMENT
OF UNSTABLE
ANGINA
8I.8
TABLE I Thrombolytic
Trials in Unstable
Study
No. Patients
Vetrovec et alz6
Angina Results of Thrombolysis
Agent/Dose
Angiography
12
SK, mean dose of 187,000 u IC
Pre 6T 7
in Unstable AngMna MD,
and Douglas H. Israel,
Wdhin the last decade, it has been appreciated that the acute coronary syndromes of unstable angina, non-Q-wave, and Q-wave myocardial infarctiin often share a common pathogenesis based on plaque disruption and thrombosis. Such “acute” lesions frequently have a characteristic angiographii appearance wtth sharp overhanging edges, irregular borders, and intraluminal lucencye This review focuses on the benefits and limitations of qualiiie assessment of coronary lesion morphology, with respect to the sensitiitty, specificity, and prognostk significance of complex lesions and intracoronary thrombi. Angiographic findings following thrombolysis for unstable angina are dii, as well as the possible role for thrombolytii therapy as an adjunct to angioplasty in unstable angina. (Am J Cardiil199136&78B44B)
MD
he clinical syndrome of unstable angina has held the fascination of cardiologists for > 30 years. Much has been written about it or one of its pseudonyms, e.g., coronary insufficiency, preinfarction angina, intermediate coronary syndrome, and various mechanismshave been suggested for its development. Early studies suggested that rest angina was related to a transient imbalance between myocardial oxygen supply and demand similar to that in stable angina. In the 1970sthe concept of vasospasmwas implicated not only to explain the pathogenesis of Ptinzmetal’s angina, but also that of rest angina with ST depression or T-wave inversions. Within the last 5 years, there have been convincing data suggestinga different pathogenetic mechanism for unstable angina and the other acute coronary syndromes of non-Q- and Q-wave myocardial infarction. All syndromes appear to share a common pathogenesiswith plaque disruption and thrombus formation as the underlying substrate in a majority of patients.
T
COMPLEX LESIONS AND INlRACOHONAHY THHOMBI Angiographic features of compjicated lesions and thrombi in unstable angina: Unstable
From the Cardiac Catheterization Laboratory, Mount Sinai Hospital, New York, New York. Address for reprints: John A. Ambrose, MD, Cardiac Catherization Laboratory, Mount Sinai Hospital, 1 Gustave Levy Place, New York, New York 10029. 78B
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
68
angina may be defined as ischemic cardiac pain occurring at rest or at minimal workloads. In some cases, the syndrome occurs de novo, and in many others it represents an abrupt acceleration of a previously stable angina1pattern. Sequential studies in patients undergoing angiography before and after the development of unstable angina have, in fact, shown that the transition to the unstable state is associated with progression of coronary stenosis in about 75% of cases1and that these new unstable lesions have a specific coronary morphology. In fact, although stable and unstable angina do not differ in the usual angiographic variables of the number of diseased vesselsor the percent stenosis in the involved vessels,2’3the 2 syndromes may be reliably differentiated in most cases by the angiographic morphology of the lesion. Coronary morphology refers to the qualitative assessment of coronary lesions at angiography, with special attenSEPTEMBER
3, 1991
tion to the symmetry of the lesion and whether or not its borders are regular or irregular. Morphology should be determined in orthogonal views in projections that avoid foreshortening of the lesion or overlap of vessels. Since morphology is a qualitative assessment, it is best evaluated by a consensus of angiographers similar to that of subjective analysis of percent coronary narrowing. The classic angiographic features of lesions associated with the acute coronary syndromes, including irregular ragged borders and intraluminal lucency, were first demonstrated by Levin and Fallon using postmortem angiography in patients dying following myocardial infarction or coronary bypass surgery. In our studies, we have found that coronary lesion morphology determined at angiography was predictive of unstable angina.5-8Unstable angina-producing lesions were eccentric, with a narrow neck, overhanging edges or irregular borders. Lesions with some or all of these features were found in 71% of patients with unstable angina. These eccentric and irregular stenoses, which we have called type II eccentric lesions, occur in only lo-20% of patients with stable angina.6 These qualitative observations have been confirmed by other investigators who have described lesions with similar angiographic characteristics as “T” lesions,g intracoronary thrombi,” or lesions with complex morphology.” Our original classification of coronary lesions is illustrated in Figure 1. A modification of this classification is also included (Figure 2), which illustrates the most common coronary lesion geometries found at angiography. Since on occasion concentric or symmetrical lesions may be highly irregular and occur in ischemia- or infarct-related arteries in unstable angina or myocardial infarctionI we now favor the term “complicated” or “complex” lesions, as opposed to type II eccentric lesions, to describe these angiographic findings in the acute syndrome. It is also important to note that in some cases unstable angina may develop with ischemia-producing lesions on angiography that are smooth or symmetrical. These are the usual characteristics of coronary lesions in stable angina. In this situation, arteriography may have been performed some time after the acute event, with remodeling of the lesion by the time of angiography. In yet other cases, the development of unstable symptoms may occur due to transient increases in myocardial oxygen demand or other supply-related variables, such as coronary spasm or the development of anemia. In these latter situations, the presence of a complex plaque also may not be necessary.
CONCENTRIC LESIONS
ECCENTRIC LESIONS
Type’~~~ ~ ;’..:; ...: :,:... j MULTIPLE
IRREGULARITIES
FIGURE l. 9~hmatk drawlngs of the dtffsrsnt ConflFiWratkns of coronary stenotk kskns. Concsntrk kskns were synunetrkal and usually smooth. Typs I eccentric leskns were asymmetrical and smooth and most wars of the type dspkted at ths r&M. Typs II accwmc kskns were eRher smooth with a narrow nsck due to overhanging sdges (feffj, or had lrmgular borders (ffg/W Multiple Irrsgularltles lm&ulsd vessels with serial kslons or severe dlffusedlseass.
Recently, quantitative techniques have been applied to the assessment of coronary morphology. Using a complex computer algorithm, Kalbfleisch et all3 verified the predictive value of lesion irregularity for identifying patients with unstable symptoms. Although analysis of arterial borders with automated edge detection may allow for a more objective assessment of lesion irregularity or roughness, such techniques do not incorporate an assessment of translucency or filling defects within the borders of the lesion. Angiographic evidence of thrombus formation in unstable angina: The incidence of intracoronary thrombi at angiography in unstable angina varies widely according to the study quoted. This incidence ranges between 1% and 52%.14 Two recent publications noted an incidence of 45% and A SYMPOSIUM:
MANAGEMENT
OF UNSTABLE
ANGINA
798
C.M. OF DISCRETE LESIONS Simple
Complex
Because a patent ischemia-related artery is the rule rather than the exception in unstable angina, this would apply to approximately SS-90% of patients with this syndrome. We have defined an intracoronary thrombus as a filling defect located proximal or distal to a significant stenosis (Figure 3) surrounded by contrast on at least 3 sides and visible in multiple projections, or as a lesion irregularity that resolves following thrombolytic therapy (Figure 2). Otherwise, we characterize a filling defect within a stenosis as a complex lesion.17 Despite these caveats,the distinction between a complex lesion and an intracoronary thrombus is by no means absolute. Pathologic studies in patients succumbing to acute ischemic syndromes have shown that the causativemajor plaque disruptions, including plaque fissures, ulcers, and frank atheromatous rupture, are complicated by thromDirect angioscopic observabosis in most cases.18-20 tions have also confirmed that complex plaques in patients with unstable angina usually contain thrombotic material, but that such thrombi are often angiographically inapparent or indefinite.21 Even though it is likely that most complex plaques contain thrombi, it has been our anecdotal experience that only proximal or distal thrombi, but not a complex lesion alone, increase the risk of acute vessel closure during angioplasty. Therefore, the location or volume of thrombus in these lesions may have clinical relevance when angioplasty is considered. Prognostic significance
FIGURE 2. New schema of dlscrete simple versus complex lesions showing the most frequent lesion geometries noted.
41%.15J6Angiographic detection of thrombus is related to a number of factors,’ including whether or not the patient was on heparin prior to catheterization and the timing of angiography in relation to the onset of unstable angina or the last episode of rest pain. Given the marked variability in the reported incidence of coronary thrombus, it is likely that some of these differences may be spurious. Not only is the definition of unstable angina variable among these studies, but, importantly, there is also no standardized angiographic definition of intracoronary thrombus, especially when the ischemia-related vessel is < 100% occluded. SOB
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 68
of coronary morphol-
ogy: Recent data suggest that angiographic lesion morphology may be predictive of the risk of adverse coronary events. In a case-control study using angiographic data from the Coronary Artery Surgery Study registry, Ellis et al” studied morphologic features of the left anterior descending artery in 118 medically treated patients with a subsequent anterior myocardial infarction during a 3-year follow-up, compared with 141 medically treated patients with no infarction during follow-up. By multivariate analysis,lesion “roughness” and length strongly predicted risk for infarction. Eccentricity, ulceration, and thrombus also predicted increased risk, but their incidence was low in this clinically stable population. In a prospective study, Freeman et all6 randomized nearly 80 patients with new onset unstable angina to coronary angiography within 24 hours of hospital admission, or later angiography within 1 week of hospitalization. Patients with ongoing chest pain crossed over to late urgent angiography. Coronary lesions were analyzed for complex morSEPTEMBER 3, 1991
FlGURE 3. Lslrge fllllng defect distal to a stenotk leslon In the right coronary artery from a patient wlth unstable anglna. large arrow lndkates leslon and small arrows hlghllght distal thrombus.
Acute management of unstable angina: The role of thrombolytic therapy in the acute management of unstable angina has been evaluated in a number of small studies. Except for patients with totally occluded ischemia-producing vessels, the angiographic benefits of thrombolytic therapy have not been overwhelming (Table I). In fact, most of the studies that have assessed the angiographic response to thrombolytic therapy in culprit arteries not totally occluded have shown that decreases in percent coronary stenosis are relatively minor, when they occur at all. In studies utilizing quantitative analysis of coronary anatomy after thrombolysis in unstable angina, the studies of Ambrose et alz3and Top01 et al” showed no consistent angiographic improvement, whereas the study of DeZwaan et al” showed improvement in a subset of patients with subtotally occluded arteries as well as patients with total coronary occlusion. In this latter study, 33% of patients with arteries >90% and < 100% stenosed demonstrated small improvements, and 3 other patients demonstrated improved distal flow after thrombolysis while the lesions remained > 90% stenotic. This is consistent ANGlOGRAPHIC FINDINGS FOLLOWING with the concept that significant improvements in THROMDOLYSIS IN UNSTABLE ANGINA blood flow may accompany minimal improvements Thrombolytic therapy in the management of in arterial patency, since the pressure gradient acute myocardial infarction is of proven efficacy. across a stenosis is inversely related to the fourth The role of thrombolytic therapy in unstable an- power of the lumen diameter.25 This may also help gina is presently under evaluation. Thrombolysis in explain why Top01 et al” were able to demonstrate unstable angina has been utilized in two situations: an increase in the pacing threshold to ischemia the acute management of unstable angina, and as following thrombolytic therapy in unstable angina adjunctive therapy to angioplasty in patients with despite a lack of definite angiographic improveor without acute closure complicating the proce- ment. In studies analyzing angiographic responses dure. to thrombolysis in unstable angina without the use phology defined as irregularity and overhanging edges, or thrombus defined as filling defect or luminal staining. Thrombus was detected in 43% of the early angiography group, 75% of the late urgent group, and 21% of the late elective group. Complex morphology occurred in about 40% of each group of patients. The risk of an adverse cardiac outcome (infarction, death or need for revascularization) was greatest in the patients with intracoronary thrombus, followed by those with multivessel disease. The pathogenic and prognostic significance of thrombus is underscored by its high frequency of detection and the high cardiac event rate in the patients with late urgent angiography. Similarly, angiographic resolution of thrombi in the late elective group, whose symptoms stabilized, is paralleled by a low cardiac event rate. This study emphasizes the dynamic nature of coronary thrombi in unstable angina, the importance of the timing of angiography for the detection of such thrombi, and may help to explain why thrombolytic therapy is of less certain benefit in unstable angina than in acute myocardial infarction (see later).
A SYMPOSIUM:
MANAGEMENT
OF UNSTABLE
ANGINA
8I.8
TABLE I Thrombolytic
Trials in Unstable
Study
No. Patients
Vetrovec et alz6
Angina Results of Thrombolysis
Agent/Dose
Angiography
12
SK, mean dose of 187,000 u IC
Pre 6T 7
