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Angioscopy of Culprit Coronary Lesions in Unstable Angina Pectoris and Correlation of Clinical Presentation With Plaque Morphology
Angioscopy of Culprit Coronary Lesions in Unstable Angina Pectoris and Correlation of Clinical Presentation With Plaque Morphology Richard W. Nesto, MD, Sergio Waxman, MD, Murray A. Mittleman, MD, DrPH, Michael A. Sassower, MD, Philip J. Fitzpatrick, MD, Stanley M. Lewis, MD, David E. Leeman, MD, Samuel J. Shubrooks Jr., MD, Karen Manzo, RN, and Stuart W. Zarich, MD
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nstable angina is thought to be caused by plaque disruption and thrombosis in most cases.1 Postmortem and angiographic studies of coronary lesions responsible for this syndrome have led to the implementation of therapy with antithrombotic and antiplatelet agents. These methods of study are limited by patient selection (nonsurvivors in autopsy studies) and the inability of coronary angiography to accurately define plaque morphology. Initial studies with coronary angioscopy in patients with unstable angina revealed a high frequency of thrombus at the culprit lesion site.2,3 These studies, however, described small numbers of patients with selected clinical presentations and may not reflect the wide array of patients with the diagnosis of unstable angina. The objectives of this study were: (1) to compare the angioscopic morphology of culprit coronary lesions among different clinical subtypes of patients with unstable angina, and (2) to determine the overall frequency of plaque disruption and thrombus in these lesions as assessed by angioscopy. •••
We performed coronary angioscopy before angioplasty in 45 patients with unstable and postinfarction angina at the Deaconess Hospital. Patients were considered candidates for angioscopy if: (1) they met criteria of unstable angina as defined below, (2) the culprit lesion was anatomically suitable for angioscopy, and (3) angioscopy equipment and staff skilled in angioscopy were available at the time of angioplasty. The protocol was approved by the institutional review board of our institution and written informed consent was obtained from all patients before angioplasty. Unstable angina was defined as chest discomfort of new onset, occurring at rest or with a crescendo pattern, lasting .5 minutes but ,6 hours. The discomfort must have been accompanied by objective evidence of ischemic heart disease, such as electrocardiographic changes or a history of previous myocardial infarction, and by creatine kinase enzyme levels less than twice the upper limit of normal. Patients were categoFrom the Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. This study was supported by internal funds from the Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Massachusetts. Dr. Waxman’s address is: Beth Israel Deaconess Medical Center–West Campus, One Deaconess Road, Boston, Massachusetts 02215. Manuscript received May 7, 1997; revised manuscript received and accepted October 16, 1997. ©1998 by Excerpta Medica, Inc. All rights reserved.
rized based on the Braunwald classification4 into the following groups: (1) new-onset or accelerated angina without rest pain (class IB); (2) rest angina (both acute and subacute, classes IIB and IIIB); or (3) postinfarction angina (recurrent angina within 2 weeks after a documented myocardial infarction, class C). Patients with angiographic restenosis from a previous angioplasty were considered as a separate group for this analysis. In patients with 1-vessel disease the culprit lesion was considered to be the most severely stenosed lesion in the affected vessel. In patients with multivessel disease, the culprit lesion was defined as the most severe stenosis in the artery supplying the ischemic area as identified by electrocardiographic or radionuclide test localization. A lesion was considered suitable for angioscopy if it was located in the proximal to middle portion of a coronary artery with a luminal diameter .2.0 and ,4.0 mm, the proximal segment of the artery was nontortuous, and cuff balloon inflation of the angioscope could be done without occluding a major side branch. All procedures were performed through a percutaneous femoral approach. All patients received aspirin before the procedure and intravenous heparin to maintain an activated clotting time of .300 seconds. The culprit lesion was crossed with an 0.014-inch guidewire and angioscopy was performed before angioplasty with a Baxter Imagecath™ (Baxter Healthcare Corporation, Irvine, California). The position of the angioscope in relation to the culprit lesion was confirmed by fluoroscopy. All angioscopic assessments were done from anterograde visualization of the culprit lesion. After angioscopy was performed, coronary angioplasty was carried out as planned. Data were collected prospectively. Angiographic and angioscopic images were reviewed separately and independently by 2 investigators blinded to the clinical syndrome. Stenosis severity by angiography was measured by visual assessment and expressed as percent luminal narrowing of the vessel. Angiographic lesion morphology was categorized as complex or noncomplex using criteria adapted from Ambrose et al.5 A complex lesion was defined as a type II eccentric stenosis or a lesion with multiple irregularities, and a noncomplex lesion as a concentric or type I eccentric stenosis. Angiographic thrombus was defined as an intraluminal filling defect with rounded, globular, or polypoid shapes protruding into the lumen, or contrast medium staining at the site of coronary stenosis or occlusion. Angioscopic definitions 0002-9149/98/$19.00 PII S0002-9149(97)00889-8
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mean percent stenosis, angiographic lesion complexity, or the presence of angiographic thrombus between the 4 groups (new-onset or accelerated angina, rest angina, postinfarction angina, and restenosis). Angioscopy identified thrombus at the culprit lesion site in 22 of the 39 patients (56%). Disruption was seen in 23 of 38 lesions (61%) in which the plaque could be adequately visualized; in the remaining lesion, thrombus prevented asFIGURE 1. Arteriogram (left) and angioscopic image (right) of the left circumflex artery of a patient with rest angina (Braunwald class IIIB). The arteriogram reveals a concentric stenosessment of the plaque surface. sis in the middle portion of the artery (arrow). The corresponding angioscopic image of the Eighteen of 37 lesions (49%) lesion demonstrates a smooth white plaque without evidence of disruption or thrombus. appeared yellow by angioscopy and 19 (51%) were white; the were based on a classification system developed by color could not be determined in 2 lesions because of the European Working Group on Coronary Angios- the presence of a large overlying thrombus. Of the 22 copy.6 The predominant color of the culprit lesion, lesions in which thrombus was seen, 16 (73%) were either yellow or white, was recorded. Plaque disrup- yellow and disrupted. White, nondisrupted plaques tion was considered to be present when the surface of without thrombus were seen in 15 patients. Excluding the lesion had a rough, ulcerated, or irregular appear- restenosis lesions, the frequencies for thrombus, disance with visible cracks, fissures, or intimal flaps. A ruption, and yellow color of the plaque were 65%, lesion was considered nondisrupted when its surface 68%, and 53%, respectively. A comparison of the appeared smooth and/or shiny without irregularities angioscopic characteristics of the culprit lesions (Figure 1). Thrombus was defined as a red, white, or among the different groups is shown in Table II. mixed intraluminal, superficial or protruding mass, Patients with postinfarction angina were more likely adherent to the vessel surface but clearly a separate to have plaque disruption and thrombus than subjects structure that persisted despite flushing with a saline with rest angina, new-onset or accelerated angina, and solution (Figure 2). A white thrombus had to fulfill the patients with restenosis (p 5 0.015 and p 5 0.017 for additional criteria of having a shaggy, irregular, ‘‘cot- disruption and thrombus, respectively). Restenosis lesions were white, nondisrupted, and without thrombus ton-wool’’ appearance. Descriptive data are presented as medians and in all cases, and in a post hoc analysis were signifimean 6 SD. Comparisons of angiographic and angio- cantly different from lesions in all other groups comscopic variables between groups of patients were bined (p 5 0.046 for color, p 5 0.006 for disruption, made using 2-tailed Fisher’s exact test for discrete and p 5 0.011 for thrombus). Treatment with heparin variables. Differences in percent stenosis across the 4 or aspirin for $24 hours was not associated with categories of unstable angina was assessed using the significant differences in the frequency of thrombus compared with that in patients who had no antithromKruskall-Wallis test. Forty-five patients with unstable angina underwent botic treatment before angioplasty (p 5 0.29 for hepangioscopic imaging of the culprit lesion before an- arin, p 5 0.63 for aspirin). Ten of the 22 thrombi gioplasty. There were no complications related to an- (45%) that were visualized were mixed red and white gioscopy. Adequate images could not be obtained in 6 in color, 8 (37%) were white, and 4 (18%) were red. To account for a possible effect of the time interval patients. The clinical and angiographic characteristics of the remaining 39 patients are shown in Table I. between angina to angioscopy on the presence of Twenty-nine patients (74%) had primary unstable an- thrombus, a second analysis was performed in the 28 gina (Braunwald class B), whereas 10 (26%) patients patients in whom the time of the last episode of angina presented with postinfarction angina (Braunwald class before angioscopy was available. No significant difC). Seven of the 29 patients with class B unstable ferences were found between patients who underwent angina had new-onset or accelerated angina without angioscopy within or after 48 hours of the last episode rest pain; the remaining 22 patients had rest angina. of angina (Table III). The median interval between the last episode of an••• gina and angioscopy in 28 patients in whom these data This study demonstrates that plaque disruption and were available was 2 days (range 0 to 14). Angio- thrombus are absent in a considerable number of patients graphic evidence of restenosis at a previous angio- with unstable angina and that culprit lesion morphologies plasty site was seen in 5 patients (13%), all of them in as assessed by angioscopy may differ among the various the rest angina group, and were considered as a sep- clinical subsets of patients. Although the predominant arate group in all analyses as described in the Methods finding in postinfarction angina is a disrupted yellow section. There were no significant differences in the plaque with thrombus, the frequency of yellow plaque 226 THE AMERICAN JOURNAL OF CARDIOLOGYT
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thrombus in postinfarction angina has also been reported by Tabata and colleagues,7 who identified thrombus by angioscopy in 100% of patients with postinfarction angina. In their study, plaque disruption and yellow color were evident in 50% of cases, perhaps underestimated since thrombus may have prevented visualization of the underlying plaque. In these patients, ischemia could result not only from the physical obFIGURE 2. Arteriogram (left) and angioscopic image (right) of the left anterior descending struction from residual thromartery of a different patient with rest angina (Braunwald class IIIB). The arteriogram reveals bus, but also from the fragmenan eccentric ulcerated stenosis with intraluminal filling defect consistent with thrombus (artation of thrombus with microrow). The corresponding angioscopic image of the lesion demonstrates a disrupted yellow embolization and occlusion of plaque with red and white thrombus. small intramyocardial arteries, or the local formation of additional thrombus by stimulation of thrombin generation TABLE I Clinical and Angiographic Characteristics of 39 and release of platelet secretory products and inflamPatients With Unstable Angina Who Underwent matory mediators that lead to vasospasm. Angioscopy Before Coronary Angioplasty Although early angioscopic studies2,3 demonGender strated a high frequency of thrombus in patients with Men 27 (69%) rest angina, other groups have recently reported lower Women 12 (31%) frequencies of plaque ulceration and thrombus ranging Age Mean 6 SD 60 6 11 yrs from 40% to 70%.8 –10 In such studies, as in ours, it is Range 36–80 yrs possible that some thrombi may have been missed by Clinical syndrome the time angioscopy was performed due to spontaneUnstable angina 29 (74%) ous lysis or the institution of antithrombotic therapy. Postinfarction angina 10 (26%) Interval between last episode of angina However, analysis of patients for whom documentaand angioscopy* tion was available regarding the last episode of angina Mean 6 SD 363d did not demonstrate any significant difference in the Median 2d frequency of disruption and thrombus as a function of Range 0–14 d time. Disruption and thrombus were more frequent in Treatment before PTCA ($24 hours) Heparin 27 (69%) the rest angina group than in patients with new-onset Aspirin 34 (87%) or accelerated angina without rest symptoms, and are Coronary risk factors likely to cause ischemia through the mechanisms menPrior myocardial infarction 5 (13%) tioned previously. In patients whose culprit lesions Diabetes mellitus 15 (38%) Hyperlipidemia 24 (62%) appear smooth and white, however, other processes Hypertension 23 (59%) may account for ischemia. Rapid progression of athFamily history 14 (36%) erosclerosis could cause a reduction in oxygen supply Smoking 25 (64%) in the absence of obstructive thrombosis. Flugelman et No. of Diseased Vessels al11 reported an increased abundance of smooth mus1 31 (80%) 2 6 (15%) cle cells and expression of acidic and basic fibroblast 3 2 (5%) growth factors comparable to restenosis lesions in Culprit vessel atherectomy specimens of patients with unstable anLeft anterior descending 22 (56%) gina, suggesting that smooth muscle cell proliferation Left circumflex 7 (18%) Right 10 (26%) may lead to accelerated plaque expansion with lumiPercent stenosis nal narrowing in some patients. Because a significant Mean 6 SD 86 6 9 stenosis (.70% reduction in angiographic lumen diRange 60–100 ameter) was present in all our patients, ischemia could Restenosis lesions 5 (13%) also have been precipitated by either increases in *Data obtained for 28 patients. myocardial oxygen requirement and/or a reduction in supply. Autonomic tone and sympathovagal balance could alter the ischemic threshold in the presence of and thrombus in patients with rest angina or with new- coronary artery disease without the need for acute onset or accelerated angina is more variable. In patients structural changes at the level of the plaque (disrupwith unstable angina secondary to restenosis, the lesion tion) or obstruction to blood flow (thrombosis).12 Inis usually white, nondisrupted, and without thrombus. creased local vasoconstriction in patients with unstaThe high frequency of plaque disruption and ble angina compared to patients with stable angina13 BRIEF REPORTS
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TABLE II Angioscopic Characteristics of Culprit Lesions in 39 Patients With Unstable Angina
Yellow Disruption Thrombus
New-onset/ Accelerated Angina (n 5 7)
Rest Angina (n 5 17)
Post-MI Angina (n 5 10)
Restenosis (n 5 5)
p Value*
3 (43%) 3 (43%) 3 (43%)
9 (53%) 12 (71%) 11 (65%)
6 (60%) 8 (80%) 8 (80%)
0 0 0
0.109 0.015 0.017
*p value for Fisher’s exact test evaluating whether the angioscopic characteristics differed across the 4 clinical syndromes.
TABLE III Angioscopic Characteristics of Culprit Lesions in 28 Patients With Unstable Angina by Time Between Last Episode of Angina and Angioscopy
Deaconess Medical Center for their technical support.
Interval Between Last Episode of Angina and Angioscopy
Yellow Disruption Thrombus
Within 48 Hours* (n 5 17)
.48 Hours† (n 5 11)
p Value
7 (41%) 10 (59%) 9 (53%)
9 (82%) 9 (82%) 8 (73%)
0.054 0.249 0.435
*Of these, 2 patients had crescendo angina, 10 had rest angina, 3 had postinfarction angina, and 2 had a restenosis lesion. Sixteen and 14 patients were receiving aspirin and heparin, respectively. † Of these, 3 patients had crescendo angina, 3 had rest angina, and 5 had postinfarction angina. Nine and 6 patients were receiving aspirin and heparin, respectively.
suggests that abnormal vasoreactivity may be responsible for ischemia in some patients. Eichhorn et al14 suggested that cyclic flow variations secondary to platelet/thrombin–mediated stimuli at sites of endothelial injury, with decline in coronary blood flow, could be responsible for the development of unstable coronary artery disease. Similar mechanisms could be operative in restenosis, as atherectomy studies have revealed neointimal proliferation with smooth muscle cell activation and abundance of matrix proteins.15 White et al16 reported that restenosis lesions are generally white and fibrotic in appearance, just as we observed despite the presentation of angina at rest. Further studies are required to determine the mechanism by which ischemia is caused in the absence of disruption and thrombus. This study demonstrates that plaque disruption and thrombus, as assessed by angioscopy, are absent in a considerable number of patients with unstable angina and that their frequency may vary with the clinical presentation. Acknowledgment: We would like to express our appreciation to John Snyder and the staff of the cardiac catheterization laboratory at the Beth Israel
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1. Fuster V, Badimon L, Badimon JL, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med 1992;326:242–250. 2. Mizuno K, Satomura K, Miyamoto A, Arakawa K, Shibuya T, Arai T, Kurita A, Nakamura H, Ambrose JA. Angioscopic evaluation of coronary-artery thrombi in acute coronary syndromes. N Engl J Med 1992;326:287–291. 3. Sherman CT, Litvack F, Grundfest W, Lee M, Hickey A, Chaux A, Kass R, Blanche C, Matloff J, Morgenstern L, Ganz W, Swan HJC, Forrester J. Coronary angioscopy in patients with unstable angina pectoris. N Engl J Med 1986;315: 913–919. 4. Braunwald E. Unstable angina: a classification. Circulation 1989;80:410 – 414. 5. Ambrose JA, Winters SL, Arora RR, Haft JL, Golstein J, Renthrop KP, Gorlin R, Fuster V. Coronary angiographic morphology in myocardial infarction: a link between the pathogenesis of unstable angina and myocardial infarction. J Am Coll Cardiol 1985;6:1233–1238. 6. Den Heijer P, Foley DP, Hillege H, Lablanche JM, van Dijk RB, Franzen D, Morice MC, Serra A, De Scheerder I, Serruys PW, Lie KI. The ‘‘Ermenonville’’ classification of observations at coronary angioscopy. Evaluation of intra- and inter-observer agreement. Eur Heart J 1994;15:815– 822. 7. Tabata H, Mizuno K, Arakawa K, Satomura K, Shibuya T, Kurita A, Nakamura H. Angioscopic identification of coronary thrombus in patients with postinfarction angina. J Am Coll Cardiol 1995;25:1282–1285. 8. De Feyter PJ, Ozaki Y, Baptista J, Escaned J, Di Mario C, de Jaegere PT, Serruys PW, Roelandt JRTC. Ischemia-related lesion characteristics in patients with stable or unstable angina. A study with intracoronary angioscopy and ultrasound. Circulation 1995;92:1408 –1413. 9. Silva JA, Escobar A, Collins TJ, Ramee SR, White CJ. Unstable angina: a comparison of angioscopic findings between diabetic and nondiabetic patients. Circulation 1995;92:1731–1736. 10. Thieme T, Wernecke KD, Meyer R, Brandenstein E, Habedank D, Hinz A, Felix SB, Baumann G, Kleber FX. Angioscopic evaluation of atherosclerotic plaques: Validation by histomorphologic analysis and association with stable and unstable coronary syndromes. J Am Coll Cardiol 1996;28:1– 6. 11. Flugelman MY, Virmani R, Correa R, Yu ZX, Farb A, Leon MB, Elami A, Fu YM, Casscells W, Epstein SE. Smooth muscle cell abundance and fibroblast growth factors in coronary lesions of patients with nonfatal unstable angina. A clue to the mechanism of transformation from the stable to the unstable clinical state. Circulation 1993;88:2493–2500. 12. McLenachan JM, Weidinger FF, Barry J, Yeung A, Nabel G, Rocco MB, Selwyn AP. Relations between heart rate, ischemia, and drug therapy during daily life in patients with coronary artery disease. Circulation 1991;83:1263–1270. 13. Bogaty P, Hackett D, Davies G, Maseri A. Vasoreactivity of the culprit lesion in unstable angina. Circulation 1994;90:5–11. 14. Eichhorn EJ, Grayburn PA, Willard JE, Anderson HV, Bedotto JB, Carry M, Kahn JC, Willerson JT. Spontaneous alterations in coronary blood flow velocity before and after coronary angioplasty in patients with severe angina. J Am Coll Cardiol 1991;17:43–52. 15. Waller BF, Johnson DE, Schnitt SJ, Pinkerton CA, Simpson JB, Baim DS. Histologic analysis of directional coronary atherectomy samples. A review of findings and their clinical relevance. Am J Cardiol 1993;72:80E– 87E. 16. White CJ, Ramee SR, Mesa JE, Collins TJ. Percutaneous coronary angioscopy in patients with restenosis after coronary angioplasty. J Am Coll Cardiol 1991;17:46B– 49B.
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nstable angina is thought to be caused by plaque disruption and thrombosis in most cases.1 Postmortem and angiographic studies of coronary lesions responsible for this syndrome have led to the implementation of therapy with antithrombotic and antiplatelet agents. These methods of study are limited by patient selection (nonsurvivors in autopsy studies) and the inability of coronary angiography to accurately define plaque morphology. Initial studies with coronary angioscopy in patients with unstable angina revealed a high frequency of thrombus at the culprit lesion site.2,3 These studies, however, described small numbers of patients with selected clinical presentations and may not reflect the wide array of patients with the diagnosis of unstable angina. The objectives of this study were: (1) to compare the angioscopic morphology of culprit coronary lesions among different clinical subtypes of patients with unstable angina, and (2) to determine the overall frequency of plaque disruption and thrombus in these lesions as assessed by angioscopy. •••
We performed coronary angioscopy before angioplasty in 45 patients with unstable and postinfarction angina at the Deaconess Hospital. Patients were considered candidates for angioscopy if: (1) they met criteria of unstable angina as defined below, (2) the culprit lesion was anatomically suitable for angioscopy, and (3) angioscopy equipment and staff skilled in angioscopy were available at the time of angioplasty. The protocol was approved by the institutional review board of our institution and written informed consent was obtained from all patients before angioplasty. Unstable angina was defined as chest discomfort of new onset, occurring at rest or with a crescendo pattern, lasting .5 minutes but ,6 hours. The discomfort must have been accompanied by objective evidence of ischemic heart disease, such as electrocardiographic changes or a history of previous myocardial infarction, and by creatine kinase enzyme levels less than twice the upper limit of normal. Patients were categoFrom the Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. This study was supported by internal funds from the Cardiovascular Division, Beth Israel Deaconess Medical Center, Boston, Massachusetts. Dr. Waxman’s address is: Beth Israel Deaconess Medical Center–West Campus, One Deaconess Road, Boston, Massachusetts 02215. Manuscript received May 7, 1997; revised manuscript received and accepted October 16, 1997. ©1998 by Excerpta Medica, Inc. All rights reserved.
rized based on the Braunwald classification4 into the following groups: (1) new-onset or accelerated angina without rest pain (class IB); (2) rest angina (both acute and subacute, classes IIB and IIIB); or (3) postinfarction angina (recurrent angina within 2 weeks after a documented myocardial infarction, class C). Patients with angiographic restenosis from a previous angioplasty were considered as a separate group for this analysis. In patients with 1-vessel disease the culprit lesion was considered to be the most severely stenosed lesion in the affected vessel. In patients with multivessel disease, the culprit lesion was defined as the most severe stenosis in the artery supplying the ischemic area as identified by electrocardiographic or radionuclide test localization. A lesion was considered suitable for angioscopy if it was located in the proximal to middle portion of a coronary artery with a luminal diameter .2.0 and ,4.0 mm, the proximal segment of the artery was nontortuous, and cuff balloon inflation of the angioscope could be done without occluding a major side branch. All procedures were performed through a percutaneous femoral approach. All patients received aspirin before the procedure and intravenous heparin to maintain an activated clotting time of .300 seconds. The culprit lesion was crossed with an 0.014-inch guidewire and angioscopy was performed before angioplasty with a Baxter Imagecath™ (Baxter Healthcare Corporation, Irvine, California). The position of the angioscope in relation to the culprit lesion was confirmed by fluoroscopy. All angioscopic assessments were done from anterograde visualization of the culprit lesion. After angioscopy was performed, coronary angioplasty was carried out as planned. Data were collected prospectively. Angiographic and angioscopic images were reviewed separately and independently by 2 investigators blinded to the clinical syndrome. Stenosis severity by angiography was measured by visual assessment and expressed as percent luminal narrowing of the vessel. Angiographic lesion morphology was categorized as complex or noncomplex using criteria adapted from Ambrose et al.5 A complex lesion was defined as a type II eccentric stenosis or a lesion with multiple irregularities, and a noncomplex lesion as a concentric or type I eccentric stenosis. Angiographic thrombus was defined as an intraluminal filling defect with rounded, globular, or polypoid shapes protruding into the lumen, or contrast medium staining at the site of coronary stenosis or occlusion. Angioscopic definitions 0002-9149/98/$19.00 PII S0002-9149(97)00889-8
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mean percent stenosis, angiographic lesion complexity, or the presence of angiographic thrombus between the 4 groups (new-onset or accelerated angina, rest angina, postinfarction angina, and restenosis). Angioscopy identified thrombus at the culprit lesion site in 22 of the 39 patients (56%). Disruption was seen in 23 of 38 lesions (61%) in which the plaque could be adequately visualized; in the remaining lesion, thrombus prevented asFIGURE 1. Arteriogram (left) and angioscopic image (right) of the left circumflex artery of a patient with rest angina (Braunwald class IIIB). The arteriogram reveals a concentric stenosessment of the plaque surface. sis in the middle portion of the artery (arrow). The corresponding angioscopic image of the Eighteen of 37 lesions (49%) lesion demonstrates a smooth white plaque without evidence of disruption or thrombus. appeared yellow by angioscopy and 19 (51%) were white; the were based on a classification system developed by color could not be determined in 2 lesions because of the European Working Group on Coronary Angios- the presence of a large overlying thrombus. Of the 22 copy.6 The predominant color of the culprit lesion, lesions in which thrombus was seen, 16 (73%) were either yellow or white, was recorded. Plaque disrup- yellow and disrupted. White, nondisrupted plaques tion was considered to be present when the surface of without thrombus were seen in 15 patients. Excluding the lesion had a rough, ulcerated, or irregular appear- restenosis lesions, the frequencies for thrombus, disance with visible cracks, fissures, or intimal flaps. A ruption, and yellow color of the plaque were 65%, lesion was considered nondisrupted when its surface 68%, and 53%, respectively. A comparison of the appeared smooth and/or shiny without irregularities angioscopic characteristics of the culprit lesions (Figure 1). Thrombus was defined as a red, white, or among the different groups is shown in Table II. mixed intraluminal, superficial or protruding mass, Patients with postinfarction angina were more likely adherent to the vessel surface but clearly a separate to have plaque disruption and thrombus than subjects structure that persisted despite flushing with a saline with rest angina, new-onset or accelerated angina, and solution (Figure 2). A white thrombus had to fulfill the patients with restenosis (p 5 0.015 and p 5 0.017 for additional criteria of having a shaggy, irregular, ‘‘cot- disruption and thrombus, respectively). Restenosis lesions were white, nondisrupted, and without thrombus ton-wool’’ appearance. Descriptive data are presented as medians and in all cases, and in a post hoc analysis were signifimean 6 SD. Comparisons of angiographic and angio- cantly different from lesions in all other groups comscopic variables between groups of patients were bined (p 5 0.046 for color, p 5 0.006 for disruption, made using 2-tailed Fisher’s exact test for discrete and p 5 0.011 for thrombus). Treatment with heparin variables. Differences in percent stenosis across the 4 or aspirin for $24 hours was not associated with categories of unstable angina was assessed using the significant differences in the frequency of thrombus compared with that in patients who had no antithromKruskall-Wallis test. Forty-five patients with unstable angina underwent botic treatment before angioplasty (p 5 0.29 for hepangioscopic imaging of the culprit lesion before an- arin, p 5 0.63 for aspirin). Ten of the 22 thrombi gioplasty. There were no complications related to an- (45%) that were visualized were mixed red and white gioscopy. Adequate images could not be obtained in 6 in color, 8 (37%) were white, and 4 (18%) were red. To account for a possible effect of the time interval patients. The clinical and angiographic characteristics of the remaining 39 patients are shown in Table I. between angina to angioscopy on the presence of Twenty-nine patients (74%) had primary unstable an- thrombus, a second analysis was performed in the 28 gina (Braunwald class B), whereas 10 (26%) patients patients in whom the time of the last episode of angina presented with postinfarction angina (Braunwald class before angioscopy was available. No significant difC). Seven of the 29 patients with class B unstable ferences were found between patients who underwent angina had new-onset or accelerated angina without angioscopy within or after 48 hours of the last episode rest pain; the remaining 22 patients had rest angina. of angina (Table III). The median interval between the last episode of an••• gina and angioscopy in 28 patients in whom these data This study demonstrates that plaque disruption and were available was 2 days (range 0 to 14). Angio- thrombus are absent in a considerable number of patients graphic evidence of restenosis at a previous angio- with unstable angina and that culprit lesion morphologies plasty site was seen in 5 patients (13%), all of them in as assessed by angioscopy may differ among the various the rest angina group, and were considered as a sep- clinical subsets of patients. Although the predominant arate group in all analyses as described in the Methods finding in postinfarction angina is a disrupted yellow section. There were no significant differences in the plaque with thrombus, the frequency of yellow plaque 226 THE AMERICAN JOURNAL OF CARDIOLOGYT
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thrombus in postinfarction angina has also been reported by Tabata and colleagues,7 who identified thrombus by angioscopy in 100% of patients with postinfarction angina. In their study, plaque disruption and yellow color were evident in 50% of cases, perhaps underestimated since thrombus may have prevented visualization of the underlying plaque. In these patients, ischemia could result not only from the physical obFIGURE 2. Arteriogram (left) and angioscopic image (right) of the left anterior descending struction from residual thromartery of a different patient with rest angina (Braunwald class IIIB). The arteriogram reveals bus, but also from the fragmenan eccentric ulcerated stenosis with intraluminal filling defect consistent with thrombus (artation of thrombus with microrow). The corresponding angioscopic image of the lesion demonstrates a disrupted yellow embolization and occlusion of plaque with red and white thrombus. small intramyocardial arteries, or the local formation of additional thrombus by stimulation of thrombin generation TABLE I Clinical and Angiographic Characteristics of 39 and release of platelet secretory products and inflamPatients With Unstable Angina Who Underwent matory mediators that lead to vasospasm. Angioscopy Before Coronary Angioplasty Although early angioscopic studies2,3 demonGender strated a high frequency of thrombus in patients with Men 27 (69%) rest angina, other groups have recently reported lower Women 12 (31%) frequencies of plaque ulceration and thrombus ranging Age Mean 6 SD 60 6 11 yrs from 40% to 70%.8 –10 In such studies, as in ours, it is Range 36–80 yrs possible that some thrombi may have been missed by Clinical syndrome the time angioscopy was performed due to spontaneUnstable angina 29 (74%) ous lysis or the institution of antithrombotic therapy. Postinfarction angina 10 (26%) Interval between last episode of angina However, analysis of patients for whom documentaand angioscopy* tion was available regarding the last episode of angina Mean 6 SD 363d did not demonstrate any significant difference in the Median 2d frequency of disruption and thrombus as a function of Range 0–14 d time. Disruption and thrombus were more frequent in Treatment before PTCA ($24 hours) Heparin 27 (69%) the rest angina group than in patients with new-onset Aspirin 34 (87%) or accelerated angina without rest symptoms, and are Coronary risk factors likely to cause ischemia through the mechanisms menPrior myocardial infarction 5 (13%) tioned previously. In patients whose culprit lesions Diabetes mellitus 15 (38%) Hyperlipidemia 24 (62%) appear smooth and white, however, other processes Hypertension 23 (59%) may account for ischemia. Rapid progression of athFamily history 14 (36%) erosclerosis could cause a reduction in oxygen supply Smoking 25 (64%) in the absence of obstructive thrombosis. Flugelman et No. of Diseased Vessels al11 reported an increased abundance of smooth mus1 31 (80%) 2 6 (15%) cle cells and expression of acidic and basic fibroblast 3 2 (5%) growth factors comparable to restenosis lesions in Culprit vessel atherectomy specimens of patients with unstable anLeft anterior descending 22 (56%) gina, suggesting that smooth muscle cell proliferation Left circumflex 7 (18%) Right 10 (26%) may lead to accelerated plaque expansion with lumiPercent stenosis nal narrowing in some patients. Because a significant Mean 6 SD 86 6 9 stenosis (.70% reduction in angiographic lumen diRange 60–100 ameter) was present in all our patients, ischemia could Restenosis lesions 5 (13%) also have been precipitated by either increases in *Data obtained for 28 patients. myocardial oxygen requirement and/or a reduction in supply. Autonomic tone and sympathovagal balance could alter the ischemic threshold in the presence of and thrombus in patients with rest angina or with new- coronary artery disease without the need for acute onset or accelerated angina is more variable. In patients structural changes at the level of the plaque (disrupwith unstable angina secondary to restenosis, the lesion tion) or obstruction to blood flow (thrombosis).12 Inis usually white, nondisrupted, and without thrombus. creased local vasoconstriction in patients with unstaThe high frequency of plaque disruption and ble angina compared to patients with stable angina13 BRIEF REPORTS
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TABLE II Angioscopic Characteristics of Culprit Lesions in 39 Patients With Unstable Angina
Yellow Disruption Thrombus
New-onset/ Accelerated Angina (n 5 7)
Rest Angina (n 5 17)
Post-MI Angina (n 5 10)
Restenosis (n 5 5)
p Value*
3 (43%) 3 (43%) 3 (43%)
9 (53%) 12 (71%) 11 (65%)
6 (60%) 8 (80%) 8 (80%)
0 0 0
0.109 0.015 0.017
*p value for Fisher’s exact test evaluating whether the angioscopic characteristics differed across the 4 clinical syndromes.
TABLE III Angioscopic Characteristics of Culprit Lesions in 28 Patients With Unstable Angina by Time Between Last Episode of Angina and Angioscopy
Deaconess Medical Center for their technical support.
Interval Between Last Episode of Angina and Angioscopy
Yellow Disruption Thrombus
Within 48 Hours* (n 5 17)
.48 Hours† (n 5 11)
p Value
7 (41%) 10 (59%) 9 (53%)
9 (82%) 9 (82%) 8 (73%)
0.054 0.249 0.435
*Of these, 2 patients had crescendo angina, 10 had rest angina, 3 had postinfarction angina, and 2 had a restenosis lesion. Sixteen and 14 patients were receiving aspirin and heparin, respectively. † Of these, 3 patients had crescendo angina, 3 had rest angina, and 5 had postinfarction angina. Nine and 6 patients were receiving aspirin and heparin, respectively.
suggests that abnormal vasoreactivity may be responsible for ischemia in some patients. Eichhorn et al14 suggested that cyclic flow variations secondary to platelet/thrombin–mediated stimuli at sites of endothelial injury, with decline in coronary blood flow, could be responsible for the development of unstable coronary artery disease. Similar mechanisms could be operative in restenosis, as atherectomy studies have revealed neointimal proliferation with smooth muscle cell activation and abundance of matrix proteins.15 White et al16 reported that restenosis lesions are generally white and fibrotic in appearance, just as we observed despite the presentation of angina at rest. Further studies are required to determine the mechanism by which ischemia is caused in the absence of disruption and thrombus. This study demonstrates that plaque disruption and thrombus, as assessed by angioscopy, are absent in a considerable number of patients with unstable angina and that their frequency may vary with the clinical presentation. Acknowledgment: We would like to express our appreciation to John Snyder and the staff of the cardiac catheterization laboratory at the Beth Israel
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