Relation of Coronary Angioscopic Findings at Coronary Angioplasty to Angiographic Restenosis
Background Discordant results have been reported regarding morphological predictors of restenosis after percutaneous transluminal coronary angioplasty (PTCA). These discrepancies may be related to the limitations of angiography in the study of plaque morphology.
Methods and Results We studied 117 consecutive patients who underwent successful PTCA and who underwent coronary angioscopy before and immediately after the procedure. Angiographic follow-up was performed in 99 (85%) patients. We analyzed the relationship between angioscopic variables at the time of PTCA and the occurrence of restenosis assessed by quantitative coronary angiography. Plaque shape and color had no effect on late loss in luminal diameter (late loss: smooth lesions, 0.55±0.68 mm; complex lesions, 0.76±0.60 mm; white plaques, 0.51±0.56 mm; yellow plaques, 0.65±0.72 mm; P=NS). An angioscopic protruding thrombus at the PTCA site was associated with significantly greater loss in luminal diameter (late loss: no thrombus, 0.47±0.54 mm; lining thrombus, 0.59±0.67 mm; protruding thrombus, 1.07±0.77 mm; P<.05). Dissection assessed by angioscopy immediately after PTCA had no effect on late loss in luminal diameter (late loss: no dissection, 0.60±0.60 mm; simple dissection, 0.82±0.75 mm; complex dissection, 0.57±0.80 mm; P=NS).
Conclusions These results show that coronary angioscopy may be helpful in predicting the risk of restenosis after PTCA. The high rate of angiographic recurrence observed when PTCA is performed at thrombus-containing lesions supports a role for thrombus in the process of luminal renarrowing after PTCA.
Previous studies have demonstrated that clinical factors affect the likelihood of restenosis after percutaneous transluminal coronary angioplasty (PTCA). We and others have observed a high rate of recurrence when unstable lesions,1 2 3 infarct-related lesions,4 and lesions that recur rapidly after a first successful procedure5 6 7 are treated with PTCA. Angiographic classifications, while useful as indicators of the risk of acute complication after PTCA,8 have not proved useful to identify lesions at high risk of restenosis. Discordant results have been reported regarding, for example, the risk of restenosis at angiographically defined complex lesions9 10 or thrombus-containing lesions.11 12 13 These discrepancies may be related to the limitations of angiography for studying plaque morphology.14 15
Coronary angioscopy is a relatively new technique that provides direct visualization of the intravascular lumen and permits a more complete description of plaque morphology.14 15 The purpose of this study was to investigate whether the morphological characteristics of the plaque assessed by angioscopy at the time of PTCA were predictive of angiographic restenosis assessed at 6-month follow-up.
Between May 1992 and December 1993, 133 consecutive patients underwent coronary angioscopy before a single-lesion PTCA procedure in our institution. Adequate angioscopy (defined as a procedure in which clear images of more than two thirds [240°] of the vessel circumference were obtained) was performed in 120 (90%) patients. A successful angioplasty procedure was performed immediately after angioscopy in 117 (97%) patients. Systematic 6-month angiographic follow-up was proposed to all patients and was performed (6.4±1.9 months later) in the 99 patients (85%) who form the study population.
Coronary angioscopy was performed with the ImageCath system (Baxter Edwards, LIS Division), which includes an angioscopy catheter, an irrigation system, a light source, and a video system. The angioscopy catheter has an outer diameter of 4.5F (1.5 mm) and includes a mobile fiber bundle that can be moved independent of the catheter over a 5-cm distance. Visualization of the coronary lumen is performed during low-pressure inflation of a proximal, distensible, low-pressure occlusion cuff with continuous flushing of normal (0.9%) saline at 30 to 45 mL/min through the irrigation channel of the angioscope by means of a power injector. All angioscopy sequences were recorded on videotape for subsequent analysis.
Angioscopy was performed before PTCA in all patients. After administration of 10 000 IU of heparin, the lesion was crossed with a standard 0.014-in guide wire. The angioscopy catheter then was advanced over the guide wire, and an initial series of images was obtained while the angioscope was advanced through the lesion; subsequently, another recording was obtained while the angioscope was withdrawn. In 49% of the pre-PTCA procedures, no attempt was made to cross the lesion because of the severity of the stenosis. In these patients, pre-PTCA angioscopy comprised imaging of the segment proximal to the lesion and of the lesion itself. The guide wire was left in place, and the angioscopy catheter then was exchanged for a standard PTCA catheter. Angioplasty was performed as previously described.5 6 At the discretion of the operator, an angioscopy procedure was repeated immediately after PTCA by exchanging the balloon catheter for the angioscope. When angioscopy was performed after PTCA, the lesion was crossed by the angioscope in all cases. Complications related to the angioscopy procedure were ventricular fibrillation in 1 patient (with no clinical consequences), a small coronary dissection that required no intervention in 1 patient, and transient atrioventricular block in 1 patient.
All videotapes were reviewed by two physicians who were unaware of the angiographic findings. The definitions and classifications used (Table 2⇓) are adapted from the angioscopic classification system that was developed and evaluated by the European Working Group on Coronary Angioscopy.16 Intraobserver and interobserver agreements of angioscopic recordings evaluated by this working group have been published recently.16
The angioscopic plaque evaluation before PTCA comprised an assessment of the shape of the narrowing and of plaque color. The shape of narrowing was classified as smooth concentric, smooth eccentric, complex, or ulcerated; a lesion was classified as smooth eccentric if a segment of normal appearing wall was visualized at the site of the lesion; a complex narrowing was defined as an irregular plaque with jagged edges; and an ulcerated plaque was defined as an area of lining red clot surrounded by irregular plaque. The predominant color of the plaque was classified as white, light yellow, or dark yellow. A lesion was classified as a thrombus-containing lesion when a thrombus was seen either before or after PTCA. Angioscopic thrombus (Figure⇓) was defined as an intraluminal, superficial (lining), or protruding mass adherent to the vessel surface but clearly a separate structure. Thrombi were further classified by color (white, red, or mixed red and white). A white thrombus was defined as a shaggy, irregular, and cotton-wool–like mass. Angioscopic dissection was defined as visible cracks or fissures of either the plaque or of the adjacent normal wall. Dissections were classified as simple (one or two well-delineated fissures) or complex (multiple fissures associated with large structures protruding into the lumen or with a thick flap more or less occluding the lumen).
Quantitative computer-assisted angiographic measurements of the dilated lesion were performed on end-diastolic frames by a single investigator unaware of the angioscopic findings with the caesar (Computer Assisted Evaluation of Stenosis And Restenosis) system. A detailed description of this system has been reported previously.17 We routinely perform angiography in at least two projections after intracoronary injection of isosorbide dinitrate (2 mg), just before, and immediately after angioplasty. These projections are recorded in our database, and the follow-up angiogram is performed after the intracoronary injection of isosorbide dinitrate in the same projections. The following definitions were used: the acute gain associated with the procedure was defined as the difference between the minimal lumen diameter (MLD) immediately after PTCA and the MLD before PTCA; the late loss during the follow-up period was defined as the difference between the MLD immediately after PTCA and the MLD at follow-up; the loss index is the late loss normalized for the acute gain; finally, to define restenosis, we used the classic criterion of an increase from <50% diameter stenosis immediately after PTCA to ≥50% at follow-up.
Angiographic evidence of intracoronary thrombus was defined as the presence of an intraluminal filling defect surrounded by contrast material seen in multiple projections.
Data are presented as mean value±SD. Differences between means were assessed with the use of ANOVA, the Student-Newman-Keuls test for multiple comparisons, and unpaired Student’s t test for comparisons between two groups. Differences between proportions were assessed by χ2 analysis. A value of P<.05 was considered to indicate statistical significance.
The baseline characteristics of the study population are detailed in Table 1⇓. Most patients were men. Mean age was 58±11 years. PTCA was performed for unstable angina in 19% of patients; 42% had experienced a recent (<1 month) myocardial infarction. PTCA was most often performed in the left anterior descending artery (51%) and less frequently in the right coronary or circumflex arteries. Eight patients had evidence of intracoronary thrombus before PTCA on angiography.
The angioscopic characteristics of the lesions before and immediately after PTCA are summarized in Table 2⇓. By definition, all patients had an adequate angioscopy procedure before PTCA. Eighty-one percent of the 99 patients had an adequate angioscopy procedure repeated immediately after PTCA. A majority of lesions were smooth; yellow plaques were slightly more frequent than white plaques. Half of the patients had an angioscopically visible thrombus at the PTCA site; lining thrombi were more frequent than protruding thrombi; thrombus color was mixed in 75% of cases; a cotton-wool–like thrombus was observed in only 3 patients. Immediately after PTCA, dissections were observed at 60% of lesions.
The relationship between angioscopic and quantitative angiographic variables are summarized in Tables 3 through 5⇓⇓⇓. When plaque shape before PTCA was defined as smooth or complex, we found no statistically significant differences in terms of restenosis between groups (Table 3⇓); however, there was a trend for higher late loss at complex lesions (P=.16). Within the complex lesion group the late loss was similar for complex shaped (0.82±0.64 mm) and for ulcerated lesions (0.73±0.60 mm). Plaque color before PTCA had also no impact on restenosis. The late loss and the rate of restenosis tended to be higher when yellow plaque was present, but this difference did not reach statistical significance (Table 3⇓).
To assess the role of an angioscopically visible thrombus at the PTCA site on the risk of restenosis, patients were classified into three groups: no thrombus, lining thrombus, and protruding thrombus (Table 4⇑). Before PTCA, lesions in the protruding thrombus group were more severe than that without thrombus; by contrast, immediately after PTCA, stenosis severity was similar. At follow-up, the lesions in the protruding thrombus group were more severe than lesions without thrombus or with a lining thrombus. These differences were caused by the higher late loss and loss index at lesions with protruding thrombus. When restenosis was defined as a ≥50% diameter stenosis at follow-up, there was a trend for a higher rate of restenosis in the presence of an angioscopically visible thrombus (absence of thrombus, 38%; lining thrombus, 47%; protruding thrombus, 65%). A totally occluded vessel at follow-up was more frequently observed in the protruding thrombus group (P<.01). When the 4 patients with total occlusion at follow-up were excluded from the analysis, the late loss in patients with a protruding thrombus (0.85±0.67 mm) was still significantly (P<.05) higher than that observed in patients without thrombus (0.47±0.54 mm). Thrombus color had no impact on restenosis (red thrombus: late loss, 0.75±0.72 mm; mixed thrombus: late loss, 0.72±0.73 mm, P=NS).
Table 5⇑ shows that the presence of dissection assessed by angioscopy after PTCA was not associated with restenosis. Minimal lumen diameter and percent stenosis were similar in patients with no dissection, with simple dissection, and with complex dissections. Acute gain, late loss, and loss index were also similar among groups.
Numerous angiographic studies that have tried to relate pre- or post-PTCA lesion-related variables to the occurence of restenosis10 12 13 have provided discordant results. These discrepancies may be related to the limitations of coronary angiography in the assessment of plaque morphology. Angioscopy can provide a precise assessment of the appearance of the lesion before and after PTCA and thus may be more sensitive in determining plaque characteristics associated with a higher risk of restenosis. To the best of our knowledge, this is the first report of angioscopic predictors of restenosis in a large series of patients with a high rate of systematic angiographic follow-up. Our results show that a protruding coronary thrombus at the PTCA site is associated with an unfavorable long-term angiographic outcome. Although we observed a trend for higher restenosis rates at complex stenoses and at lesions with yellow plaque, these differences did not reach statistical significance. Angioscopic dissection was not a risk factor for restenosis.
The possible association between thrombus at the PTCA site and restenosis in humans is not clear. Halon et al11 observed restenosis in 67% of patients with intracoronary thrombus compared with restenosis in only 19% of patients without thrombus. Hirshfeld et al,12 however, found that restenosis occured in 40% of the patients without thrombus at the PTCA site and in 41% of patients with thrombus. These discrepancies between studies probably are related to the low sensitivity of angiography for the detection of intracoronary thrombus.14 15
Coronary angioscopy is to date the reference technique for the detection of intracoronary thrombus in humans. More than 50% of the thrombi detected by angioscopy are not detected by angiography.14 15 However, angioscopy may be limited by technical aspects such as the inability to cross severe stenoses before PTCA or to exclude the presence of a thrombus in the “shadow area” of a severe stenosis; in the present study, thrombus at the PTCA site was defined as the presence of thrombus immediately before or immediately after PTCA. On occasion, a lining thrombus may be difficult to distinguish from a wall hemorrhage. A hemorrhage usually has irregular borders and is in the same plane as the plaque; conversely, a thrombus usually has a well-defined overhanging edge. However, on some occasions, a small thrombus may fill in a depression and appear to be contained within the plaque and thus be difficult to distinguish from a wall hemorrhage.
Our results demonstrate an association between thrombus and late luminal renarrowing. Patients with a protruding thrombus at the PTCA site had an exaggerated restenotic process when compared with patients without thrombus. The 65% restenosis rate in this subgroup clearly reflects the unfavorable midterm angiographic outcome when PTCA is performed in this setting. The mechanisms by which an intraluminal thrombus might increase the risk of restenosis after a successful PTCA procedure are not known specifically, but at least three hypotheses may be invoked.
First, experimental studies have provided evidence of an important role for platelets and thrombus formation in neointimal proliferation. In a canine model of endothelial injury, the intensity of cyclic flow variations related to platelet accumulation was a major determinant of neointimal thickening.18 Similarly, in a rat model of balloon denudation, the administration of antibodies directed against platelets was associated with a significant decrease in neointimal thickening.19 In addition, thrombin by itself has potent growth factor properties for smooth muscle cells,20 and antithrombin drugs inhibit experimental restenosis.21
Second, the volume of thrombus at the PTCA site also may play a role on the subsequent restenotic process. An alternative proposal for the cellular mechanisms leading to neointimal hyperplasia has been recently advanced by Schwartz et al22 ; this hypothesis based on the porcine coronary injury model suggests that the volume of the intracoronary thrombus at the time of PTCA may determine the subsequent volume of neointima. If such a mechanism also were important in humans, it would explain why protruding thrombi (which are usually large thrombi) are more likely to be associated with restenosis than lining thrombi (usually smaller).
Finally, a significant proportion of the restenoses observed after PTCA of lesions with protruding thrombus were in fact due to total occlusion of the vessel at follow-up. These occlusions may occur as a final step at severely restenotic lesions but also may be the consequence of a thrombotic event occuring early after PTCA. We have previously reported that PTCA performed at an infarct-related lesion is associated with a high rate of total occlusion at follow-up.4 The present study suggests that this phenomenon may occur in a subgroup of patients, namely those with a protruding thrombus at the PTCA site. Angioscopy may help us to identify patients that may benefit from an aggressive antithrombotic approach to prevent total occlusion of the dilated site.
Plaque Morphology and Color
Discordant results have been published regarding the risk of restenosis after PTCA of angiographically defined complex lesions. Ellis et al10 found that the only angiographic characteristic associated with restenosis was bend location and that other lesion characteristics such as eccentricity, an irregularly shaped lumen, or the presence of ulceration had no impact on restenosis. Conversely, Tousoulis et al9 reported that before PTCA, complicated coronary stenosis morphology assessed by computerized quantitative coronary angiography was a risk factor for restenosis. In this angioscopic study, we found no statistically significant differences between smooth and complex lesions with respect to late loss, loss index, and the rate of restenosis. This suggests that stenosis complexity is not a major risk factor for restenosis; however, it should be pointed out that there was a tendency for a higher restenotic process in the complex lesion group (restenosis rate, 52% versus 38%) and that the limited number of complex lesions (27) may have accounted for the lack of statistical significance.
Although there was a trend for higher late loss and loss index and a higher proportion of restenoses at lesions with yellow plaque compared with white plaque (49% versus 37%), these differences did not reach statistical significance. The color assessed by angioscopy is likely to be an indicator of the structure of the plaque. It has been demonstrated recently that there is a relationship between high serum lipid levels and the presence of yellow plaque.23 It is conceivable that the lipid content of the plaque may influence restenosis after PTCA. The HMG CoA reductase inhibitor lovastatin reduces intimal hyperplasia after balloon angioplasty in the atherosclerotic hypercholesterolemic rabbit24 but has not been shown to be effective in humans.25
Although an angiographic dissection can increase the risk of acute closure, it is also very often observed during successful procedures. Previous studies have shown that PTCA results in an angiographically visible dissection at approximately 30% of the dilated lesions.26 27 28 Although an angiographically visible dissection has theoretically been associated with more severe injury and might thus trigger an excessive proliferative response,29 angiographic studies have demonstrated that the occurence of a dissection is not a risk factor for restenosis.26 27 28 Intimal dissections, however, are often observed at angioscopy despite an optimal angiographic result14 ; the 60% rate of angioscopic dissection observed in the present study is concordant with these previous reports. However, our results demonstrate that the occurence of an angioscopic dissection has no impact on the subsequent occurence of restenosis and support the concept that dissection is more a mechanism than a complication of balloon angioplasty.
Coronary angioscopy allows a precise description of the vascular lumen before and after PTCA and may be helpful in predicting the risk of restenosis. Based on the findings of this pilot study, we believe that there is a need for a multicenter trial designed to assess the angioscopic predictors of angiographic and clinical restenoses in a larger study population. Such a study may improve our knowledge of the mechanisms leading to the long-term failure of 30% to 50% of initially successful PTCA procedures.
- Received February 21, 1995.
- Revision received May 8, 1995.
- Accepted June 8, 1995.
- Copyright © 1995 by American Heart Association
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