Stenting of Culprit Lesions in Unstable Angina Leads to a Marked Reduction in Plaque Burden: A Major Role of Plaque Embolization?
A Serial Intravascular Ultrasound Study
Background— Intravascular ultrasound (IVUS) studies have shown that a mechanism of plaque compression/embolization contributes toward the poststenting increase in lumen area. The aim of this IVUS study was to compare the mechanisms of lumen enlargement after coronary stenting in 54 consecutive patients with unstable angina (UA) (group 1) and 56 with stable angina (group 2) to verify whether plaque embolization plays a major role in the former.
Methods and Results— Both groups underwent the IVUS assessment (speed, 0.5 mm/sec) before the intervention and after stent implantation. The lumen area, the external elastic membrane area, and the plaque+media area (PA) were measured at 0.5-mm intervals. PA reduction in the lesion site was significantly greater in group 1 (−2.50±1.97 versus −0.53±1.43 mm2, P<0.001). After stenting, 47% of the lumen area increase in group 1 was obtained by means of PA reduction, and 53% was attributable to external elastic membrane area increase; the corresponding figures in group 2 were 13% and 87% (P<0.05). Decrease in PA after stenting was the only significant predictor of the MB fraction of creatinine kinase (CK-MB) release in a multiple regression model (P=0.047).
Conclusions— Serial volumetric IVUS assessment revealed in UA lesions a marked poststenting reduction in plaque volume, which is significantly greater than in stable angina and is associated with postprocedural CK-MB release. The decrease in PA during the procedure predicts CK-MB release in a multiple regression model. These findings suggest that stent deployment is often associated with plaque embolization in patients with UA.
Received November 26, 2002; revision received February 20, 2003; accepted February 26, 2003.
Although stenting has proved to be a valid approach for the treatment of coronary artery disease, its use in the clinical setting of unstable angina (UA) is frequently hampered by cardiac enzyme release, probably because of the embolization of atherosclerotic plaques that have large thrombotic appositions.1–4
Recent intravascular ultrasound (IVUS) studies have shown that in the clinical setting of stable angina (SA), plaque compression/embolization contribute to poststenting lumen enlargement.5,6 It is reasonable to speculate that stent deployment in patients with UA leads to a greater reduction in plaque volume attributable to a mechanism of embolization. The aim of the present study was to compare the mechanisms of lumen enlargement after coronary stenting in patients with UA and in patients with SA to verify whether plaque embolization plays a major role in the former.
The study involved 110 patients with SA or UA who underwent IVUS-guided procedures of balloon angioplasty followed by stent implantation. The mechanism of lumen enlargement after stenting was compared in 54 patients with UA (group 1) versus 56 patients with SA (group 2). The MB fraction of creatinine kinase (CK-MB) was evaluated in all cases to correlate CK-MB levels with plaque reduction.
We screened 256 patients who consecutively underwent IVUS-guided interventional procedures at our institutions between January and December 2000. Clinical, procedural, and angiographic criteria for entering the study were UA Braunwald classification IIB or IIB7 or SA,8 single-vessel stenting with a Multilink stent (Guidant Co), no use of platelet GP IIB/IIIA inhibitors or clopidogrel, the absence of preprocedural CK-MB levels above the upper reference limit, a lesion length of <18 mm, the absence of side branches originating in the stented segment, and the absence of angiographically visible calcifications. A total of 110 patients fulfilled the study inclusion criteria, 54 with UA (group 1) and 56 with SA (group 2).
Unstable angina was defined according to Braunwald classification.7 Only the most severe presentation of UA (Braunwald classification IIB and IIIB) entered the study. Stable angina was defined according to the Canadian Cardiovascular Society classification (classes 1 through 4).8
Culprit lesions were identified by the association of electrocardiographic signs of ischemia and lesion angiographic aspect.9 Angiograms were then matched with IVUS examinations, obtained with a continuous speed mechanical pullback, to identify the ultrasonographic location of the culprit lesions.
Postprocedural myocardial infarction was defined as the presence of an increase in the release of CK-MB to >3 times the upper reference limit. CK-MB enzyme release was measured before and 12 and 24 hours after the procedure.
All of the patients had the procedure performed through a femoral access using guiding catheters with diameters ranging from 6F to 8F. Before the procedure, all of the patients were administered acetylsalicylic acid (300 mg/24 h) and 500 mg/24 h of ticlopidine to be continued for 30 days. After the insertion of the arterial sheath, every patient received 70 to 100 IU/kg of heparin and an additional bolus to maintain an activated clotting time of >250 seconds. The stents were implanted after balloon inflation in all cases.
Both groups underwent the IVUS examinations before the intervention. IVUS examinations were repeated after stent implantation and final postdilation, if needed.
The imaging probe was positioned distally to the target lesions and withdrawn at a constant speed of 0.5 mm/sec, using a motorized pullback device. The IVUS images were recorded onto high-resolution s-VHS videotape for offline analysis.
Quantitative IVUS Analysis
Cross-sections were analyzed for every second of videotape using commercially available software (Tape Measure, INDEC Co); each analyzed coronary segment was thus axially divided into several 0.5-mm segments.
On the basis of reproducible arterial landmarks (side branches, calcium deposits, the aortocoronary junction), the same arterial segments were identified at the preintervention and poststenting assessments. The analyzed arterial segment encompassed the stented segments and 5 mm of the proximal and distal reference segments.10
The data are presented as mean values and included lumen area (LA), the total vessel area delimited by the external elastic membrane (EEM) area, and the plaque area (PA), measured as plaque+media area in both the stented and the reference segments. Furthermore, the cross-section with the narrowest point was identified in every case. The differences in mean LA, PA, and EEM areas between the procedural steps were calculated.
A volumetric analysis was performed in a group of stents having the same length to enable a more accurate assessment of changes in plaque dimensions both at stent site and reference segments. Therefore, the volumetric analysis was made of 32 13-mm-long stents (40% of the total population), with EEM, lumen, and plaque volumes being measured using Simpson’s formula.5,6
Qualitative and Quantitative IVUS Definitions
The qualitative plaque characteristics were defined as follows: fibrous plaques: lesions with a predominantly dense fibrous composition that produces bright, heterogeneous echoes having an echoreflectivity equal or superior to that of the adventitia; calcific plaques: lesions with a >90-degree calcific arc (highly echogenic segments having a greater density than that of the adventitia and causing an acoustic shadowing); and soft plaques: lesions with a highly cellular fibromuscular composition or diffuse lipid infiltration, which have a low level of echoreflectivity (lower than that of the adventitia). Furthermore, lipid/necrotic areas were defined as large echolucent areas within the plaque, circumscribed by tissue with a higher echodensity. The lipid necrotic areas were assessed in the narrowest plaque cross-section.11
The remodeling index (RI) was defined as the ratio of the EEM area at the lesion site to the reference EEM area (calculated as the average of proximal and distal reference sites).12 Positive remodeling was defined as RI >1.05, negative remodeling as RI <0.95, and absence of remodeling as RI between 0.95 and 1.05.
Quantitative Coronary Angiography
The offline quantitative coronary angiography analyses were made at the European Imaging Laboratory by 2 technicians who were unaware of the IVUS measurements. The angiographic measurements were made using a computer-assisted system and an automated edge detection algorithm (MEDIS Co) as previously described.10
Assessment of CK-MB Release
Blood samples were routinely acquired from all of the patients before and 12 and 24 hours after the procedure. CK-MB levels were determined at the Central Hospital Biochemistry Laboratory using the mass-determination method (normal range, 0 to 25 UI/mL).
The data were statistically analyzed using STATISTICA 5.1 software (Stat Soft Co). The continuous variables are expressed as mean±SD and were analyzed using 2-tailed paired and unpaired t tests. To assess interobserver variability, the results were compared using the K-test of concordance for categorical data and correlation analysis for continuous variables. Relationships between studied variables were assessed by linear regression. A multivariate logistic regression analysis was made to identify independent predictors of CK-MB elevation; the model included IVUS measurements that correlated significantly with CK-MB elevations in the univariate analyses. P<0.05 was considered statistically significant.
There were no baseline differences between the 2 groups in terms of demographic, clinical, or procedural data (Tables 1 and 2⇓). In the UA group, most patients (63%) had the most severe form of angina (Braunwald class IIIB). The electrocardiographic changes occurring during rest angina were T-wave inversion in 53% of patients, ST depression in 44%, and nonspecific changes in 3%.
Preprocedural Quantitative and Qualitative IVUS Assessment of Plaque Dimensions
Qualitative IVUS revealed a higher prevalence of lipid pools in group 1 (38.3% versus 25.4%, P=0.27) (Table 2). The test of concordance for lipid-necrotic pool visualization by 2 independent observers was 0.68; P<0.0001.
The RI was significantly greater in the UA group (1.43±0.52 versus 1.21±0.37, P<0.001). Positive remodeling was more frequent in the UA group (70.3% versus 48.7%, P=0.035). Conversely, negative remodeling was more common in the SA group (30.8% versus 13.5%, P=0.029). Preintervention PA values were 69.1% in group 1 and 60.6% in group 2, P<0.001 (Table 3).
Variations in Plaque and Vessel Dimensions
On the basis of IVUS measurements, stenting led to similar absolute lumen dimensions in both groups, although the increase in LA was significantly greater in the patients with UA (Table 3; Figure 1), who also showed a significantly larger reduction in plaque area (−2.49±1.97 vs −0.53±1.43 mm2; P<0.001). On the contrary, the increase in EEM after the procedure was slightly larger in group 2 than group 1 (3.61±2.80 vs 2.80±2.65 mm2; P=0.15).
IVUS assessment revealed that 47% of the poststenting lumen enlargement in group 1 was attributable to plaque reduction and 53% to vessel wall expansion; the corresponding figures in group 2 were 13% and 87% (P<0.05).
Volumetric analysis of the 32 13-mm-long stents showed that lumen, EEM, and plaque volumes in group 1, respectively, varied from 95.92±52.72 to 169.18±50.95 mm3, from 259.28±78.01 to 318.37±97.23 mm3, and from 163.36±51.68 to 126.97±54.75 mm3; in group 2, the respective changes were from 95.87±38.26 to 160.39±41.95 mm3, from 250.96±93.73 to 302.48±102.2 mm3, and from 155.10±60.72 to 144.31±60.52 mm3.
As shown in Figure 2, the reduction in plaque volume was significantly greater in group 1 than group 2 (−36.39±17.76 versus −10.78±4.78 mm3; P<0.001). A slight axial plaque shift was observed in the proximal and distal reference segments.
The mean CK-MB levels measured before the intervention were similar in the 2 groups (20.7±5.8 UI/mL in group 1 and 18.9±5.1 UI/mL in group 2, P=0.06), but those measured 12 and 24 hours after the intervention were significantly higher in group 1 (12 hours: 49.9±22.7 versus 23.7±16.7 UI/mL; P<0.01; 24 hours: 48.8±24.2 versus 23.8±17.7 UI/mL; P<0.01).
Table 4 refers to the percentage of patients in whom the release of CK-MB was more than 1, 2, or 3 times above the laboratory reference range. On the basis of CK-MB levels, non-ST elevation myocardial infarction was diagnosed 24 hours after the procedure in 5 patients in group 1 (14%) and none in group 2.
A steady and significant increase in plaque area change was also observed in the 3 subgroups of patients in whom the release of CK-MB was more than 1, 2, and 3 times above the upper reference limit (Figure 3).
As shown in Table 5, decreases in PA, preintervention PA, and RI significantly correlated with CK-MB release; these correlations were present at both the 12-hour and 24-hour CK-MB assessments. Plaque composition at IVUS was not significantly related with PA decrease (r=0.11). In additional analysis with a multiple regression model that adjusted CK-MB release for decrease in PA, RI, and preintervention PA (%), decrease in PA was found to be the only significant predictor of the CK-MB release (P=0.047).
The major findings of the present study are that, in patients with UA, a considerable amount of the lumen enlargement obtained after stenting is attributable to plaque reduction and that the amount of plaque reduction after stenting is significantly related to postprocedural CK-MB release. These findings suggest that plaque embolization plays an important role in the mechanism of poststenting lumen enlargement in the clinical setting of UA.
There is considerable evidence showing that the culprit lesions in patients with UA have an ulcerated or fissured plaque with an overlying thrombus.13,14 More recently, postmortem studies showed that atherosclerotic lesions exhibiting vessel remodeling and lipid compositions are associated with unstable presentations.15,16 These pathological findings have been more recently confirmed by IVUS studies showing that the clinical presentation of coronary artery disease is related to plaque composition and arterial remodeling,12,17 with soft plaques showing compensatory EEM dilatation (known as positive vessel remodeling) being frequently found in patients with UA or acute myocardial infarction.
The fact that plaque reduction plays a role in the mechanism of poststenting lumen enlargement is a recent finding coming from IVUS assessments during stent implantation. Ahmed et al6 found a significant decrease in mean PA (from 10.2±6.2 to 7.2±6.1 mm2; P=0.0001) after stenting and a significant reduction in mean PA, even when the plaque was measured in the lesion plus reference segments (from 8.6±6.2 to 7.5±6.1 mm2; P=0.0001).
Our results confirm the preliminary impression that plaque reduction plays a prominent role in the mechanism of poststenting lumen enlargement and demonstrate that the reduction in PA is greater in UA than SA patients. They thus provide additional evidence in support of the theory that plaque embolization plays an important role in stenting procedures performed in the setting of acute coronary syndromes. Thrombotic apposition on ulcerated plaque (possibly with a large lipid pool) acts as a pathological substrate favoring the distal embolization of thrombotic material and cholesterol debris.18
Unfortunately, IVUS does not allow the accurate assessment and quantification of thrombotic material19 and so cannot be used to assess whether the reduction in PA is mainly caused by the embolization of thrombus or cholesterol debris or, alternatively, by a mechanism of plaque compression. However, the finding of a significant positive correlation between the decrease in plaque burden and postintervention CK-MB release supports the theory that the plaque reduction is mainly caused by the embolization of its components. In line with this clinical observation, histological studies have revealed that the culprit lesions in UA patients have a large thrombotic burden and are therefore likely to produce more microparticles and macroparticles that embolize the distal coronary microcirculation and cause CK-MB release.
Some reports have stressed the fact that the long-term outcome of interventional procedures is affected by postintervention CK-MB release.20,21 Furthermore, previous studies aimed at identifying the lesion characteristics associated with postintervention CK-MB rise; the increase in postintervention CK-MB was found to be related to a greater lesion and reference segment plaque burden and to positive vessel remodeling.22–24 In the present study, a multiple regression model identified in plaque reduction the only significant predictor of CK-MB rise, likely caused by plaque embolization.
Additional studies addressing the microcirculatory function are needed to confirm that after stenting of UA lesions, plaque reduction is mainly attributable to its thrombotic components and is responsible for CK-MB increases. These findings would additionally support the use of either platelet GP IIB/IIIA inhibitors25,26 or devices to trap embolic materials18 to halt the detrimental effect of thrombotic embolization during unstable lesion stenting.
Although this was not a randomized study, 2 groups with similar baseline clinical, angiographic, and IVUS characteristics were compared. Because IVUS does not allow the assessment of a thrombus with adequate accuracy, no attempt was made to evaluate preintervention and poststenting thrombotic material.
It is noteworthy that in the present study, platelet GP IIB/IIIA inhibitors were not used, although their use should be encouraged for percutaneous interventions in patients with unstable angina. The TIMI frame count was not analyzed in the present study. Therefore, we could not provide a definite demonstration that massive plaque reduction, occurring after stenting in UA patients, is caused by plaque embolization and is responsible for CK-MB increases. Lesions with heavy calcifications have been excluded; this is a well-known limitation of IVUS that hampers the evaluation of a subset of lesions.27
Serial volumetric IVUS assessment revealed in UA lesions a marked poststenting reduction in plaque volume, which is significantly greater than in SA and is associated with postprocedural CK-MB release. The decrease in PA during the procedure predicts CK-MB release in a multiple regression model. These findings suggest that stent deployment is often associated with plaque embolization in patients with UA.
We thank Professor Mario Motolese for reviewing the manuscript.
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