Atherosclerotic Plaque Burden and CK-MB Enzyme Elevation After Coronary Interventions. Intravascular Ultrasound Study of 2256 Patients

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1 Atherosclerotic Plaque Burden and CK-MB Enzyme Elevation After Coronary Interventions Intravascular Ultrasound Study of 2256 Patients Roxana Mehran, MD; George Dangas, MD, PhD; Gary S. Mintz, MD; Alexandra J. Lansky, MD; Augusto D. Pichard, MD; Lowell F. Satler, MD; Kenneth M. Kent, MD, PhD; Gregg W. Stone, MD; Martin B. Leon, MD Background Elevation of serum creatine kinase MB fraction (CK-MB) after percutaneous coronary interventions has been associated with early and late mortality; however, the pathogenesis of CK-MB elevation is still unknown. We hypothesized that CK-MB elevation was related to atherosclerotic plaque burden as assessed by preintervention intravascular ultrasound (IVUS). Methods and Results We studied 2256 consecutive patients who underwent intervention of 2780 native coronary lesions and had complete high-quality preintervention IVUS imaging in the era before routine use of platelet glycoprotein IIb/IIIa inhibitors. Patients were divided into 3 groups: CK-MB within normal range (1675 patients; 2061 lesions); CK-MB elevation 1 to 5 times upper limit of normal (292 patients; 355 lesions); and CK-MB elevation 5 times upper limit of normal (289 patients; 364 lesions). Qualitative angiographic lesion morphology and quantitative analysis were similar among the 3 groups. On preintervention IVUS, progressively more reference segment and lesion site plaque burden and lesion site calcium occurred in the groups with CK-MB elevation. Positive remodeling was more common in lesions with CK-MB elevation. As levels of CK-MB increased, cross-sectional narrowing (percentage plaque burden) increased, both at the reference site (mean cross-sectional narrowing values were 45.1%, 49.3%, and 52.2% for normal CK-MB, 1 to 5 times upper limit of normal, and 5 times upper limit of normal groups, respectively; P 0.03) and at the lesion site (81.9%, 85.4%, and 87.1%, respectively; P 0.04). Multivariate analysis indicated that de novo lesions, atheroablative technique, plaque burden at the lesion and reference segments, and final minimal lumen diameter were independent predictors of CK-MB elevation. Conclusions CK-MB elevation correlates with a greater atherosclerotic plaque burden. CK-MB elevation after intervention may be a marker of diffuse atherosclerotic disease or a consequence of catheter-based intervention in more diseased arteries or both. (Circulation. 2000;101: ) Key Words: necrosis, myocardial angioplasty stents Elevated serum creatine kinase MB fraction (CK-MB) occurs in 5% to 30% of patients undergoing percutaneous coronary intervention. 1 4 Secondary analyses of large trials have indicated that CK-MB elevation may be associated with increased mortality. 5,6 Previous studies that attempted to understand the pathogenesis of CK-MB elevation have focused primarily on procedural rather than lesion-related explanations. 5 8 Although angiography has been the gold standard for assessment of coronary atherosclerosis, the luminogram is still far from perfect for assessment of extent of coronary artery disease. 9 Studies with intravascular ultrasound (IVUS) have consistently shown significantly more lesion site and reference segment calcification, extensive atherosclerotic plaque burden (average, 50%) in angiographically normal reference segments, and arterial remodeling in lesion site and reference segment We hypothesized that CK-MB elevation after coronary intervention was related, at least in part, to lesion and reference atherosclerotic plaque burden and plaque characteristics as assessed by preintervention IVUS. Methods Patient Population The Cardiovascular Research Foundation Database was queried to identify 2256 consecutive patients who underwent intervention of 2780 native coronary lesions and had complete high-quality preintervention IVUS imaging from January 1, 1994, to December 31, Received June 18, 1999; revision received August 30, 1999; accepted September 20, From the Cardiovascular Research Foundation, New York and the Cardiac Catheterization Laboratory, Washington Hospital Center, Washington, DC. Presented in part at the 71st Scientific Sessions of the American Heart Association, Dallas, Tex, November 8 11, 1998, and published in abstract form (Circulation. 1998;98[suppl I]:I-496.). Correspondence to George Dangas, MD, PhD, Cardiovascular Research Foundation, 55 East 59th Street, 6th Floor, New York, NY American Heart Association, Inc. Circulation is available at 604

2 Mehran et al Atherosclerotic Burden and CK-MB Elevation 605 IVUS cross-sectional imaging of the vessel wall enables planimetry to be done of the area within the EEM and of the lumen area. P M area is calculated as the difference between EEM and lumen areas; IVUS imaging does not discriminate effectively between atherosclerotic plaque and thrombus. CSN (percentage plaque burden) can be derived as the ratio of P M area/eem area We excluded patients with saphenous vein graft intervention (n 788), acute ST-segment elevation myocardial infarction within 72 hours (n 129), in-stent restenosis (n 205), or elevated baseline preintervention CK-MB (n 176); without IVUS imaging (n 594); or with poor-quality IVUS (n 18). Clinical, angiographic, and preintervention IVUS findings were used to determine predictors of CK-MB enzyme elevation. Hospital charts were reviewed independently by a dedicated data coordinating center. During the study period, platelet glycoprotein IIb/IIIa inhibitors were used in 3% of cases. Blood samples were routinely acquired from all patients before intervention and at 8 and 16 to 24 hours after the procedure. If CK-MB levels were elevated, serial measurements were performed every 8 hours and the peak level was recorded. All CK-MB determinations were performed in the Clinical Chemistry Laboratory by use of the mass-determination method (normal range, 0 to 4 ng/ml). Patients were divided into 3 groups: normal CK-MB (1675 patients; 2061 treated lesions); CK-MB elevation 1 to 5 times upper limit of normal (292 patients, 355 treated lesions); and CK-MB elevation 5 times upper limit of normal (289 patients; 364 treated lesions), according to a prespecified definition of non-q-wave myocardial infarction (CK-MB 5 times normal). Angiographic Analysis All cineangiograms were analyzed by use of computer-assisted, automated edge-detection algorithm (ARTREK, Quantitative Cardiac Systems) by a core laboratory that was blinded to the ultrasound and clinical findings. Standard qualitative and quantitative definitions and measurements were used. 14 The outer diameter of the contrast-filled catheter (as the calibration) and minimal lumen diameter (MLD) were obtained from the single worst view. IVUS Imaging IVUS imaging was performed before intervention and only after 0.2 mg IC of nitroglycerin was administered. Studies were performed with 1 of 2 commercially available systems: (1) InterTherapy/Cardiovascular Imaging Systems Inc, with a 25-MHz transducer, and (2) Boston Scientific Corporation/Cardiovascular Imaging Systems Inc, with a 30-MHz transducer. With both systems, the transducer was withdrawn automatically at 0.5 mm/s to perform the imaging sequence, which started 10 mm distal to the lesion and ended at the aorto-ostial junction. IVUS studies were recorded on 1/2-in highresolution s-vhs videotape for off-line analysis. 15 IVUS Analysis Validation of plaque composition and measurements of external elastic membrane (EEM) cross-sectional area (CSA), lumen CSA, and plaque and media P M EEM Lumen, where P is plaque and M is media) CSA by IVUS have been reported previously The lesion site selected for analysis was the image slice with the smallest lumen CSA; if several image slices had an equally small lumen, the image slice with the largest P M CSA was analyzed. The reference segment was the most normal-looking cross-section proximal and distal to the stenosis but between major side branches. 19 Lesion site and reference segment EEM CSA and lumen CSA were measured with computer planimetry (Figure). Cross-sectional narrowing (CSN), also called plaque burden, was calculated as (P M) EEMCSA To assess reproducibility and intraobserver variability of sequential IVUS measurements in our laboratory, 40 consecutive ultrasound studies were analyzed at least 3 months apart. This reanalysis began with the original videotapes and, therefore, included the error that resulted from repeated selection of the same image slice and the error that resulted from performance of the cross-sectional measurements. Differences in the measurements were as follows: EEM CSA, mm 2 ; lumen CSA, mm 2 ; and P M CSA, mm 2. Intraclass correlation coefficient for repeated measurement of EEM CSA was 0.99; of lumen CSA, 0.92; and of P M CSA, Target lesion and reference segment plaque compositions were assessed visually to identify calcium. Calcium produced brighter echoes than those of the reference adventitia, with acoustic shadowing of deeper arterial structures. The largest arc of calcium was measured by use of a protractor centered on the lumen. 19 Lesion site remodeling index was determined by dividing target lesion EEM CSA by average reference segment EEM CSA. Positive remodeling

3 606 Circulation February 15, 2000 TABLE 1. Baseline Patient Characteristics 5 Normal 1 5 Normal Normal P n Age, y Men 210 (72.4) 188 (64.6) 1204 (71.9) 0.01 Diabetes 76 (26.4) 86 (29.3) 469 (28.0) 0.12 Unstable angina 215 (74.4) 202 (69.4) 1156 (69.2) 0.19 Angina at rest within 48 hours 89 (30.8) 83 (28.4) 485 (28.9) 0.43 Postinfarction angina 55 (19.0) 45 (15.4) 268 (16.1) 0.28 Hypertension 168 (58.1) 169 (58.6) 985 (58.8) 0.73 Hyperlipidemia 186 (64.4) 189 (64.8) 1092 (65.2) 0.88 Previous myocardial infarction 148 (51.3) 158 (54.2) 779 (46.5) 0.07 Previous bypass surgery 52 (18.1) 57 (19.5) 337 (20.2) 0.62 Renal insufficiency 20 (7.1) 12 (4.2) 90 (5.4) 0.09 Ejection fraction Values are n(%) or mean SD, as indicated. index was 1.0, and intermediate/negative remodeling was defined as index Statistics Statistical analysis was performed with SAS software (Statistical Analysis Systems, SAS Institute Inc) in a dedicated data analysis center. Data are presented as mean SD. Continuous variables were compared among the 3 CK-MB groups by use of 3-way factorial ANOVA. Categorical variables were compared by use of 2 test. We conducted multivariate logistic regression analysis to identify independent predictors of CK-MB elevation. The model included clinical, lesion, procedure, luminal, and IVUS measurements that correlated significantly with CK-MB elevation in the univariate analyses. Statistical significance was defined as P TABLE 2. Lesion and Procedural Characteristics Results Clinical and Procedural Findings Patient demographics are presented in Table 1. No statistically significant differences existed among the 3 groups, except that (1) patients with CK-MB elevation were older and (2) the CK-MB 1 to 5 times normal group included more women. 5 Normal 1 5 Normal Normal P No. of lesions Right coronary artery 134 (36.9) 132 (37.3) 831 (40.3) 0.12 Left anterior descending 159 (43.8) 154 (43.5) 841 (40.8) 0.21 Left circumflex artery 70 (19.3) 69 (19.4) 389 (18.9) 0.82 Total occlusions 17 (4.8) 9 (2.5) 70 (3.4) 0.45 Restenotic lesions 82 (22.4) 78 (22.1) 664 (32.2) 0.01 No. of lesions treated Rotational atherectomy 70 (19.2) 77 (21.6) 89 (4.3) 0.04 Excimer laser angioplasty 25 (6.8) 29 (8.2) 113 (5.5) 0.04 Directional atherectomy 109 (30.1) 119 (33.5) 552 (26.8) 0.10 Atheroablation 204 (56.1) 225 (63.4) 754 (36.5) Stent 164 (45.1) 132 (37.1) 826 (40.1) 0.06 No. of stents Maximal balloon diameter, mm Balloon/artery ratio Maximal stent diameter, mm Maximum ACT value, s Final ACT value, s Procedure time, min Values are n(%) or mean SD, as indicated.

4 Mehran et al Atherosclerotic Burden and CK-MB Elevation 607 TABLE 3. Angiographic Results 5 Normal 1 5 Normal Normal P Lesion type Ostial 5 (2.6) 2 (1.2) 18 (0.9) 0.34 Ulcerated 16 (8.7) 24 (12.1) 132 (10.5) 0.57 Thrombotic 6 (3.3) 4 (2.0) 46 (3.6) 0.47 Calcified 71 (38.2) 56 (36.8) 396 (32.3) 0.14 AHA/ACC type B 2 50 (26.9) 56 (27.8) 329 (26.5) 0.91 AHA/ACC type C 33 (17.5) 30 (15.2) 192 (15.6) 0.69 Lesion length, mm Reference diameter, mm Preprocedure MLD, mm Preprocedure DS, % Final MLD, mm Final DS, % Values are n(%) or mean SD, as indicated. AHA/ACC indicates American Heart Association/ American College of Cardiology classification; DS, diameter stenosis. Lesion location and procedural information are given in Table 2. More restenotic lesions occurred in the normal CK-MB group. Significant differences existed in interventional device use among the groups. Atheroablative devices were used more often in the groups with CK-MB elevation. Stent use tended to be more common, number of stents used was greater, and stent sizes were larger in patients with CK-MB elevation. Similarly, balloon sizes and balloon/artery ratios were also larger in patients with CK-MB elevation. Angiographic Findings Angiographic lesion morphology did not differ among the 3 groups (see Table 3 for angiographic findings). Angiographic success was achieved in 100% of cases. Evidence of dissection during intervention was more frequent in patients with elevated CK-MB: 57 of 364 (18.8%) versus 61 of 355 TABLE 4. Intravascular Ultrasound Results (19.7%) versus 208 of 2061 (12.6%) in the CK-MB 5 times normal versus 1 to 5 times normal versus normal groups, respectively; P Similarly, abrupt closure was more frequent in patients with CK-MB elevation: 12 of 364 (3.3%) versus 6 of 355 (1.8%) versus 10 of 2061 (0.5%), respectively; P Final angiographic dimensions were superior (ie, larger MLD and smaller diameter stenosis) in the group with CK-MB 5 times normal and intermediate in the CK-MB 1 to 5 times normal group compared with the normal CK-MB group. IVUS /Findings Progressively more reference segment and lesion site plaque burden (CSN) and lesion site calcium occurred in the groups with CK-MB elevation (Table 4). Positive remodeling was identified in 1181 of 2780 lesions (42.5%). Lesions with 5 Normal 1 5 Normal Normal P Reference EEM CSA, mm Lumen CSA, mm CSN, % Lesion EEM CSA, mm Lumen CSA, mm CSN, % Arc of calcium, Final lesion Lumen CSA, mm CSN, %* Values are mean SD. *In nonstented lesions.

5 608 Circulation February 15, 2000 TABLE 5. Independent Predictors of CK-MB Elevation by Multivariate Analysis Odds Ratio 95% CI P De novo lesion Atheroablative technique CSN, reference segment CSN, lesion site, preintervention Final MLD CI indicates confidence intervals. positive remodeling had 15.9% CK-MB 1 to 5 times normal group and 14.6% CK-MB 5 times normal group, both of which were significantly higher than the percentages seen in lesions with intermediate/negative remodeling (10.4% and 11.9%, respectively; P 0.01 for both). After intervention, lesion site plaque burden was less in the groups with CK-MB elevation. Multivariate Analysis Independent predictors of CK-MB elevation are listed in Table 5 and include increased atherosclerotic plaque burden both at the lesion and reference segment. Exclusion of all patients treated with atheroablative techniques yielded qualitatively similar results. Age, sex, diabetes, and IVUS lumen dimensions at the lesion site before and after intervention did not correlate with CK-MB elevation in this multivariate model. Discussion The pathophysiology of CK-MB release during percutaneous interventions has been related to development of no-reflow, side-branch occlusion, abrupt vessel closure, and atherothrombotic or platelet embolization. 7,8,21 Although the first 3 causes may be clinically apparent, the latter may be entirely asymptomatic and occur even during or after angiographically uneventful procedures. 2,7,8,21,22 The dominant role of platelets in this phenomenon is supported by evidence that a marked decrease in CK-MB elevation can be achieved with administration of potent antiplatelet agents such as glycoprotein IIb/IIIa inhibitors. 15,17,21,23 The present study suggests that lesion-specific factors may also be important for determination of CK-MB elevation. We found a strong relationship between baseline lesion characteristics (as assessed by preintervention IVUS) and subsequent CK-MB elevation. Greater lesion and reference segment plaque burden, lesion arc of calcium, and positive remodeling were all associated with CK-MB elevation. By multivariate analysis, extensive atherosclerotic plaque burden both at the lesion and reference segment were independent predictors of CK-MB elevation. Additionally, a more aggressive interventional approach was used in patients who had CK-MB elevation. Thus, CK-MB elevation may be either a marker of more diffuse atherosclerotic disease or a consequence of catheter-based intervention in more diffusely diseased arteries or both. Lesion Characteristics and CK-MB Elevation Several studies have linked CK-MB elevation with increased early and late mortality and recurrent myocardial infarction. 1 8,21 23 Compelling evidence suggests that the correlation of CK-MB elevation with poor clinical outcome is independent of the specific interventional device used ,26 28 Known relationships exist between long-term patient outcome, atherosclerotic plaque burden, coronary calcification, and (even potentially) lesion remodeling characteristics. Previous clinical findings have indicated that cardiovascular mortality and morbidity are highly dependent on the extent and severity of atherosclerosis (ie, overall plaque burden). 29 In addition, pathological and IVUS studies have showed that lesion-associated coronary artery calcium increases with extent and severity of atherosclerosis and correlates with volume of the atherosclerotic plaque. 30,31 We found a greater final angiographic MLD in the CK-MB elevation groups but similar final lumen CSA by IVUS in all 3 groups. Existence of a greater arc of calcium in the CK-MB elevation groups might have led to a relatively eccentric lumen enlargement with greater angiographic MLD but without significantly greater IVUS CSA than in cases with normal CK-MB. We classified lesions as having characteristics of intermediate/negative remodeling (58% of the total cohort) versus positive remodeling and showed more CK-MB elevation with positive remodeling. Others have related positive remodeling with hypercholesterolemia, 32 unstable clinical presentation, 33 and less fibrocalcific plaque elements. 34 The latter 2 findings suggest that positive remodeling lesions are younger and less stable, whereas intermediate/negative remodeling lesions are older and more mature. In support of this, recent studies have implicated positive remodeling in pathogenesis of unstable coronary syndromes. 35,36 Restenotic lesions in the present study had less CK-MB elevation; a previous report has shown that restenotic lesions have less plaque burden than do de novo lesions. 37 Second, male sex and increased patient age were associated with CK-MB elevation in the present study; these have been associated with greater reference segment plaque burden. 38 In multivariate analysis, de novo lesions, atheroablative technique, plaque burden at the lesion and reference segments, and final MLD remained independent predictors of CK-MB elevation. Procedural Correlates of CK-MB Elevation In addition to atherosclerotic plaque burden, more aggressive intervention (atheroablative device use, stent use, number and sizes of stents, larger balloon/artery ratio, and larger final balloon size) appeared to be associated with greater levels of CK-MB elevation, consistent with other studies. 2,5,7 However, use of interventional devices and techniques is often clinically driven by the extent of disease; ie, specific techniques are selected to obtain an optimal angiographic result in patients with diffuse disease or heavy calcification. Thus, no conclusions can be drawn as to whether equivalent outcomes without CK-MB elevation would have been obtained if only less aggressive balloon angioplasty was used. Moreover, by multivariate analysis, diffuse atherosclerotic disease was an independent predictor of CK-MB release, distinct from atheroablation and stent use. However, greater final MLD independently correlated with CK-MB elevation, which sug-

6 Mehran et al Atherosclerotic Burden and CK-MB Elevation 609 gests that strategies that maximize lumen dimensions (to reduce restenosis) may result in the tradeoff of greater CK-MB release. CK-MB elevation was also associated with procedural complications such as abrupt closure and angiographic dissection. However, abrupt closure occurred infrequently, even in the group with the highest CK-MB elevation, and dissection alone was not an independent determinant of CK-MB release. Side-branch occlusion may contribute to CK-MB elevation, but its systematic evaluation was beyond the scope of the present study. Finally, we found statistically significant differences among groups with respect to activated clotting time (ACT) values; the highest ACT value was at the highest CK-MB elevation group, and all 3 mean values were 300 s. This finding excludes inadequate anticoagulation as an explanation for CK-MB elevation and at the same time reflects the inadequacy of intense heparin therapy for prevention of CK-MB elevation. Limitations First, this was a retrospective analysis. To offset this limitation, data were collected prospectively by independent monitors and entered into a dedicated database, and separate, independent core laboratories interpreted all angiographic IVUS studies. Second, the mechanism through which extensive plaque burden results in CK-MB elevation may not be determined from the present study, and we did not attempt to link plaque burden and CK-MB elevation with long-term patient outcome. Third, in the case of multivessel intervention, lesions might belong to vessels of different plaque burdens. It would be very difficult to attribute CK-MB elevation to a specific lesion. This limitation acknowledges the difficulty in derivation of definitive correlation between individual lesion characteristics and patient outcome during multivessel intervention. Fourth, a theoretic possibility always exists of missed CK-MB release due to the chosen diagnostic window; however, we used a widely accepted protocol of periodic CK-MB determination that complies with current clinical practice. Fifth, the incidence of angiographic thrombus was low among the study population, which included only patients who underwent native coronary artery intervention. Sixth, we did not attempt to differentiate between atherosclerotic plaque and thrombus because of the inability of IVUS imaging to accurately distinguish between the 2 entities. Thus, the conclusions do not necessarily apply to patients who are undergoing angioplasty in saphenous vein grafts or with lesions that contain abundant thrombus. 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