Abnormal Coronary Flow Velocity Reserve After Coronary Intervention Is Associated With Cardiac Marker Elevation
Background—Residual reduction of relative coronary flow velocity reserve (rCVR) after successful coronary intervention has been related to microvascular impairment. However, the incidence of cardiac enzyme elevation as a surrogate marker of an underlying embolic myocardial injury in these cases has not been studied.
Methods and Results—A series of 55 consecutive patients with successful coronary stenting, periprocedural intracoronary Doppler analysis, and determination of creatine kinase (CK; upper limit of normal [ULN] for women 70 IU/L, for men 80 IU/L) and cardiac troponin T (cTnT; bedside test, threshold 0.1 ng/mL) before and 6, 12, and 24 hours after intervention were studied. Postprocedural rCVR was the only intracoronary Doppler parameter that independently correlated with cTnT (r=−0.498, P<0.001) and CK outcome (r=−0.406, P=0.002). Receiver operating characteristic analysis identified a postprocedural rCVR of 0.78 as the best discriminating value, with a sensitivity of 83.3% and 69.2% and a specificity of 79.1% and 76.2% for detection of cTnT and CK elevation, respectively. Stratified according to this cutoff value, the incidence of cTnT elevation was 52.6% in patients with (n=19) and 5.6% in patients without (n=36) a postprocedural rCVR <0.78 (P<0.001), associated with a CK elevation >1 times the ULN in 36.8% and 5.6% (P=0.005) of patients, respectively.
Conclusions—Cardiac marker elevation can frequently be found after coronary procedures that are associated with a persistent reduction of rCVR, indicating procedural embolization of atherothrombotic debris with microvascular impairment and myocardial injury as a potential underlying mechanism.
Embolization of atherosclerotic debris during coronary procedures has been considered a rare event until recent trials with new protection devices demonstrated retrieval of particulate matter in percutaneous interventions of both saphenous vein grafts and native coronary arteries.1 2 Before this era, various clinical studies only indirectly outlined the incidence and significance of microvascular obstruction due to percutaneous coronary intervention (PCI), using cardiac enzymes as surrogate markers of myocardial injury.1 2 3 4
On a functional level, procedural embolization has been suggested as one of the potential explanations for abnormal coronary Doppler flow parameters after PCI, which have been well documented in a number of clinical trials.5 6 7 8 9 Moreover, in an experimental model, it has been shown that acute embolic myocardial injury is associated with an early increase in coronary blood flow due to adenosine release from the ischemic myocardium.10 11 Notably, this functional effect was recorded at the electromagnetic flow probe attached to the bypass tube that was used to inject microspheres into the left anterior descending coronary artery.10 11 Whether or not these alterations in Doppler parameters also occur during coronary intervention, with the coronary artery being both the site of Doppler recording and the origin of release of particulate debris, is unknown and is the aim of the present study.
This study examined a consecutive series of 55 patients with successful coronary stenting for routine clinical indication12 and periprocedural Doppler analysis at the University Clinic Essen. Procedural success was defined as a reduction of lumen diameter stenosis to <30% without incidence of death, CABG, or Q-wave acute myocardial infarction (AMI). Exclusion criteria were (1) elevation of cardiac markers before intervention; (2) AMI during the last 4 weeks before the procedure; (3) terminal renal insufficiency, hypothyroidism, or skeletal muscle injury; (4) chronic occlusion, bifurcation lesion, or in-stent restenosis; (5) multivessel intervention; (6) side-branch occlusion or prolonged vasospasm; and (7) contraindication for antiplatelet medication. The study was approved by the local ethics committee, and all patients gave written informed consent.
Implantation of tubular slotted stents was performed in a routine manner using the femoral route for vascular access and 6F or 8F guiding catheters for intubation of the target vessel.13 14 Intravenous heparin medication was started before intervention (10 000 IU bolus and 1000 IU/h infusion). After coronary stenting was performed, ticlopidine (500 mg/d) or clopidogrel (75 mg/d) was given for 4 weeks in addition to lifelong aspirin medication (100 mg/d).
Intracoronary Doppler Analysis
Intracoronary Doppler Analysis (ICD) parameters were analyzed with a 0.014-inch Doppler-tipped guidewire (FloWire, Endosonics, Inc) 3 to 5 minutes after intracoronary application of 200 μg of nitroglycerin. A stable signal was secured before baseline parameters were recorded. Peak hyperemic flow conditions were determined by intracoronary bolus injection of adenosine (12 μg for the right coronary artery and 18 μg for the left circumflex artery and the left anterior descending coronary artery). Coronary flow velocity reserve (CVR) was computed as the ratio of hyperemic average peak velocity (hAPV) to baseline average peak velocity (bAPV). All measurements were made in duplicate with calculation of the mean value from 2 consecutive measurements. ICD parameters were measured in a nonstenosed reference vessel and at least 2 cm distal to the stenosis before and after PCI in the target vessel. Relative coronary flow velocity reserve (rCVR) was defined as the ratio of CVR in the target vessel to CVR in the reference vessel.14
Intravascular Ultrasound Analysis
Intravascular ultrasound (IVUS) analysis was performed with either the Endosonics Cardiovascular Imaging System, with a 20-MHz transducer, or the Boston Scientific Corporation Cardiovascular Imaging System, with a 30-MHz transducer, to control the postprocedural result wherever possible and only after injection of 200 μg of nitroglycerin.15 All IVUS images were recorded in a digital format for offline analysis of lesion sites and distal and proximal reference sites. Cross-sectional narrowing (CSN), also called plaque burden, was calculated as (EEM CSA−lumen CSA)/EEM CSA, where EEM is external elastic membrane and CSA is cross-sectional area.15 16
Quantitative Coronary Analysis
Quantitative coronary angiographic analysis was performed with a computer-based system (CMS, Medis), which provided automated vessel-edge detection and the following standard parameters before and after intervention: reference diameter (mm), minimal lumen diameter (mm), diameter stenosis (%), and lesion length (mm).17 Angiographic lesion characteristics were classified according to the modified American Heart Association/American College of Cardiology classification.18 All procedural complications were noted based on commonly used definitions.19
Determination of Cardiac Markers
Venous blood samples were taken before and 6, 12, and 24 hours after PCI. Immediate serum marker analysis was done by an enzymatic assay (Bayer Diagnostics; activator N-acetylcysteine) for determination of total creatine kinase (CK) activity (upper limit of normal [ULN] 70 IU/L for women, 80 IU/L for men). For cardiac troponin T (cTnT), a point-of-care test was used with a threshold value of 0.1 ng/mL (Roche Diagnostics) as described previously.20
Data were analyzed by SPSS software package 9.0. Continuous variables were reported as mean±SD, categorical variables as percentages. Either a Student’s t test or a Mann-Whitney U test (continuous variables) or a Fisher’s exact test (categorical variables) was used for group comparison. Univariate analysis followed by multivariate logistic regression analysis was used to identify predictors of cardiac marker elevation that included all available study data. Independent predictors were presented as odds ratio (95% CI) and corresponding P value. Receiver operating characteristic analysis was presented with area under the curve (AUC), 95% CI, and corresponding P value. For all analyses, a P value <0.05 was considered statistically significant.
Clinical and procedural variables for the entire study population are presented in Tables 1 through 4⇓⇓⇓⇓. Stratification is based on the results of cardiac marker outcome and Doppler flow parameters.
Cardiac Marker Outcome
The overall incidence of cTnT elevation was 21.8%, associated with a CK elevation 1 to 2 times the ULN and >2 times the ULN in 12.7% and 5.6% (P=NS) of patients, respectively. Postprocedural/preprocedural bAPV ratio (r=0.280, P=0.04), postprocedural/preprocedural lesion length ratio (r=−0.353, P=0.01), postprocedural CVR (r=−0.385, P=0.004), and postprocedural rCVR (r=−0.498, P<0.001) correlated with postprocedural cTnT elevation in the univariate analysis. Parameters that were associated with postprocedural CK elevation in the univariate analysis included postprocedural/preprocedural bAPV ratio (r=0.278, P=0.04), postprocedural CVR (r=−0.294, P=0.03), and postprocedural rCVR (r=−0.406, P=0.002) (Figure 1⇓). Postprocedural rCVR was identified as the only independent predictor of cTnT and CK elevation (0.001 [0.000 to 0.084], P=0.002 and 0.011 [0.000 to 0.321], P=0.009).
By receiver operating characteristic curve analysis, a postprocedural rCVR of 0.78 was identified as the best discriminating value between positive and negative cTnT outcome (Figure 2⇓). Thus, for a postprocedural rCVR<0.78, the sensitivity, specificity, positive predictive value, and negative predictive value for a positive cTnT test result were 83.3%, 79.1%, 52.6%, and 94.4%, respectively, and 69.2%, 76.2%, 47.4%, and 88.9%, respectively, for a CK elevation >1 times the ULN. The likelihood ratio was 3.99 for rCVR <0.78 and cTnT elevation and 2.91 for rCVR<0.78 and CK elevation.
Stratification of cardiac marker outcome revealed a higher incidence of cTnT elevation for patients with postprocedural rCVR <0.78 (52.6% versus 5.6%, P<0.001; Figure 3⇓). This was associated with CK elevation 1 to 2 times the ULN in 26.3% versus 5.6% (P=0.03) and CK elevation 2 to 3 times the ULN in 10.5% versus 0.0% of the cases (P=0.05). No patient had CK elevation >3 times the ULN.
Stratified Baseline Parameters
Demographic and angiographic data are presented in Tables 1⇑ and 2⇑. Patients with rCVR <0.78 tended more frequently to have a positive history of AMI (42% versus 17%, P=0.06). However, there was no substantial difference concerning history of AMI in the region of the target vessel (21% versus 14%, P=0.5).
Stratified Procedural Parameters
Procedural parameters are presented in Table 3⇑. IVUS analysis was available in 64% of the patients. There was no difference between patients with rCVR <0.78 and patients with rCVR ≥0.78 concerning CSN at the reference site (45.0±11.0% versus 42.6±10.5%, P=NS) and CSN at the lesion site after PCI (48.1±6.5% versus 48.3±6.0%, P=NS). However, plaque burden at the lesion site before PCI was higher in the patient group with rCVR <0.78 (76.4±11.4% versus 68.9±8.1%, P=0.03).
Stratified Doppler Parameters
Before intervention, absolute and relative CVR values were lower in patients with postprocedural impairment of CVR because of a slightly lower hAPV. After intervention, this difference was even more pronounced, because bAPV increased in these patients (19.9±7.6 versus 28.8±9.8, P=0.002) while it remained nearly unchanged in patients without residual impairment of CVR. In both groups, there was a significant increase in hAPV after PCI (P≤0.001; Table 4⇑).
In this prospective study, we found that postprocedural rCVR <0.78 was independently predictive of postprocedural elevation of a cardiac marker. The incidence of cTnT and CK elevation was 9 and 6 times higher in patients with such residual rCVR impairment.
Postprocedural Impairment of CVR
Various clinical trials reported on abnormal Doppler flow parameters in a large percentage of successful PCI, ranging from 33% after balloon angioplasty to 86% after rotablation.5 6 In the most recent study, Kern et al7 reported on residual impairment of CVR (<2.0) in 30% of the patients undergoing coronary stenting, with 53% of these patients having a reduction of both absolute and relative CVR.
In the present study, we found nearly the same rate of residual reduction of absolute CVR (32.7%), with a concomitant reduction of rCVR <0.78 in 77.7%. This overall high incidence of microvascular impairment confined to the region of the target vessel (25.5%) was associated with a high incidence of both cTnT and CK elevation, supporting the idea of procedural embolization, resulting in myocardial injury.5 6 7
In analogy to the model of Hori et al,10 11 procedural embolization of atherothrombotic debris could cause (1) an increase in postprocedural bAPV and (2) an impairment of both absolute and relative CVR, which were observed in the present study. Moreover, the overall better correlation between cardiac marker outcome and CVR is explained by the experimental finding that an increase in bAPV preferably characterizes minor forms of embolic myocardial injury.10 11 However, further trials with distal protection devices would be required to define procedural embolism as the common denominator of both cardiac marker elevation and abnormal Doppler flow parameters.
Alternative Mechanisms of CVR Reduction
Repeated brief periods of ischemia might cause CVR reduction by sustained postprocedural bAPV increase.21 However, inflation periods were similar in both study groups, and no correlation between the number or duration of inflations and postprocedural cardiac marker and Doppler status was noted.
Frequent injection of contrast material is another mechanism that can reduce CVR by increasing postprocedural bAPV.22 23 Nevertheless, there was neither a difference in the amount of contrast dye nor a correlation between the volume of contrast material used and postprocedural Doppler parameters.
Alteration in the regulation of vasomotor tone on the level of both the microcirculation and the epicardial conduit vessel and differences in pharmacological therapy are additional factors to be considered.24 25 However, prolonged vasospasm was a predefined exclusion criteria, and patient groups did not differ in drug therapy.
The overall higher rate of prior AMI in patients with residual rCVR impairment is of particular interest. Subanalysis according to the region of the target vessel, however, did not demonstrate a substantial difference between the 2 study groups. Furthermore, exclusion of all patients with prior AMI did not change the study outcome (data not shown).
Extent of epicardial disease and extent of residual stenosis might have differed considerably between the 2 study groups despite the favorable angiographic result.26 However, IVUS analysis did not reveal a substantial difference in CSN either at the reference site or at the lesion site after the coronary procedure. Nevertheless, the higher initial plaque burden in patients with rCVR impairment must be taken into consideration for the outcome of both Doppler parameters and cardiac markers.
Alternative Mechanisms of Cardiac Marker Elevation
Various predictors of postprocedural elevation of cardiac markers have been identified.2 4 Among these, aggressiveness of the coronary procedure and atherosclerotic burden are considered most important.16 However, catheter-based interventions other than coronary stenting and procedural complications such as side-branch occlusion were excluded from the present study to limit the extent of interfering variables. As far as coronary dissection is concerned, this complication was equally distributed among the study groups and was not associated with cardiac marker elevation in the present study.
Procedural embolization as an underlying mechanism of cardiac marker elevation and rCVR impairment is further supported by the finding that extent of lesion length reduction correlated with cTnT elevation in univariate analysis. Moreover, atherosclerotic plaque burden and number of stents were higher in patients with a postprocedural rCVR <0.78, resembling the findings by Mehran et al16 on the complex interplay between extent of atherosclerotic disease, extent of coronary intervention, and myocardial injury.
The technical limitations of ICD analysis are well known, including the dose of adenosine used in this and other trials before.6 7 14 However, the systematic nature of this error is very unlikely to cause a substantial difference between the study groups. Likewise, the diagnostic window used in the present study must be considered as a potential source of systematic error, and the limitations of cTnT point-of-care analysis must be acknowledged. The most important limitation of this study remains its small size. Therefore, prospective trials with distal protection devices and/or glycoprotein IIb/IIIa receptor inhibitors are warranted to provide further insight into a causal relationship between procedural embolism and cardiac marker and ICD outcome.
Cardiac marker elevation can frequently be found after coronary procedures that are associated with a persistent reduction of rCVR, suggesting procedural embolization of atherothrombotic debris with microvascular impairment and myocardial injury as a potential underlying mechanism.
This study was supported by a grant from the Deutsche Forschungsgemeinschaft (DFG 155/4-2).
- Received December 12, 2000.
- Revision received February 27, 2001.
- Accepted February 28, 2001.
- Copyright © 2001 by American Heart Association
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