Elevations in Troponin I After Percutaneous Coronary Interventions Are Associated With Abnormal Tissue-Level Perfusion in High-Risk Patients With Non–ST-Segment–Elevation Acute Coronary Syndromes
Background— In the setting of non–ST-segment–elevation (NSTE) acute coronary syndromes (ACS), the pathophysiological mechanisms underlying post–percutaneous coronary intervention (PCI) cardiac troponin I (cTnI) elevation remain unclear.
Methods and Results— We evaluated the relationship between troponin elevation and tissue-level perfusion using the TIMI flow grade, corrected TIMI frame count, TIMI myocardial perfusion grade (TMPG), and myocardial contrast enhancement by intracoronary myocardial contrast echocardiography (MCE) before and immediately after PCI performed within 24 to 48 hours of hospital admission in 42 high-risk (angina at rest, unequivocal ST-segment depression, and cTnI elevation) patients with NSTE-ACS. All patients were treated with glycoprotein IIb/IIIa inhibitors (27 with tirofiban and 15 with abciximab) and had successful PCI. Fourteen patients had a postprocedural cTnI elevation, whereas 28 did not. TMPG 0/1 after PCI was observed more frequently in patients with postprocedural cTnI elevation (43% versus 7%; P<0.02). cTnI levels were higher among patients with TMPG 0/1 versus patients with TMPG 2/3 (5.3±2.7 versus 1.5±1.3 ng/mL; P<0.0001). Patients with postprocedural cTnI elevation also presented a significantly lower number of perfused segments at MCE (59% versus 81%; P=0.02) as well as a lower MCE score index (0.65±0.38 versus 0.89±0.21; P<0.02).
Conclusions— Postprocedural cTnI elevation in high-risk patients with NSTE-ACS is associated with an abnormal tissue-level perfusion.
Received April 26, 2004; revision received July 22, 2004; accepted July 29, 2004.
Cardiac troponins are sensitive and specific biomarkers for myocardial injury. Their elevation independently predicts an adverse outcome among patients presenting with non–ST-segment–elevation acute coronary syndromes (NSTE-ACS).1–4 It is generally believed that elevated troponins in this setting indicate the presence of a thrombus at culprit lesions, and such an elevation may thus be a marker for consequent thromboembolization at distal vascular beds.5–7 This may occur spontaneously but also when the artery is directly manipulated via balloon angioplasty, stenting, or other endovascular therapeutic techniques. Recent studies have shown, in fact, that biomarker release in patients with NSTE-ACS is associated with impaired tissue-level reperfusion as assessed by the Thrombolysis in Myocardial Infarction (TIMI) myocardial perfusion grade, which, in turn, is associated with an adverse clinical outcome.8,9 These data provide a potential pathophysiological link between impaired tissue-level perfusion, myocardial damage, and adverse clinical outcome. However, the significance of further increases of troponin levels after percutaneous coronary interventions (PCIs) in high-risk patients with NSTE-ACS has not yet been fully investigated.
The purpose of this prospective study was therefore to verify the hypothesis that post-PCI elevated troponin I (TnI) levels in high-risk patients with NSTE-ACS may be associated with abnormal tissue-level perfusion by examining the relationship between elevations of troponin and tissue-level perfusion as assessed using the corrected TIMI frame count, TIMI myocardial perfusion grade (TMPG), and myocardial contrast enhancement by intracoronary myocardial contrast echocardiography (MCE).
Patients and Study Protocol
We prospectively studied 57 patients with high-risk NSTE-ACS selected from 176 patients consecutively referred to our Coronary Care Unit for angina at rest between March 2003 and September 2003. The study inclusion criteria were as follows: (1) angina at rest lasting >10 minutes within 12 hours of hospital admission; (2) unequivocal changes (transient or persistent pathological ST-segment depression ≥0.1 mV or T-wave inversion in at least 2 adjacent leads without pathological Q waves) on ECG during angina; and (3) TnI elevation. No upper age limit was used. All patients were required to undergo coronary angiography within 24 to 48 hours of admission, with revascularization with PCI as appropriate.
Exclusion criteria were as follows: (1) inability to provide informed consent; (2) concomitant noncardiac life-threatening disease; (3) severe hemodynamic impairment or cardiogenic shock (hypotension with systolic blood pressure <90 mm Hg and tachycardia >100 bpm not caused by hypovolemia and requiring inotropic support or balloon counterpulsation); and (4) significant other cardiac disease.
Of the 57 patients initially selected for the study, 10 were excluded because of 3-vessel coronary artery disease (CAD) requiring coronary artery bypass grafting and 5 for the absence of significant CAD at the angiogram. Thus, 42 patients (33 men, 9 women; mean age, 63.4±9.1 years; range, 43 to 81 years) represent the final study group. The study protocol was approved by the hospital’s ethics committee, and written informed consent was obtained from all patients before catheterization. All patients underwent PCI within 24 to 48 hours of admission. Intracoronary MCE was performed on completion of coronary angioplasty. Angiographic markers of epicardial flow and tissue-level perfusion were assessed on completion of diagnostic coronary angiography and shortly after PCI. Blood samples for cardiac TnI (cTnI), creatine kinase (CK), and CK-MB levels were obtained on admission and every 6 hours thereafter up to 48 hours and at 6, 12, 18, and 24 hours after PCI.
cTnI was measured using the commercially available Dimension RxL immunoassay (DADE-Behring). The Dimension RxL assay for cTnI is an automated system using a 2-site sandwich immunoassay and direct chemiluminometric technology. The manufacturer reports the minimum detectable concentration as 0.01 ng/mL. The total imprecision determined in the laboratory was characterized by a coefficient of variation of 10% at 0.05 ng/mL. The threshold used to define a positive cTnI was 0.1 ng/mL.
A postprocedural elevation in cTnI and CK-MB was defined as an increase by ≥50% above the highest preprocedural value in at least 1 of the postprocedural samples. Patients were divided into 2 groups: those with and those without postprocedural elevation in cTnI levels.
PCI and Concomitant Drugs
Coronary angioplasty and stent implantation were performed according to institutional standards. In patients with single-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 a substantially stenosed lesion in the vessel that corresponded most closely to the ischemic area, as determined by ST-T–segment changes during chest pain. Heparin was given intravenously to achieve an activated clotting time of 250 to 300 seconds, or ≥200 seconds if abciximab was used. Postprocedural heparin infusion was continued for 12 hours. All patients were treated with glycoprotein IIb/IIIa inhibitors: 27 patients were pretreated with tirofiban at a loading dose of 0.4 μg · kg−1 · 30 min−1, followed by a maintenance infusion of 0.15 μg · kg−1 · min−1 for at least 12 hours after PCI, and 15 patients were treated in the catheterization laboratory with abciximab, with a bolus of 0.25 mg/kg given 10 minutes before PCI, followed by 0.125 μg · kg−1 · min−1 for 12 hours. Abciximab was chosen for patients undergoing PCI within 4 hours of admission; otherwise, “upstream” tirofiban was used.
All patients received aspirin (100 to 300 mg) before and after PCI. Ticlopidine (500 mg) or clopidogrel (loading dose, 300 mg, followed by 75 mg/d) was administered before PCI and daily thereafter for at least 30 days. Twenty-eight patients received clopidogrel, 16 at least 24 hours before PCI and 8 in the catheterization laboratory just before PCI.
All coronary angiograms were evaluated by 2 readers without knowledge of clinical or troponin status. Additional data regarding the visibility of coronary thrombus were collected. Angiographic coronary thrombus was defined as a filling defect or haziness near the lesion that was visible on at least 2 orthogonal views.
Flow in the epicardial arteries was assessed for TIMI flow grade and corrected TIMI frame count by use of previously described methods.10,11 The TMPG was used to assess myocardial tissue-level perfusion.12 TMPG was defined as follows: grade 0, no angiographic blush; grade 1, stain or prolonged persistence of dye on next contrast injection; grade 2, slow dye transit, dye bright at the end of injection and gone by the next injection; and grade 3, normal ground-glass appearance of blush.12 A “closed” microvasculature was defined as either TMPG 0 or 1, with TMPG 2 or 3 representative of an “open” microvasculature.12 TMPG was assessed only in the area supplied by the culprit vessel.
Myocardial Contrast Echocardiography
Intracoronary MCE was performed on completion of coronary angioplasty. Two-dimensional contrast echocardiographic images were analyzed by 2 readers who had no knowledge of the clinical, troponin, and angiographic data. The left ventricle was divided according to a 16-segment model.13 The echocardiographic view that best delineated the vascular territory of the culprit vessel was chosen for contrast echocardiographic analysis. In this view, the contrast effect was determined in the postinjection cycles that showed the best delineation between contrast-enhanced and nonenhanced myocardium. A score of 1 within a segment of the area of interest after angioplasty was interpreted as adequate perfusion. A patient was considered to have adequate perfusion if ≥50% of the segments in the area of interest had an homogeneous contrast effect (score=1). In each patient, an MCE score index was derived by averaging the scores from each segment within the area of interest. Details pertaining to acquisition and analyses of echocardiographic data were reported elsewhere.14
On the basis of literature data,8,9 we hypothesized a 30% incidence of high postprocedural TnI levels, with a rate of TMPG 0/1 of 40% among patients with versus 10% among those without high postprocedural troponin levels. A sample size of 68 patients was calculated to allow a power of 80% to detect such a difference. Because of the high attrition rate related to the complexity of the study protocol and the strict inclusion criteria used, we actually enrolled 42 patients, with a consequent power of 60% to detect a difference between groups of 40% TMPG 0/1 versus 10%. Continuous data are expressed as mean±SD. Baseline data were compared by means of the χ2 test for categorical variables and unpaired t test for continuous variables. The primary analysis in this study was based on the dichotomous comparison of patients with or without postprocedural elevation of cTnI levels. A value of P<0.05 was considered statistically significant. Statistical analyses were performed with SPSS 8.0 for Windows.
Baseline Clinical Characteristics
Fourteen patients (33%) had a postprocedural cTnI elevation; of these, 9 also had a postprocedural increase in the serum CK-MB fraction. All patients with post-PCI cTnI elevation had immediate pre-PCI cTnI above the upper normal limit; furthermore, 9 (64%) of the 14 patients had a downward curve of cTnI before PCI. No significant relationship between clopidogrel versus ticlopidine treatment and postprocedural cTnI levels (2.1±2.4 versus 2.2±2.1 ng/mL, respectively; P=0.9) was found, as well as between timing of clopidogrel treatment and cTnI levels (1.9±2.3 among pretreated patients versus 2.6±2.6 ng/mL among patients treated in the catheterization laboratory; P=0.5).
Clinical characteristics of the study population stratified according to presence or absence of postprocedural cTnI elevations are summarized in Table 1. Patients with postprocedural cTnI elevation were significantly younger than those without. No other statistically significant differences in the baseline distribution of clinical and demographic characteristics between the 2 groups were found (Table 1).
Angiographic Findings and Postprocedural Troponin Levels
Overall, 21 patients (50%) had a TIMI flow grade of 0 to 2 and 25 (59%) a closed microvasculature as assessed by TMPG (0/1) before PCI. There was a trend toward higher pre-PCI levels of cTnI in patients with TMPG 0/1 perfusion compared with those with TMPG 2/3 perfusion before PCI that did not reach statistical significance (4±5.4 versus 2.6±5.2 ng/mL; P=0.38).
All patients underwent successful PCI with a TIMI flow grade of 3 after the procedure. There was no significant difference in the distribution of the culprit lesion, the frequency of angiographic thrombus, the angiographic morphology of the culprit lesion, and pre- and post-PCI TIMI grade flow and TIMI frame count between the postprocedural cTnI-positive group and cTnI-negative groups (Table 2). Patients with postprocedural cTnI elevation were less likely to have patent (TIMI 2/3) epicardial arteries before intervention (59% versus 79%) compared with patients without, but this difference did not reach statistical significance. After PCI, TMPG 0/1 perfusion was observed more frequently among patients with postprocedural cTnI elevation compared with those without (43% versus 7%; P=0.017) (Figure 1A). Quantitatively, cTnI levels after PCI were significantly higher in patients with TMPG 0/1 perfusion compared with those with TMPG 2/3 perfusion (5.3±2.7 versus 1.5±1.3 ng/mL; P<0.0001) (Figure 1B).
Perfusion by MCE and Postprocedural Troponin Levels
MCE analysis was not performed in 5 patients because of inadequate echocardiographic image quality. MCE was evaluated in a total of 111 segments; of these, 79 (71%) showed homogeneous contrast effect (score 1) and 32 partial or no contrast enhancement. A significantly lower number of perfused segments (score=1) was observed among patients with postprocedural cTnI elevation compared with those without (59% versus 81%; P=0.02). Also, MCE score index was significantly lower among patients with postprocedural cTnI elevation compared with those without (0.65±0.38 versus 0.89±0.21; P<0.02) (Figure 2B). Analysis by patient showed that patients with postprocedural cTnI elevation more frequently had an abnormal tissue-level perfusion by MCE than those without (50% versus 11%; P<0.02) (Figure 2A).
The pivotal role of cardiovascular biomarker troponin in risk stratification of patients who present with NSTE-ACS is well established.1–4 Furthermore, previous studies with angiography have shown that patients with NSTE-ACS and an elevated troponin level on presentation have more extensive CAD, have more complex lesions, and more often demonstrate impaired TIMI flow and thrombi at the site of a culprit lesion.7,15–18 However, the significance and pathophysiological mechanisms underlying post-PCI troponin elevations in this setting remain unclear.
Impaired Myocardial Perfusion and Troponin Elevations in NSTE-ACS
The major findings of the present study are as follows.
Despite an aggressive antithrombotic therapy, an abnormal tissue perfusion (TMPG 0/1) was found in a high percentage of patients (59%) before PCI.
Postprocedural cTnI elevation was associated with an additional abnormal tissue-level perfusion, even if all patients had epicardial TIMI grade 3 flow at the completion of the intervention.
Taken together, these findings confirm and expand previous observations relating troponin elevations to disease in the epicardial arteries in patients with NSTE-ACS,7,15–18 indicating that troponin elevation on presentation is related to impaired tissue-level perfusion on the diagnostic angiogram and that after PCI, a further increase of cTnI is related to an additional impairment in tissue-level perfusion as assessed by use of both angiographic TMPG and myocardial contrast enhancement by intracoronary MCE. The consistency and reproducibility of the results achieved by use of different techniques to explore different aspects of microvascular integrity further enhance the strength of the tested hypothesis, even if the study was not optimally powered to detect small changes in the perfusion end points.
These results also suggest that, similar to what reported for ST-segment–elevation myocardial infarction,19 factors other than lumen geometry and epicardial patency are associated with troponin release and myocardial damage after PCI in NSTE-ACS patients. Interestingly, abnormal tissue-level perfusion was correlated with postprocedural troponin elevations rather than with troponin elevations on presentation, raising the possibility that a causal relationship exists between the direct manipulation of the artery via balloon angioplasty and stenting and myocardial damage, as detected by troponin elevation. The pathophysiological mechanisms of impaired myocardial perfusion after PCI in the setting of NSTE-ACS remain unclear. Mechanical manipulation during PCI or stent implantation can lead to embolization of debris or calcified plaque material or exposure of thrombogenic material at intravascular sites.20 The embolization also includes microparticulate atheromatous material, because it has been routinely demonstrated through the use of embolus capture devices.5 The corpuscular nature of embolic material may explain the relative inefficacy of glycoprotein IIb/IIIa inhibitors in preventing impairment of tissue perfusion in some patients. Finally, mechanisms other than mechanical embolization, such as capillary edema, inflammation, and vasospasm mediated by the release of vasoconstrictors, may play at least some role.19,20
The main limitation of our study is its relatively small sample size, which limits its power and precludes broad generalizations regarding the clinical implications of the results. Conversely, the present study integrated different means of investigating the coronary circulation at the epicardial and tissue levels with a complete angiographic and echocardiographic analysis to obtain high-quality data.
Obviously, the definition adopted in the study of postprocedural cTnI elevation is an arbitrary one. Because all patients had troponin elevation before PCI, we preferred to choose a less sensitive but more specific definition of postprocedural TnI elevation as >50% above the highest preprocedural value rather than the value immediately before the procedure.
Finally, we cannot demonstrate definitively that postprocedural cTnI elevation was solely a result of the procedure, rather than a reflection of pre-PCI cTnI levels. However, abnormal tissue-level perfusion was correlated with postprocedural troponin elevations rather than with troponin elevations on presentation, raising the possibility that a causal relationship exists between the direct manipulation of the artery via balloon angioplasty and stenting and myocardial damage, as detected by troponin elevation. Furthermore, 9 (64%) of 14 patients with post-PCI cTnI elevation had a biphasic cTnI curve, downward before PCI and upward after PCI, suggesting a critical role of the procedure in generating the second cTnI peak.
In high-risk patients with NSTE-ACS treated by means of PCI, postprocedural troponin elevation is a frequent finding and is associated with impaired tissue-level perfusion independently of the presence of thrombus, lesion characteristics, and abnormal flow in the epicardial culprit vessel.
Because attention has shifted to adequacy of tissue perfusion in NSTE-ACS, new pharmacological and mechanical treatment modalities should be used to specifically improve tissue-level perfusion in these patients.
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