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Factors affecting thrombolysis in myocardial infarction myocardial perfusion frame count: insights of myocardial tissue-level reperfusion from a novel index for assessing myocardial perfusion

Jun, PU; Pei-ren, SHAN; Song, DING; Zhi-qin, QIAO; Li-sheng, JIANG; Wei, SONG; Yong-ping, DU; Jie-yan, SHEN; Lin-hong, SHEN; Shu-xuan, JIN; Ben, HE

Section Editor(s): WANG, Mou-yue; LIU, Huan

doi: 10.3760/cma.j.issn.0366-6999.2011.06.013
Original article
Free
SDC

Background Myocardial tissue-level perfusion failure is associated with adverse outcomes following ST-elevation myocardial infarction (STEMI) despite successful epicardial recanalization. We have developed a new quantitative index—thrombolysis in myocardial infarction (TIMI) myocardial perfusion frame count (TMPFC)—for assessing myocardial tissue level perfusion. However, factors affecting this novel index of myocardial perfusion are currently unknown.

Methods A total of 255 consecutive STEMI patients undergoing primary angioplasty were enrolled. Myocardial tissue level perfusion was assessed by TMPFC, which measures the filling and clearance of contrast in the myocardium using cine-angiographic frame counting. We differentiate three groups with two cut off values for TMPFC: a TMPFC of 90 frames was the upper boundary of the 95% confidence interval (CI) for the TMPFC observed in normal arteries, and a TMPFC of 130 was the 75th percentile of TMPFC.

Results STEMI patients with TMPFC >130 frames (68 patients, 26.7%) had higher clinical and angiographic risk factor profiles as well as a higher 30-day MACE rate compared with those with TMPFC <90 frames and those with TMPFC >90 and <130 frames. Multivariable analysis identified that the independent predictors of TMPFC >130 frames were age ≥75 years (OR 2.08, 95% CI 1.21 to 3.58, P=0.007), diabetes (OR 1.37, 95% CI 1.01 to 1.86, P=0.042), Killip class ≥2 (OR 1.52, 95% CI 1.05 to 2.21, P=0.027), and prolonged pain-to-balloon time (OR 1.73, 95% CI 1.07 to 2.79, P=0.013). TMPFC >130 frames was identified as the strongest independent predictor of 30-day major adverse cardiac event (MACE) (OR 2.77, 95% CI 1.21 to 6.31, P=0.008), along with age ≥75 years (OR 2.19, 95% CI 1.11 to 4.33, P=0.016), female gender (OR 1.67, 95% CI 1.03 to 2.70, P=0.038), and Killip class ≥2 (OR 1.83, 95% CI 1.07 to 3.14, P=0.021).

Conclusions STEMI patients with poor myocardial perfusion assessed by TMPFC had higher risk factor profiles. Advanced age, diabetes, higher Killip class, and longer ischemia time were independent predictors of impaired TMPFC after primary percutaneous coronary intervention. These results emphasize that particular attention should be paid on myocardial microvascular reperfusion in STEMI patients with these risk factors.

Edited by

Department of Cardiology, Shanghai Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China (Pu J, Shan PR, Ding S, Qiao ZQ, Jiang LS, Song W, Du YP, Shen JY, Shen LH, Jin SX and He B)

Department of Cardiology, First Affiliated Hospital of Wenzhou Medical College, Wenzhou, Zhejiang 325000, China (Shan PR)

Correspondence to: Dr. HE Ben, Department of Cardiology, Shanghai Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China (Tel: 86-21-68383477. Fax: 86-21-68383609. Email: heben1025@hotmail.com)

This work was supported by the grants from the Program of Shanghai Subject Chief Scientist (No. 35508XD14026), Shanghai Natural Science Foundation (No. 09ZR1418100), and Shanghai Jiao Tong University Science and Technology Foundation (No. YZ1005).

(Received January 20, 2011)

Successful restoration of epicardial blood flow in an infarct-related coronary artery (IRA) has been long recognized as the goal of reperfusion therapy.1 Primary percutaneous coronary intervention (PPCI) has become the most effective way to restore epicardial blood flow and the preferred strategy for acute reperfusion therapy in patients with ST-elevation myocardial infarction (STEMI)2 However, we and other investigators have documented that, despite successful recanalization with an apparently normal epicardial flow following PPCI, a substantial number of patients still fail to achieve complete myocardial tissue-level reperfusion, which contributes to the increased cardiac mortality and morbidity following STEMI.1,3,4

There are two main methods of angiographic assessment of myocardial tissue-level perfusion; thrombolysis in myocardial infarction (TIMI) myocardial perfusion grading (TMPG)5 and myocardial blush grading (MBG).6 Both methods have proven useful for the assessment of myocardial tissue-level reperfusion and the prediction of clinical outcome after STEMI. However, they are limited by their subjective and categorical natures. Recently, we have developed a simple, more objective continuous variable index of myocardial tissue perfusion by angiographic frame counting, called TIMI myocardial perfusion frame count (TMPFC).7,8 TMPFC allows quantification of TMPG, and can serve as a discerning tool to predict the outcome in patients with STEMI undergoing reperfusion therapy.7 However, factors affecting this novel index of myocardial perfusion are currently unknown. This study was undertaken to investigate the predictors of impaired TMPFC with the aim to provide insights into myocardial tissue-level reperfusion from this novel index of myocardial microvascular flow.

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METHODS

Patients

This study was performed in accordance with the Declaration of Helsinki and the study protocol was approved by the Institutional Review Board. Consecutive patients who were over 18 years of age with STEMI lasting <12 hours, admitted to the coronary care unit of the Shanghai Renji Hospital and referred for PPCI were included in the study. The diagnosis of STEMI was based on typical chest pain lasting >30 minutes, with new ST-segment elevation in at least two contiguous electrocardiograph (ECG) leads with cut-off points ≥0.2 mV in leads V1, V2, or V3 and ≥0.1 mV in other leads. Written informed consent was obtained from all patients before cardiac catheterization.

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Coronary angiography and primary angioplasty

All procedures were performed according to standard techniques. In patients with multivessel disease, PPCI was performed only in the IRA. Stenting of the IRA was strongly recommended during PPCI. All patients were treated with a loading dose of aspirin (300 mg), clopidogrel (300-600 mg), and single dose of heparin (100 U/kg), followed by a typical daily dosing of aspirin (100 mg) and clopidogrel (75 mg). The use of glycoprotein IIb/IIIa inhibitors was at the discretion of the operator.

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Angiographic analysis and definitions

Angiographic data were analyzed off-line with a computer-based cardiovascular angiographic analysis system by two independent, experienced angiographers. 7 TMPFC, a novel method to standardize and quantify myocardial perfusion by timing the filling and washout of contrast in the myocardium using cine-angiographic frame-counting was assessed as we have previously described.7,8 Briefly, the first frame of TMPFC was defined as the frame that clearly demonstrated the first appearance of myocardial blush beyond the IRA (F1). The last frame of TMPFC was then defined as the frame where contrast or myocardial blush disappeared (F2). TMPFC is F2-F1 frame counts at a filming rate of 15 frames/sec, or (F2-F1) × 2 frame counts at the corrected filming rate of 30 frames/sec (Figure 1). The left anterior descending artery (LAD) and left circumflex artery (LCX) systems were usually best assessed in the left anterior oblique views with caudal angulations. The right coronary artery (RCA) system was usually best assessed in the left anterior oblique projection with steep cranial angulation. Inter-observer coefficients of variation were 7.16% for TMPFC, and the intraclass correlation coefficients (ICC) for TMPFC was 0.976 (0.968-0.983). Intra-observer variability yielded good concordance for TMPFC, with the coefficient of variation was 5.33%. TMPG was assessed as described previously.5 Epicardial coronary flow in the infarct-related artery was graded according to the TIMI flow grade.9 Distal embolization was defined as a distal filling defect with an abrupt cut-off in one or more peripheral coronary branches of the IRA, distal to the angioplasty site. Collaterals to the infarct related artery before PPCI were graded according to Rentrop’s classification.10

Figure 1.

Figure 1.

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Data collection, follow-up, and study endpoint

Detailed in-hospital and follow-up data were recorded and entered into the database prospectively. Patients were followed up via clinical visits or telephone calls to the referring physician. The angiography endpoint was post-procedural myocardial tissue-level reperfusion assessed by the TMPFC. Clinical end-points were the composite occurrence rate of major adverse cardiac events (MACE), including all-cause death, recurrent myocardial infarction, recurrent angina, and heart failure at the 30-day follow-up.

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Statistical analysis

Data analyses were performed using SAS9.13 (SAS Institute Inc., Cary, NC, USA). In our presentation of the data, continuous baseline and outcome variables are given as the mean ± standared deviation (SD), while discrete variables are given as absolute values, percentages, or both. Continuous variables were compared using the Student’s t test if normally distributed and the Wilcoxon rank-sum if not. To examine the normal distribution, the Shapiro-Wilk test was used. Categorical variables were compared using chi-square with normal approximation or Fisher’s exact test when appropriate. Logistic regression analysis was performed to evaluate the significance of risk predictors of impaired microvascular flow and the incidence of 30-day MACE. Odds ratios and 95% confidence intervals (CIs) were calculated. To evaluate the inter-observer and intra-observer variability for TMPFC, the coefficient of variation was evaluated by linear regression, and the reliability of the measurements was also evaluated by their reproducibility (ICC). A two-tailed P value less than 0.05 was considered to be statistically significant for all analyses.

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RESULTS

Baseline characteristics of patients

Altogether 271 consecutive patients who presented with acute STEMI within 12 hours of undergoing PPCI at our institution were enrolled. Among them, 16 (5.9%) patients were excluded from final analysis due to the poor quality of the coronary angiogram. Thus, 255 patients were included in the final analysis. We divided these patients into three groups with two cut-off values for TMPFC: (1) a TMPFC of 90 frames was the upper bound of the 95% CI for the TMPFC observed in normal arteries, and (2) a TMPFC of 130 was the 75th percentile of TMPFC. Finally, there were 88 patients in group I (TMPFC ≤90 frames), 99 patients in group II (90 frames <TMPFC ≤130 frames), and 68 patients in group III (TMPFC >130 frames).

As shown in Table 1, STEMI patients with TMPFC >130 frames (group III) were older (P=0.007), more often had hypertension (P=0.0164) and diabetes (P=0.0272), and had fewer current smokers (P=0.0316) compared with group I and group II. Patients in group III had significantly longer pain to balloon time (P=0.0183) and a higher Killip class on admission (P=0.0283) compared with those in group I and group II.

Table 1

Table 1

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Angiographic characteristics of patients

As shown in Table 2, there were no significant differences among the three groups with regard to the incidence of multiple-vessel disease, rates of stent implantation, number of implanted stents, or the grade of collateral blood flow. However, the infarct-related arteries of patients in group III had smaller vessel size (P=0.0194), poorer baseline TIMI grade (P=0.0030), and more distal embolization (P=0.0286) compared with those in group I and group II.

Table 2

Table 2

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Determinants of impaired TMPFC

By multivariate analysis after adjustment for the baseline variables, age ≥75 years (OR 2.08, 95% CI 1.21 to 3.58, P=0.007), diabetes (OR 1.37, 95% CI 1.01 to 1.86, P=0.042), Killip class ≥2 (OR 1.52, 95% CI 1.05 to 2.21, P=0.027), and prolonged pain-to-balloon time (OR 1.73, 95% CI 1.07 to 2.79, P=0.013) were independently associated with impaired TMPFC (Figure 2).

Figure 2.

Figure 2.

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TMPFC and TMPG

Group III patients with TMPFC >130 frames had a higher incidence (33.82%) of impaired TMPG (TMPG 0/1) than group II patients (3.03%) and group I (0) patients (P <0.001). By multivariate analysis, age ≥75 years (OR 1.94, 95% CI 1.19 to 3.22, P=0.011) and prolonged pain-to-balloon time (OR 1.44, 95% CI 1.02 to 2.03, P=0.035) were independent predictors of impaired TMPG. Diabetes was weakly predictive of impaired TMPG (OR 1.21, 95% CI 0.97 to 1.51, P=0.073).

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TMPFC and clinical outcome

Patients in group III had a higher 30-day mortality rate (8.82%) when compared with group II (2.02%) and group I (1.14%) patients (P=0.0142). The crude rate of total MACE for patients in groups I, II, and III were 29.41% 14.14% and 4.55%, respectively (P <0.0001). In order to assess independent determinants of clinical endpoint 30-day MACE, multivariable Logistic regression analysis was carried out. As shown in Figure 3, multivariable analysis of baseline variables in Tables 1 and 2 with a univariate P value for comparison of 0.10 identified TMPFC >130 frames as the strongest independent predictor of 30-day MACE (OR 2.77, 95% CI 1.21 to 6.31, P=0.008), along with age ≥75 years (OR 2.19, 95% CI 1.11 to 4.33, P=0.016), female gender (OR 1.67, 95% CI 1.03 to 2.70, P=0.038), and Killip class ≥2 (OR 1.83, 95% CI 1.07 to 3.14, P=0.02l).

Figure 3.

Figure 3.

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DISCUSSION

The primary goal of reperfusion therapy is not only restoration of upstream epicardial anterograde flow but also successful reperfusion of downstream myocardial tissue.1 For the assessment of myocardial perfusion, two different angiographic methods have been described. One is TMPG, a semiquantitative index that can be used to characterize the filling and washout of myocardial perfusion by calculating cardiac cycles of contrast persist time, which needs to be adjusted for the heart rate of the patient.5 The other is MBG, an angiographic surrogate based on the contrast dye density of the infarcted myocardium by comparing with that of a non-infarctrelated myocardium. 6 These two angiographic methods have been reported to be highly useful in assessing myocardial tissue-level perfusion and predicting clinical prognosis. However, visual assessment of these methods is categorical and operator dependent. Recently, we developed a simple quantitative method to evaluate the degree of myocardial tissue perfusion by angiographic frame counting, called TMPFC.7,8 TMPFC is a simple, continual variable which quantify myocardial perfusion by timing the filling and washout of contrast in the myocardium using cine-angiographic frame-counting. TMPFC allows quantification of TMPG, and can accurately predict the outcomes in STEMI patients undergoing reperfusion therapy.7 However, the factors affecting this novel index of myocardial perfusion have not been systematically investigated. The main findings of the present study are that: (1) STEMI patients with impaired TMPFC had higher clinical risk factor profiles (i.e., advanced age, more hypertension and diabetes, longer pain to balloon time, and higher Killip class on admission) and angiographic risk factor profiles (i.e. smaller vessel size, poor baseline TIMI grades, more distal embolization); (2) Multivariate analysis identified age ≥75 years, Killip class ≥2, diabetes, and prolonged pain-to-balloon time as the independently determinants of impaired TMPFC; (3) Impaired myocardial perfusion assessed by TMPFC was the strongest predictor of 30-day MACE, independent of other clinical and angiographic variables.

One of the interesting findings in the present study was that, although patients with impaired TMPFC had many higher clinical and angiographic risk factor profiles (except for fewer current smokers), multivariate analysis only identified age ≥75 years, Killip class ≥2, diabetes, and prolonged pain-to-balloon time as the independently determinants of impaired TMPFC. The following mechanisms may explain the impaired TMPFC in these patients: (1) Previous studies4,11 suggested that both advanced age and diabetes were associated with the prothrombotic state and microvascular endothelial dysfunction due to increased oxidative stress accompanied by reduced endothelial nitric oxide bioavailability; (2) “Time is muscle”—delay in reperfusion is associated with increased damage to microcirculation, higher incidence of distal microembolisation, and less myocardial salvage;12 (3) Advanced Killip class at presentation may be associated with more severe edema of myocardial cells and damage of microcirculation.13 Thus, particular attention should be paid to the myocardial tissue-level perfusion in patients with these unfavorable risk factors. Smaller vessel size has been shown to be associated with a worse prognosis in both acute coronary syndrome (ACS) and stable angina patients.14,15 Our study showed that impaired TMPFC had smaller vessel size in IRA, suggesting that impaired myocardial reperfusion in patients with smaller IRA vessel might contribute to the impaired prognosis in these patients. However, the association between impaired TMPFC and smaller vessel size was not significant after correction for baseline confounding factors. Previous studies showed that STEMI patients with smaller vessel size (IRA <3 mm) were more frequently elderly and female and more likely to have diabetes compared with patients with IRA >3 mm.14 Thus, the larger prevalence of the elderly and diabetes patients, that is associated with diffuse coronary disease and microvascular dysfunction, may contribute to the observed impaired reperfusion in patients with small vessels.16 Interestingly, although smoking has been identified as a major risk factor for coronary heart disease, the impaired TMPFC group had fewer current smokers in the present study. This is consistent with the previous studies that active smoking is associated with better short-term clinical outcome than non-smoking in STEMI patients undergoing PPCI, a phenomenon termed “smoker” s paradox.17

In the present study, impaired TMPFC was identified by as the strongest predictor of 30-day MACE, independent of advanced age, female gender, advanced Killip class, and other variables. These results not only confirmed the practical value of TMPFC as a quantitative index for the assessment of myocardial perfusion in the cardiac catheterization laboratory, but also added new evidence that poor myocardial tissue-level reperfusion is a key determinant of future cardiac events after reperfusion therapy. In a preliminary study, we found TMPFC to be more suitable and sensitive in evaluating the effect of intracoronary drugs on myocardial perfusion by comparing the differences in myocardial perfusion before and after drug administration by calculating the difference of frame rather than observing the cardiac cycle. Thus, for studying myocardial perfusion, the required sample size of clinical trials could be smaller when using TMPFC as the endpoint of myocardial perfusion than with traditional methods such as TMPG. In addition, the qualitative nature of TMPFC might render it less dependent on the technical skill of the observer because the number of frames can be counted on-line or off-line in the cardiac catheterization laboratory.

Several limitations of our study should be taken into account in order to place our findings in proper interpretation. First, the prognostic value of TMPFC obtained from a single center study needs to be further validated by future multicenter studies. Second, although data in our study are prospectively collected and blindly analyzed, the sample size is relatively small. Furthermore, although TMPFC is a simple quantitative index for assessment of myocardial perfusion that could be used in the cardiac catheterization laboratory, new modalities such as cardiac magnetic resonance imaging has recently been shown great potential for the assessment of myocardial reperfusion injury and might be used to provide more accurate information on tissue-level perfusion.18

STEMI patients with poor myocardial tissue-level perfusion assessed by TMPFC had higher risk factor profiles. Among these risk factor profiles, advanced age, diabetes, higher Killip class, and longer ischemia time were independent predictors of impaired TMPFC after PPCI, emphasizing the particular importance of successful microvascular reperfusion in patients with these risk factors. To further improve the outcomes of STEMI patients with these risk factors, efforts should be aimed at improving myocardial perfusion (i.e., adjunctive pharmacological therapies and mechanical devices) beyond epicardial recanalization.

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Keywords:

myocardial infarction; perfusion; angioplasty; outcome

© 2011 Chinese Medical Association