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.
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.
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.
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
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.
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.
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.
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.
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).
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).
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).
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.
1. Roe MT, Ohman EM, Maas AC, Christenson RH, Mahaffey KW, Granger CB, et al. Shifting the open-artery hypothesis downstream: the quest for optimal reperfusion. J Am Coll Cardiol 2001; 37: 9-18.
2. Boden WE, Eagle K, Granger CB. Reperfusion strategies in acute ST-segment elevation myocardial infarction
: a comprehensive review of contemporary management options. J Am Coll Cardiol 2007; 50: 917-929.
3. Pu J, Shan P, Ding S, Qiao Z, Jiang L, Song W, et al. Gender differences in epicardial and tissue-level reperfusion in patients undergoing primary angioplasty
for acute myocardial infarction
. Atherosclerosis 2010; Epub ahead of print.
4. Pu J, Ding S, Shan P, Qiao Z, Song W, Du Y, et al. Comparison of epicardial and myocardial perfusions after primary coronary angioplasty
for ST-elevation myocardial infarction
in patients under and over 75 years of age. Aging Clin Exp Res 2010; 22: 295-302.
5. Gibson CM, Cannon CP, Murphy SA, Ryan KA, Mesley R, Marble SJ, et al. Relationship of TIMI myocardial perfusion
grade to mortality after administration of thrombolytic drugs. Circulation 2000; 101: 125-130.
6. van ‘t Hof AW, Liem A, Suryapranata H, Hoorntje JC, de Boer MJ, Zijlstra F. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty
for acute myocardial infarction
: myocardial blush grade. Zwolle Myocardial Infarction
Study Group. Circulation 1998; 97: 2302-2306.
7. Ding S, Pu J, Qiao ZQ, Shan P, Song W, Du Y, et al. TIMI myocardial perfusion
frame count: a new method to assess myocardial perfusion
and its predictive value for short-term prognosis. Catheter Cardiovasc Interv 2010; 75: 722-732.
8. Pu J, Ding S, He B. TIMI myocardial perfusion
frame count: an angiographic method to assess flow in the myocardium but not in the epicardial artery. Catheter Cardiovasc Interv 2010; 76: 1073-1075.
9. TIMI Study Group. The Thrombolysis in Myocardial Infarction
(TIMI) trial/ Phase I findings. N Engl J Med 1985; 312: 932-936.
10. Rentrop KP, Cohen M, Blanke H, Phillips RA. Changes in collateral channel filling immediately after controlled coronary artery occlusion by an angioplasty
balloon in human subjects. J Am Coll Cardiol 1985; 5: 587-592.
11. Prasad A, Stone GW, Stuckey TD, Costantini CO, Zimetbaum PJ, McLaughlin M, et al. Impact of diabetes mellitus on myocardial perfusion
after primary angioplasty
in patients with acute myocardial infarction
. J Am Coll Cardiol 2005; 45: 508-514.
12. De Luca G, van ‘t Hof AW, de Boer MJ, Ottervanger JP, Hoorntje JC, Gosselink AT, et al. Time-to-treatment significantly affects the extent of ST-segment resolution and myocardial blush in patients with acute myocardial infarction
treated by primary angioplasty
. Eur Heart J 2004; 25: 1009-1013.
13. De Luca G, Gibson CM, Huber K, Zeymer U, Dudek D, Cutlip D, et al. Association between advanced Killip class at presentation and impaired myocardial perfusion
among patients with ST-segment elevation myocardial infarction
treated with primary angioplasty
and adjunctive glycoprotein IIb-IIIa inhibitors. Am Heart J 2009; 158: 416-421.
14. Brodie BR, Stuckey TD, Hansen C, Kissling G, Muncy D. Influence of vessel size on early and late outcomes after primary angioplasty
for acute myocardial infarction
. J Invasive Cardiol 2000; 12: 13-19.
15. Elezi S, Kastrati A, Neumann FJ, Hadamitzky M, Dirschinger J, Schömig A. Vessel size and long-term outcome
after coronary stent placement. Circulation 1998; 98: 1875-1880.
16. De Luca G, Suryapranata H, de Boer MJ, Ottervanger JP, Hoorntje JC, Gosselink AT, et al. Impact of vessel size on distal embolization, myocardial perfusion
and clinical outcome
in patients undergoing primary angioplasty
for ST-segment elevation myocardial infarction
. J Thromb Thrombolysis 2009; 27: 198-203.
17. Albertal M, Cura F, Escudero AG, Thierer J, Trivi M, Padilla LT, et al. Mechanism involved in the paradoxical effects of active smoking following primary angioplasty
: a subanalysis of the protection of distal embolization in high-risk patients with acute myocardial infarction
trial. J Cardiovasc Med (Hagerstown) 2008; 9: 810-812.
18. Vicente J, Mewton N, Croisille P, Staat P, Bonnefoy-Cudraz E, Ovize M, et al. Comparison of the angiographic myocardial blush grade with delayed-enhanced cardiac magnetic resonance for the assessment of microvascular obstruction in acute myocardial infarctions. Catheter Cardiovasc Interv 2009; 74: 1000-1007.