In ST elevation myocardial infarction (STEMI), intracoronary thrombolysis after primary percutaneous coronary intervention (PPCI) was found to improve microvascular perfusion, yet without improvement in left ventricular (LV) remodeling. Our study aimed to find out possible effect on LV longitudinal function.
102 anterior STEMI patients eligible for PPCI were divided into: Alteplase group (53 patients; received intracoronary 0.3 mg/kg alteplase after PPCI) and control group (49 patients; treated with PPCI only). LV longitudinal function was assessed using tissue Doppler imaging (to measure mean S' and maximum Q-S' time difference) and speckle tracking (to measure global longitudinal strain (GLS)) 48 hours and 6 months after PPCI. In alteplase group, epicardial (p value < 0.001 for corrected TIMI frame count) and myocardial perfusion (p value for myocardial blush grade 0.03) were significantly higher. GLS and LV synchrony were better in alteplase group both at 48 hours (p value 0.02 and < 0.001 respectively) and at 6 months (p value < 0.001 for each). No difference in bleeding rates was noted between groups.
Adjunctive low-dose alteplase infusion after PPCI improves microvascular perfusion and LV longitudinal function without increasing bleeding risk.
The corner stone in ST elevation myocardial infarction (STEMI) management is timely and successful recanalization of infarct related artery (IRA) using primary percutaneous coronary intervention (PPCI) . However, this may be hampered by the occurrence of tissue-level non-perfusion termed microvascular occlusion (MVO) which adversely affects final infarct size  and LV function [3-7]. In addition to the metabolic derangement of reperfusion injury [8,9], both proximal embolization [10,11] and microvascular in-situ thrombosis  play role in microvascular damage.
Recently, global longitudinal strain (GLS) has emerged as a readily accessible and reproducible tool for estimation of microvascular damage  and final infarct size  comparable to the gold standard cardiac magnetic resonance (CMR). To the best of our knowledge, we are the first to study the acute and intermediate term effects of intra-coronary alteplase on GLS.
We included 106 consecutive STEMI patients eligible for PPCI. Theywere divided into 2 groups: Alteplase group (53 patients who received intracoronary alteplase after successful PPCI) and control group (53 patients who were treated with successful PPCI only). All patients were given the necessary information about the study. Zagazig University, Faculty of Medicine ethics committee approved our study, and written informed consent was obtained from all patients.
- First anterior wall STEMI suitable for PPCI of the infarct related artery (IRA).
- TIMI coronary flow grade 0-1 and TIMI thrombus grade > 2 at initial angiography.
- Previous myocardial infarction, or previous PCI or coronary artery by-pass grafting (CABG).
- Patients with atrial fibrillation, complete left bundle branch block or significant valvular lesions.
- TIMI flow grade 3 at initial angiography.
- Angiographically unsuccessful PPCI defined as TIMI flow 0-1, no-reflow, > 20% residual stenosis at the culprit lesion and/or mechanical complication (e.g. spasm or dissection).
- Presence of additional lesion causing > 50% stenosis distal to the culprit lesion or in the non-IRA.
- Patients with contraindications for alteplase.
- Patients who were not adherent or compliant to maximum tolerable medical treatment during follow-up.
- Patients with poor echocrdiographic windows.
All patients were subjected to the following:
With emphasis on coronary artery disease (CAD) major risk factors (hypertension, diabetes mellitus, smoking, dyslipidemia). Killip classification  was used to determine the degree of patient's decompensation.
On admission and 90 min after PPCI. Successful ST resolution was defined as > 50% resolution of ST-segment in the lead(s) with maximum ST elevation at 90 min of reperfusion in relation to the baseline ECG .
Level on admission and serially every 24 hours to determine the peak level. A 20% or greater elevation of troponin level from the previous sample is considered reinfarction when associated with chest pain with or without dynamic ECG changes .
Using Judkins technique through radial approach. Computer-assisted randomization of patients was done. Balloon dilatation and stenting was left to the discretion of the attending operator. Export® catheter was used for manual thrombectomy as well as alteplase infusion for patients in alteplase group. The dose used was 0.3 mg/kg as previously  which was infused just proximal to stent level over 5 minutes. The last angiogram was taken 15 minutes after completing the infusion.
Pre- and post-procedural TIMI thrombus grade (TTG) and TIMI flow were assessed as previously described . Corrected TIMI frame count (cTFC) was assessed as described by Gibson, et al. . Myocardial blush grade (MBG) was grades as described by van't Hof, et al. .
Before PCI, oral aspirin (300 mg) and oral ticagrelor (180 mg) were given. During the procedure, intravenous unfractionated heparin was given at a dose of 60 U/kg followed by additional boluses to reach and maintain an activated clotting time around 250 and 280 s. A bolus of tirofiban (0.1 µg/kg) was given 3 minutes after thestart of the procedure, followed by continuous infusionat 0.15 µg/kg/minute for 12 hours. After PCI, aspirin 75-100 mg/24 h, ticagrelor 90 mg/12 h, maximum guideline-directed tolerable doses of beta-blockers, statins, and angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers.
Adverse in-hospital bleeding events were defined as any bleeding within 24 h after PPCI and were graded according to TIMI criteria .
Was done 48 h and 6 months after PPCI.
Volumes of left ventricle at end-diastole (LVEDV) and end-systole (LVESV) and LV ejection fraction (LVEF) from the apical four-chamber view were calculated in accordance with recommendations of the American Society of Echocardiography.
Was performed to assess peak systolic velocity (S') in the apical 4-chamber and 2-chamber views at the level of the septal, lateral, inferior, and anterior mitral annulus. Measurements were taken separately and averaged . The degree of LV longitudinal dyssynchrony was measured as the maximum difference between Q-S' times from different sites of mitral annulus. Q-S' time represent the period between the Q wave in the simultaneous ECG and peak S' wave .
To measure global longitudinal strain (GLS) from optimal 4-chamber, 2-chamber and 3-chamber views and the average was taken .
Data were imported into SPSS version 16.0 software (SPSS Inc., Chicago, IL) to be analyzed. Results were presented as mean ± SD for continuous variables and as frequency (%) for categorical variables. Data were tested for normality using the Kolmogorov-Smirnov test. Means were compared using the Student t test or Mann-Whitney test. Categorical data were compared using the χ2 Test. P value was set at < 0.05 for significant results and < 0.001 for highly significant results.
Of the 53 patients in control group, 4 patients were not adherent to medical treatment so they were excluded. Table 1 shows demographic and procedural data of the study population. It was a relatively young population with male preponderance. Diabetes mellitus and hypertension were the most commonly encountered risk factors.
Table 1: Comparison between groups regarding demographic and procedural data. View Table 1
ST resolution > 50% was encountered in 44 and 31 patients of alteplase and control groups respectively (p value 0.033). Peak troponin I level was significantly lower in alteplase group. Despite final TIMI flow was comparable, cTFC was significantly lower and MBG was significantly higher in alteplase group reflecting better epicardial and myocardial flow. No TIMI major bleeding occurred in either group. TIMI minor/minimal bleeding rates were similar in both groups (p value 0.24). Regarding other clinical outcome endpoints, no significant difference was noted (Table 2).
Table 2: Comparison between groups regarding clinical and angiographic outcome. View Table 2
Regarding echocardiographic data, mean GLS and longitudinal dyssynchrony were significantly improved in alteplase group both at 48 hours after PPCI and at 6 months follow-up. On the contrary, LV volumes and LVEF were comparable between both groups; with a trend toward higher improvement in LV geometry and LVEF in alteplase group (Table 3).
Table 3: Comparison between echocardiographic data of both groups. View Table 3
The main findings in our study are that intracoronary alteplase after PPCI resulted in:
1. Significant improvement in epicardial and myocardial coronary flow without significant difference in TIMI major bleeding.
2. Significant improvement in LV longitudinal function (both acutely and at 6 months)with a trend toward improvement in LV volumesand LVEF (at 6 months).
To date, no large randomized trials evaluating the effect of intracoronary t-PA are available. Small studies on intracoronary thrombolysis performed in the 1980's and 1990's were confusing in terms of safety [27-29]. The largest experience reported was the Intracoronary t-PA Registry,which enrolled 198 patients and found significant increase in TIMI flow as well as significant decrease in thrombus grade (P < 0.0001 for each).In this registry,bleeding rate was 9.2%, post-PCI MI rate was 17.6%, repeat PCI rate was 4.9%, 9.2% of patients needed CABG, and in-hospital mortality rate was 7% . More confusion had risen by studies on facilitated PCI. However, with the high incidence of MVO and no-reflow in the current PCI era, we tried to find a new solution with an old weapon.
This study was conducted on 102 patients presenting with STEMI who were randomly divided into two groups; control group (49 patients) who underwent PPCI only and alteplase group (53 patients) who underwent PPCI followed by intracoronary alteplase infusion. Both groups were matched for age and gender and there was no significant difference between both groups regarding coronary risk factors, Killip class at admission, pain to needle time, TIMI thrombus grade and final TIMI flow grade.
In our study, significant improvements in epicardial (cTFC) and myocardial (MBG) coronaryflow were found with the use of low dose intracoronary alteplase. Using different intracoronary thrombolytics, Sezer, et al.  (using streptokinase) Boscarelli, et al.,  (using alteplase and tenectplase) and Jayagopal and SarjunBasha,  (using tenectplase) found the same results. More physiologically, Sezer, et al.  found that coronary flow reserve, index of microvascular resistance and Pressure derived collateral flow index were significantly lower in the group that received streptokinase (< 0.001 each).
In the present study, GLS was found to be significantly higher in the group that received alteplase in spite of no difference in LV volumes or LVEF. We are the first to address the effect of post-PCI intracoronary thrombolysis on LV longitudinal function. Taking CMR as the reference, Biere, et al.  found that GLS correlated significantly with MVO and final infarct size. Moreover, in the speckle tracking sub study of the EXPIRA trial, Cimino, et al.  found that GLS was closely related to the degree of MVO.
In the present study, the percent of patients with > 50% ST resolution at 60 minutes were significantly higher in the alteplase group (p value 0.04). Using streptokinase, Sezer, et al.  did not find significant difference. Despite the strong correlation between ST resolution and microvascular integrity, some confounding factors are still to be considered e.g. effect of dyskinetic segments and dynamic nature of ST segment elevation.
In the present study, peak levels of troponin I were significantly less in the group that received alteplase reflecting, possibly, better microvascular perfusion and higher myocardial salvage. Peak troponin level after PPCI has been found to correlate infarct size  as well as microvascular perfusion .
The use of intracoronary alteplase did not increase the risk of TIMI major bleeding in our study. This may be due to many factors: First, the relatively young age of the study group with male preponderance. Secondly, using radial access in all cases mitigated the risk of access site bleeding. Finally, the administration of intracoronary alteplase through the suction catheter may have permitted local effect only.
In our study, we found that adjunctive intracoronary alteplase was associated with significantly higher GLS as well as a trend towards improvement in LV volumes and LVEF. This can be considered delayed effect of improved microvascular perfusion secondary to intracoronary thrombolysis.
Post-primary PCI, the final infarct size and LV volumes and function are determined primarily by microvascular perfusion rather than epicardial TIMI flow. As a result, 20-32% of STEMI patients were found to exhibit LV remodeling in spite of TIMI 3 flow in IRA [4,34].
Diao, et al.  performed a meta-analysis on 765 patients included in 11 trials to find the correlation between GLS and late gadolinium enhancement-measured infarct size. The pooled correlation was found to be 0.70 (95% CI: 0.64, 0.74) suggesting that GLS can be a surrogate parameter of infarct size. The correlation is rather superiorto conventional indices, including LVEF. In their 3-D echocardiography study, Iwahashi, et al.  recruited 190 patients with their first STEMI and found that GLS and longitudinal dyssynchrony are closely related to final infarct size and LV remodeling.
Thus, in our study, intracoronary alteplase could have limited the final infarct size and prevented subtle deterioration in LV function.
Low-dose intracoronary alteplase infusion immediately after successful primary PCI was compared to standard primary PCI. We found acute improvement in microvascular perfusion as well as better LV GLS and longitudinal dyssynchrony without increasing bleeding risk.
The small sample size precludes definite conclusions, yet, to date, this is the largest randomized study evaluating the role of intracoronary alteplase. The relatively few bleeding events may reflect selection bias. Cases with no-reflow were excluded because of its complex mechanism. Larger studies enrolling patients with cardiogenic shock and intra-aortic balloon bump are recommended.