Several experimental models have shown that myocardial perfusion is important for the treatment of myocardial infarction (MI). The normal coronary flow can improve left ventricular (LV) function, alleviate clinical syndromes, reduce in-hospital mortality, and improve prognosis. The consequences are based on the recovery of ischemic myocardium in patients after optimal myocardial reperfusion. However, part of patients who have received revascular therapy are still ischemic and the prognosis is not ameliorated since myocardial reperfusion is not at the level of myocardium tissue.1,2 It has proved that adenosine can reduce MI area and improve acute myocardial infarction (AMI) within 6 hours by perfusion,3 but few data are available on the late perfusion. Other medicines are used to improve myocardial perfusion,4-7 but the results are not exciting. The late reopening of an occluded infarct related artery could improve left ventricular ejection fraction (LVEF) and long-term outcomes,8-10 but these findings are based on the clinical follow-up or coronary artery flow grading, lacking of quantitative data about myocardial perfusion. Myocardial contrast echocardiography (MCE) has been used to evaluate myocardial perfusion in recent years because of its high sensitivity and quantitative real-time image.11-13 This study evaluated the effect of adenosine to improve myocardial perfusion on late reperfused MI as well as the value of MCE.
From December 2004 to June 2005, 26 patients with the first onset of anterior wall MI were admitted to our coronary units to undergo percutaneous coronary intervention (PCI) for the totally occluded infarct related artery (IRA). They were divided into 2 groups at random: adenosine group (n=12) and normal saline group (n=14). No patients had been treated with percutaneous transluminal coronary angioplasty (PTCA) or thrombolysis. The inclusion criteria were as follows: first onset of anterior wall MI, age <70 years, no diabetes and hypertension, MI for 3 to 12 weeks, total occlusion of left anterior descending coronary artery (LAD), and side-branch TIMI flow below one grade.
Written informed consent was obtained from all patients before the procedure. Coronary angiography and PCI were attempted with a 6 French guiding catheter through the femoral artery. The angiographic images were acquired with a GE INOVA-2000 single-plane system at a cine rate of 30 frames/s. Patients were pretreated with aspirin 300 mg and clopidogrel 300 mg before the procedure, and no patients were given glycoprotein IIb/IIIa receptor blockers. In each group, adenosine (20 mg diluted to 20 ml, 2 mg/min, 10 minutes) or normal saline (2 ml/min, 10 minutes, total 20 ml) was given to the coronary artery when the guiding wire was crossed the lesion in the course of PCI. Soon after the balloon was dilated at the lesion, the stent (Cypher/Cypher select, Johnson & Johnson, USA) was implanted. The totally occluded coronary artery was defined as a coronary artery with 100% pre-PTCA luminal narrowing without antegrade flow or with either antegrade or retrograde filling through collateral vessels. Antegrade perfusion of the IRA was graded by the TIMI criteria and collateral flow was scored according to the Rentrop classification.14
Echocardiography and MCE
All patients underwent two dimensional echocardiography and MCE with a color Doppler ultrasound system (c256, Sequoia) with a 2.5-3.5 MHz transducer. Instrument settings were held constant for each experiment. Contrast was produced by the continuous infusion of 0.8 ml Sonovue (Bracco Company, Italy) in one minute via the coronary route. The dose was selected on the basis of pilot experiments. Contrast pulse-sequencing MCE was done before PCI and 30 minutes later after PCI in real-time imaging. LVEF and MCE were determined by the same independent operators blinded to clinical and angiographic data. The LAD perfusion regions of interest were selected according to contrast video densitometry absence and adjacent nonattenuated segment (Figure 1A), but high-intensity signals were excluded from the epicardium and endocardium. The interesting regions included ischemic segment, medial segment and normal segment. Video densitometry reflecting myocardial microvascular perfusion and contrast filled-blank area (Figure 1B) were calculated with the CUSQ off-line software.
Follow-up and definition of events
LVEF was assessed by 2-dimensional echocardiography before PCI and repeated after 72 hours. Heart function and cardiac events were followed up within 30 days. Major adverse cardiac events (MACEs) included sudden death, heart failure, re-infarction, angina pectoris, etc. All patients were followed up and data were stored in our database.
Continuous variables are presented as mean ± standard deviation (SD) and categorical variables as absolute numbers. Statistical differences between the two groups were assessed with Student’s t test for continuous variables and the chi-square test for categorical variables. A P value <0.05 was considered statistically significant. The software for statistical analysis was SPSS 10.0.
There were no significant differences in the baseline clinical characteristics of the two groups (Table 1 ).
PCI was successful and the TIMI flow was grade III. No residual stenosis and dissection were observed. Clear images of the myocardium could be obtained immediately after coronary angiography and contrast echocardiography.
Perfusion of the myocardium
Results of myocardium perfusion were shown in Table 2. In all patients no perfusion or decreased perfusion was observed in the segments of the culprit occlusive coronary before PCI, and in patients of the adenosine group good perfusion was seen in the segments of the critically occlusive coronary and local microvascular blood flow also increased after PCI. The result of video densitometry at reperfusion area was better in the adenosine group than in the saline group (5.7±0.29 vs 4.95±1.22, P<0.05). The result of video densitometry at critical segments between ischemic and normal myocardial areas in the two groups was improved (4.27±0.81 vs 5.53±0.36, 4.45±0.38 vs 5.26±0.35, P<0.05). The normal myocardial segment was not influenced (P>0.05) but the ischemic myocardial segment was deminished significantly after PCI in the adenosine group ((2.38±0.99) cm2 vs (0.83±0.49) cm2, P<0.05). The ischemic myocardial area was also deminished after PCI in the saline group ((2.26±0.75) cm2 vs (1.24±0.79) cm2, P<0.05). The ameliorated myocardial area was larger in the adenosine group than in the saline group ((1.56±0.60) cm2 vs (1.02±0.56) cm2, P<0.05).
The results of LVEF are shown in Figure 2. The LV function after 72 hours of PCI was greatly improved in the two groups (EF (54±9)% vs (67±6)% and (55±10)% vs (62±7)%, P<0.05), but LVEF after PCI was not significantly different between the two groups ((67±6)% vs (62±7)%, P>0.05). No in-hospital MACE was found in the two groups. There were three cases of MACE including one case of heart failure and two cases of angina pectoris in the saline group but none in the adenosine group in the 30 days of follow-up (P<0.05). Those patients with MACE had ill perfusion segments.
We evaluated the value of adenosine in improving myocardium perfusion in late reperfused MI by MCE techniques and found that adenosine could improve myocardial microvascular perfusion in the late reopening of an occluded infarct related artery (3 to 12 weeks after AMI) and clinical outcome in the follow-up period although this study could not determine the mechanism of this benefit. Myocardial microvascular perfusion is a powerful predictor of clinical events.
Adenosine is an endogenous nucleoside and a useful agent for evaluation and treatment of the cardiovascular system. It has also been shown to reduce infarct size and improve the clinical outcome in the treatment of AMI with an onset within 6 hours.3,15,16 During elective PCI, adenosine reduced ST segment shifts and ischemic symptoms.17 In addition, it is used to prevent no-reflow phenomenon by improved myocardial perfusion in the primary PCI of AMI.18,19 MCE as an imaging tool for the assessment of the myocardial microcirculation utilizes gas-filled microbubbles that are inert and remain entirely within the vascular space and possess an intravascular rheology similar to that of red blood cells.20 Therefore, the amount of contrast microbubbles can reflect myocardial microvascular perfusion accurately. In our study, ischemic myocardial segments in the adenosine group were significantly reduced, and the value of contrast video densitometry at each segment was higher in the adenosine group than in the saline group after PCI. The reperfused segments in the saline group were greatly improved after PCI but less than normal myocardial segments. However, each myocardial segment in the adenosine group had similar result of video densitometry, indicating that patients in the adenosine group had better myocardial microvascular perfusion though the patients in the two groups had normal coronary flow (grade III) and adenosine took a affirmative action on myocardial microvascular perfusion. Follow-up for 30 days showed 3 patients with MACE including one with heart failure and two with angina pectoris in the saline group but none in the adenosine group. These patients all had ill perfusion segments, possibly because part of the patients who had received revascular therapy had worse prognosis inspite of normal coronary blood flow (TIMI 3 grade). These findings suggested that adenosine could improve clinical outcome through improved myocardial microvascular perfusion, and that intracoronary adenosine could improve myocardial perfusion in late reperfused MI better than PCI.
Piscione and colleagues21 have reported that late reopening of an occluded infarct related artery could improve LV function and long-term clinical outcome. Quintana and colleagues22 reported that the LV function was not affected by adenosine in AMI but trendency towards improved survival was observed in patients with anterior MI localization. We also found that LVEF was greatly improved after PCI but no distinction between the adenosine and saline groups. These results suggest that intracoronary adenosine in late reopening of an occluded artery was good to clinical outcome but not to LVEF as compared with PCI only. We could not explain the result though adenosine improved myocardial perfusion. We suggest that the factors including inclusion criteria and sample size and follow-up period might have an effect on the result of the study.
In this single centre study with a relatively small sample size, coronary angiography and MCE were not repeated in the period of follow-up, thus restenosis could not be excluded, and myocardial perfusion in 3 patients in the saline group produced MACE during follow-up. Since follow-up lasted for only 30 days, we could not detect the long outcomes of the two groups.
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