a Department of Cardiology, Isala Klinieken, Locatie Weezenlanden, Groot Wezenland 20, 8011 JW Zwolle, The Netherlands
b Department of Cardiology, University Hospital Groningen, Groningen, The Netherlands
* Tel.: +31-3842-42374; fax: +31-3842-43222
E-mail address: v.derks{at}diagram-zwolle.nl
Received 30 October 2002; revised 18 February 2004; accepted 11 March 2004
Abstract
Aims The role of collateral flow in the first hours of infarction remains unclear. Our aim was to determine whether the presence of coronary collateral flow, as evidenced by angiography, has a beneficial effect on infarct size and left ventricular function in acute myocardial infarction (MI) treated by means of early percutaneous coronary intervention (PCI).
Methods Between 1994 and 2001, 1059 patients with acute MI treated with primary PCI, TIMI (Thrombolysis in Myocardial Infarction) 0 or 1 flow at first contrast injection and technically adequate angiograms for collateral flow detection were analysed.
Results Comparison of collateral flow grades 0, 1, and 2/3 showed that increased collateral flow was associated with a lower incidence of Killip class 2 at presentation (12% vs. 10% vs. 3%,
for trend 0.02), less need for intra-aortic balloon pumping after PCI (17% vs. 13% vs. 5%,
for trend 0.005), better myocardial blush grade (MBG) in infarcts related with the left anterior descending coronary artery (LAD) (MBG3: 14% vs. 18% vs. 34%,
for trend 0.01), and smaller enzymatic infarct size (cumulative lactate dehydrogenase release 36 h after symptom onset [LDHQ36]) (1932±1531 U/l vs. 1870±1458 U/l vs. 1217±762 U/l,
for trend 0.041). These beneficial effects were particularly evident in LAD-related infarcts.
Conclusion The presence of angiographically detectable collaterals has a protective effect on enzymatic infarct size and pre- and postintervention haemodynamic conditions in patients with acute MI treated by primary PCI, in particular when Rentrop grade 2/3 is present and the LAD is involved in the infarct.
Key Words: Primary coronary angioplasty Myocardial infarction Collateral circulation Enzymatic infarct size
Introduction
The role of collateral circulation to the myocardium at risk in the setting of acute coronary occlusion has been of special interest in the last decades. Animal studies have shown that collateral flow has a protective effect on infarct size in terms of reducing the area at risk.1,2 In humans, angiographic studies after thrombolytic therapy has shown better preserved left ventricular function in patients who responded to failure of reperfusion therapy with early collateral flow.3,4 Coronary collateral flow to the infarcted area in the presence of persistent coronary occlusion tends to increase in the days and weeks following the acute event.5,6 This late recruitment of coronary collaterals is associated with left ventricular functional recovery in patients with late mechanical reperfusion of the infarct artery.7,8 Whether early coronary collateral blood flow to the infarct-related artery in the first hours after acute coronary occlusion has a beneficial effect on infarct size and mortality in patients with successful reperfusion therapy is still unclear. In a selected population of patients with anterior myocardial infarction, angiographic evidence of collateral circulation was associated with better haemodynamics at presentation and lower in-hospital mortality.9 Other studies showed no clinical benefit of early collateral circulation in acute myocardial infarction treated with primary percutaneous coronary intervention (PCI) or thrombolysis.10,11 Coronary collateral flow may be identified by several different techniques. We studied coronary collateral flow as detected by angiography because it is easy to incorporate into the routine clinical practice of acute myocardial infarction treatment with PCI. Our aim was to determine whether early angiographic evidence of collateral circulation to the infarct-related coronary artery is related to infarct size, morbidity and mortality in patients treated with PCI within 6 h of the onset of symptoms.
Methods
Patients
Between December 1994 and June 2001, 1702 patients with ST-segment-elevation myocardial infarction (MI) and symptoms lasting <6 h were treated with PCI. In 860 patients, the diagnosis of acute MI was established at the patient's home by the ambulance crew or at the emergency department of the referring hospital. These patients received aspirin (500 mg intravenously) and heparin (4000 IU intravenously) before transportation to our hospital. In 842 patients, the diagnosis of acute MI was established in the emergency room of our hospital. These patients received aspirin and heparin intravenously in the emergency room and were transported immediately to the catheterization laboratory. None of these patients received fibrinolytic therapy or glycoprotein IIb/IIIa blockers before PCI.12 We excluded patients with left main and venous graft-related infarcts and patients with antegrade flow in the infarct-related artery at first contrast injection.13 In 178 patients, collateral flow could not be graded for technical reasons. We included 1059 patients with Thrombolysis in Myocardial Infarction (TIMI) flow 0 or 1; details regarding other inclusion and exclusion criteria have been published previously.14,15 Inclusion criteria were symptoms of acute myocardial infarction lasting more than 30 min, with more than 1 mm (0.1 mV) ST-segment elevation in two or more contiguous electrocardiographic leads. Coronary angiography was performed as quickly as possible. Collateral flow from the patent vessels to the infarct-related artery was graded using the classification developed by Rentrop.16 Grade 0: no visible filling of any collateral channel; grade 1: filling of the side branches of the occluded artery, with no dye reaching the epicardial segment; grade 2: partial filling of the epicardial vessel; and grade 3: complete filling of epicardial vessel by collateral vessels. Both TIMI flow and myocardial blush were graded on the angiograms made immediately after the primary coronary angioplasty procedure by two experienced investigators who were not informed of the data accompanying the coronary angiograms. Arterial patency was determined as TIMI grade 3 flow. Myocardial blush grade (MBG) was graded according to the classification described earlier.17 Grade 0: no myocardial blush or contrast density; grade 1: minimal myocardial blush; grade 2: moderate myocardial blush; and grade 3: normal myocardial blush. The indication for intra-aortic balloon pumping (IABP) was made by the operator based on haemodynamic and clinical parameters. The left ventricular ejection fraction (LVef) was measured within 1 week post-MI with a radionuclide technique, as described earlier.14 Left ventricular function may improve over time after acute MI treated with early reperfusion therapy due to functional recovery of stunned myocardium.18 Therefore LVef was measured at 6 months post-MI follow-up. Infarct size was measured by calculating cumulative lactate dehydrogenase release 36 h after symptom onset (LDHQ36).19 Samples were obtained at admission and every 12 h up to 36 h. An area under the curve was calculated from these measurements. Measurements and calculations were performed at the department of clinical chemistry by technicians who were unacquainted with the clinical data. Based on collateral flow grade at first contrast injection in the contralateral coronary artery, patients were divided into three groups: Rentrop grade 0, grade 1, and grade 2/3. All data were analysed by an independent core laboratory (Diagram, Zwolle, The Netherlands).
Statistical analysis
Continuous baseline and outcome variables are presented as mean±SD, whereas discrete variables are expressed as absolute values and percentages. Patients were divided into three groups based on the degree of collateral flow. Trend analyses were performed, adjusted for the infarct-related artery (left anterior descending coronary artery [LAD] vs. non-LAD).20 When the interaction between flow and artery was significant, separate analyses for LAD and non-LAD related infarcts were performed. Linear, logistic, and proportional hazard regressions were used for trend analysis of the respective continuous, discrete survival variables. The fit of the various models was assessed by inspecting raw means (and distribution) and raw log (odds) and log (-log) plots, respectively. A possible lack of fit was observed only for LDHQ36, but as additional analyses produced similar results, the outcome of the originally planned method is reported. Survival rates were calculated by KaplanMeier analysis. Differences for the main effects were considered statistically significant at (two-sided test). A total of 6 outcome measures were analyzed and 3 statistically significant results were found. As no adjustment was made, the total error rate may exceed 0.05. This approach was chosen in view of the exploratory nature of the study. Interactions were considered statistically significant at a level of 15%.
Results
A total of 1059 patients with total coronary occlusion during initial coronary angiography were included in the analysis. All patients presented within 6 h after onset of symptoms. The 30-day follow-up was completed in all patients and 1-year follow-up in 881 (83%) patients. LVef was measured for the first time in 854 (81%) patients at 4±6 days post-MI and for the second time in 463 (44%) patients at 190±31 days post-MI. Complete LDHQ36 was available for 810 (76%) patients. Rentrop grade 3 flow was present in only 7 patients so Rentrop grades 2 and 3 were merged in the analyses. Baseline characteristics are shown in Table 1. Early collateral recruitment was present more often in patients with a non-LAD-related infarct than in patients with a LAD-related infarct. No differences were seen in the prevalence of risk factors for coronary artery disease, previous coronary events, previous revascularisation procedures, presence of multivessel disease, or success or failure of the PCI procedure. Table 2 shows the outcome measures. The higher the Rentrop grade of the collaterals was, the lower the Killip class rate was on admission. In patients with grade 2/3 collateral flow, enzymatic infarct size was smaller compared to patients with grade 1 or no collateral flow (1932±1531 U/l vs. 1870±1458 U/l vs. 1217±762 U/l, for trend 0.041). The presence and extent of collateral flow was associated with progressively less use of intra-aortic balloon pumping (IABP) post-PCI (17% vs. 13% vs. 5%,
for trend 0.005). In the adjusted analyses for LAD and non-LAD-related infarcts, we first evaluated interaction. Interaction was significant only for MBG3
, so a separate analysis for LAD and non-LAD was made (Table 3). The higher the Rentrop grade of the collaterals to an occluded LAD was, the higher the incidence of normal myocardial blush was (MBG3) (Rentrop 0: 14% vs. Rentrop 1: 18% vs. Rentrop 2/3: 34%,
for trend 0.01). Collateral flow to an occluded non-LAD did not influence the incidence of normal myocardial blush. One-year survival rates were 95% versus 96.2% versus 97.2% for Rentrop grades 0, 1, and 2/3, respectively
. The hazard ratio, adjusted for LAD or non-LAD, for patients with Rentrop grade 2/3 versus Rentrop grade 0 was 1.54 (95%CI: 0.475.26;
).
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This study shows that in patients with acute ST-segment-elevation myocardial infarction, treated with PCI early after the onset of symptoms, Rentrop grade 2/3 collateral circulation to the occluded coronary artery was associated with (1) better microvascular reperfusion of the myocardium, as reflected by a higher incidence of normal myocardial blush after PCI in LAD-related infarcts, and (2) smaller enzymatic infarct size. Furthermore, patients with grade 2/3 collateral flow presented in lower Killip class and needed postintervention IABP support less often. Early collateral recruitment was more frequently present in patients with acute non-LAD occlusion, suggesting a more extensive collateralisation from the LCA to the RCA. After successful restoration of antegrade flow in the LAD, Rentrop grade 2/3 collateral flow was associated with a better microvascular perfusion of the myocardium, expressed as a higher incidence of normal myocardial blush. This beneficial effect of collateral flow is not seen in the non-LAD-related infarcts. In patients with persistent coronary occlusion, the development of collaterals increases in the days and weeks following acute occlusion. Our study showed that even in the first 6 h following acute coronary occlusion, collateral flow may increase considerably over time. Experimental studies have shown that after coronary occlusion, collateral flow to the centre of the infarct zone was lowest at the base of the left ventricle and increased toward the apex, resulting in a relatively greater salvage of jeopardised myocardium from base to apex.21 Also, the extent of intact myocardium between the lateral and epicardial edge of the risk area and transmural necrosis is markedly broader in the interventricular septum than in the left ventricular free wall.22 Since the LAD perfuses predominantly the interventricular septum and apex, these physiologic characteristics could explain our finding that adequate collateral flow had a protective effect most notable in acutely occluded LADs. In patients with anterior infarction the area of jeopardised myocardium is larger than in patients with inferior infarction.23 So, although our results showed no protective effect on microvascular perfusion of collateral flow to acutely occluded non-LAD-related infarcts, there is still a possibility that this effect was present but that its detection is problematic due to the smaller area at risk. These findings are the first to support the hypothesis that the presence of collateral flow plays an important role in sustaining jeopardised myocardium until reperfusion is accomplished, even in the first hours after acute coronary occlusion.
Angiographic collateral flow detection provides only an estimate of the absolute collateral flow that may be present since only collaterals >100 µm in diameter are identified. Despite this limitation, the association of grade 2/3 collateral flow with a higher incidence of normal myocardial blush and smaller enzymatic infarct size after early PCI of an occluded LAD are parameters for the presence of adequate arteriolar and myocardial collateral flow. Other techniques for collateral flow detection, such as myocardial contrast-echocardiography, radionuclide techniques, and pressure-derived collateral flow index, are indirect methods with better quantification of collateral flow.7,24,25 Unfortunately these methods are not easy to incorporate into routine clinical practice for acute myocardial infarct treatment with PCI. A limitation of our study is that our population was a selected group of patients with first acute myocardial infarction undergoing mechanical reperfusion soon after the onset of symptoms. Another limitation is that LVef and LDHQ36 could not be measured in all patients.
In conclusion, the presence of angiographically detectable collaterals had a protective effect on enzymatic infarct size, microvascular perfusion of the myocardium, and pre- and postinterventional haemodynamic conditions in patients with acute ST-segment-elevation myocardial infarction treated with PCI, in particular when Rentrop grade 2/3 is present and the infarct-related vessel is the LAD.
References