Limitations of Using a GuardWire® Temporary Occlusion and Aspiration System in Patients with Acute Myocardial Infarction:
Multi

Early reperfusion is critically important in the treatment of acute myocardial infarction (AMI). The efficacy of percutaneous coronary intervention (PCI) as a reperfusion strategy in AMI has been established. Despite the success of early reperfusion, however, microcirculatory impairment, or so-called no-reflow, may occur and is strongly associated with the prognosis, including left ventricular remodeling. It has also been reported that the rate of no-reflow due to distal embolization after PCI is 2–5%, and is especially high after PCI for AMI or saphenous vein graft (SVG) intervention.^1–8
Recent attention has shifted from epicardial artery patency to microvascular status. The use of a distal embolic protection device (DPD) was first demonstrated clinically for cerebral protection during carotid angioplasty and stenting. Current applications are expanding to include interventions on SVGs, renal arteries and patients with acute coronary syndrome. The SAFER trial, a large-scale randomized study of PCI for SVG, where the no-reflow phenomenon is likely to occur, demonstrated the safety and efficacy of DPD.⁹ Atheromatous components were mostly obtained from these distal embolic protection devices.^9,10 The feasibility of using a protection device in native coronary arteries to prevent distal embolization of particulate matter during PCI was preliminarily reported.11 However, there are few reports by multicenter randomized studies regarding the use of distal protection devices as a treatment strategy of AMI.¹²
The purpose of the present study was to investigate the safety and efficacy of the GuardWire^® distal protection balloon system (Medtronic, Inc., Minneapolis, Minnesota) during PCI in patients with AMI.

Materials and Methods

Protocol and subjects. The Multicenter Investigation of Coronary Artery protection with a Distal Occlusion device in acute myocardial infarction (MICADO) trial is a prospective study involving 14 centers throughout Japan. Individuals eligible for enrollment were patients 18 years or older with AMI, and patients with ST-elevation AMI within 24 hours after onset who had chest pain for 30 minutes or more and showed ST-elevation on electrocardiography (ECG) on at least 2 leads. Patients with severe blood, hepatic or renal disease with a history of internal organ bleeding within the past month, and those who were allergic to antiplatelets or anticoagulant agents were excluded. Patients with chronic renal failure with a creatine of 2.6 mg/dl or more were also excluded. Emergency coronary angiography was performed in patients enrolled in the trial after written informed consent was obtained.
Cardiac catheterization (coronary angiography). Thrombolytic therapy was permitted before intervention. Aspirin 100 mg and ticlopidine 200 mg were administered sublingually before the procedure. Intravenous heparin 5,000 U was administered. This was added to maintain the procedural activated clotting time at >250 seconds. Coronary angiography was performed by the conventional method with a ≥6 Fr system. The decision to perform aspiration before the procedure was left to the discretion of the operator. Furthermore, according to the angiographic findings, patients whose vascular diameter 3 cm distal to the culprit lesion was 3 mm or more and had no severe tortuosity or kinks were selected and randomized into the following two groups by the envelope method: (1) the GuardWire group, in which a distal protection device was used during PCI, and (2) the control group, in which PCI was performed by the conventional method without a distal protection device.
When the culprit lesions showed complete occlusion, they were classified into the abrupt type, where no-reflow is likely to occur during PCI, and the tapered type, where no-reflow is relatively rare, according to the patterns.¹³ The evaluations of coronary artery blood flow before and after intervention were expressed as thrombolysis in myocardial infarction (TIMI) flow grade. TIMI myocardial perfusion (TMP) grade as an indicator of blood flow at the myocardial level was evaluated.^14,15 Left ventriculography was performed using the right anterior oblique veiw, and the area was divided into segments 1 through 5. Wall motion was quantified using 4 levels: 1 = normal, 2 = decreased, 3 = no contraction, and 4 = paradoxical contraction, and the total was set as the total wall motion coefficient.¹⁶ Left ventricular ejection fraction (LVEF) was calculated by the area-length method or the Simpson method. Clinical success was defined as residual stenosis of ≤30%, with a flow of ≥TIMI 2, and the absence of death or need for emergency bypass surgery. Distal protection device. The GuardWire Plus was the distal protection device used. The GuardWire consists of a 0.014 inch guidewire incorporating a central inflation lumen to which an elastomeric balloon is attached distally. The main part of the 0.014 inch profile was passed through the culprit lesion. In doing so, it allowed the normal PCI wire to pass first and advance the GuardWire using the “buddy wire” technique. The crossing profile of 0.036 inches results in balloon inflation with the subsequent cessation of antegrade blood flow. Liberated debris is suspended within a stagnant column of blood and is aspirated through the 5 Fr monorail Export catheter. The GuardWire balloon is then deflated and flow restored.
Electrocardiography. An ECG was recorded before PCI and at 30 minutes and 6 hours after PCI. Regarding ST resolution, with the sum total of ST-elevation in the infarct-related area as ∑ST, each ∑ST before PCI and at 30 minutes after PCI was calculated. The reduction of ∑ST by 70% or more after PCI was defined as the achievement of complete ST resolution.³
Pathologic assessment. The material collected with the GuardWire was fixed with 10% formalin and made into a paraffin block. Thin sections of 4 mm were HE-stained and the polymorphoneutrophils (PMNs) counted at 4 random points. Immunostaining with anti-CD68 antibody was performed at the same time to fix macrophages, and the ratio of PMNs to macrophages per field was calculated. Clinical follow up. The patient’s clinical condition after 1 month and the clinical condition, coronary angiography and left ventriculography after 6 months were followed.
Endpoints. The primary endpoints were no-reflow during and after intervention, TIMI flow grade and TMP grade in the final angiography after PCI. The secondary endpoints were major cardiac events during 1 and 6 months of follow up, which were defined as death, nonlethal myocardial infarction, heart failure and ischemia-driven revascularization.
Statistics. Continuous variables were recorded in mean and standard deviation, and tested by the unpaired Student’s t-test when they followed normal distribution, and by the Wilcoxon test when they did not. Category variables were recorded as number and percentage, and tested by the Chi-square test or Fisher’s exact test. In addition, a logistic regression model was used to analyze the independent factors of the primary endpoints and the independent factors for major adverse clinical events (MACE) after 1 and 6 months and 95% confidence intervals. Statistical analysis was performed using SPSS version 13.0 for Windows (SPSS, Inc., Chicago, Illinois).

Results

Between December 1, 2003 and April 2004, 167 patients from 14 centers throughout Japan were enrolled and randomized. Among them, PCI was performed in 154 patients — 80 in the GuardWire group and 74 in the control group. One hundred fifty-one patients — 79 in the GuardWire group and 72 in the control group — except the dropouts, were followed and examined.
Patient population. The clinical characteristics of the study population are summarized in Table 1. The GuardWire group experienced a significantly higher frequency of cardiogenic shock than the control group. Table 2 summarizes the angiographic findings. In the GuardWire group, the left anterior descending artery (LAD) was the more likely infarct-related artery, though not significantly so than was the case in the control group. In addition, there was significantly less collateral artery development in the GuardWire group than in the control group. The rate of total occlusion (74% vs. 76%) and the rate showing an abrupt cutoff pattern were also equivalent (Table 2). No significant differences were observed in TIMI flow or TMP prior to intervention. The rate of thrombolysis before PCI was 11% in the GuardWire group, and 7% in the control group, and the rate of thrombectomy before balloon inflation was high, but was equivalent in both groups (63% vs. 68%) (Table 3). Although the procedure time was longer in the GuardWire group than in the control group (76 minutes vs. 53 minutes; p <0.05), no significant differences were observed in the elapsed time before reperfusion (5.2 hours vs. 4.4 hours) (Table 3). Stents with a significantly larger diameter were deployed in the GuardWire group (Table 3). GuardWire procedural results. Clinical success in the GuardWire group was observed in all patients. Visible debris was obtained in 54 (67%) of 80 patients. Balloon inflation was required to pass the GuardWire through the lesion in 7 patients (9%), and the buddy wire was used in 59 patients (73%). During all procedures, a distal protection balloon was used in 72 patients (89%), and the procedural success with the GuardWire was achieved in 77 patients (93%). The breakdown of the 5 procedural failures is as follows: 1 patient in whom the protection balloon could not be used at an appropriate site; 1 patient in whom the distal occlusive balloon at the end of GuardWire did not inflate; 1 patient in whom the balloon could not be deflated; 1 case of coronary dissection by distal occlusive balloon inflation; and 1 case of coronary dissection by the wire end of the GuardWire. However, there were no serious complications attributable to these procedural failures.
Microvascular injury and left ventricular performance. The rate of complete ST resolution was equivalent: 51% in the GuardWire group and 53% in the control group (p = 0.85). No-reflow was nearly equivalent in both groups, occurring in 3 patients (4%) in the GuardWire group, and in 2 patients (3%) in the control group. Distal cut was observed on angiography in 5 patients (6%) in the GuardWire group, and in 4 patients (5%) in the control group, showing no significant differences between the groups. In the final angiography, the rate of TIMI 3 flow was 80% in the GuardWire group and 76% in the control group, showing no statistically significant differences. The rate of TMP 3 was 58% in the GuardWire group and 44% in the control group. Although no statistically significant differences were observed, the GuardWire group tended to show a better TMP result (p = 0.054) (Table 3).
Table 4 displays determinants associated with TMP 3 failure after PCI in univariate and multivariate modeling. Diabetes was significantly related on univariate analysis. Use of the GuardWire and hyperlipidemia were slightly, but not significantly related. Multivariate analysis selected diabetes and hyperlipidemia as the only independent determinants of TMP <3 after PCI. Use of the GuardWire did not show statistically significant differences.
Table 5 demonstrates subgroups and relative risks of GuardWire use for TMP <3 when the patients were limited according to their characteristics in the univariate model. In patients with a culprit lesion in the RCA and patients >70 years of age, it was shown that GuardWire use contributed statistically to attaining TMP 3. LVEF and left ventricular (LV) total wall motion coefficient after intervention were also equivalent (58% vs. 60%; p = 0.99 8.1 vs. 7.7; p = 0.30).
One-month and 6-month clinical outcomes. The breakdown of cardiac events at 1 month, the number and incidence in the two groups, and the relative risks of using the GuardWire for each event are shown in Table 6. No significant differences were observed in other events. There was no statistical significance in the relative risks of using the GuardWire for each event.
LVEF at 6 months was 61.9% in the GuardWire group, and 62.7% in the control group, showing equivalence (p = 0.36). The left ventricular total wall motion coefficient was 7.5 in the GuardWire group, and 7.4 in the control group (p = 0.86), also showing equivalence. Use of the GuardWire was not statistically related to the death rate or to other cardiac events (Table 6).
LVEF and MACE were evaluated considering the clinical outcomes at 6 months in subgroups in which GuardWire use was very effective for TMP 3 achievement after PCI. The LVEF and left ventricular total wall motion coefficient at 6 months in patients with an infarct-related right coronary artery (RCA) were similar, with or without GuardWire use (61.5% vs. 58.0%, 7.1 vs. 7.6, respectively). Among patients >70 years of age, LVEF and left ventricular total wall motion coefficients were also similar, with or without GuardWire use (57.9% vs. 60.2%; 7.5 vs. 7.4, respectively). In these two subgroups, the incidence ratios of cardiac events at 6 months were the same.
Pathologic assessment. Thrombotic pathology in patients in the GuardWire group was examined, and the mean cell number per field was 61 ± 55, as shown in Figure 1. PMNs were dominant in almost all thrombi, and the ratio of PMNs to macrophages was calculated as 9.1 per field on average. The ratio of foam cells and cholesterol crystals was about 30%. The ratio of PMNs to macrophages was significantly higher in patients who could not achieve TMP3 than in those who could, as shown in Figure 1.

Discussion

Safety of the GuardWire. The procedural success rate with the GuardWire system, a balloon occlusion distal protection device, was 93%, and the clinical success rate was 100%; however, the GuardWire was not easy to manipulate, requiring the use of a buddy wire in 73% of cases. The GuardWire system was safe, but significantly prolonged the procedure time.
Microcirculatory impairment after PCI. As typified by the no-reflow phenomenon, distal myocardial reperfusion may not be achieved even if superficial blood vessels are kept open, which is reported to be related to long-term prognosis.^16,17 The presence of microcirculatory impairment was also demonstrated by a new modality in recent reports.^3,6,14,17,18 Therefore, we highlighted TMP as the evaluation of myocardial microcirculatory reperfusion immediately after PCI and expected that the use of the GuardWire would improve the rate of TMP 3. However, DPD did not show significant correlation with the prevention of microcirculatory impairment after PCI, which was the primary endpoint. Several reasons may explain this: (1) Endothelial and myocardial dysfunction. This study demonstrated that diabetes and hypercholesterolemia were independent predictors of failure to achieve TMP 3. Some clinical studies reported that acute hyperglycemia may lead to endothelial dysfunction and myocardial damage, resulting in microcirculatory deterioration,^19,20 and another study reported that hypercholesterolemia induced microvascular dysfunction.²¹ (2) Reduction of thrombotic volume also may have attenuated the GuardWire’s effects. Thrombectomy before balloon inflation was possible in about 50% of patients in both groups, which was not associated with reaching TMP 3 in our study. Some retrospective studies reported that thrombectomy significantly prevented microvascular dysfunction and LV remodeling.^22,23 Thrombectomy may have reduced embolic materials. It has been reported that the risk of no-reflow after PCI for AMI is higher in patients with larger-diameter vessels,²⁴ with lower TIMI flow before intervention and with angiographic distal cut.¹³ It is also reported that no-reflow is likely to occur during PCI of the RCA.²⁵ A large thrombus volume can be expected in all such cases. In our investigation, however, these factors had no relationship with achieving TMP 3 after PCI. (3) Disadvantage of the GuardWire system. All procedures to prepare the GuardWire, dilate the occlusive balloon and finally aspirate, may prolong recanalization time. Vessel occlusion or aspiration of debris by the balloon may not have been complete, as mentioned. In particular, our study population in the GuardWire group had more LAD infarct-related arteries, which had more unprotected branches by DPD. (4) Impact of neutrophils on microcirculation. Furthermore, the GuardWire was not able to prevent the release of chemical mediators which caused microvessel injuries such as endothelial bleb, collapse by edematous myocardium and white cell plugging. In fact, our thrombotic pathology demonstrated a greater number of neutrophils than macrophages, which have been mainly reported to play an important role in AMI.^26,27 In addition, we confirmed that the more neutrophils found in thrombi, the less TMP 3 after PCI. Since the 1980s, the direct role of neutrophils in tissue damage has been reported,^27,28 and a significantly high number of neutrophils in thrombi are reported in patients with acute coronary syndromes, supporting our study.²⁸ In the patients with chronic coronary disease, plaque stability is regulated by the integrity of pericellular matrix of the endothelial cells and smooth muscle cells of the fibrous cap. On the contrary, a plaque becomes unstable by apoptosis of smooth muscle cells and foam cells, and leads to rupture in the patients with AMI. Then, inflammatory cells like neutrophils and macrophages are activated and secrete a variety of humoral factors, which result in acute inflammation.²⁷
These reports suggest that microcirculatory impairment is not solely caused by the distal embolization of atheromatous or thrombotic debris. Microcirculatory impairment is also considered to be caused by neutrophils by the direct effect of inflammatory mediators, including myeloperoxidase, elastase and PR3, on microcirculation, or by their effect on the myocardium, leading to myocardial damage.^27–30 Therefore, we think that balloon occlusion DPD, like the GuardWire, cannot prevent the above-mentioned cells and humoral factors from flowing into the distal microcirculation, which directly or indirectly causes microcirculatory impairment by this mechanism and leads to limitations.
Possible GuardWire benefits. As a result of subanalyzing various conditions, we recognized that TMP3 could be significantly achieved by using the GuardWire in patients >70 years of age and in patients whose infarct-related lesion was in the RCA. It was thought that the RCA was suitable for complete occlusion and aspiration because it has fewer branches than the LAD. Similarly, it was thought to be useful in patients >70 years of age because aging causes the impaired myocardial capillary bed to decrease coronary flow reserve. In this situation, any small embolic debris may easily cause no-reflow. As mentioned above, it was considered that microcirculatory impairment after PCI could be prevented by the GuardWire system by limiting the cases, however, because this study population was not large enough to be analyzed, further investigation is needed.
Prognosis. Although efficacy in preventing microcirculatory impairment after PCI was observed if the cases were limited, it had no effect on prognosis, including long-term LVEF. The lack of differences in the ratio of TMP 3 after PCI between the two groups led to the same prognosis at 6 months in both groups. In addition, we presumed two other reasons why the GuardWire did not improve long-term prognosis. First, neutrophils and platelets directly occluded micro blood vessels because the GuardWire could not prevent all distal embolization and flowed into the myocardial capillary bed, directly or indirectly, through inflammatory mediators, causing myocardial damage as previously mentioned.^27–29,31 Neutrophils, on which we focused in a substudy of this investigation, are reported not only to affect microcirculation, but also to cause systemic inflammation by turning into activated neutrophils through the coronary circulation, as suggested by the increase in interleukin-6 and C-reactive protein (CRP).³² It has also been reported that neutrophils in AMI act in a systemically inflammatory manner, leading to LV myocardial damage.³³ Furthermore, there is also a report that myeloperoxidase released from neutrophils is a strong predictive factor for cardiovascular events after AMI.³⁴ Second, both study groups demonstrated good LV function at baseline. A recent clinical study reported that the long-term prognosis of AMI depends on LVEF at baseline, and the long-term improvement in LVEF has a negative correlation with LVEF at baseline.³⁵ In this investigation, the mean percent LVEF at baseline was 58% in the GuardWire group, and 60% in the control group. The rate of patients with LVEF <40% was only 4% in the GuardWire group, and 8% in the control group, showing good LVEF at baseline in both groups. Since the prognosis was good and the improvement rate was very low in both groups, we considered that no statistical differences were observed between the groups.

Study limitations. Although this was a randomized, prospective study, the following limitations apply: the number of patients was small, lesion morphology was not assessed by intravascular ultrasound, DPD could not be used throughout all PCI procedures in all patients in the GuardWire group, and it is possible that the protocol, which allowed thrombectomy with aspiration in the two groups, might have changed the thrombus volume.

Conclusion

The use of a distal protection device in AMI succeeded in preventing microcirculatory impairment after PCI in patients with a culprit lesion in RCA and patients >70 years of age, but did not improve LV remodeling or long-term prognosis.

References

1. Robert N, Piana RN, Paik GY, et al. Incidence and treatment of “no-reflow” after percutaneous coronary intervention. Circulation 1994;89:2514–2518.
2. Ito H, Maruyama A, Iwakura K, et al. Clinical implications of the “no reflow” phenomenon: A predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction. Circulation. 1996;93:223–228.
3. Shah A, Wagner GS, Califf RM, et al. Comparative prognostic significance of simultaneous versus independent resolution of ST segment depression relative to ST segment elevation during acute myocardial infarction. J Am Coll Cardiol 1997;30:1478–1783.
4. Claeys MJ, Bosmans J, Veenstra L, et al. Determinants and prognostic implications of persistent ST-segment elevation after primary angioplasty for acute myocardial infarction. Circulation 1999;99:1972–1977.
5. Lepper W, Hoffmann R, Kamp O, et al. Assessment of myocardial reperfusion by intravenous myocardial contrast echocardiography and coronary flow reserve after primary percutaneous transluminal coronary angiography in patients with acute myocardial infarction. Circulation 2000;101:2368–2374.
6. Stone GW, Cox D, Garcia E, et al. Normal flow (TIMI-3) before mechanical reperfusion therapy is an independent determinant of survival in acute myocardial infarction. Circulation 2001;14:636–641.
7. Yamamoto K, Ito H, Iwakura K, et al. Two different coronary blood flow velocity patterns in thrombolysis in myocardial infarction flow grade 2 in acute myocardial infarction. J Am Coll Cardiol 2002;40:1755–1760.
8. Trono R, Sutton C, Hollman J, et al. Multiple myocardial infarctions associated with atheromatous emboli after PTCA of saphenous vein grafts. Cleve Clin J 1989;56:581–584.
9. Baim DS, Wahr D, George B, et al on behalf of the Saphenous vein graft angioplasty Free of Emboli Randomized (SAFER) trial investigators. Circulation 2002;105:1285–1290.
10. Webb JG, Carere RG, Virmani R, et al. Retrieval and analysis of particulate debris after saphenous vein graft intervention. J Am Coll Cardiol 1999;34:468–475.
11. Sutsch G, Kiowski W, Bossard A, et al. Use of an emboli containment and retrieval system during percutaneous coronary angioplasty in native coronary arteries. Schwiez Med Wochenschr 2000;130:1135–1145.
12. Stone GW, Webb J, Cox DA, et al. Distal microcirculatory protection during percutaneous coronary intervention in acute ST-segment elevation myocardial infarction. JAMA 2005;293:1063–1072.
13. Yip H, Wu CJ, Chang HW, et al. Angiographic morphologic features of infarct-related arteries and timely reperfusion in acute myocardial infarction: Predictors of slow-flow and no-reflow. Chest 2002;122:1322–1332.
14. van‘t Hof AW, Liem A, Suryapranata H, et al. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction myocardial blush grade. Circulation 1998;97:2302–2306.
15. Gibson CM, Cannon CP, Murphy SA, et al. Relationship of TIMI myocardial perfusion grade to mortality after administration of thrombolytic drug. Circulation 2000;101:125–130.
16. Ban K, Nakajima T, Iseki H, et al. Evaluation of global and regional left ventricular function obtained by quantatative gated SPECT using 99mTc-tetrofosmin for left ventricular dysfunction. Internal Med 2000;39;612–618.
17. Okamura A, Ito H, Iwakura K, et al. Detection of embolic particles with the Doppler guide wire during coronary intervention in patients with acute myocardial infarction. J Am Coll Cardiol 2005;45;212.
18. Ito H, Terai K, Iwakura K, et al. Hemodynamics of microvascular dysfunction in patients with anterior wall acute myocardial infarction. Am J Cardiol 2004;94:209–212.
19. Williams SB, Goldfine AB, Timimi FK, et al. Acute hyperglycemia attenuates endothelium-dependent vasodilation in humans in vivo. Circulation 1998;97:1695–1701.
20. Ishihara M, Kojima S, Sakamoto T, et al. Japanese Acute Coronary Syndrome Study Investigators. Acute hyperglycemia is associated with adverse outcome after acute myocardial infarction in the coronary intervention era. Am Heart J 2005;150:814–820.
21. Porcel MR, Lerman A, Ritman EL, et al. Altered myocardial microvascular 3D architecture in experimental hypercholesterolemia. Circulation 2000;102:2028.
22. Kondo H, Suzuki T, Fukutomi T, et al. Effects of percutaneous coronary arterial thrombectomy during acute myocardial infarction on left ventricular remodeling. Am J Cardiol 2004;93:527–531.
23. Tguchi I, Kanaya T, Toi T, et al. Comparison of the effects of a distal embolic protection device and an aspiration catheter during percutaneous coronary intervention in patients with acute myocardial infarction. Circ J 2005;69:49–54.
24. Tanaka A, Kawarabayashi T, Nishibori Y, et al. No-reflow phenomenon and lesion morphology in patients with acute myocardial infarction? Circulation 2002;105:2148–2152.
25. Nagata Y, Usuda K, Uchiyama A, et al. Characteristics of the pathological images of coronary artery thrombi according to the infarct-related coronary artery in acuter myocardial infarction. Circ J 2004;68849:308–314.
26. Varnava AM, Mills PG, Davies MJ. Relationship between coronary artery remodeling and plaque vulnerability. Circulation 2002;105:939–943.
27. Lindstedt KA, Leskinen MJ, Kovanen PT. Proteolysis of the pericellular matrix. A novel element determining cell survival and death in the pathogenesis of plaque erosion and rupture. Arterioscler Thromb Vasc Biol 2004;24:1350–1358.
28. Hansen PR. Role of neutrophils in myocardial ischemia and reperfusion. Circulation 1995;91:1872–1885.
29. Reimer KA, Murry CE, Richard VJ. The role of neutrophils and free radicals in the ischemic-reperfused heart: Why the confusion and controversy? J Mol Cell Cardiol 1989;21:1225–1239.
30. Naruko T, Ueda M, Haze K, et al. Neutrophil infiltration of culprit lesions in acute coronary syndromes. Circulation 2002;106:2894–2900.
31. Michaels AD, Gibson CM, Barron HV. Microvascular dysfunction in acute myocardial infarction: Focus on the roles of platelet and inflammatory mediators in the no-reflow phenomenon. Am J Cardiol 2000;85:50B–60B.
32. Buffon A, Biasucci LM, Liuzzo G, et al. Widespread coronary inflammation in unstable angina. N Engl J Med 2002;347:5–12.
33. Vasilyev N, Williams T, Brennan ML, et al. Myeloperocidase-generated oxidants modulate left ventricular remodeling but not infarct size after myocardial infarction. Circulation 2005;112:2812–2820.
34. Baldus S, Heeschen C, Meinertz T, et al. on behalf of the CAPTURE Investigators. Circulation 2003;10:1440–1445.
35. Halkin A, Stone GW, Dixon SR, et al. Impact and determinants of left ventricular function in patients undergoing primary percutaneous coronary intervention in acute myocardial infarction. Am J Cardiol 2005;96:325–331.