Plaque Gruel of Atheromatous Coronary Lesion May Contribute to the No-Reflow Phenomenon in Patients With Acute Coronary Syndrome
Background— No-reflow associated with direct angioplasty (PCI) of patients with acute coronary syndromes (ACS) is associated with unfavorable results.
Methods and Results— We used a new thrombectomy device to treat 51 lesions in 48 consecutive ACS patients (40 male and 8 female; mean age 63 years) and conducted a microscopic analysis of aspirates and blood samples retrieved from the culprit coronary artery. The first aspirate was collected before PCI and the second was collected separately after percutaneous transluminal coronary angioplasty or stenting, including samples from the no-reflow lumen. Light microscopy showed that the materials obtained from the pre-PCI aspiration consisted of thrombus in 37.5%, thrombus and atheroma in 35.0%, and atheromatous plaque in 27.5%. The materials collected from the post-PCI aspiration were thrombus in 8.3%, thrombus and atheroma in 41.7%, and atheromatous plaque in 50.0%. We then compared the 9 lesions (19.1%) with no-reflow to those without no-reflow. There was no difference in the pre-PCI aspirates. However, after PCI, there was more atheromatous plaque retrieved from patients with no-reflow (P<0.001) as well as significantly more platelet and fibrin complex, macrophages, and cholesterol crystals in the blood aspirated from no-reflow cases. Aspiration of these elements improved the no-reflow in 7 of 9 lesions to TIMI-3 flow.
Conclusions— No-reflow after angioplasty may be caused by gruel that formed from an atheroma attributable to mechanical plaque disruption during intervention.
Received May 5, 2002; revision received June 28, 2002; accepted June 28, 2002.
Percutaneous coronary intervention (PCI) is the most common strategy for treating acute coronary syndromes (ACS).1–3⇓⇓ However, PCI fails to achieve TIMI-3 flow in 12% to 30% of cases, mainly because of the no-reflow phenomenon.4,5⇓ Strategies that are successful in preventing or treating experimental models of no-reflow have not worked in human trials. One possibility is that the mechanisms of no-reflow in experimental and clinical settings are different.6–7⇓ Recently, there have been reports that distal protection devices may be effective in preventing distal embolization.8 However, these reports did not identify the cause of no-reflow, because only visible particles were analyzed.
The present study investigates the mechanisms of slow or no-reflow in humans undergoing PCI for ACS. Using the RESCUE thrombectomy catheter (SciMED/BSC, Inc), intraluminal coronary artery blood samples were collected before intervention and during no-reflow. These samples were analyzed histologically and hematologically to identify lesion components that might contribute to this phenomenon.
Forty-eight consecutive patients with ACS who were treated with PCI using the RESCUE thrombectomy catheter from May 1, 2000, to March 31, 2001, were included. All had acute myocardial infarction (MI) within 72 hours of onset or unstable angina of Braunwald class IIIB (rest angina within 48 hours with no CK-MB elevation). All patients except one were treated by primary PCI. One acute MI patient received intravenous thrombolysis before transfer to our hospital. Risks and benefits of reperfusion therapy were fully explained to each patient; and written consent was obtained. Patient demographics were confirmed by hospital chart review. Risk factors included diabetes mellitus (diet-controlled and oral agent–treated or insulin-treated), hypertension (medication-treated), hypercholesterolemia (treated or >220 mg/dL), and present smoking.
Description of the RESCUE Thrombectomy Catheter
As shown in Figure 1, this device has the following components: (1) a 135-cm-long aspiration catheter with a 4.5F shaft and a 25-cm-long distal monorail wire lumen that is 0.014 in–percutaneous transluminal coronary angioplasty guidewire compatible; (2) a console box that is attached to the aspiration catheter to generate a vacuum (maximum vacuum force is 650 mm Hg); and (3) 150-mL collection bottles that include a filter made of a 400-micron mesh net.
Heparin (10 000 IU) was administered intravenously, and 162 mg of chewable aspirin was given. None of the patients received glycoprotein IIb/IIIa inhibitors; at the time of this study, these drugs were not approved in Japan.
Coronary aspiration was performed several times. The first aspiration was performed before any intervention other than passage of the thrombectomy device (first bottle). Then we changed collection bottles (to the second bottle) and performed an intervention for the lesions that presented >30% stenosis. The second aspiration was performed after each balloon dilatation (n=16) or stent implantation (n=31). Stents were implanted in the case of coronary dissection or when results were suboptimal after balloon angioplasty (provisional stent strategy).
Quantitative coronary angiography was performed using the CMS (MEDIS Inc) system. Qualitative analysis was performed by 2 angiographers blinded to the clinical and pathological data according to the method adopted in previous reports10,11⇓ using Thrombolysis In Myocardial Infarction (TIMI) flow grade and corrected TIMI frame count (CTFC). No-reflow was defined as decrease in TIMI flow immediately after mechanical dilatation by at least one grade compared with TIMI flow before mechanical dilatation—ie, balloon or stent implantation—with no evidence of thrombus, spasm, or dissection.
Visible specimens that were caught by the filter of the collection bottles were fixed in 10% neutral buffered formalin and processed for light microscopy. These materials were sliced into 4-μm-thick paraffin-embedded sections and stained with hematoxylin and eosin, azan, elastic–van Gieson, and silver stains.
We also analyzed the blood that passed through the filter into the collection bottles. This blood was centrifuged, the plasma was removed, and preparation smears were stained (Wright stain) and analyzed hematologically.
All results are reported as mean±SEM. Comparisons between the two groups were made using unpaired t test or Mann-Whitney U test (continuous variables), Fisher’s exact test, or χ2 test (categorical variables, StatView 5.0, SAS Institute Inc). Statistical significance was defined as P<0.05.
Procedural success (defined as successful thrombectomy with or without adjunct balloon dilatation or stent implantation) was achieved in 47 of 51 lesions in 46 patients. One lesion could not be crossed with the guidewire. In another, the RESCUE thrombectomy catheter could not cross the lesion because of a severe bend in the proximal artery and severe calcification of the lesion. After thrombectomy, 25 of 47 lesions (53.2%) showed TIMI-3 flow.
No-reflow occurred in 9 of 47 lesions (19.1%). However, at the end of the procedure, TIMI-3 flow was achieved in 40 of 47 lesions (85.1%). The baseline characteristics of the lesions with and without no-reflow are listed in Table 1.
Angiographic findings, including CTFCs, are shown in Table 2. Quantitative angiography showed no differences between the two groups. The distribution of CTFC was similar in the two groups at baseline and before mechanical dilatation; however, postmechanical dilatation and the end-of-procedure CTFC were larger in the no-reflow group (P<0.0001 and P<0.01, respectively).
Histological Analysis of the Material From the First Bottle
Materials were caught by the filter in 40 of 47 initial aspirations (85.1%). Light microscopy showed that the materials obtained from the initial aspirations consisted of thrombus in 15 cases (37.5%), thrombus and atheroma in 14 cases (35.0%), and atheromatous plaque in 11 cases (27.5%). Examples are shown in Figures 2 and 3⇓.
Histological Analysis of the Material From the Second Bottle
Materials were caught by the filter from the postmechanical dilatation lumen in 12 of 47 cases (25.5%). However, this material (aspirated after PCI) showed thrombus in 1 case (8.3%), thrombus and atheroma in 5 cases (41.7%), and atheromatous plaque in 6 cases (50.0%).
Comparison of Histology From Aspirates of Patients With and Without No-Reflow
We compared patients with and without no-reflow (no-reflow versus reflow) during angioplasty. The frequency of aspiration was similar in the two groups (Table 3). There was no difference in the total number or weight of accumulated thrombi in the no-reflow and reflow groups.
The results of the histological and hematological assessments are shown in Figure 4. There was no difference in the materials obtained in the first bottle comparing no-reflow versus reflow groups. However, the materials in the second bottle differed significantly. With regard to materials that were caught by the filter, there was more atheromatous plaque retrieved from patients with no-reflow (P<0.001). With regard to materials that passed through the filter, there were significantly more platelet and fibrin complexes, macrophages, and cholesterol crystals in no-reflow cases. These results suggest that the aspirates after mechanical dilatation contained atheromatous plaque and plaque components rather than thrombus and that the flow reduction was not caused by residual (intrinsic) thrombus burden at the lesion but by secondary mechanical plaque disruption.
Efficacy of Aspiration From the No-Reflow Vessel
The aspiration that was performed after mechanical dilatation (during which mostly plaque elements were retrieved) was able to improve TIMI flow in most lesions, and it contributed to good final TIMI flow. TIMI flow changes of no-reflow patients are listed in Table 4.
The principal finding of this present study is that no-reflow during PCI in patients with acute coronary syndromes is not just attributable to the thrombus burden but also to plaque components of the atheromatous lesions. There was a shift in intraluminal particulate matter from thrombotic to atherosclerotic debris comparing pre-PCI to post-PCI aspirates, especially in no-reflow lesions. In particular, most no-reflow lesions improved when this intraluminal atherosclerotic debris was removed.
No-Reflow During Mechanical Reperfusion Therapy
The electron microscopic findings in animal experiments of no-reflow suggest that the mechanism is an increase in microvascular impedance to flow secondary to neutrophil plugging of capillaries, myocyte contracture and edema, and endothelial blistering.12,13⇓ However, it is not clear whether these findings apply to no-reflow in humans after PCI treatment of ACS. It has been suggested that ACS in humans are associated with secondary intracoronary thrombus formation and that this thrombus burden may cause distal thromboembolism during PCI.8,9,14⇓⇓ This additive event may blunt the effects of the drugs used to treat this phenomenon.
The present study suggests another possible explanation for no-reflow during PCI of acute coronary syndrome. In the present study, no-reflow occurred in 19.1% of lesions immediately after mechanical reperfusion therapy. Microscopic analysis of the aspirate at the time of no-reflow detected plaque elements—including foam-shaped macrophages, aggregated platelets, and cholesterol crystals—as well as thrombi in the debris. Therefore, it is probable that no-reflow after PCI was attributable not only to distal embolism of thrombus (including atheroemboli) but also to plugging of the coronary microvasculature with plaque components. Especially, activated platelets are known to release vasoactive substances, and, therefore, a potential mechanism for the no-reflow might be arterial contraction, in addition to capillary plugging.
The atheromatous core of the atherosclerotic plaque contains significant amounts of tissue factor.15–17⇓⇓ It has also been reported that vulnerable plaques have the greatest platelet deposition and largest thrombus formation compared with collagen-rich lesions.15 Furthermore, the coronary arteries of the culprit vessel in patients with acute MI are widely diseased with multiple nondisrupted plaques.18 Therefore, sudden flow reduction might be caused by mechanical residual plaque disruption of lipid-rich (atheromatous core) atheroma with secondary platelet and fibrin accumulation. The present study suggests that one of the mechanisms of no-reflow during mechanical reperfusion therapy is iatrogenic plaque disruption. This is consistent with the results of TIMI-II.19,20⇓ In TIMI-II, PCI was performed subsequent to thrombolysis and was associated with worse outcomes.19
A possible alternative explanation is that in those lesions that had no-reflow, thrombus was more likely to be embolized and induce no-reflow, giving the impression that these lesions contained less clot. However, this present study showed a similar degree of stenosis in no-reflow and reflow patients after the initial aspiration. Angiogram being a mere luminogram, this suggested a similar degree of residual intraluminal thrombus in the two groups. This supports our view that it is unlikely that the no-reflow was caused by emboli of residual thrombus.
In the present study, all second aspirates contained platelet aggregates or fibrin-platelet complexes, suggesting that glycoprotein IIb/IIIa inhibitors may attenuate the complications during PCI for ACS patients, although a previous report indicated that the glycoprotein IIb/IIIa was not effective for atheromatous materials.21 Meanwhile, in our study, no-reflow was improved immediately after coronary aspiration in almost all patients. Therefore, bailout use of the direct coronary aspiration strategy may be effective in cases where flow is reduced during PCI.
This study also suggests that a distal protection device may be effective in preventing the secondary embolization associated with PCI. In developing these devices, it is essential to pay attention to the size at which the filters are woven. The present study showed that microscopic materials—those <400 μm—may be important in the pathogenesis of no-reflow.
The number of patients with no-reflow was small. It is uncertain whether the aspiration catheter was able to retrieve embolic materials from the capillary circulation.
We acknowledge the help of the pathology division of the Kansai Rosai Hospital (Dr Hideo Morino and Dr Satoru Munakata) and the excellent technical assistance of Yuriko Urase, Sanae Oohata, and Michiaki Yamane.
Presented in part at the 74th Scientific Sessions of the American Heart Association, Anaheim, Calif, November 11-14, 2001.
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- ↵Grube E, Gerckens U, Yeung AC, et al. Prevention of distal embolization during coronary angioplasty in saphenous vein grafts and native vessels using porous filter protection. Circulation. 2001; 104: 2436–2441.
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- ↵Asakura M, Ueda Y, Yamaguchi O, et al. Extensive development of vulnerable plaque as a pan-coronary process in patients with myocardial infarction: an angioscopic study. J Am Coll Cardiol. 2001; 5: 1284–1288.
- ↵Gersh BJ, Chesebro JH, Braunwald E, et al. Coronary artery bypass graft surgery after thrombolytic in the thrombolysis in myocardial infarction trial, phase II (TIMI-II). J Am Cardiol. 1995; 25: 395–402.
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