Fluffy Luminal Surface of the Non-Stenotic Culprit Coronary

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Advance Publication by J-STAGE Circulation Journal Official Journal of the Japanese Circulation Society http://www.j-circ.or.jp Fluffy Luminal Surface of the Non-Stenotic Culprit Coronary Artery in Patients With Acute Coronary Syndrome – An Angioscopic Study – Yasumi Uchida, MD; Yasuto Uchida, MD; Takeshi Sakurai, MD; Masahito Kanai, MD; Seiichiro Shirai, MD; Tomomitsu Oshima, MD; Atsushi Koga, MD; Akimasa Matsuyama, MD; Tsuyoshi Tabata, PhD

Background: Approximately 15% of acute coronary syndrome (ACS) cases have no significant coronary stenosis. Mechanisms underlying the attacks are, however, unknown.

Methods and Results: The clinical study had 254 patients with ACS; 38 patients (31 females and 7 males; aged 51.0±8.0 years) had no significant coronary stenosis on angiography. They underwent a dye-staining angioscopy of the suspected culprit coronary artery using Evans blue, which selectively stains fibrin and damaged endothelial cells. A fluffy coronary luminal surface was observed in the suspected culprit artery in all 38 patients. The fluffy luminal surface was stained blue with Evans blue. In animal experiments involving 5 beagles, 10% hydrogen peroxide solution was injected into the iliac arteries to damage endothelial cells, which was then followed by blood reperfusion, and then the artery was examined by intravascular microscopy and histology. In the beagles, the arterial segment, where the thrombus had been formed, exhibited a fluffy luminal surface after a washout of the thrombus, and the surface was stained blue. Histologically, the fluffy surfaces were composed of damaged endothelial cells attached by multiple fibrin threads and platelets.

Conclusions: It was considered that the coronary segment exhibiting a fluffy luminal surface was the culprit lesion and that the fluffy surface was caused by residual thrombi after dispersion of an occlusive thrombus, which had formed on the damaged endothelial cells.

Key Words: Acute coronary syndrome; Dye-staining angioscopy; Endothelial cell damages; Fibrin and platelets; Fluffy coronary luminal surface

cute coronary syndrome (ACS) is generally caused by nary stenosis frequently exhibit impaired coronary flow, as an occlusive thrombus formed on a disrupted plaque. assessed angiographically, coronary microvascular dysfunc- A There are ACS patients in whom significant coro- tion was proposed as a causative mechanism for the attacks; nary stenosis (>50% luminal diameter stenosis) is not ob- however, definitive evidence has not yet been demonstrated served angiographically. Nesto et al reported that 13% of to support this.5 patients with unstable angina (UA) had no significant coro- Angioscopy has been clinically used for imaging the nary stenosis on angiography.1 Hochman et al reported that changes in the coronary artery.6–13 During angioscopic exam- 15% of patients with UA and non-ST elevation myocardial ination of the culprit coronary arteries in patients with ACS, infarction (NSTEMI) had no significant coronary stenosis.2 the authors of the present study noticed the culprit but non- Similar findings have been reported by others.3,4 stenotic coronary artery had a fluffy luminal surface in patients As patients with UA/NSTEMI without significant coro- with ACS. Therefore, the incidence and mechanism(s) of

Received May 7, 2010; revised manuscript received June 22, 2010; accepted June 28, 2010; released online September 4, 2010 Time for primary review: 19 days Japan Foundation for Cardiovascular Research, Funabashi (Y.U.); Cardiovascular Center, Toho University Medical Center Sakura Hospital, Sakura (Y.U., T.S., M.K.); Department of Cardiology, Tokyo Jikei University School of Medicine, Tokyo (Y.U., A.K., A.M.); Department of Cardiology, Toho University Medical Center Ohmori Hospital, Tokyo (Yasuto Uchida); Department of Cardiology, Funabashi-Futawa Hospital, Funabashi (S.S., T.O.); and Clinical Physiology, Toho University Medical Center Sakura Hospital, Sakura (T.T.), Japan Mailing address: Yasumi Uchida, MD, Japan Foundation for Cardiovascular Research, 2-30-17 Narashinodai, Funabashi 274-0063, Japan. E-mail: [email protected] ISSN-1346-9843 doi: 10.1253/circj.CJ-10-0422 All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected] Advance Publication by J-STAGE UCHIDA Y et al.

Figure 1. A smooth surfaced white plaque in the left anterior descending artery, demonstrated for comparison with a fluffy luminal surface. A 60-year-old male with stable angina. (A) Angiogram of the left coronary artery showing a stenosis in the middle segment of the left anterior descending artery (arrow B). (B) Angioscopic image of a white plaque (arrow) that corresponded to the stenotic portion in (A). The surface of the plaque was smooth and sharply margined.

Figure 2. Fluffy luminal surface of the left anterior descending artery. A 51-year-old female with unstable angina (UA). (A) An- giogram of the left coronary artery. Arrow: The middle segment of the left anterior descending artery observed by angioscopy is shown by the arrow B. The margin of the segment was irregular. (B-1) Angioscopic image of the same segment. The entire circumference of the luminal surface was fluffy (diffuse type) and white (arrows). Arrowhead: guidewire. (B-2) The fluffy surface was diffusely stained blue with Evans blue (arrow).

this angioscopic changes were examined. Tokyo, Japan), a 5-F angioscope (VecMover; Clinical Supply Co, Gifu, Japan) and a color chilled charge-coupled device (CCD) camera (CSVEC-10; Clinical Supply). Before carry- Methods ing out the angioscopic examination, the white balance of Clinical Study the camera was adjusted for color correction. The system Subjects From 1 April 2000 to 31 March 2009, 254 has been approved for clinical use by the Japanese Ministry patients with ACS underwent coronary angioscopy at our of Health, Labor and Welfare. Details of this system are hospitals. Of these patients, 38 (31 females and 7 males; described elsewhere.11,14 mean ± SD age, 51.0±8.0 years; 25 with UA, 11 with NSTEMI Conventional Angioscopy Coronary angioscopy was car- and 2 with ST-elevation myocardial infarction (STEMI)) ried out at the Toho University Sakura Hospital (Sakura, had no significant stenosis of the suspected culprit coronary Japan) and Funabashi-Futawa Hospital (Funabashi, Japan) artery, whereas 216 (64 females and 152 males; age 60.0± with the approval of their Institutional Review Boards. All 7.1 years; 75 with UA, 40 with NSTEMI and 115 with patients in the present study provided their informed consent STEMI) had significant stenoses of the suspected culprit with regard to all the procedures followed herein. coronary arteries. All patients received heparin (5,000 IU iv) just before Coronary Angioscopy System The angioscopy system was the procedure and nitroglycerin (200μ g, ic) just before the composed of a light source (OTV-A; Olympus Corporation, coronary angiography. The diameter stenosis of the coronary Advance Publication by J-STAGE Fluffy Coronary Luminal Surface in ACS

Figure 3. Diffuse and patchy types of the fluffy coronary luminal surface. (A-1) A diffuse type of the fluffy luminal surface before EB (arrows). (A-2) The same portion after EB. The fluffy portion was stained blue (arrows). Arrowheads in (A-1) and (A-2): guidewire. (B-1) A patchy type of fluffy luminal surface before EB (arrows). (B-2) The same portion after EB. The surface was stained blue in a patchy fashion (arrows). EB, Evans blue.

artery was measured by TCS Symphony 2.02 (McKesson Co, Animal Experiments North Charleston, SC, USA), and expressed as a percentage. Animal experiments were performed not to produce an ACS After a coronary angiography of a culprit coronary artery model but to examine what happened when blood was per- was performed, which was suspected by electrocardiography, fused into the artery after diffuse endothelial cell damage. ultrasonic echocardiography and angiography, an angioscope Animal experiments were carried out at the Institute for was introduced into the artery. The balloon of the angioscope Animal Experiments of the Jikei University School of Medi- was inflated to stop the blood flow therein. The fiberscope cine (Tokyo). The protocols followed when conducting the incorporated into the angioscope was slowly advanced up experiments on animals were approved by the University to 7 cm distally to facilitate successive observations of the Administrative Panel on Laboratory Animal Care. artery while displacing the blood by infusion of heparinized Five beagles were anesthetized with pentobarbital sodium saline solution (10 IU/ml) at a rate of 2 ml/s for 10–20 s (30 mg/kg, iv). The abdominal aorta below the renal arteries through the flash channel of the angioscope. and both right and left iliac arteries and their branches were To confirm the accurate location of the angioscope tip constricted with threads. One 8-F catheter and one 9-F cathe- (and accordingly the observed portion), the angioscopic and ter were introduced in retrograde fashion into the left and fluoroscopic images were displayed simultaneously on a tele- right iliac arteries, respectively. Subsequently, a saline solu- vision monitor. tion was infused at a rate of 20 ml/min through the left iliac Dye-Staining Coronary Angioscopy Evans blue is a blue artery into the right iliac artery. Next, a 9-F intravascular dye that had been used clinically for cardiac output measure- microscope, which enables observation of a target at up to ment for many years. Since 1995, this dye has been clinically x350 magnification, was introduced into the right iliac artery administered into the arterial system for staining damaged for observation. The 5 ml of 10% hydrogen peroxide solution endothelial cells and fibrin without obvious side effects.14,15 was then injected into the perfusion circuit to damage the Beneficial effects of this dye in the prevention of coronary endothelial cells, and the blood from the aorta was allowed to restenosis has been proven.16 drain into the right iliac artery by the loosening of the aortic Thirty-eight patients who had no significant stenosis of the occlusion. Five minutes later, the luminal changes in the right suspected culprit coronary artery underwent a dye-staining iliac artery were observed again followed by an injection coronary angioscopy. After observation by conventional of 0.2 ml 2.5% Evans blue solution into the perfusion circuit. angioscopy, 1 ml of 2.5% Evans blue solution was injected After repeated intravascular microscopic observation, the during balloon inflation into the artery through the flush beagles were sacrificed by an intravenous administration of channel of the angioscope to stain the damaged endothelial pentobarbital sodium (100 mg/kg) and potassium chloride cells and fibrin, and then the balloon was deflated to allow (50 mg/kg), and the right iliac artery was excised and fixed for blood flow restoration. One to 2min later, the balloon was with 10% formaldehyde solution. The artery was then cut into inflated again and the coronary luminal surface was observed 10-μm thick slices, and the slices were stained by Giemsa angioscopically. The details are described elsewhere.14 staining for platelets and by Mauritius Scarlet-blue staining Advance Publication by J-STAGE UCHIDA Y et al.

Table. Backgrounds of ACS Patients With a Non-Stenotic Culprit Coronary Artery With a Fluffy Luminal Surface and Those With Coronary Occlusion Fluffy surface Coronary occlusion P value group (n=38) group (n=216) Age years (mean ± SD) 51.0±8.0 60±7.1 0.033 Female gender, n (%) 31 (81) 55 (25) 0.0001 ACS subgroups, n (%) UA 25 (66) 75 (35) 0.048 NSTEMI 11 (29) 40 (18) NS STEMI 2 (5) 115 (53) 0.01 Culprit vessel, n (%) LAD 19 (50) 122 (56) NS LCx 7 (18) 38 (18) NS RCA 12 (32) 56 (26) NS No. of non-stenotic (<50% diameter stenosis) vessel, n (%) 38 (100) 0 (0) 0.00011 No. of diseased (>– 75% diameter stenosis) vessels 1 0 (0) 130 (60) 0.0001 2 0 (0) 65 (30) 0.0009 3 0 (0) 21 (10) NS Risk factors, n (%) Diabetes mellitus 2 (5) 51 (24) 0.025 Hypertension 11 (29) 101 (47) NS Dyslipidemia 8 (21) 102 (47) NS Current smoking 20 (52) 70 (32) 0.044 Medicines before attack Nitrates 2 (5)* 34 (16) NS Aspirin 0 (0) 22 (10) NS Ticlopidine 0 (0) 9 (4) NS No medicines 36 (95) 182 (84) NS ACS, acute coronary syndrome; UA, unstable angina; NSTEMI, non-ST elevation myocardial infarction; STEMI, ST-elevation myocardial infarction; NS, not significant. *Two patients had been treated for vasospastic angina. There were significant (P<0.05) differences in age, gender, UA, STEMI, diabetes mellitus, and current smoking between the 2 groups. for fibrin. A slice was also used for electron microscopic stained in patchy fashion in 9 patients (patchy type). study. Details of the intravascular microscopy are described Exposed atheromatous tissues indicating disrupted plaques, elsewhere.15 or concave portions suggesting erosion/ulcer were not observed in the fluffy portions. Statistical Analysis In 1 patient with NSTEMI not included in Table, the proxi- The age of patients were expressed as the mean ± SD and was mal segment of the right coronary artery was not stenotic but evaluated by the Student’s t-test. Other data were evaluated showed a fluffy luminal surface, and a streamer-like throm- by the χ2 test. A P<0.05 was considered significant. bus was detected in the middle-to-distal segments of the same artery (Figure 4). The thrombus disappeared after a selec- tive injection of a plasminogen activator with monteplase Results (27,500 U) was made into the artery. Angioscopically, no Clinical Study disrupted plaque was detectable in the segments where the Fluffy Coronary Luminal Changes Figure 1 shows the thrombus had been located, suggesting that the thrombus angioscopic appearances of a coronary plaque without a had detached from the fluffy portion and had flown distally. fluffy surface as a reference. The plaque surface was smooth Before dye staining, the fluffy luminal surface, both the and sharply margined. This is the characteristic appearance diffuse and patchy types, were confined to a coronary seg- of non-disrupted plaques. ment at most approximately 2 cm in length, not throughout Figure 2 shows a representative example of a fluffy coro- the proximal to distal segments, and exhibited a white color in nary luminal surface in a patient with UA. In this patient, 31 patients, and a yellow color in the remaining 7 patients. there was no significant coronary stenosis (>50% diameter The time required for conventional and dye-staining stenosis). The proximal segment of the left anterior descend- angioscopy was 10–15 min. No complications attributable ing coronary artery showed a white and fluffy luminal surface, to the dye were noted. and this segment was stained blue with Evans blue. Predictors of Fluffy Coronary Luminal Changes Table A similar fluffy luminal surface was observed in the sus- summarizes the backgrounds of patients having a non-ste- pected culprit coronary arteries in all of the other 37 patients. notic coronary artery with a fluffy luminal surface and those As shown in Figure 3, the entire circumference of a coro- with occlusion or significant stenosis of the suspected culprit nary segment was fluffy and stained blue in 29 patients (dif- artery. fuse type), and a part of the circumference was fluffy and Of 254 ACS patients, 38 had non-stenotic (<50% diame- Advance Publication by J-STAGE Fluffy Coronary Luminal Surface in ACS

Figure 4. Fluffy luminal surface of the proximal segment of the right coronary artery and a thrombus in the middle-to-distal segments. A 56 year-old-female with non-ST elevation myocardial infarction (NSTEMI). (A) Angiogram of the right coronary artery. The middle-to-distal segments showed a typical lead-pipe sign, indicating thrombus (between the arrowheads). (B-1) Fluffy luminal surface of the entire circumference of the proximal segment (arrows), which corresponded to the segment indicated by the arrow B in (A) (diffuse type). Arrowhead: guidewire. (B-2) The same proximal segment stained blue with Evans blue (arrows). Arrowhead: guidewire. (C) The head of the thrombus (arrow) that corresponded to arrowhead-1 in (A).

Figure 5. Fluffy luminal changes reproduced in the iliac artery in a beagle. Intravascular microscopic images of the right iliac artery before (A) and after endothelial cell damage by administration of hydrogen peroxide solution followed by blood reperfusion (B). The luminal surface that was smooth before (arrow in A) became fluffy after blood reperfusion (arrows in B). (C) Intravas- cular microscopic image magnified at ×100 of the same portion. The fluffy surface was composed of seaweed-like structures stained blue with Evans blue (arrows). (D) Platelets (arrows) attached on fibrin threads arising from the luminal surface. Giemsa stain. (E) A fibrin thread arising from the luminal surface (arrow) Mauritius-Scarlet blue stain. (F) Vacuolated endothelial cells (arrows) demonstrated by electron microscopy. Horizontal bars in (D) and (E): 20μ m. Horizontal bar in (F): 10μ m. Advance Publication by J-STAGE UCHIDA Y et al. ter stenosis) coronary arteries, while 216 had significant coro- Histologically, vascular erosion and ulcer are defined as nary stenosis (≥75% diameter stenosis). loss of endothelium with or without loss of internal elastic Angioscopically, the luminal surface of the suspected cul- lamina, and loss of tissues extending to deeper than the inter- prit artery exhibited a fluffy luminal surface in all 38 patients nal elastic lamina, respectively. In a preliminary study on with non-stenotic arteries (fluffy surface group), whereas excised human coronary artery, the damaged endothelial the remaining 216 patients had an occlusive thrombus in the cells were stained blue with Evans blue whereas the internal suspected coronary artery (coronary occlusion group). elastic lamina and the tissues located deeper than the elastic Eighty-one percent of the fluffy surface group were females lamia (including atheromatous tissues) were not stained blue.18 and mostly suffered from UA/NSTEMI. The mean age of the Furthermore, it is known that fibrin is formed on the dam- fluffy group was less than that of the coronary occlusion group. aged endothelial cells and atheromatous tissues and not on Current smoking was more frequent in the fluffy surface other tissues such as collagen fibers.18 group (Table). In the present study, atheromatous tissues indicating plaque disruption and concave appearance suggesting erosion/ulcer Animal Experiments were not observed in the fluffy portions. It was considered Figure 5 shows a canine iliac artery before and after hydro- therefore that the fluffy surface was not caused by fibrin gen peroxide administration followed by blood reperfusion. attachment on the disrupted plaque or erosion/ulcer, but was Before hydrogen superoxide administration, the luminal sur- caused by damaged endothelial cells attached by fibrin. face was smooth and sharply margined. The majority of patients with a fluffy coronary luminal sur- In contrast, after administration of this agent followed by face suffered from UA/NSEMI. It is possible that an earlier blood reperfusion for 5 min, a globular occlusive thrombus dispersion of an occlusive thrombus resulted in blood flow was formed in the artery. After saline solution infusion for restoration and this prevented the occurrence of STEMI. 5 min, the occlusive thrombus was washed distally and dis- Scirica et al reported that approximately one-third of pa- persed, and the luminal surface where the thrombus existed tients with UA/NSTEMI without a significant coronary ob- exhibited a fluffy luminal surface. The surface was stained struction exhibited impaired coronary blood flow, which was blue with Evans blue. Intravascular microscopy revealed that assessed angiographically, and they suggested participation the fluffy luminal surface was composed of seaweed-like of coronary microvascular dysfunction in this phenomenon.5 structures stained blue with Evans blue. Although the myocardial microcirculation was not examined, Histological examinations revealed multiple fibrin threads the findings in the present study suggest that occlusion of dis- arising from the endothelial cells attached by platelets. An tal microvessels, with the microemboli formed as a conse- electron microscopic study revealed the endothelium con- quence of dispersion of the occlusive thrombus, participates sisted of vacuolated endothelial cells. in microvascular flow disturbance. Women constitute a larger proportion of the population of UA/NSTEMI patients without significant coronary steno- Discussion sis.2,4,5,19 Similarly, the majority of patients with a fluffy lumi- In the present angioscopic study, no significant stenosis was nal surface of a non-stenotic coronary artery in the present observed in the suspected culprit coronary artery in 38 of study were also women. The reason for this sex-related dif- 254 patients with ACS. The non-stenotic culprit coronary ference is obscure. The coronary segment that exhibited a artery exhibited a fluffy luminal surface, while the other 216 fluffy luminal surface was white in color in the majority of patients had a stenotic culprit coronary artery with occlusive patients, indicating that lipid deposition was not the major thrombi. Animal experiments revealed that an occlusive cause of the fluffy luminal change. A sex-related difference thrombus was formed and it disappeared after saline solution in the susceptibility of vascular endothelial cells to mechani- perfusion and the fluffy luminal changes remained at the site cal and/or humoral factors might be one mechanism account- where the thrombus existed. In terms of histology, the fluffy ing for the difference in incidence of fluffy coronary luminal luminal surfaces were due to fibrin threads and platelets changes between women and men. attached to the damaged endothelial cells. In 1 patient, the The patients with a fluffy coronary luminal surface were proximal segment of the right coronary artery had a fluffy younger than those having occlusive thrombi; however, the luminal surface and a streamer-like thrombus was detected reason for this difference also remains unknown. in the downstream segments. After successful thrombolysis, Smoking was prevalent in the patients with a fluffy luminal any disrupted plaque was detectable in the segments, sug- surface in the present study. Ueda et al observed a low inci- gesting that the thrombus had detached from the proximal dence of thrombus on disrupted coronary plaques in young coronary of segment and moved downstream. Taking into (<40 years) patients with acute myocardial infarction. One consideration the results of the animal experiments, it is clinical characteristic of these patients was a high prevalence believed that the fluffy luminal structures in this patient and of smoking, which is similar to that in the present study.20 others were residual thrombi that had remained after detach- Smoking is a well-known coronary risk factor that promotes ment and dispersion of an occlusive thrombus. It is therefore atherosclerosis. Smoking might have played a role in endo- conceivable that the coronary segment exhibiting a fluffy thelial damage and consequent thrombosis in the present luminal surface was the culprit lesion for the attacks and that study. obstruction of the distal epicardial coronary arteries and/or A thrombus that has formed on a disrupted yellow plaque small vessels with the detached thrombus also contributed to does not detach easily because the disrupted yellow plaques the attacks. are highly thrombogenic, and therefore have strong affinity In a previous study, an angioscopy of the coronary artery to thrombi. It is conceivable that because the fluffy portion after spasm provocation with acetylcholine was performed. where the thrombus formed was not a disrupted plaque, the The coronary segment, where the spasm was induced, did not thrombus was weakly attached to the damaged endothelial exhibit a fluffy luminal surface.17 It is therefore unlikely that cells and was detached easily and dispersed, and so the fluffy the fluffy luminal surface was the change caused by a spasm. luminal changes (ie, residual thrombus) remained. Advance Publication by J-STAGE Fluffy Coronary Luminal Surface in ACS

agement of unstable angina pectoris (the GUARANTEE registry). Conclusions Am J Cardiol 1999; 84: 1145 – 1150. A fluffy luminal surface was observed in the culprit but non- 6. Takano M, Mizuno K. Coronary angioscopic evaluation for serial changes of luminal appearance after pharmacological and catheter stenotic coronary artery in 38 of 254 patients with ACS. interventions. Circ J 2010; 74: 240 – 245. Eighty-one percent of them were female patients who were 7. Hirayama A, Saito S, Ueda Y, Takayama T, Honye J, Komatsu S, afflicted with UA/NSTEMI. Female gender, a smoking habit et al. Qualitative and quantitative changes in coronary plaque asso- and a younger age were the predictors of this phenomenon. ciated with atorvastatin therapy. Circ J 2009; 73: 718 – 725. 8. Ueda Y, Ogasawara N, Matsuo K, Hirotani S, Kashiwase K, Hirata The fluffy luminal surface was stained blue with Evans blue, A, et al. Acute coronary syndrome: Insight from angioscopy. Circ J which selectively stains damaged endothelial cells and fibrin. 2010; 74: 411 – 417. The same change was reproduced in an animal artery after 9. Uchida Y. Coronary angioscopy: From tissue imaging to molecular endothelial cell damage. Histologically, the fluffy luminal sur- imaging. Current Cardiovasc Imaging Reports 2009; 22: 284 – 292. 10. Uchida Y, Uchida Y, Kawai S, Kanamaru R, Kameda N. Imaging face was composed of damaged endothelial cells attached by of lysophosphatidylcholine in human coronary plaques by color fibrin threads and platelets. The fluffy luminal change was fluorescence angioscopy.Int Heart J 2010; 51: 129 – 133. therefore considered to be caused by the residual thrombi after 11. Uchida Y, Uchida Y, Kawai S, Kanamaru R, Sugiyama Y, Tomaru dispersion of an occlusive thrombus formed on the damaged T, et al. Detection of vulnerable coronary plaques by color fluores- cent angioscopy. JACC Imaging 2010; 3: 398 – 408. endothelial cells. The mechanism for this extensive endo- 12. Inami S, Ishibashi F, Waxman S, Okamatsu K, Seimiya K, Takano thelial cell damage, however, remains to be elucidated. It is M, et al. Multiple yellow plaques assessed by angioscopy with quan- well known that catecholamines induce damage to vascular titative colorimetry in patients with myocardial infarction. Circ J endothelial cells by apoptosis via the catecholamine-β-recep- 2008; 72: 399 – 403. tor-caspase-3 or catecholamine-Bcl-2-caspase-cascades.21,22 13. Takano M, Yamamoto M, Inami S, Xie Y, Murakami D, Okamatsu K, et al. Delayed endothelialization after polytetrafluoroethylene- Whether this mechanism participated in damaging endothe- covered stent implantation for coronary aneurysm. Circ J 2009; 73: lial cells in ACS without significant coronary stenosis remains 190 – 193. to be elucidated. 14. Terasawa K, Fujimori Y, Morio H, Matsuo T, Ozegawa M, Uchida Y. 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