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 ste- nosis. 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 corre- sponded 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 por- tion 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 sur- face 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.