Advanced Atheroscrelotic Plaque as a Potential Cause of No-reflow in Elective Percutaneous Coronary Intervention — Intravascular

No-reflow sometimes occurs in percutaneous coronary intervention (PCI) as a terrible complication with an incidence of 2–5%.^1,2 No-reflow has been reported to be related to the presence of thrombus, lipid pool (vulnerable plaque), and other factors in acute coronary syndrome and occurs at a higher rate than in non-acute coronary syndrome. Thus, no-reflow is relatively rare in elective PCIs for native coronary arteries, having an incidence of about 1.0%.³ We have experienced 3 directional coronary atherectomy (DCA) cases that developed no-reflow, most likely due to distal atheroembolism with characteristic intravascular ultrasound (IVUS) images similar to each other in stable angina pectoris. We discuss the relationship between the IVUS imagings and histological findings in three cases with no-reflow due to distal embolism. Case 1. An 80-year-old diabetic man with a history of old myocardial infarction (OMI) had suffered from stable angina pectoris (AP) for 5 years since his first PCI for an unknown lesion at another hospital. His current Canadian Cardiovascular Society (CCS) class was II. He underwent coronary angiograms that showed ostial 90% stenosis in the left anterior descending coronary artery (LAD) and 75% stenosis in the proximal right coronary artery (RCA). He underwent PCI for the ostial LAD de novo lesion on April 20, 2002 (Figures 1 and 2). The angiograms showed it to be moderately calcified and focal. According to the IVUS imagings, this stenosis was composed of eccentric and mixed plaque. There was attenuation of echogenicity (disappearance of backward echo) where there was no massive calcification. Deeply located calcification was detected near the minimal lumen cross sectional area (MinCSA) site. Superficial calcification was also detected at the reference segment. We selected DCA with a Flexicut (large size) for this lesion. After 4 cuts at 1 atmosphere (atm), no-reflow that was possibly due to distal embolization occurred and the hemodynamics deteriorated. His blood pressure recovered by intervention that included intra-aortic balloon pumping, intra-aortic noradrenaline, and intracoronary nicorandil, and we were able to continue with the DCA procedure. We performed 69 cuts at the highest pressure of 10 atm. A total of 56.4 mg of plaque was excised and sent to our pathology laboratory. Final coronary angiograms demonstrated optimal results. Pathologically, the DCA specimens consisted predominantly of hyalinization and a significant amount of calcification. There were also many cholesterin clefts. There were no lipids or foamy macrophages. These findings suggested that this plaque was very old and was advanced atherosclerosis, which could be termed type VIII according to the Stary classification.⁴ Case 2. A 68-year-old man with inferior OMI had suffered from AP for 15 years. His coronary risk factors were diabetes mellitus and hypertension. His current CCS class was II. Coronary angiograms performed on April 10, 2002 showed a diffuse restenotic lesion with moderate bending in the proximal segment of the LAD and chronic total occlusion in the proximal RCA. Since the RCA was small and was the infarction-related artery, we thought an LAD lesion was the culprit lesion. This lesion was dilated with a cutting balloon 6 years earlier. IVUS demonstrated this plaque was eccentric, hypoechoic with positive remodeling, mildly calcified, and had attenuation of echogenicity without calcification (Figure 3). There was no angiographically detected calcification. Despite calcification and bending, we classified this plaque as being soft in the MinCSA site by IVUS and decided to treat by DCA. After 6 cuts at 1 atm using a Flexicut (large type), no-reflow occurred. We implanted a BxVelocity 4.0–18 mm (Cordis Corporation, Warren, New Jersey) for this lesion and post-dilated it with a Quantum 4.0–15 mm (Boston Scientific, Natick, Massachusetts) at 15 atm. This lesion was found to be optimally dilated on the angiograms, as well as by IVUS (Figure 4). The no-reflow was treated with only intracoronary nicorandil. The pathologic findings of the DCA specimen showed it consisted predominantly of hyalinization with a small number of fibroblasts and a few calcium deposits. There were no lipids or foamy macrophages. This plaque may have been very old, but was at an earlier stage of atherosclerosis than that of case 1. Case 3. A 73-year-old man with hypertension and hyperlipidemia was diagnosed with AP 8 years earlier at another hospital. His CCS class was II. He underwent coronary angiograms on October 29, 2001 that revealed diffuse calcified stenosis in the mid LAD and 75% ostial stenosis in the LAD. After successful ablation with a Rotablator for a diffuse LAD lesion on November 1, 2001, an ostial LAD lesion was treated on March 4, 2002. This lesion was tubular and mildly calcified according to the angiogram. IVUS showed the plaque was eccentric and composed of a very massive hypoechoic component with small, scattered, high echogenicity in the opposite to the left circumflex artery (Figure 5). Attenuation of echogenicity was observed where there was no obvious calcification. Superficial calcification also existed next to the MinCSA site. A total of 42 mg of plaque was excised by 30 cuts at a maximum pressure of 14 atm with a Flexicut (large size). No-reflow that occurred during the DCA procedure could be corrected by intracoronary nicorandil alone. The final angiographic and IVUS images showed excellent results using DCA alone (Figure 6). A small contrast defect, probably by atheromatous plaque, was detected in the distal segment confirming the distal embolization as a cause of no-reflow. The histological findings were similar to case 1. This plaque was predominantly composed of hyalinization with calcification. Discussion. The IVUS images and histological findings of athersclerotic plaque as well as the procedural outcomes in the three present cases were similar. The plaques were hypoechoic with attenuation of backward echogenicity despite a lack of obvious calcification within the stenosis. There was also superficial calcification in the reference segment. The angiogram and IVUS imagings did not suggest thrombus. Histologically, the plaques appeared to be very advanced atherosclerosis that consisted predominantly of hyalinization with scattered, small areas of calcification, and were not only hard but also fragile, leading to fracture during the DCA procedure and distal atheroembolism. Atheromatous plaques are divided into a soft type, a fibrous type, and a mixture of the two based on the IVUS findings. Although hypoechoic plaque is generally classified as soft, IVUS cannot always discriminate the histological origin. With IVUS, lipid-laden lesions appear hypoechoic, fibromuscular lesions generate low-intensity or soft echoes, and fibrous or calcified tissues are echogenic.⁵ However, the sensitivity is not high^6,7 and different tissue components may look quite similar. Therefore, more cases in which the IVUS images and histological findings are correlated should be accumulated. According to the histological evaluation in this study, hypoechoic plaque with attenuation despite the absence of concordant calcification was found to be very advanced stable plaque that consisted predominantly of hyalinization and calcification. The presence of massive calcification in the reference segments might confirm the advanced stage of atherosclerosis in these 3 lesions. Histologically, advanced atherosclerosis classified as type VII or VIII according to Stary⁴ might be very hard. We suspected that the hyalinization might be fragile if compressed by a balloon or stent at high pressure, which would lead to no-reflow due to distal embolism. The prominent feature of the baseline patient characteristics found in three cases was that two of them were associated with diabetes mellitus and all were elderly with a long history of angina pectoris. It is well known that diabetic patients tend to have diffuse coronary stenosis and even angiographically normal segments also have intimal hyperplasia.⁸ However, to the best of our knowledge, a correlation between diabetes and qualitative plaque characteristics by IVUS has not been found. Three plaques were relatively segmental short lesions, which did not indicate stenosis typical of diabetic patients. Although we cannot completely eliminate the diabetes as a potential cause of the no-reflow, no-reflow did not seem to be related to diabetes even in the two diabetic cases. Based on the results of the OARS⁹ and ABACAS¹⁰ trials, we ablated the plaque aggressively with IVUS-guidance to achieve less than 50% of % plaque area at the Min CSA site and reduce restenosis. We usually perform DCA in this manner, however, this method might be partially associated with no-reflow. In cases 1 and 2, no-reflow occurred after initial cuttings at low pressure. In case 3, aggressive debulking might be related to the no-reflow. The mechanisms of coronary no-reflow in PCI cases have been possibly conceptualized as distal embolization of plaque and/or thrombus from the lesion site.¹¹ A loss of capillary autoregulation with the local release of vasoconstrictor substances (microvascular spasm) has also been postulated as an additional mechanism.¹¹ We cannot completely deny the possibility of the latter mechanism. We administered intracoronary nitroglycerin and nicorandil for the no-reflow, but they were not very effective suggesting the former mechansim. There are some limitations when discussing these results. First, the no-reflow might have been due to the DCA procedure itself,¹² and not to the atheroma alone. Thus, the fragility of the plaque, as mentioned above, should be examined in future studies. Second, we were unable to detect the exact location of where the DCA specimens were extracted in the IVUS imagings. Furthermore, the DCA specimens collected do not explain the entire plaque. However, we evaluated all of the DCA specimens and found that the histological features were similar to each other. Third, the mechanism of the backward attenuation seen in the hypoechoic or mixed plaque is unknown, although this characteristic of IVUS has been suggested to be a potential predictor of distal embolism in coronary intervention. The presence of scattered tiny areas of calcification and hyalinization may partially explain this phenomenon. Conclusions. The present findings should remind us that low echogenicity with backward attenuation without massive calcification has the potential to cause distal embolization in elective PCI.

1. Resnic FS, Wainstein M, Lee MK, et al. No-reflow is an inde-pendent predictor of death and myocardial infarction after percu-taneous coronary intervention. Am Heart J 2003;145:42–46. 2. Piana RN, Paik GY, Moscucci M, et al. Incidence and treatment of no reflow after percutaneous coronary intervention. Circulation 1994;89:2514–2518. 3. Ishizaka N, Issiki T, Saeki F, et al. Predictors of myocardial infarction after distal embolization of coronary vessels with percutaneous transluminal coronary angioplasty. Experience of 21 consecutive patients with distal embolization. Cardiology 1994;84:298–304. 4. Stary HC. The Histological Classification of Atherosclerotic Lesions in Human Coronary Arteries. In: Fuster V, Ross R, and Topol J, editors. Atherosclerosis and coronary artery disease. Philadelphia: Lippincott-Raven Publishers, 1996:463–474. 5. Nissen SE, Yock P. Intravascular ultrasound. Novel pathophysiological insights and current clinical applications. Circulation 2001;103:604–616. 6. Hiro T, Leung CY, De Guzman S, et al. Are soft echoes really soft? Intravascular ultrasound assessment of mechanical properties in human atherosclerotic tissue. Am Heart J 1997;133:1–7. 7. Prati F, Arbustini E, Labellarte A, et al. Intravascular ultrasound insights into plaque composition. Z Kardiol 2000;89:117–123. 8. Ito S, Suzuki T, Katoh O, et al. The influence of diabetes mellitus on plaque volume and vessel size in patients undergoing percutaneous coronary intervention —an intravascular ultrasound study. Jpn Heart J 2004;45:573–580. 9. Simonton CA, Leon MB, Baim DS, et al. Optimal directional coronary atherectomy: final results of the Optimal Atherectomy Restenosis Study (OARS). Circulation. 1998;97:332–339. 10. Suzuki T, Hosokawa H, Katoh O, et al. Effects of adjunctive balloon angioplasty after intravascular ultrasound-guided optimal directional atherectomy: The results of Adjunctive Balloon Angioplasty After Coronary Atherectomy Study (ABACAS). J Am Coll Cardiol 1999;34:1028–1035. 11. Eeckout E, Kern MJ. The coronary no-reflow phenomenon: A review of mechanisms and therapies. Eur Heart J 2001;22:729–739. 12. Waksman R, Douglas JS Jr, Scott NA, et al. Distal embolization is common after directional atherectomy in coronary arteries and saphenous vein grafts. Am Heart J 1995;129:430–435.