Angioscopically-Determined Extent of Coronary Atherosclerosis Is Associated with Severity of Acute Coronary Syndrome

Acute myocardial infarction and unstable angina pectoris have been reported pathologically and angioscopically to share the common pathophysiology of plaque disruption with thrombosis. Both are classified as acute coronary syndromes (ACS). Although they have different prognoses depending on the difference in the severity of myocardial damage, the difference in their intracoronary morphology, especially of the nonculprit segments, has not been thoroughly clarified. Therefore, we attempted to differentiate their intracoronary morphology by angioscopy in prospectively and consecutively enrolled patients with ACS by classifying them as having large myocardial infarction (CK-elevation-ACS, CKE-ACS), or having small, or no myocardial infarction (non-CK-elevation-ACS, NCKE-ACS) according to the level of CK-MB elevation. An angioscopic comparison was made on the morphology of the culprit lesion and on the extent of atherosclerosis in the culprit vessel. We hypothesized that the extent of angioscopically-evaluated atherosclerosis would reflect the risk of suffering ACS and, furthermore, of suffering CKE-ACS. Methods Study patients. We prospectively and consecutively enrolled 76 patients with ACS on whom emergent catheterization and angioscopic examination of the culprit vessel was successfully performed. Emergent catheterization was performed on all the patients (n = 348) who were suspected of having ACS, taking into consideration chest pain, ST-elevation/depression by electrocardiography, left ventricular wall motion abnormality on echocardiography, defect on SPECT, and/or serum CK elevation. Chest pain at rest, new onset of exertional chest pain, and worsening (longer duration or higher frequency) of exertional chest pain were considered to be symptoms of ACS. ST-elevation or depression on electrocardiography, left ventricular wall motion abnormality on echocardiography, and/or defect on SPECT suggested the culprit vessel. If the coronary stenosis (> 50%) or occlusion corresponding to these abnormalities was demonstrated by angiography, the patient was diagnosed with ACS. However, the patients who had multiple stenoses or occlusions (n = 41), or those who had no stenosis at all (n = 31) were not included in the present study because the culprit lesion could not be determined in those patients. Angioscopic examination was performed before primary PCI. Angioscopic examination was not performed when: 1) the target vessel was too tortuous or too small (n = 73); 2) the patient had shock status (n = 50); or 3) an angioscopist was not available (n = 63). The culprit vessel was observed by angioscopy, and the prevalence of thrombus and the color grade of yellow plaques were evaluated. Patients were not included in this study if clear angioscopic images were not acquired (n = 14). Therefore, the study patients were those with suspected ACS who had angiographically significant coronary stenosis or occlusion diagnosed as the cause of ACS and received primary PCI and successful angioscopic examination. Patients were diagnosed as having CKE-ACS when the elevation (> twice the normal upper limit) of CK-MB was detected; otherwise, patients were diagnosed as having NCKE-ACS. CK-MB was measured serially every 4 hours to detect the peak value. Oral aspirin (160–330 mg) and intravenous heparin (200 U/kg body weight) were administered before catheterization in all patients. Thrombolysis was not performed in any patient. New antiplatelet agent glycoprotein IIb/IIIa blockers were not used for any patient because they were not approved for clinical use in Japan. Well-trained research nurses assessed patients’ characteristics using a structured questionnaire. Informed written consent was obtained from all patients. The study protocol was approved by the Osaka Police Hospital’s Ethics Committee. Angiographic examination. Catheterization was performed via the femoral artery approach using an 8 Fr or 7 Fr sheath and catheters. Coronary angiograms were recorded using the Advantx Medical System (General Electric, Milwaukee, Wisconsin). Left coronary arteries were evaluated from at least 4 views, and right coronary arteries from at least 2 views. Culprit lesions were determined by angiography, taking into consideration changes in the electrocardiogram, left ventricular wall motion evaluated by echocardiography and/or a defect detected by SPECT. Angioscopic procedures and evaluation. We used the angioscope MC-800E (Nihon Kohden, Tokyo, Japan) and the fiber optic AS-003 (Nihon Kohden). Angioscopic observations were performed while blood was cleared away from view by the injection of 3% dextran-40, as described previously.¹ We continuously examined the culprit vessel from distal segments to the ostium whenever the lumen diameter was > 2 mm. Although angioscopy (4 Fr) usually crossed the stenotic or occluded culprit lesion, predilatation with a 1.5-mm diameter balloon was performed in the event that angioscopy could not cross the lesion. Actually, predilatation was required in 21 (39%) CKE-ACS patients and in 4 (18%) NCKE-ACS patients. There were no complications associated with angioscopic procedures except for the transient sign of myocardial ischemia. Thrombus (Figure 1) was defined as white or red material that had a cotton-like or ragged appearance being fragmented or peeling off from the vascular wall, which might be protruding into lumen or adhering to the luminal surface. The prevalence of thrombus at the culprit lesion (CT) and in nonculprit segments (NT) was evaluated. The color of plaques were graded as 0 (white), 1 (slight yellow), 2 (yellow), or 3 (intense yellow) according to the standard colors, as reported previously. Next, the color grade of the culprit lesion (CC) and number (NP) and maximum color grade (MC) of yellow plaques in the nonculprit segments were determined (Figure 2). The plaque index (PI) was calculated as NP x MC. We have previously reported2 that PI was associated with the risk of a secondary ACS event in the patients with a first acute MI. Evaluation of angioscopic images was performed by two angioscopy specialists blinded to the clinical data, and in cases of disagreement, a third reviewer decided upon the interpretation. Statistical analysis. Continuous data were expressed as mean ± SD. Statistical analysis was performed using the Chi-square test for categorical data and by the Student’s t-test for continuous data. Because there were some differences in the background data between CKE-ACS and NCKE-ACS patients, multiple logistic regression analysis was performed to identify the factors that had a significant effect on the angioscopic findings. A p-value Patient characteristics. Table 1 shows the patients’ clinical characteristics. A higher percentage of NCKE-ACS patients than of CKE-ACS patients were taking nitrates, calcium blockers, beta-blockers, angiotensin-converting enzyme inhibitors (ACEI), and antiplatelet agents. There were more current smokers among the CKE-ACS patients. Angioscopic findings. Although the yellow color grade (CC: 1.9 ± 0.9 vs. 1.7 ± 0.8; p = 0.3) of culprit lesions (Figure 3) was not different between CKE-ACS and NCKE-ACS, a trend towards a higher prevalence of thrombus (CT: 93% vs. 77%; p = 0.06) at the culprit lesions of CKE-ACS patients compared to NCKE-ACS patients was observed. However, the majority of culprit lesions (Figure 4) in both CKE-ACS and NCKE-ACS had yellow plaque and predominantly white and partially red thrombus. Culprit vessels (Figure 3) of CKE-ACS patients had more plaques, with the higher yellow color intensity in the nonculprit segments than those of NCKE-ACS, as shown by the higher value of NP (2.2 ± 1.6 vs. 1.4 ± 1.2; p = 0.03), MC (1.8 ± 0.9 vs. 1.2 ± 0.9; p = 0.008) and PI (4.8 ± 4.4 vs. 2.4 ± 3.1; p = 0.03). Furthermore, the prevalence of thrombus in the nonculprit segments (NT: 39% vs. 11%; p = 0.02) was significantly higher in CKE-ACS than in NCKE-ACS patients. Multiple logistic regression analysis revealed that no factor had a significant effect on CC or CT, however, the group (CKE- or NCKE-ACS) had a significant effect on NP (p = 0.02), MC (p = 0.01), PI (p = 0.01), and NT (p = 0.01). Among the classic coronary risk factors (age, gender, hyperlipidemia, diabetes mellitus, hypertension, smoking and obesity), only the effect of hyperlipidemia (p = 0.04) and hypertension (p = 0.01) on PI was revealed. No significant effect of medications was revealed. Discussion Although the morphology of culprit lesions was similar, yellow plaques of higher yellow color intensity were more prevalent in the nonculprit segments of CKE-ACS patients than in those of NCKE-ACS patients. Furthermore, the prevalence of thrombosis in the nonculprit segments was higher in CKE- than in NCKE-ACS patients. We evaluated, for the first time, the extent of coronary atherosclerosis by angioscopy, which revealed that CKE-ACS patients compared with NCKE-ACS patients had advanced coronary atherosclerosis with more yellow plaques of higher yellow color intensity and thrombosis in the nonculprit segments. Angioscopic evaluation of the culprit lesion. Previous pathological and angioscopic studies have revealed that thrombus covers the disrupted yellow atheromatous plaques in patients with ACS.^1–5 It has been reported that angioscopy is much more sensitive than angiography in identifyingintracoronary thrombus. Although we could not reveal the statistical difference in the angioscopic appearance of culprit lesions between CKE- and NCKE-ACS, a trend (p = 0.06) towards a higher prevalence of thrombus at the culprit lesions of CKE-ACS patients compared to NCKE-ACS patients was observed. Thrombus at the culprit lesion of CKE- or NCKE-ACS, which was coarse, fragile, and cotton- or ragged-like material easily fragmented or peeled off from the vascular wall, was easily identified by angioscopy. Thrombus¹ directly adhering to the vessel wall is usually white and becomes redder in the center of the coronary lumen compared with thrombus near the vessel wall. This may be explained by the fact that the fibrin network captures an increasing number of red blood cells as blood flow is disturbed by white platelet-fibrin thrombus. Although thrombus in an occluded coronary artery appears stable by angioscopy, thrombus at a severe stenosis appears actively generated, fragmented and washed away into the distal artery. This difference is supported by previous reports^6,7 that the platelet count is lower and the D-dimer higher in unstable angina (which often signifies severe coronary stenosis) than in acute myocardial infarction (which often signifies coronary artery occlusion), suggesting the ongoing process of platelet consumption and thrombosis at a severe stenosis. Because medical therapy for angina pectoris (e.g., beta-blockers, nitrates and antiplatelet drugs) appeared to have started earlier in the patients with NCKE-ACS, these drugs might have affected the angioscopic appearance of the culprit lesion; i.e., antiplatelet drugs might have reduced the prevalence of thrombus. However, this fact would indicate that the patients with NCKE-ACS suffered a gradual worsening of angina, while the patients with CKE-ACS suffered rather abrupt onset of angina or infarction. This difference in the clinical course might have been caused by the difference in the extent of coronary atherosclerosis evaluated by angioscopy, suggesting that the disruption of yellow plaque in the more advanced stage of atherosclerosis would cause more rapid progression of more severe stenosis or occlusion at the culprit lesion via the formation of more thrombus. Angioscopic evaluation of nonculprit segments. The extent of atherosclerosis evaluated by the formation of yellow plaques appeared more advanced in CKE-ACS than in NCKE-ACS. This angioscopic observation is consistent with a previous IVUS study8 in which more soft plaques were detected in the nonculprit segments of acute myocardial infarction (CKE-ACS) than in those of unstable angina (NCKE-ACS). The prevalence of thrombosis in the nonculprit segments also appeared higher in CKE-ACS than in NCKE-ACS. This may be because: 1) yellow plaques in the nonculprit segments might be more vulnerable in CKE- than in NCKE-ACS, as they had higher yellow color intensity, or because: 2) systemic factors such as platelets or coagulation factors had higher thrombogenic potential in CKE- than in NCKE-ACS. Because medical therapy (e.g., beta-blockers, nitrates and antiplatelet drugs) for angina pectoris appeared to have started earlier in the patients with NCKE-ACS, these drugs might have affected the angioscopic appearance of the nonculprit segments; i.e., antiplatelet drugs might have reduced the prevalence of thrombus. However, no drugs were known to cause the regression of yellow plaque other than lipid-lowering drugs, which were not different between the patients with CKE-ACS and those with NCKE-ACS. Evaluation of coronary atherosclerosis by angioscopic examination. For each plaque, yellow color intensity has been regarded as a marker of plaque vulnerability. On the other hand, yellow plaques are formed as a “pan-coronary process”⁹ in the coronary artery trees, and patients with acute myocardial infarction have multiple yellow plaques equally in the culprit and nonculprit vessels. Therefore, we hypothesized¹⁰ that patients who had more yellow plaques of higher yellow color intensity would have a higher risk of suffering ACS. Because plaque rupture and thrombosis is not a rare event as reported by pathologic studies, it may silently occur in the early stages of coronary atherosclerosis evaluated by angioscopy. It may, however, cause ACS in the advanced stages. We have previously reported² that the angioscopically-evaluated extent of coronary atherosclerosis is associated with the risk of future ACS events. Furthermore, according to the results of the present study, the angioscopically-evaluated extent of coronary atherosclerosis is also associated with the severity of ACS, and thus, plaque rupture may cause CKE- rather than NCKE-ACS in the more advanced stages. Study limitations. Because the culprit lesion was crossed by a 4 Fr guiding catheter before observation, only the thrombus firmly adhering to the vessel wall was supposed to be visualized, and the prevalence of thrombus might have been reduced. Although we measured the extent of atherosclerosis by the number and maximum color grade of yellow plaques, the size of each yellow plaque was not considered. However, the sizes of yellow plaques were similar, and large yellow plaques formed by the fusion of multiple yellow plaques were not detected among the present study patients. Although the number of patients enrolled was small, we minimized the introduction of possible bias by enrolling the patients prospectively and consecutively, and by blinding the angioscopy reviewers to the clinical data or classification of the patients. Although the statistical difference was not detected on the angioscopic appearance of culprit lesions, the difference in the prevalence of thrombus might reach statistical significance if the number of patients were increased. Because we excluded the patients without stenotic lesions (> 50%), those with multiple lesions, those with small or tortuous target vessels and those with shock, the results of this study may not apply to those types of ACS patients. Conclusions The culprit lesions of CKE- and NCKE-ACS had similar yellow color grades; however, the culprit lesions of CKE-ACS showed a trend towards a higher prevalence of thrombus. More yellow plaques of higher yellow color grade were observed in nonculprit segments of CKE- than in NCKE-ACS. The prevalence of thrombus in those segments was also higher in CKE- than in NCKE-ACS. Finally, the angioscopically-evaluated extent of coronary atherosclerosis was more advanced in CKE- than in NCKE-ACS patients.

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