Although rupture of vulnerable plaque with subsequent thrombosis is the most common mechanism of acute coronary syndromes, a significant percentage of patients with acute coronary syndrome may not have plaque rupture. We used angioscopy and virtual histology intravascular ultrasound (VH-IVUS) to investigate the underlying morphology of coronary thrombosis. We correlated the angioscopic diagnosis of coronary thrombosis in 42 lesions (37 patients) with gray-scale and VH-IVUS findings of the underlying plaque. By angioscopy plaque rupture was present in 19 thrombotic lesions (45.2%), whereas 23 (54.8%) had no rupture. VH-IVUS findings comparing thrombotic lesions with to those without angioscopic plaque rupture were remarkably similar except that angioscopic nonruptures tended to have more necrotic core (NC) at the minimum lumen area site (22.2 ± 12.5% vs 16.3 ± 9.3%, p = 0.09) and at the maximum NC site (32.7 ± 12.8% vs 25.0 ± 12.1%, p = 0.053) compared to angioscopic ruptures. Furthermore, among 19 lesions with angioscopic plaque rupture, there were 11 VH thin-cap fibroatheromas (TCFAs; 57.9%); among 23 lesions without angioscopic rupture, there were 17 VH-TCFAs (73.9%, p = 0.22). In conclusion, the similarity of VH-IVUS plaque composition (percentage of NC and percentage of VH-TCFA) in lesions with or without angioscopic plaque rupture suggest a spectrum of underlying morphologies to explain thrombosis in the absence of a ruptured plaque including classic erosions, small (and undetectable) plaque ruptures, and potentially unruptured TCFAs with superimposed thrombosis.
Pathologic studies have demonstrated that most acute coronary syndromes occur from coronary thrombosis caused by rupture of a thin fibrous cap or surface erosion in the absence of cap disruption. Thin-cap fibroatheroma (TCFA) is currently regarded the main type of rupture-prone and thrombosis-prone vulnerable plaque. Similar studies with angioscopy have revealed disruption of lipid-rich yellow plaques and subsequent thrombosis. Yellow color intensity as evaluated by angioscopy is determined by thickness of the fibrous cap and is associated with plaque vulnerability. Gray-scale intravascular ultrasound (IVUS) imaging is limited with regard to analysis of plaque composition. Virtual histology (VH) IVUS was developed to assess plaque composition. VH-IVUS characterizes plaque as fibrous tissue, fibrofatty plaque, dense calcium, and necrotic core (NC). Although pathologic analysis of material retrieved by thrombectomy is enlightening, there are still limited in vivo data regarding coronary thrombus in relation to underlying plaque morphology. The aim of the present study was to investigate the underlying morphology of coronary thrombosis using VH-IVUS and angioscopy.
Methods
From January 2006 through May 2008, 37 patients presenting with various manifestations of coronary artery disease, but mostly with acute coronary syndromes (33 of 37, 89%) were included in the present study. All patients had ≥1 angiographically visible thrombotic lesion in the culprit vessel, but some patients had >1 lesion with thrombus in the culprit vessel. Angiographic definition of coronary thrombus was the presence of a filling defect. All primary and secondary thrombotic lesions were then divided into 2 groups according to whether there was an angioscopically defined ruptured plaque. These lesions were matched to gray-scale and VH-IVUS studies using angiographic landmarks. Informed consent was obtained from all patients. The protocol was approved by the Osaka Police Hospital ethical committee.
Lipid disorder was defined as total cholesterol level ≥200 mg/dl, low-density lipoprotein cholesterol ≥100 mg/dl, high-density lipoprotein cholesterol <50 mg/dl, triglycerides ≥150 mg/dl, or medication use. Hypertension was defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or use of an antihypertensive drug. Patients with diabetes mellitus had a confirmed diagnosis or were under antidiabetic treatment at the time of their study.
Catheterization was performed by the radial, brachial, or femoral approach using 6Fr or 7Fr sheaths and catheters. Intravenous heparin (100 U/kg) was administered at the beginning of catheterization. The culprit vessel was examined first by angioscopy and then by IVUS. Of the 37 examined patients 12 had aspiration thrombectomy and 6 had balloon predilation before IVUS or angioscopy was performed.
Angioscopy was performed only in patients with angiographically visible coronary thrombus. Angioscopic observation was performed from the distal segment to the ostium of the vessel before and, if necessary, after percutaneous coronary intervention to study the entire target vessel. An angioscope (RX-3310A and MV-5010A, Machida, Tokyo, Japan) and optic fiber (DAG-2218LN, Machida) were used. Angioscopic observations were made while blood was cleared from view by an injection of 3% dextran-40 as previously reported. Angioscopic images were viewed in real time on a monitor and afterward from recordable compact disks.
A phased-array, 20-MHz, 3.2Fr IVUS catheter (Eagle Eye, Volcano Corporation, Rancho Cordova, California) was placed into the distal coronary artery after intracoronary administration of nitroglycerin 0.2 mg and was pulled back manually to the aorto-ostial junction. During pullback, gray-scale IVUS was recorded, raw radiofrequency data were captured at the top of the R wave, and reconstruction of the color-coded map by a VH-IVUS data recorder was performed (In-Vision Gold and S5, Volcano Corporation). Gray-scale IVUS and captured radiofrequency data were copied to a recordable digital video disk for off-line analysis.
Thrombus-containing lesions were classified as having plaque rupture or, in the absence of criteria for plaque rupture, nonrupture. Angioscopically, plaque rupture required ≥2 of the following criteria: (1) >50% of luminal area occupied by thrombus or protruded plaque content, (2) presence of a large cavity or fissure, (3) thrombus over yellow plaque, and (4) distal embolism observed by angioscopy.
Yellow plaque was defined as a yellow area on the luminal surface with a smooth or irregular surface with or without protrusion into the lumen. Number of yellow plaques in the culprit artery and yellow color intensity of each of those plaques were also evaluated. Yellow color was graded as 1 (light yellow), 2 (yellow), or 3 (intense yellow) as previously reported. If a thrombus-containing lesion had multiple yellow color grade values, the highest score was reported.
Angioscopic images were interpreted by 2 angioscopic specialists (Y.U. and T.K.); disagreement was settled by a third reviewer. There were no cases in which each of the 3 reviewers judged different color grades; in all cases ≥2 reviewers agreed on color classification.
Off-line gray-scale and VH-IVUS analyses were performed using pcVH 2.1 and VIAS 3.0 (Volcano Corporation). Gray-scale IVUS measurements of lumen, external elastic membrane (EEM), and plaque and media (defined as EEM minus lumen) cross-sectional areas and plaque burden (defined as plaque and media divided by EEM) were performed for every recorded frame. Remodeling index was calculated as lesion EEM divided by mean reference EEM. VH-IVUS analysis was also performed for every recorded frame. The 4 VH-IVUS plaque components were reported as percent plaque area. Lesions were classified by 2 experienced independent observers (E.S. and A.M.) based on plaque composition according to previous published definitions : pathologic intimal thickening, VH-IVUS–derived TCFA (VH-TCFA), thick-cap fibroatheroma (ThCFA), fibrotic plaque, and fibrocalcific plaque. In particular, VH-TCFA was a fibroatheroma without evidence of a fibrous cap: >10% confluent NC with >30° NC abutting the lumen in ≥3 consecutive frames. ThCFA was a fibroatheroma (>10% of confluent NC in ≥3 consecutive frames) with a definable fibrous cap.
Statistical analysis was performed with StatView 5.0 (SAS Institute, Cary, North Carolina). Continuous variables were presented using mean ± SD. Categorical variables were summarized as absolute value and percentage. Continuous variables were tested for normal distribution by nonparametric 1-sample Kolmogorov–Smirnov test; all showed normal distribution and were compared using unpaired Student’s t test. Categorical variables were compared to chi-square or Fisher’s exact test. A p value <0.05 was considered statistically significant.
Results
Baseline patient characteristics are listed in Table 1 . Acute myocardial infarction was present in most patients (24 of 37, 59.5%) with ST-elevation myocardial infarction in 14 patients. At time of catheterization, 5 of 37 patients (13.5%) had complete thrombotic occlusion.
| Variable | Overall | Nonrupture | Rupture | p Value |
|---|---|---|---|---|
| (n = 37) | (n = 19) | (n = 18) | ||
| Age (years) | 60 ± 12 | 57 ± 11 | 61 ± 12 | 0.29 |
| Men | 30 (81%) | 12 (63%) | 18 (100%) | 0.004 |
| Women | 7 (19%) | 7 (37%) | 0 (0%) | |
| Risk factors | ||||
| Hyperlipidemia | 30 (81%) | 17 (90%) | 13 (72%) | 0.35 |
| Hypertension | 25 (68%) | 13 (68%) | 12 (67%) | 0.54 |
| Diabetes mellitus | 12 (32%) | 8 (42%) | 4 (24%) | 0.41 |
| Current smokers | 15 (41%) | 8 (42%) | 7 (39%) | >0.99 |
| Clinical syndrome | 0.65 | |||
| Acute myocardial infarction | 24 (60%) | 14 (74%) | 10 (56%) | |
| Unstable angina pectoris | 9 (30%) | 3 (16%) | 6 (33%) | |
| Stable angina pectoris | 2 (5%) | 1 (5%) | 1 (6%) | |
| Silent ischemia | 2 (5%) | 1 (55%) | 1 (6%) | |
| Target coronary vessel | 0.08 | |||
| Left anterior descending | 16 (43%) | 10 (53%) | 6 (33%) | |
| Right | 14 (38%) | 4 (21%) | 10 (56%) | |
| Left circumflex | 7 (19%) | 5 (26%) | 2 (11%) | |
| Lesion distribution | 0.16 | |||
| Patients with 1 lesion | 32 (87%) | 15 (79%) | 17 (94%) | |
| Patients with 2 lesions | 5 (14%) | 4 (21%) | 1 (6%) |
Thirty-two patients had 1 thrombotic lesion and 5 patients had 2 thrombotic lesions. Patients with 2 thrombotic lesions had angioscopic rupture or no rupture, but never the 2 together. Overall, 18 patients had 1 angioscopic plaque rupture or 2 angioscopic plaque ruptures, whereas 19 did not have any angioscopic plaque rupture. Men had more lesions with plaque rupture than lesions without plaque rupture (p = 0.004); conversely, no woman had a plaque rupture. There were no other significant differences regarding age, risk factors, clinical syndrome, and treated coronary artery between the 2 groups.
Overall, there were 42 discrete lesions with angioscopic thrombus. Angioscopic plaque rupture was present in 19 thrombotic lesions (45.2%); conversely, 23 (54.8%) were classified as nonruptures. Angioscopic rupture was associated with more yellow plaques, more grade 3 yellow plaques, and more adherent red/white thrombus than lesions without angioscopic plaque rupture ( Table 2 ).
| Variable | Overall | Nonrupture | Rupture | p Value |
|---|---|---|---|---|
| (n = 42) | (n = 23) | (n = 19) | ||
| Number of yellow plaques | 1.9 ± 1.4 | 1.5 ± 1.2 | 2.5 ± 1.4 | 0.01 |
| Grade | 0.001 | |||
| 3 | 30 (71%) | 11 (48%) | 19 (100%) | |
| 2 | 10 (24%) | 10 (44%) | 0 (0%) | |
| 1 | 2 (5%) | 2 (9%) | 0 (0%) | |
| Thrombus | <0.00001 | |||
| Mixed (red/white thrombus) | 22 (52%) | 3 (13%) | 19 (100%) | |
| Red thrombus | 14 (33%) | 14 (61%) | 0 (0%) | |
| White thrombus | 6 (14%) | 6 (26%) | 0 (0%) |
Angioscopic ruptures occurred in larger vessels (larger EEM) than lesions without angioscopic plaque rupture. However, there were no other gray-scale IVUS differences between the 2 groups ( Table 3 ).
| Variable | Overall | Nonrupture | Rupture | p Value |
|---|---|---|---|---|
| (n = 42) | (n = 23) | (n = 19) | ||
| Virtual histologic lesion phenotype | 0.53 | |||
| Thin-cap fibroatheroma | 28 (66%) | 17 (74%) | 11 (58%) | |
| Thick-cap fibroatheroma | 12 (29%) | 5 (22%) | 7 (37%) | |
| Pathologic intimal thickening | 2 (5%) | 1 (4%) | 1 (5%) | |
| Proximal reference site | ||||
| External elastic membrane area (mm 2 ) | 19.0 ± 6.8 | 16.8 ± 4.8 | 21.6 ± 8 | 0.02 |
| Lumen area (mm 2 ) | 7.0 ± 2.8 | 6.5 ± 2.0 | 7.6 ± 3.4 | 0.25 |
| Plaque burden (%) | 61.1 ± 10.8 | 59.6 ± 9.3 | 62.9 ± 12.3 | 0.34 |
| Distal reference site | ||||
| External elastic membrane area (mm 2 ) | 15.0 ± 5.1 | 13.6 ± 4.7 | 16.5 ± 5.3 | 0.06 |
| Lumen area (mm 2 ) | 5.2 ± 1.8 | 4.7 ± 1.9 | 5.7 ± 1.7 | 0.11 |
| Plaque burden (%) | 63.9 ± 8.5 | 63.1 ± 9.6 | 64.8 ± 7.1 | 0.52 |
| Minimum lumen area site | ||||
| External elastic membrane area (mm 2 ) | 17.7 ± 5.3 | 15.7 ± 4.1 | 20.1 ± 5.6 | 0.005 |
| Lumen area (mm 2 ) | 3.3 ± 1.1 | 3.2 ± 1.1 | 3.5 ± 1.2 | 0.48 |
| Plaque and media area (mm 2 ) | 14.3 ± 4.9 | 12.4 ± 3.6 | 16.6 ± 5.4 | 0.04 |
| Plaque burden (%) | 80.1 ± 6.2 | 78.7 ± 5.7 | 81.8 ± 6.6 | 0.11 |
| Necrotic core (%) | 19.6 ± 11.4 | 22.2 ± 12.5 | 16.3 ± 9.3 | 0.09 |
| Dense calcium (%) | 6.4 ± 4.9 | 7.6 ± 5.2 | 5.0 ± 4.2 | 0.08 |
| Fibrofatty (%) | 12.6 ± 7.7 | 12.2 ± 7.9 | 13.0 ± 7.6 | 0.75 |
| Fibrotic (%) | 53.3 ± 9.7 | 53.4 ± 8.5 | 53.3 ± 11.1 | 0.96 |
| Remodeling index | 1.2 ± 0.5 | 1.12 ± 0.4 | 1.24 ± 0.5 | 0.42 |
| Maximum necrotic core site | ||||
| External elastic membrane area (mm 2 ) | 17.2 ± 4.8 | 16.0 ± 4.4 | 18.6 ± 5.0 | 0.07 |
| Lumen area (mm 2 ) | 4.9 ± 1.7 | 4.7 ± 1.6 | 5.2 ± 1.7 | 0.29 |
| Plaque and media area (mm 2 ) | 12.2 ± 4.3 | 11.3 ± 3.6 | 13.4 ± 4.8 | 0.11 |
| Plaque burden (%) | 70.3 ± 8.2 | 69.9 ± 7.7 | 70.8 ± 8.9 | 0.73 |
| Necrotic core (%) | 29.2 ± 12.7 | 32.7 ± 12.8 | 25.0 ± 12.1 | 0.053 |
| Dense calcium (%) | 9.9 ± 7.0 | 11.2 ± 8.3 | 9.2 ± 4.7 | 0.17 |
| Fibrofatty (%) | 6.8 ± 6.6 | 6.0 ± 4.8 | 7.6 ± 6.3 | 0.43 |
| Fibrotic (%) | 45.0 ± 12.7 | 45.5 ± 12.1 | 44.4 ± 9.3 | 0.73 |
| Remodeling index | 1.1 ± 0.4 | 1.12 ± 0.4 | 1.14 ± 0.4 | 0.91 |
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