It remains uncertain whether the histology of culprit coronary plaques differs between ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI). We compared intravascular ultrasound (IVUS) and histologic findings in coronary culprit plaques among patients presenting with STEMI and NSTEMI. Atherectomy specimens were obtained from 96 patients, 70 with STEMI and 26 with NSTEMI, who underwent directional coronary atherectomy for de novo coronary artery lesions. IVUS examinations were performed before directional coronary atherectomy. IVUS and histologic data were analyzed. Clinical characteristics were largely similar between the 2 groups; however, normal antegrade flow before angioplasty was less frequently observed in patients with STEMI than those with NSTEMI. Plaque rupture was more common on the proximal side of the minimal lumen site. There were no differences in vessel area, lumen area, calcification, plaque burden, or remodelling index at the reference and culprit sites. However, the arc of the ruptured cavity was significantly greater in patients with STEMI than those with NSTEMI (69.4 ± 27.9° vs 51.8 ± 20.0°, respectively, p = 0.008). The proportion of atheroma, fibrocellular, and thrombus areas was not different between the 2 groups. Similarly, the relative areas immunopositive for CD31, smooth muscle α-actin, and CD68 were similar in the 2 groups. In conclusion, coronary culprit lesions in patients with STEMI show more severe plaque rupture with similar histologic features than those in patients with NSTEMI, supporting the idea that a large plaque rupture is more likely in STEMI patients.
Plaque rupture and acute thrombus formation is the key mechanism of ST-segment elevation myocardial infarction (STEMI) or non-STEMI (NSTEMI). Distinguishing STEMI from NSTEMI is clinically important because their treatment and prognosis are different. Intravascular ultrasound (IVUS) and optical coherence tomography studies have shown that plaque rupture is identical in STEMI and NSTEMI patients with different plaque morphologies. The ruptured plaque contains numerous inflammatory cells, and inflammation is recognized as a central feature in the events leading to acute myocardial infarction. However, it remains uncertain whether the histology of coronary culprit plaques differs between STEMI and NSTEMI patients. In the present study, we compared IVUS and histologic findings in coronary culprit plaques from patients with STEMI and NSTEMI.
Methods
Specimens of coronary atherosclerotic plaques from 96 consecutive patients with either STEMI (n = 70) or NSTEMI (n = 26) were obtained from a local biobank that collects atherectomy-derived tissues. Patient demographic and clinical characteristics, and the procedures applied to each patient were prospectively recorded. Patients were considered suitable for directional coronary atherectomy if they had a significant stenotic lesion with a large plaque burden but lacked heavy thrombi in a nontortuous epicardial coronary artery >3 mm in diameter. Each sample corresponded to a de novo lesion from a single patient. Directional coronary atherectomy was performed with a Flexi-Cut catheter (Abbott Laboratories/Guidant Vascular Interventions, Santa Clara, California) under IVUS guidance. The study protocol was approved by the local Institutional Review Committee, and all patients provided written informed consent.
Following intracoronary administration of 0.2 mg nitroglycerin and the guide wire passage, IVUS examinations were performed before directional coronary atherectomy using a motorized transducer pullback system (0.5 mm/sec) and a commercial scanner (SCIMED/Boston Scientific, Natick, Massachusetts) consisting of a rotating 40-MHz transducer. IVUS measurements were taken by a colleague who was blind to the clinical data. A ruptured plaque was defined as a plaque containing a cavity that communicated with the lumen and that also showed an overlying residual fibrous cap fragment. A thrombus was defined as an intraluminal mass with a layered or lobulated appearance, showing evidence of blood flow (microchannels) within the mass, and demonstrating speckling or scintillation. Using computerized planimetry, the external elastic membrane (EEM) and lumen cross-sectional area (CSA; mm 2 ) were measured in culprit and reference segments. When there was a thrombus in the cavity, the area occupied by the thrombus was included in the cavity area measurement. Cavity length was measured between the proximal and distal edges of the cavity, and the arc of the ruptured cavity was measured from the middle of the lumen. A reference segment was defined as the most normal-appearing cross section within a 5 mm region proximal and distal to the lesion but before any side branch. The remodeling index was calculated as the lesion EEM CSA divided by the mean reference EEM CSA, and the plaque burden was calculated as plaque + media CSA divided by EEM CSA.
Tissue specimens were formalin-fixed and embedded in donor paraffin blocks. Tissue microarrays were produced by reembedding tissues from the preexisting donor paraffin blocks into an array on a recipient paraffin block. Sections from the master block were cut with a microtome, mounted on microscope slides, and used for subsequent staining procedures. Standard hematoxylin and eosin staining was performed to determine cellularity and general morphologic features. The area of each plaque was measured with a microscopic image analysis system (Motic Images Advanced 3.2, Motic, Xiamen, China). Plaques were classified as atheromatous (i.e., with necrotic cores and cholesterol clefts, but without connective tissue matrix) or fibrocellular portions. All slides were graded by 2 pathologists (C.-S. Park and I. Hwang) who were blinded to the clinical status of the patient. Discrepancies among their findings were resolved by discussion. Sections of each tissue specimen were stained with monoclonal antibodies (mAbs) against smooth muscle α-actin (1:200, mouse antihuman macrophage antibody clone 1A4; DAKO, Carpinteria, California), CD31 (1:200, mouse antihuman endothelial cell antibody clone WM59; BD Biosciences, Franklin Lakes, New Jersey), and CD68 (1:200, mouse antihuman macrophage antibody clone KP-1; DAKO). Staining was performed with the Envision-Plus Immunostaining Kit and 3,3-diaminobenzidine or 3-amino-9-ethylcarbazole as the chromogen, according to the manufacturer’s instructions (DAKO). Briefly, samples were incubated with primary antibodies (diluted in antibody diluent, DAKO) for 1 hour, washed twice (5 min each) with Tris-buffered saline/Tween-20, incubated with secondary antibodies conjugated with horseradish peroxidase (HRP)-labeled polymer (DAKO) for 1 hour, and washed again. As negative controls, adjacent sections were stained with species- and isotype-matched irrelevant antibodies, including normal rabbit immunoglobulin G (Abcam, Cambridge, UK). The immunopositive area was calculated as the ratio of the area of positively stained regions to the total plaque area.
Continuous variables are expressed as means ± SD or medians with interquartile ranges. Categorical variables are expressed as frequencies. Continuous variables were compared by Student t tests or Mann-Whitney U tests, and categorical variables were analyzed using the chi-squared test. Statistical significance was defined as a 2-sided p value <0.05.
Results
Clinical characteristics were largely similar between the 2 groups, except lipid profiles and medications ( Table 1 ). The median age was 57 years; 18.8% of the patients had diabetes mellitus, and 51.0% had hypertension. The median time from onset of chest pain to angioplasty was 4 hours for STEMI (n = 70) and 48 hours for NSTEMI (n = 26). Normal antegrade flow before angioplasty was less frequently observed in patients with STEMI than in patients with NSTEMI. At the time of the index procedure, beta blockers and statins were less frequently used in patients with STEMI than in those with NSTEMI.
| Characteristics | STEMI (n = 70) | NSTEMI (n = 26) | p Value |
|---|---|---|---|
| Age (yrs) | 55.5 ± 10.5 | 60.0 ± 8.3 | 0.051 |
| Male/female | 62/8 | 20/6 | 0.194 |
| Current smoker | 33 (47.1%) | 9 (34.6%) | 0.272 |
| Diabetes mellitus | 13 (18.6%) | 5 (19.2%) | 0.941 |
| Hypertension | 35 (50%) | 14 (53.8%) | 0.738 |
| Total cholesterol (mg/dl) | 194.6 ± 50.4 | 176.4 ± 27.7 | 0.084 |
| Triglyceride (mg/dl) | 196.1 ± 130.3 | 129.0 ± 49.2 | 0.002 |
| HDL cholesterol (mg/dl) | 35.2 ± 8.4 | 39.5 ± 11.3 | 0.063 |
| Hs-CRP (mg/dl) | 4.5 ± 6.0 | 4.7 ± 5.9 | 0.912 |
| Multivessel coronary disease | 32 (45.7%) | 13 (50%) | 0.708 |
| Culprit coronary artery | 0.057 | ||
| Left anterior descending | 43 (61.4%) | 9 (34.6%) | |
| Left circumflex | 8 (11.4%) | 4 (15.4%) | |
| Right | 19 (27.1%) | 13 (50%) | |
| TIMI flow grade 3 at baseline ∗ | 7 (10%) | 16 (61.5%) | <0.001 |
| Medications at the time of DCA | |||
| Aspirin | 70 (100%) | 26 (100%) | 1.0 |
| Clopidogrel | 70 (100%) | 26 (100%) | 1.0 |
| ACEI/ARB | 4 (6%) | 4 (15%) | 0.128 |
| Beta blockers | 8 (11%) | 8 (31%) | 0.024 |
| Calcium antagonists | 8 (11%) | 7 (27%) | 0.063 |
| Statins | 19 (27%) | 13 (50%) | 0.035 |
∗ Antegrade TIMI flow grade 3 through the coronary culprit lesion before coronary angioplasty.
IVUS data are shown in Table 2 . A thrombus was observed in 87.1% of patients with STEMI, compared with 80.8% of patients with NSTEMI (p = 0.432). Plaque rupture was more commonly observed at the proximal side of the minimal lumen site. Proximal and distal reference measurements were similar in the 2 groups. Likewise, there were no significant differences in EEM CSA, lumen CSA, calcification, plaque burden, or remodelling index at the rupture and minimal lumen sites, and the ruptured cavity area was similar in the 2 groups. However, the arc of the ruptured cavity was significantly greater in patients with STEMI than in those with NSTEMI (69.4 ± 27.9° vs 51.8 ± 20.0°, respectively, p = 0.008). Representative cases of plaque rupture and corresponding histopathology are shown in Figure 1 .
| Variable | STEMI (n = 70) | NSTEMI (n = 26) | p Value |
|---|---|---|---|
| Lesion length (mm) | 26 ± 11 | 25 ± 14 | 0.715 |
| Thrombus | 61 (87%) | 21 (81%) | 0.432 |
| Plaque morphology | 0.15 | ||
| Hyperechoic | 20 (29%) | 10 (39%) | |
| Mixed | 13 (19%) | 8 (31%) | |
| Hypoechoic | 37 (53%) | 8 (31%) | |
| Attenuated plaque | 39 (56%) | 16 (62%) | 0.608 |
| Calcium, superficial | 47 (67%) | 22 (85%) | 0.091 |
| Plaque rupture | 62 (89%) | 22 (85%) | 0.602 |
| Rupture location vs minimal lumen site | 0.090 | ||
| Proximal | 38 (61%) | 14 (64%) | |
| Same | 3 (5%) | 4 (18%) | |
| Distal | 21 (34%) | 4 (18%) | |
| Proximal reference | |||
| EEM CSA (mm 2 ) | 17.3 ± 5.0 | 16.3 ± 6.0 | 0.145 |
| Lumen CSA (mm 2 ) | 9.5 ± 2.9 | 9.2 ± 4.2 | 0.691 |
| Distal reference segment | |||
| EEM CSA (mm 2 ) | 10.8 ± 4.0 | 10.7 ± 4.6 | 0.899 |
| Lumen CSA (mm 2 ) | 6.2 ± 2.4 | 6.1 ± 2.5 | 0.834 |
| Minimal lumen site | |||
| EEM CSA (mm 2 ) | 14.5 ± 4.3 | 14.9 ± 6.0 | 0.742 |
| Lumen CSA (mm 2 ) | 1.2 ± 0.4 | 1.3 ± 0.5 | 0.082 |
| Plaque burden (%) | 91 ± 4 | 90 ± 5 | 0.178 |
| Remodeling index | 1.1 ± 0.2 | 1.1 ± 0.2 | 0.251 |
| Rupture site | |||
| EEM CSA (mm 2 ) | 15.3 ± 3.9 | 15.6 ± 6.2 | 0.835 |
| Lumen CSA (mm 2 ) | 3.0 ± 1.6 | 3.2 ± 1.5 | 0.537 |
| Plaque burden (%) | 81 ± 8 | 78 ± 11 | 0.171 |
| Arc of cavity, degree | 69 ± 28 | 52 ± 20 | 0.008 |
| Cavity length (mm) | 2.2 ± 2.1 | 2.1 ± 2.0 | 0.935 |
| Cavity area (mm 2 ) | 1.2 ± 1.8 | 1.2 ± 1.2 | 0.949 |
| Remodeling index | 1.1 ± 0.2 | 1.1 ± 0.3 | 0.759 |
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