Association between complex coronary artery stenosis and unstable angina and the extent of plaque inflammation

PURPOSE: Patients with unstable coronary syndromes often have complex morphology of coronary stenoses at angiography. We evaluated the association between qualitative assessment of coronary stenoses and plaque inflammation determined by immunohistochemistry. METHODS: A total of 79 patients with unstable (n = 46) or stable angina (n = 33) underwent directional coronary atherectomy for culprit lesions. Qualitative analysis of coronary angiograms was performed using a modified Ambrose classification. Coronary lesions were categorized as either simple (concentric and eccentric type I, n = 29) or complex (eccentric type II and multiple irregularities, n = 50). Cryostat sections of retrieved atherosclerotic specimens were stained immunohistochemically with monoclonal antibodies, alpha-actin (smooth muscle cells), CD68 (macrophages), and CD3 (T lymphocytes). The extent of atherosclerotic inflammation within each coronary lesion was determined by the percentage of immunopositive macrophages per total tissue area (including smooth muscle cells) and the number of T lymphocytes per mm(2). RESULTS: The mean (+/- SD) percentage of macrophages in atherectomy specimens from patients with unstable angina was greater than in specimens from patients with stable angina (21% +/- 14% vs. 13% +/- 10%, P = 0.01); similar results were seen when complex coronary lesions were compared with simple lesions (23% +/- 13% vs. 9% +/- 8%, P <0.001). In multivariate linear regression models, the combination of unstable angina and lesion complexity was strongly associated with the percentage of plaque macrophages. CONCLUSION: The extent of atherosclerotic plaque inflammation is associated with angiographic grading of coronary lesion complexity and unstable angina.     

Cellular immunostaining of angiotensin-converting enzyme in human coronary atherosclerotic plaques.

OBJECTIVES: The aim of this study was to determine the cellular localization of angiotensin I-converting enzyme (ACE) in the atherosclerotic plaque and its correlation with inflammation and cellular proliferation. BACKGROUND: Angiotensin I-converting enzyme inhibitors reduce the incidence of vascular events; therefore, tissue ACE may play a determinant role in the pathophysiology of the atherosclerotic plaque. METHODS: Histology and immunocytochemistry of de novo coronary plaques retrieved with directional coronary atherectomy from 141 patients were analyzed: 87 with stable angina, 39 with subacute unstable angina, and 15 with acute unstable angina. RESULTS: Compared with stable patients, unstable patients showed more thrombotic lesions (72% vs. 27%, p < 0.0001), smaller areas of fibrous plaque (2.3 +/- 1.2 mm2 vs. 2.8 +/- 1.1 mm2, p = 0.02), higher cellular proliferative score (0.78 +/- 0.9 vs. 0.27 +/- 0.6, p = 0.003), larger content of ACE-stained cells (26.3 +/- 23% vs. 12.6 +/- 15%, p = 0.005) and larger areas of inflammation as identified by CD68 immunostaining (29.5 +/- 22% vs. 20.2 +/- 19%, p = 0.02). A significant linear correlation was found between CD68- and ACE-stained areas (mm2) among unstable patients (r = 0.6, p = 0.0001), but it was absent among stable patients (r = 0.006, p = 0.9). Co-localization of ACE, CD68, and alpha-actin was confirmed by double immunostaining. Patients with Ki-67-positive staining as an index of cell proliferation showed also significantly larger areas of ACE immunoactivity (p = 0.004). CONCLUSIONS: Our data demonstrate ACE immunoactivity in inflammatory and proliferative cells of coronary atherosclerotic plaques. In particular, patients with unstable angina showed larger areas of ACE immunoactive tissue and proliferating cells compared with stable patients. These observations support a role of the enzyme in the pathophysiology of coronary unstable plaques and suggest potentially different effects of ACE inhibitors according to clinical presentation.     

Recurrent unstable angina after directional coronary atherectomy is related to the extent of initial coronary plaque inflammation

OBJECTIVES: This study was performed to evaluate the relationship between plaque inflammation of the initial culprit lesion and the incidence of recurrent angina for one year after directional coronary atherectomy (DCA). BACKGROUND: A positive correlation between coronary plaque inflammation and angiographic restenosis has been reported. METHODS: A total of 110 patients underwent DCA. Cryostat sections were immunohistochemically stained with monoclonal antibodies CD68 (macrophages), CD-3 (T lymphocytes) and alpha-actin (smooth muscle cells [SMCs]). The SMC and macrophage contents were planimetrically quantified as a percentage of the total tissue area. T lymphocytes were counted as the number of cells/mm2. The patients were followed for one year to document recurrent unstable angina pectoris (UAP) or stable angina pectoris (SAP). RESULTS: Recurrent UAP developed in 16 patients, whereas recurrent SAP developed in 17 patients. The percent macrophage areas were larger in patients with recurrent UAP (27 +/- 12%) than in patients with recurrent SAP (8 +/- 4%; p = 0.0001) and those without recurrent angina (18 +/- 14%; p = 0.03). The number of T lymphocytes was also greater in patients with recurrent UAP (25 +/- 14 cells/mm2) than in patients with recurrent SAP (14 +/- 8 cells/mm2; p = 0.02) and those without recurrent angina (14 +/- 12 cells/mm2; p = 0.002). Multiple stepwise logistic regression analysis identified macrophage areas and T lymphocytes as independent predictors for recurrent UAP. CONCLUSIONS: There is a positive association between the extent of initial coronary plaque inflammation and the recurrence of unstable angina during long-term follow-up after DCA. These results underline the role of ongoing smoldering plaque inflammation in the recurrence of unstable angina after coronary interventions.     

Increased plasma levels of soluble selectins in patients with unstable angina

BACKGROUND: Inflammation plays an important role in the pathogenesis of unstable angina. Adhesion molecules, such as selectins, mediate the interactions between leukocytes, platelets and endothelial cells during inflammation and thrombogenesis. HYPOTHESIS: The purpose of this study was to determine whether soluble E-selectin, P-selectin and L-selectin levels are increased in patients with unstable angina (UA). METHODS: Soluble E-, P- and L-selectin levels were measured by enzyme-linked immunoassay in the peripheral blood of 23 patients with UA, 26 patients with stable angina (SA) and 15 control patients with angiographically normal coronary arteries. RESULTS: Soluble E-selectin levels were significantly higher in patients with UA (45+/-11 ng/ml) than in controls (30+/-8 ng/ml, P<0.001), or patients with SA (34+/-8 ng/ml, P=0.001). Similarly, plasma levels of P- and L-selectin were significantly higher in patients with UA (427+/-144 and 772+/-160 ng/ml, respectively) than in patients with SA (278+/-79 and 643+/-94 ng/ml, respectively, P<0.005 vs. UA for both), or control patients (189+/-43 and 601+/-126 ng/ml, respectively, P=0.001 vs. UA for both). CONCLUSIONS: Plasma levels of soluble selectins were increased in patients with UA compared with patients with SA or patients without angiographically visible coronary artery disease. Measurements of these adhesion molecules may be helpful as non-invasive markers of coronary plaque destabilization in UA.     

Increased expression of interleukin-10 in unstable plaque obtained by directional coronary atherectomy.

AIMS: The present study investigates the expression and localization of interleukin (IL)-10, an important anti-inflammatory cytokine, in atherectomy specimens from patients with stable and unstable angina. METHODS AND RESULTS: Twenty-two patients with stable angina and 21 with unstable angina who underwent directional coronary atherectomy for de novo lesions were studied. The atherectomy specimens were morphologically assessed and immunohistochemically stained with antibodies for IL-10, macrophages, smooth muscle cells, and endothelial cells. The localization and immunopositive areas were evaluated using an image analysing system. Immunoreactivity for IL-10 was detected in coronary plaques, especially in macrophages. Immunopositive areas of macrophages and IL-10, as well as the incidence of thrombus formation, were significantly greater in specimens from patients with unstable angina than in those from patients with stable angina (macrophages, P<0.001; IL-10, P<0.05; thrombus formation, P<0.05; respectively). Even after adjustment, IL-10 expression and the incidence of thrombus formation were significantly greater in the unstable angina group (P<0.05, each). The immunoreactivities for smooth muscle cells and endothelial cells did not differ between the two groups. CONCLUSION: IL-10 was more frequently expressed in specimens from patients with unstable angina. This finding might contribute to a better understanding of plaque instability.     

Involvement of C-reactive protein obtained by directional coronary atherectomy in plaque instability and developing restenosis in patients with stable or unstable angina pectoris

We investigated whether positive immunohistochemical staining of C-reactive protein (CRP) in initial culprit lesions is related to coronary plaque instability and whether it could affect the outcome of directional coronary atherectomy (DCA). The plasma level of CRP is a reliable marker of the risk of coronary events and restenosis after percutaneous coronary intervention. However, the influence of tissue CRP in atheromatous plaque on plaque vulnerability and restenosis remains unknown. Samples of DCA obtained from 12 patients with stable angina pectoris and 15 patients with unstable angina pectoris were immunohistochemically stained with a monoclonal antibody against CRP. We performed follow-up coronary angiography on 22 of 27 patients to evaluate the presence of restenosis after DCA. Immunoreactivity to CRP was localized to macrophages, smooth muscle cells, and necrotic areas. The ratio of CRP positive cells to total cells was significantly higher in DCA samples from patients with unstable (17.9 +/- 2.0%) than with stable angina (11.0 +/- 2.5%) (p <0.05). Follow-up coronary angiography showed that 12 of 22 patients developed restenosis after DCA. The ratio was also significantly higher in DCA specimens from patients with restenosis (19.3 +/- 2.8%) compared with those without restenosis (11.0 +/- 2.0%) (p <0.05). In addition, the ratio significantly correlated with late luminal loss (r = 0.428, p <0.05) and loss index (r = 0.636, p = 0.0011) after DCA. Immunoreactivity to CRP in coronary atheromatous plaque increases in culprit lesions of unstable angina, and it affects restenosis after DCA. These findings suggest that CRP in atheromatous plaque plays an important role in the pathogenesis of unstable angina and restenosis after coronary intervention.     

Effectiveness of rotational atherectomy of right coronary artery ostial stenosis

Balloon angioplasty and stenting of right coronary ostial stenosis may frequently be impeded by lesion calcification, whereas rotational atherectomy, which ablates calcified plaque, should treat these lesions effectively. Accordingly, we evaluated procedural success and longterm clinical outcome of rotational atherectomy of right coronary ostial stenosis. Procedural data were obtained from a comprehensive interventional registry and follow-up information was obtained by chart review and patient enquiry. All patients who developed recurrent angina underwent angiographic restudy. During a 5-year interval, 119 patients underwent rotational atherectomy of right coronary ostial stenosis. Multilesion interventions were performed in 55% of patients. Ostial lesions were 3.73+/-3.69 mm in length (mean +/- SD), and 57.1% were significantly calcified. Reference vessel diameter was 3.42+/-0.56 mm. Maximum burr:artery ratio was 0.64+/-0.1 with adjunct balloon angioplasty in 89.1% and adjunct stenting in 9.2%. Procedural success (<50% residual stenosis without major complication) was 97.5%, with 1.7% uncomplicated failure and 0.8% Q-wave infarction. Maximum residual stenosis was 15+/-17%. During 6-month follow-up, available in 94% of patients, 82.7% remained angina-free, 10.9% developed recurrent angina due to right coronary ostial restenosis, and 6.4% developed recurrent angina due to another lesion. Two years after intervention, target lesion revascularization rate was 16%. Predictors of symptomatic angiographic restenosis were dissection >10 mm, final minimal luminal diameter <2.5 mm, lesion length >10 mm, restenotic lesion, and diabetes. We conclude that rotational atherectomy of right coronary ostial stenosis results in excellent acute procedural success and in low incidence of clinical recurrence, with a high proportion of patients remaining angina-free 2 years after intervention.     

Tissue characteristics of restenosis after percutaneous transluminal coronary angioplasty in diabetic patients.

OBJECTIVES: The purposes of this study were to analyze coronary specimens from patients with diabetes mellitus (DM) and to compare them with specimens from patients without DM. BACKGROUND: Diabetes mellitus is associated with an increased incidence of restenosis after percutaneous transluminal coronary angioplasty (PTCA). Increased hypercellular smooth muscle cell proliferation with exaggerated intimal hyperplasia formation may be responsible for this predisposition. METHODS: Eighteen coronary atherectomy specimens with restenosis after PTCA from patients with DM were compared with 18 coronary atherectomy specimens with restenosis after PTCA from patients without DM. Total and segmental areas were quantified on trichrome-stained tissue of hypercellular tissue, collagen-rich sclerotic tissue, atheroma and thrombus. Demographic and angiographic data were similar in both groups. RESULTS: The percentage of total plaque area composed of hypercellular tissue was lower in restenotic specimens from patients with DM than in restenotic specimens from patients without DM (19 +/- 6% vs. 44 +/- 5%; p = 0.003). The percentage of collagen-rich sclerotic tissue area was larger in restenotic specimens from patients with DM than in restenotic specimens from patients without DM (77 +/- 9% vs. 53 +/- 4%; p = 0.004). The percentages of atheroma and thrombus were similar in both groups. CONCLUSIONS: Intimal hypercellular tissue content is reduced in restenotic tissue from patients with DM. Collagen-rich sclerotic content is increased in restenotic lesions from patients with DM. These results suggest an accelerated fibrotic rather than a proliferative response in diabetic lesions from patients with restenosis after PTCA.     

Noninvasive assessment of plaque morphology and composition in culprit and stable lesions in acute coronary syndrome and stable lesions in stable angina by multidetector computed tomography.

OBJECTIVES: The purpose of this study was to assess morphology and composition of culprit and stable coronary lesions by multidetector computed tomography (MDCT). BACKGROUND: Noninvasive identification of culprit lesions has the potential to improve noninvasive risk stratification in patients with acute chest pain. METHODS: Thirty-seven patients with acute coronary syndrome (ACS) or stable angina underwent coronary 16-slice MDCT and invasive selective angiography. In all significant coronary lesions two observers measured the degree of stenosis, plaque area at stenosis, and remodeling index and assessed plaque composition. Differences between culprit lesions in patients with ACS and stable lesions in patients with ACS or stable angina were determined. RESULTS: We analyzed 40 lesions with excellent image quality in 14 patients with ACS and 9 patients with stable angina. Culprit lesions in patients with ACS (n = 14) had significantly greater plaque area and a higher remodeling index than both stable lesions in patients with ACS (n = 13) and in patients with stable angina (n = 13) (17.5 +/- 5.9 mm2 vs. 9.1 +/- 4.8 mm2 vs. 13.5 +/- 10.7 mm2, p = 0.02; and 1.4 +/- 0.3 vs. 1.0 +/- 0.4 vs. 1.2 +/- 0.3, p = 0.04, respectively). The prevalence of non-calcified plaque was 100%, 62%, and 77%, respectively, and the prevalence of calcified plaque was 71%, 92%, and 85%, respectively, in culprit lesions in patients with ACS and in stable lesions in patients with ACS or stable angina. CONCLUSIONS: We introduce the concept of noninvasive detection and characterization of coronary atherosclerotic lesions in patients with ACS by MDCT. We identified differences in lesion morphology and plaque composition between culprit lesions in ACS and stable lesions in ACS or stable angina, consistent with previous intravascular ultrasound studies.     

Tenascin-C is associated with coronary plaque instability in patients with acute coronary syndromes.

BACKGROUND: Tenascin-C (TNC) is an extracellular matrix glycoprotein that increases after inflammation and injury. In cultured cells TNC has been reported to markedly induce the expression of matrix metalloproteinase-9, which stimulates collagen degradation in the fibrous cap of human atherosclerotic plaque. METHODS AND RESULTS: Immunohistochemical techniques were used to analyze the expression of TNC protein in 51 coronary atherectomy specimens obtained from patients with stable angina pectoris (SAP, n=23) or acute coronary syndromes (ACS) (n=28; unstable angina pectoris, n=20, acute myocardial infarction, n=8). Immunostaining for alpha-smooth muscle actin, CD68, CD45, and CD31 was also performed in serial sections to identify the cell types that express TNC protein. The %TNC + area (percentage of the area of immunostaining for TNC protein in the total surface area of the plaque) was larger in coronary samples with the plaque characteristics of thrombus, angiogenesis, intraplaque hemorrhage, and macrophage (CD68(+)), and lymphocyte (CD45 (+)) clusters than in coronary samples without them (52+/-3.4 vs 39+/-4.8, p<0.05; 57+/-3.7 vs 36+/-3.7, p<0.01; 51+/-3.6 vs 39+/-4.8, p<0.05; 53+/-3.4 vs 33+/-4.5, p<0.01; 56+/-4.1 vs 37+/-3.6, p<0.01, respectively). The presence of other components, such as dense fibrous tissue, neointimal hyperplasia, atheromatous gruel and calcification, was not significantly correlated with the %TNC + area. The %TNC + area was larger in coronary samples from patients with ACS than in samples from patients with SAP (56+/-3.2% vs 34+/-4.3%, p<0.01). CONCLUSIONS: The results suggest that TNC may have specific functions in coronary plaque formation and may be involved in the pathogenesis of coronary lesions in ACS.     

Recent activation of the plaque immune response in coronary lesions underlying acute coronary syndromes

Objective—To discriminate between chronic inflammation and acute activation of the plaque immune response in culprit lesions of patients with acute coronary syndromes.Design—Retrospective study.Setting—Tertiary referral centre.Subjects—71 patients having coronary atherectomy were classified according to their ischaemic syndrome: stable angina (n = 23); stabilised unstable angina (n = 18); refractory unstable angina (n = 11); and acute myocardial infarction (n = 19).Main outcome measures—Immunohistochemical measurement of interleukin 2 receptor (IL-2R) (CD25) positive cells expressed as a percentage of the total amount of (CD3 positive) T lymphocytes in frozen sections of atherectomy specimens.Results—The number of lesions containing IL-2R (CD25) positive T cells increased with severity of the ischaemic coronary syndrome (stable angina, 52%; stabilised unstable angina, 77.8%; refractory unstable angina, 90.9%; acute myocardial infarction, 89.4%). The percentage of activated T cells (CD25/CD3 ratios ×100) increased in lesions associated with refractory unstable angina (7.8%) and acute myocardial infarction (18.5%), compared with those in lesions associated with either chronic stable angina (2.2%) or stabilised unstable angina (3.3%).Conclusions—An increase in the percentage of IL-2R positive T lymphocytes in culprit lesions of patients with acute coronary syndromes indicates recent activation and amplification of the immune response within plaques. This may result in a burst of inflammatory products with tissue degrading and vasoactive properties and, hence, could initiate or accelerate the onset of an acute coronary event.     

Directional coronary atherectomy for lesions of the proximal left anterior descending artery: initial clinical results, complications and histopathological findings

Background: Directional coronary atherectomy is a percutaneous technique which extends the role of balloon angioplasty to bulky eccentric coronary lesions. Aims: To report the early experience, clinical results, complications and histopathological findings of directional coronary atherectomy (DCA) in proximal left anterior descending artery (LAD) stenosis. Methods: Study of 25 lesions in 24 patients on whom directional atherectomy was performed on the proximal LAD artery with the Simpson coronary atherectomy device. Results: Twenty-five procedures were performed on 24 patients with stenosis in the proximal LAD artery. There were 21 males and three females with a mean age of 56.5 years. Sixteen patients presented with stable angina and eight with unstable angina. Eight patients had previous myocardial infarction (MI). Angiographic success was obtained in 24 of 25 lesions (96%). The mean lesion length was 13.1 ± 3.7 mm and the mean LAD artery diameter was 3.6 ± 0.5 mm. Minimal luminal diameter improved from 0.9 ± 0.4 mm to 3.0 ± 0.5 mm and the percentage diameter stenosis reduced from 75 ± 12% to 16 ± 9%. Complications included acute occlusion in one patient, non-Q MI in three patients, local vascular complications in one patient and side-branch loss in one patient. Histology demonstrated fibrous cap of atherosclerotic plaque in 100%, media and internal elastic lamina in 28% and intimal hyperplasia in 100% of restenotic lesions and 27% of native lesions. Restenosis rates in angiographically restudied patients was 27%. The mean minimal luminal diameter at follow-up was 2.3 ± 0.9 mm and the mean percentage diameter stenosis was 35 ±21%. Conclusion: From this initial study, we conclude that DCA is an effective and safe procedure for the treatment of large proximal LAD lesions. DCA provides a large luminal diameter and a ‘smoother’ angiographic appearance compared to coronary angioplasty. Acute complication rates are low and restenosis rates were comparable with percutaneous transluminal coronary balloon angioplasty.     

Clinically stable angina pectoris is not necessarily associated with histologically stable atherosclerotic plaques.

OBJECTIVE: To investigate the extent of plaque inflammation in culprit lesions of patients with chronic stable angina. DESIGN: Retrospective study. SETTING: Amsterdam reference centre. SUBJECTS: 89 consecutive patients who underwent directional coronary atherectomy, 58 of whom met the following inclusion criteria: chronic stable angina (Canadian Cardiovascular Society classification 1-3 (group 1, n = 28)); unstable angina (Braunwald class II (group 2, n = 18)); unstable angina (Braunwald class III (group 3, n = 12)). INTERVENTIONS: Directional atherectomy in patients with angina pectoris. MAIN OUTCOME MEASURES: Tissue areas of culprit lesions occupied by inflammatory cells and smooth muscle cells related to clinically defined ischaemic syndrome. RESULTS: Areas (% of total surface area (mean (SEM)) rich in smooth muscle cells were larger in patients with chronic stable angina (group 1, 51.2 (20.9)) than in those with unstable angina (group 2, 42.1 (20.5); group 3, 29.5 (19.4)) (1 v 2 and 2 v 3, NS; 1 v 3, P < 0.004). Macrophage rich areas were significantly smaller in patients with stable angina (group 1, 21.8 (11.9)) than in those with unstable angina (group 2, 31.5 (14.6); group 3, 46.4 (16.7)) (1 v 2, P < 0.02; 2 v 3, P < 0.02; 1 v 3, P < 0.001). Mean numbers of T cells per mm2 were as follows: group 1, 17 (9.4); group 2, 25 (15.9); group 3, 41 (30.6) (1 v 2, P 0.04; 2 v 3, P 0.07; 1 v 3, P < 0.001). Areas with HLA-DR positive cells showed the same pattern as macrophages and T cells and were smaller in stable (29.9 (12.4)) than in unstable angina (group 2, 40.4 (17.6); group 3, 52.4 (12.0)) (1 v 2, P < 0.02; 2 v 3, P < 0.05; 1 v 3, P < 0.001). CONCLUSION: The inverse relation between the extent of inflammatory activity in plaque tissues of culprit lesions and the clinical stability of the ischaemic syndrome supports the concept that reduction of inflammation favours plaque stabilisation. At the same time, the considerable overlap between groups indicates that patients with clinically stable angina do not all have histologically stable plaques.     

Elevation of C-reactive protein in "active" coronary artery disease

Unstable angina occurs most commonly in the setting of atherosclerotic coronary artery disease (CAD), but there is little information concerning the mechanisms responsible for the transition from clinically stable to unstable coronary atherosclerotic plaque. Recently, increased focal infiltration of inflammatory cells into the adventitia of coronary arteries of patients dying suddenly from CAD and activation of circulating neutrophils in patients with unstable angina have been observed. To characterize the presence of inflammation in "active" atherosclerotic lesions, the acute phase reactant C-reactive protein (CRP) was measured in 37 patients admitted to the coronary care unit with unstable angina, 30 patients admitted to the coronary care unit with nonischemic illnesses and 32 patients with stable CAD. CRP levels were significantly elevated (normal less than 0.6 mg/dl) in 90% of the unstable angina group compared to 20% of the coronary care unit group and 13% of the stable angina group. The average CRP values were significantly different (p = 0.001) for the unstable angina group (2.2 +/- 2.9 mg/dl) compared to the coronary care (0.9 +/- 0.7 mg/dl) and stable angina (0.7 +/- 0.2 mg/dl) groups. There was a trend for unstable angina patients with ischemic ST-T-wave abnormalities to have higher CRP values (2.6 +/- 3.4) than those without electrocardiographic changes (1.3 +/- 0.9, p = 0.1). The data demonstrate increased levels of an acute phase reactant in unstable angina. These findings suggest that an inflammatory component in "active" angina may contribute to the susceptibility of these patients to vasospasm and thrombosis.     

Diffuse and active inflammation occurs in both vulnerable and stable plaques of the entire coronary tree: a histopathologic study of patients dying of acute myocardial infarction

OBJECTIVES: This study was undertaken to define and compare geographic coronary artery inflammation in patients who were dying of acute myocardial infarction (AMI), chronic stable angina (SA), and noncardiac causes (CTRL). BACKGROUND: Biochemical markers and flow cytometry provide indirect evidence of diffuse coronary inflammation in patients dying of acute coronary syndromes. Yet no histopathologic studies have corroborated these findings. A key unanswered question is whether the inflammatory burden involves the entire coronary tree or is limited to a few plaques. METHODS: We examined 544 coronary artery segments from 16 patients with AMI, 109 segments from 5 patients with SA, and 304 coronary segments from 9 patients with CTRL. RESULTS: An average of 6.8 +/- 0.5 vulnerable segments per patient were found in the AMI group (in addition to culprit lesions) compared with an average of 0.8 +/- 0.3 and 1.4 +/- 0.3 vulnerable lesions/patient in the SA and CTRL groups, respectively. The AMI group, independent of the type of plaque observed, showed significantly more inflammatory infiltrates compared with the SA and CTRL groups (121.6 +/- 12.4 cell x mm2 vs. 37.3 +/- 11.9 cell x mm2 vs. 26.6 +/- 6.8 cell x mm2, p = 0.0001). In AMI patients, active inflammation was not only evident within the culprit lesion and vulnerable plaques but also involved stable plaques. These showed a three- to four-fold higher inflammation than vulnerable and stable plaques from the SA and CTRL groups, respectively. CONCLUSIONS: This histopathologic study found that both vulnerable and stable coronary plaques of patients dying of AMI are diffusely infiltrated by inflammatory cells.     

Migratory activity of human smooth muscle cells cultivated from coronary and peripheral primary and restenotic lesions removed by percutaneous atherectomy.

BACKGROUND. The successful cultivation of human smooth muscle cells (SMC) from coronary and peripheral atherosclerotic lesions removed by percutaneous directional atherectomy is described. METHODS AND RESULTS. Sixty-seven patients in whom plaque material was obtained compose the study population. A total of 73 lesions from both coronary (n = 38) and peripheral (n = 35) arteries of primary (n = 50) and restenotic origin (n = 23) were studied. Successful cultivation was significantly (p less than 0.001) dependent on the quantity of plaque material submitted. Fifty-five percent of patients in whom atherectomy specimens were removed from coronary lesions yielded an adequate SMC population in comparison to 89% of those from peripheral arteries (p less than 0.01). Cultivation was not dependent on the age and sex of patients, lesion origin, risk factors, medications, or incidence of unstable angina. In an attempt to quantify SMC activity, migratory velocity was measured with a computer-assisted motion analysis system. SMC migratory velocity was found to be significantly (p less than 0.001) greater in restenotic than in primary plaque material. This finding was confirmed for both coronary and peripheral lesions. CONCLUSIONS. Our data suggest that elevated SMC migratory activity may be an important mechanism in the development of restenotic lesions.     

Plasma levels of oxidized-low-density lipoproteins are higher in patients with unstable angina and correlated with angiographic coronary complex plaques

OBJECTIVES: To measure circulating levels of oxidized-low-density lipoproteins (ox-LDL) in patients with stable and unstable angina and controls, and to investigate their correlation with the extent of coronary artery disease (CAD) and the presence of complex plaques at coronary angiography. METHODS AND RESULTS: Circulating ox-LDL were assessed, using ELISA, in patients with unstable angina (UA, n=26), stable angina (SA, n=29) and in controls (C, n=27). All patients underwent coronary angiography. The extent of CAD was evaluated using a quantitative score, while the presence of complex, vulnerable plaques was angiographically assessed. Ox-LDL were higher in UA patients than in SA patients and in C subjects, and in SA patients than in C subjects (C, 45.6+/-12.8 U/L; SA, 58.8+/-11.0 U/L; UA, 73.7+/-13.6 U/L; p<0.001). No correlation was found with the extent of atherosclerotic disease in the coronary tree. Patients with angiographic complex lesions showed significantly higher levels of ox-LDL (68.4+/-13.9 U/L versus 55.2+/-16.4 U/L, p<0.001). Multiple regression analysis showed that ox-LDL were independent predictors of the presence of complex plaques (p<0.023). CONCLUSIONS: Ox-LDL levels are higher in unstable patients and correlate with the presence of angiographically documented complex plaques. Ox-LDL might be markers of destabilization of CAD.     

Mast cell infiltration in acute coronary syndromes: implications for plaque rupture

Objectives. To define the role of mast cells in plaque destabilization.Background. Inflammation is an essential feature of human coronary plaques. Macrophages and T lymphocytes are considered to contribute to destabilization of the plaques. The role of mast cells in this setting is less well studied. We therefore counted the mast cells in coronary atherectomy specimens from patients with chronic stable angina, unstable angina and severe unstable angina.Methods. Patients studied had chronic stable angina (group 1, n = 11), “stabilized” unstable angina (group 2; Braunwald’s class I and II, n = 11) and “refractory” unstable angina (group 3; Braunwald’s class III, n = 7). Samples of culprit lesions (n = 29) were obtained by directional atherectomy, snap-frozen and analyzed immunohistochemically. The numbers of mast cells and T lymphocytes per square millimeter squared were counted and the areas containing macrophages and smooth muscle cells were measured by computed planimetry.Results. We found that the numbers of mast cells and T lymphocytes increased from group 1 through groups 2 to 3. Specimens from group 3 also contained the largest numbers of tumor necrosis factor alpha (TNF-α)-positive mast cells and of matrix metalloproteinase (MMP)-9 (92 kD gelatinase)-positive macrophages.Conclusions. Unstable coronary syndromes are associated with increased numbers of mast cells in culprit lesions. Activated mast cells secrete neutral proteases capable of degrading the extracellular matrix and TNF-α, capable of stimulating macrophages to synthesize MMP-9. Our observations suggest that mast cells, in addition to macrophages, contribute to matrix degradation and, hence, to progression of coronary syndromes.     

Thiazolidinedione treatment attenuates diffuse neointimal hyperplasia in restenotic lesions after coronary stent implantation in type 2 diabetic patients: an intravascular ultrasound study

OBJECTIVES: Thiazolidinedione treatment reduces neointimal tissue proliferation after coronary stent implantation in diabetic patients. However, in-stent restenosis still persists in patients treated with thiazolidinedione. The effect of thiazolidinedione treatment on the pattern of in-stent restenosis remains unclear. This study investigated whether thiazolidinedione treatment attenuates diffuse neointimal hyperplasia in restenotic lesions after coronary stent implantation in diabetic patients. METHODS: Volumetric intravascular ultrasound was performed at 6 months after coronary stent implantation in 76 patients with restenotic lesions who received either conventional anti-diabetic treatment (control group, n = 56) or thiazolidinedione treatment (thiazolidinedione group, n = 20). RESULTS: There were no significant differences between the two groups in stent volume (99 +/- 32 vs 90 +/- 20 mm3, respectively, p = 0.26) or in minimal lumen area in the stent (1.4 +/- 0.6 vs 1.6 +/- 0.5 mm2, respectively, p = 0.11). However, there were significant reductions in neointimal volume (56 +/- 25 vs 36 +/- 11 mm3, respectively, p < 0.01)and neointimal index (56 +/- 11% vs 41 +/- 8%, respectively, p < 0.01) in the thiazolidinedione group. Coefficient of variation of neointimal tissue accumulation was greater in the thiazolidinedione group (45.5%) than in the control group (25.2%). CONCLUSIONS: Intravascular ultrasound study demonstrated that together with reduction of overall neointimal tissue proliferation, thiazolidinedione treatment caused greater point-to-point heterogeneity in the neointimal tissue accumulation in restenotic lesions after coronary stent implantation. This finding strongly suggests that thiazolidinedione treatment attenuates diffuse in-stent restenosis in diabetic patients.