Published online before print November 18, 2002, doi: 10.1161/01.CIR.0000042674.89762.20
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2002;106:2894.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Neutrophil Infiltration of Culprit Lesions in Acute Coronary Syndromes
From the Department of Cardiology, Osaka City General Hospital (T.N., K.H., A.I.); Departments of Pathology (M.U., R.K., Y.I., M.O.) and Internal Medicine and Cardiology (Y.S., S.E., M.Y., K.T., J.Y.), Osaka City University Graduate School of Medicine, Osaka; and the Department of Cardiovascular Pathology (A.C.W., C.M.L., A.E.B.), Academic Medical Center, University of Amsterdam, the Netherlands.
Correspondence to Anton E. Becker, MD, Department of Cardiovascular Pathology, Academic Medical Center, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. E-mail m.i.schenker{at}amc.uva.nl
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background— Neutrophils in unstable atherosclerotic lesions have not received much consideration, despite accumulating evidence suggesting a link between systemic inflammation and acute coronary syndromes.
Methods and Results— Coronary artery segments were obtained at autopsy from 13 patients with acute myocardial infarction (AMI); 8 had a ruptured and 5 an eroded plaque. Patients (n=45) who had died of noncardiovascular diseases served as reference. Atherectomy specimens were obtained from 35 patients with stable angina pectoris (SAP) and from 32 patients with unstable angina pectoris (UAP). Antibodies against CD66b, elastase, myeloperoxidase, and CD11b identified neutrophils; CD10 identified neutral endopeptidase (NEP). CD66b-positive and NEP-positive neutrophils were counted and expressed as a number per square millimeter of tissue. All specimens with plaque rupture or erosion showed distinct neutrophil infiltration; the number did not differ between ruptured and eroded plaques. However, the number of NEP-positive neutrophils was significantly higher (P<0.0001) in ruptured plaques than in eroded plaques. UAP patients showed neutrophils in 14 of 32 culprit lesions; in SAP only 2 of 35 lesions contained neutrophils. The number of neutrophils and NEP-positive cells in patients with UAP was significantly higher (neutrophils, P<0.0005; NEP-positive cells, P<0.005) than in patients with SAP.
Conclusions— The observations suggest that neutrophil infiltration is actively associated with acute coronary events. The high number of NEP-positive neutrophils in ruptured plaques, compared with eroded plaques, may reflect differences in the underlying pathophysiological mechanisms.
Key Words: myocardial infarction • angina • inflammation • atherosclerosis
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Plaque rupture or erosion with mural thrombus formation is considered to represent the most important morphological changes that underlie the transformation of stable coronary lesions into clinically unstable lesions, causing unstable angina pectoris (UAP) or acute myocardial infarction (AMI).1 The pathomorphological substrate underlying such complicated lesions is heterogeneous with respect to plaque architecture and cellular composition, but the presence of a localized intraplaque inflammatory process is a common denominator.2
Presently, a growing body of literature suggests a link between systemic inflammation and acute coronary syndromes. It is of note, therefore, that the presence of neutrophils in unstable lesions has not received much consideration, despite the fact that these cells have been identified at rupture sites2 and, in general, are among the first phagocytic cells in acute inflammatory responses to tissue injury. Epidemiological studies, moreover, have shown that leukocyte counts in peripheral blood correlated positively with coronary atherosclerotic risk3 and risk of AMI4; the strongest epidemiological association is with neutrophil counts.4 Indeed, clinical studies have demonstrated that neutrophils are activated in patients with UAP and AMI,5–7 and accumulation of neutrophils, with adherence of fibrin-platelet thrombus, occurs at the site of endothelial cell denudation almost instantly after coronary artery bypass grafting.8
The major function of neutrophils at sites of tissue injury is complex but can be summarized by stating that they may endocytose foreign material or secrete enzymes, such as elastase and myeloperoxidase. Neutrophils also contain neutral endopeptidase 24.11 (NEP), a membrane protein known to modulate inflammatory responses.9 NEP can be detected on mature (segmented) neutrophils only. Immature neutrophils are NEP-negative but have a greater chemotactic response to activated complement than NEP-positive mature neutrophils.9,10 Thus, the presence or absence of NEP on neutrophils may provide some insight into their functional capacity.
The present study has focused on the question of whether there could be a role for neutrophils in the culprit lesions of acute coronary syndromes. The study is based on frozen tissue samples, because monoclonal antibodies against neutrophil markers, as well as the antibody against NEP, work well on frozen sections only.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Coronary Tissue Specimens
This study is based on 3 different groups of specimens; the first and second groups of specimens were obtained at autopsy, and the third group of specimens was obtained by atherectomy (Table 1).
|
Autopsy
Coronary artery segments (n=126) were obtained at autopsy from 58 patients; 13 had died of AMI and 45 had died of noncardiovascular diseases. The ages of the patients ranged from 21 to 77 years (noncardiovascular diseases, 61±11; AMI, 51±19; mean±SD). Of those with noncardiovascular diseases, 84% were men; for AMI, 77% were men. The following risk factors were evaluated: cigarette smoking, hypertension as defined by the Joint National Committee V,11 diabetes mellitus as defined by the WHO Study Group,12 and hypercholesterolemia (cholesterol level >220 mg/dL). Their distribution among patients with noncardiovascular diseases versus those with AMI was as follows: cigarette smoking (27% versus 62%), hypertension (18% versus 46%), diabetes mellitus (9% versus 39%), and hypercholesterolemia (27% versus 38%).
Of the patients who had died of noncardiovascular diseases, 113 segments were obtained. Twenty-six of these contained normal coronary artery with diffuse intimal thickening (AHA classification type I).13,14 The other 87 segments contained atherosclerotic lesions and were characterized histologically either as atherosclerotic lesions with hypercellularity (n=26) or as advanced atherosclerotic lesions (n=61), according to our classification described previously.15 The hypercellular lesion was defined as a cell-rich intimal lesion, predominantly composed of smooth muscle cells (SMCs) and occasional macrophages, but without an extracellular lipid core ("hypercellular lesions" are not recognized by the AHA classification).13,14 The advanced atherosclerotic lesions were additionally divided into fibrolipid (type Va; n=31) and fibrous (type Vc; n=30). In fibrous plaques, the fibrocellular tissue was the predominant component and a lipid core was inconspicuous or absent. In fibrolipid plaques, the ratio of fibrous cap tissue to a lipid core was estimated as between 25% and 75%.
Of the patients who had died of AMI, 13 segments were obtained from culprit lesions, divided into ruptured (type VI; n=8) and eroded (type VI; n=5) plaques. In ruptured plaques, the fibrous cap had ruptured completely, with the fissure extending into the lipid core, additionally complicated by intraplaque hemorrhage and luminal thrombosis. In eroded plaques, a "trans-cap" rupture was not found, despite serial sectioning. The intimal plaque showed an eroded surface, characterized by loss of the endothelial lining with lacerations of the superficial intimal layers and with thrombus overlying the site of injury. Seven of the 13 AMI patients underwent emergency percutaneous transluminal coronary angioplasty (PTCA). The time interval between onset of cardiac symptoms and death was well documented in these patients and varied from 0 to 2 days (mean interval <1 day). Age, sex, and presence of risk factors did not differ among patients with ruptured plaques or eroded plaques.
All autopsies were performed within 3 hours after death. The coronary arteries were removed from the epicardial surface and sectioned at 
2-mm intervals. The slices were snap-frozen and stored at -80°C.
Atherectomy
The atherectomy specimens were obtained from 67 patients, all of whom underwent atherectomy of the target lesion considered responsible for either stable angina pectoris (SAP) (n=35) or UAP (n=32). The demographic data (SAP versus UAP) were as follows: age (58±11 versus 59±10), male sex (83% versus 81%), cigarette smoking (67% versus 69%), hypertension (45% versus 45%), diabetes mellitus (26% versus 28%), and hypercholesterolemia (58% versus 45%). There were no statistically significant differences between patients with SAP or UAP. Immediately after atherectomy, the tissue specimens were carefully oriented along their longest axis, snap frozen, and stored at -80°C.
The snap-frozen samples, obtained either by autopsy or atherectomy, were subsequently sectioned serially at 6-µm thickness and fixed in acetone. Every first section was stained with H&E the other sections were used for immunohistochemical staining.
Immunohistochemistry
Single Staining
The sources and specificity of all antibodies used in this study are summarized in Table 2. Five different antibodies were used to identify neutrophils: anti-CD66b, elastase, myeloperoxidase (monoclonal [MPO-7] and polyclonal [MPO]), and CD11b. NEP was identified by using anti-CALLA (CD10).16 Nonimmune mouse IgG serum (DAKO, Glostrup, Denmark) served as negative control; human kidney obtained at autopsy was used as positive control.
|
Sections were incubated at 4°C overnight and then subjected to a 3-step staining procedure, using the streptavidin-biotin complex method (SABC) for detection. Peroxidase activity was visualized with 3-amino-9-ethyl-carbazole (10 minutes, room temperature), and the sections were faintly counterstained with hematoxylin.
Double Immunostaining
The simultaneous identification of SMCs and macrophages was performed on the basis of 2 primary antibodies of a different IgG subclass (1A4/CD68), as reported previously.17 The enzymatic activity of ß-galactosidase for 1A4 was visualized in turquoise (BioGenex Kit, BioGenex) and that of alkaline phosphatase for CD68 in red (New Fuchsin Kit, DAKO).
We also performed double immunostainings between macrophages (CD68) and each of the 5 neutrophil markers (CD66b, elastase, myeloperoxidase MPO-7, myeloperoxidase MPO, and CD11b), as well as between CD66b and each of the remaining 4 neutrophil markers, using modifications of procedures reported previously.17 In both double immunostainings, alkaline phosphatase was visualized with fast blue BB and peroxidase with 3-amino-9-ethylcarbazole development.
To identify neutrophils that express NEP, double immunostainings (NEP/CD66b; NEP/elastase) were performed, according to procedural modifications previously reported.17 Again, alkaline phosphatase was visualized with fast blue BB (blue: CD66b and elastase) and peroxidase with 3-amino-9-ethylcarbazole development (red: NEP).
Quantitative Methods
Numbers of CD66b-positive neutrophils and NEP-positive cells were counted in the entire tissue sections and expressed as the number of cells per square millimeter of intimal tissue. In atherectomy specimens, neutrophils or NEP-positive cells within thrombi or tissue-attached blood clots were excluded. The tissue area occupied by immunostained macrophages was quantified, using computer-aided planimetry and expressed as a percentage of the total surface area of the tissue section. The morphometric analysis was performed by a single investigator who was blinded to the patients’ characteristics and histological classifications. Data are shown as mean±SD. The 2 groups were compared with an unpaired Student’s t test or with Mann-Whitney U test when the variance was heterogeneous. Statistical comparisons between >3 groups were performed with one-way analysis of variance and post-hoc multiple comparison using Scheffe’s test. Values of P<0.05 were considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Neutrophil Identification
The staining pattern of the 5 antibodies (CD66b, elastase, myeloperoxidase MPO-7, myeloperoxidase MPO, and CD11b) used to identify neutrophils in frozen sections differed slightly. Double immunostaining analysis revealed that CD66b positivity was detected in neutrophils but not in macrophages. In contrast, CD11b positivity was found in neutrophils but occasionally also in macrophages. The double immunostainings for CD66b/elastase, CD66b/MPO-7, CD66b/MPO, macrophages/elastase, macrophages/MPO-7, and macrophages/MPO demonstrated that most elastase-positive, MPO-7–positive, and MPO-positive cells within the plaque are neutrophils (Figures 1 and 2).
|
|
Autopsy Specimens
Specimens Obtained From Patients With Noncardiovascular Diseases
Normal coronary arteries with diffuse intimal thickening contained no macrophages. In hypercellular lesions, 13 of the 26 lesions were composed almost solely of SMCs, whereas the remaining 13 lesions contained foci of macrophages. In advanced fibrous plaques, 12 of the 30 lesions had a small number of macrophages. However, in advanced fibrolipid plaques, all lesions contained macrophages, albeit to various degrees: only 2 of the 31 lesions contained some neutrophils at the shoulder region. Lesions that contained macrophages but no neutrophils (CD66b and elastase-negative) did not stain positive for MPO-7 or MPO.
NEP expression was not detected in normal coronary arteries with diffuse intimal thickening, hypercellular lesions, and advanced fibrous plaques. In the 2 fibrolipid plaques with neutrophil infiltration, the neutrophils were negative for NEP in one plaque, whereas in the other plaque, occasional neutrophils were positive for NEP.
Specimens Obtained From AMI Patients
Macrophages were abundantly present in both ruptured and eroded plaques (Figures 1A, 1B, 2A, and 2B). Distinct neutrophil infiltration was detected in all specimens with plaque rupture or erosion (Figures 1C through 1E and 2C through 2E). Double immunostaining (MPO-7/CD66b) demonstrated that most MPO-7–positive cells were neutrophils (Figures 1F and 2F). Double immunostainings for MPO-7 (or MPO) and macrophages revealed that only occasional macrophages were positive (Figures 1G, 1H, 2G, and 2H).
In ruptured plaques, neutrophils were positive for NEP (Figures 3A through 3C), whereas in eroded plaques, most neutrophils lacked NEP positivity (Figures 3D through 3F).
|
Morphometric Analysis
Morphometric results are shown in Figure 4. The macrophage-positive area was significantly higher (P<0.0001) in ruptured and eroded plaques than in normal coronary arteries with diffuse intimal thickening, hypercellular lesions, and advanced fibrous plaques. The number of CD66b-positive neutrophils did not differ between ruptured and eroded plaques; the number of neutrophils in the culprit lesion was not significantly different between AMI patients with PTCA and those without PTCA. The number of NEP-positive cells was significantly higher (P<0.0001) in ruptured plaques than in eroded plaques.
|
Atherectomy Specimens
All 32 lesions obtained from patients with UAP contained abundant macrophages, and 14 (44%) contained neutrophils (Figure 5). Double immunostaining for NEP and neutrophils showed that both NEP-positive and NEP-negative neutrophils were present in the culprit lesions in patients with UAP. In contrast, only 2 of 35 (6%) culprit lesions obtained from patients with SAP contained neutrophils, and NEP positivity was found only occasionally. Morphometric analysis demonstrated that the number of neutrophils and NEP-positive cells in patients with UAP was significantly higher (neutrophils; P<0.0005, and NEP-positive cells; P<0.005) than in patients with SAP (Figure 6).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Intraplaque inflammation is presently widely acknowledged to play a crucial role in the changing morphologies of atherosclerotic plaques, with most interest focusing on macrophages and T lymphocytes. However, given the growing notion that systemic inflammation could be involved also, the question arises to what extent local neutrophil infiltration could be involved. Previous studies, using conventional formalin-fixed sections, documented occasional neutrophils within plaques, but their functional significance was not additionally elaborated.2 To the best of our knowledge, the present study, based on frozen sections and using immunohistochemical single and double staining techniques, is the first study systematically analyzing neutrophils in culprit lesions of acute coronary syndromes.
All culprit lesions of patients who had died of AMI had neutrophils within the plaques, although the number varied widely. In contrast, neutrophils were extremely rare in coronary lesions obtained from patients who had died of noncardiovascular diseases; in only 2 of the 87 atherosclerotic lesions neutrophils were identified. Similar observations were made in patients in whom atherectomy material was studied. In patients with UAP, neutrophils within the culprit lesion were detected in 14 of 32 (44%), whereas this was the case in only 2 of 35 (6%) patients with SAP. These observations suggest that neutrophils are actively associated with acute coronary events.
These findings contrast markedly with those recently reported by Sugiyama et al.18 The authors reported that only few neutrophils were found at sites of erosion or rupture. However, they used formalin-fixed paraffin-embedded sections for the study of ruptured and eroded plaques, apparently unaware of the fact that the CD66b antibody only works on frozen samples (in accordance with the data sheet of Coulter, endorsed by our own pilot studies; data not shown). It thus seems that the negative findings by Sugiyama et al18 relate to their handling of the tissue specimens.
Previous clinical studies have demonstrated intense in vivo neutrophil activation in UAP and AMI.5-7 Mehta et al5 reported a 15-fold increase in plasma levels of peptide Bß, a marker of elastase release, in patients with UAP compared with those in patients with SAP. Biasucci et al7 measured the index of intracellular neutrophil myeloperoxidase and showed a significant release of myeloperoxidase from neutrophils related to their activation in patients with AMI and UAP. Mazzone et al19 also revealed increased expression of CD11b/CD18 integrins in neutrophils in UAP patients. These clinical observations together with our present findings suggest that neutrophil activation may be one of the inflammatory components of acute coronary syndromes. Activated neutrophils are known to release a variety of proteolytic enzymes, all of which have the potential for tissue destruction. In particular, neutrophil elastase has been shown to mediate both degradation of basement membrane constituents and endothelial damage.6 Hence, it is conceivable that neutrophils contribute to the pathogenesis of plaque destabilization in human atherosclerotic plaques.
In this study, 7 of the 13 AMI patients underwent emergency PTCA, and, therefore, one could consider the presence of neutrophils a result of PTCA-related injuries.20 However, there were no significant differences in numbers of neutrophils within culprit lesions of patients with and without PTCA. Moreover, neutrophils were found in the atherectomy specimens in 40% of the UAP patients, indicating that neutrophils occur in culprit lesions in UAP and AMI patients, irrespective of a PTCA procedure.
The present study also focused on the presence of NEP.9 The fact that NEP expression occurs primarily at the fully mature polymorphonuclear stage of neutrophil development is of interest, given our observation that ruptured plaques contain a significantly higher number of NEP-positive neutrophils than do eroded plaques. The pathobiology of this phenomenon remains unknown as yet. However, the observation that plaque erosions predominantly contain NEP-negative neutrophils suggests a rapid and relatively sudden outburst of neutrophils, like that seen in acute and severe inflammatory states.
In conclusion, the distinct presence of neutrophils in atherosclerotic plaques underlying UAP and AMI strongly suggests that neutrophils play a role in mediating destabilization of atherosclerotic plaques.
Received July 18, 2002; accepted September 11, 2002.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Davies MJ, Thomas AC. Plaque fissuring: the cause of acute myocardial infarction, sudden ischemic death, and crescendo angina. Br Heart J. 1985; 53: 363–373.
2. van der Wal AC, Becker AE, van der Loos CM, et al. Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation. 1994; 89: 36–44.
3. Kostis JB, Turkevich D, Sharp J. Association between leukocyte count and the presence and extent of coronary atherosclerosis as determined by coronary arteriography. Am J Cardiol. 1984; 53: 997–999.[CrossRef][Medline] [Order article via Infotrieve]
4. Friedman GD, Klatsky AL, Siegelaub AB. The leukocyte count as a predictor of myocardial infarction. N Engl J Med. 1974; 290: 1275–1278.[Medline] [Order article via Infotrieve]
5. Mehta J, Dinerman J, Mehta P, et al. Neutrophil function in ischemic heart disease. Circulation. 1989; 79: 549–556.
6. Dinerman JL, Mehta JL, Saldeen TG, et al. Increased neutrophil elastase release in unstable angina pectoris and acute myocardial infarction. J Am Coll Cardiol. 1990; 15: 1559–1563.[Abstract]
7. Biasucci LM, Donofrio G, Liuzzo G, et al. Intracellular neutrophil myeloperoxidase is reduced in unstable angina and acute myocardial infarction, but its reduction is not related to ischemia. J Am Coll Cardiol. 1996; 27: 611–616.[Abstract]
8. Sasaki Y, Suehiro S, Becker AE, et al. Role of endothelial cell denudation and smooth muscle cell dedifferentiation in neointimal formation of human vein grafts after coronary artery bypass grafting: therapeutic implications. Heart. 2000; 83: 69–75.
9. Connelly JC, Skidgel RA, Schulz WW, et al. Neutral endopeptidase 24.11 in human neutrophils: cleavage of chemotactic peptide. Proc Natl Acad Sci U S A. 1985; 82: 8737–8741.
10. McCormack RT, Nelson RD, Solem LD, et al. Decreased expression of the common acute lymphoblastic leukemia antigen (CALLA/CD10) on neutrophils from patients with thermal injury. Br J Haematol. 1988; 69: 189–195.[Medline] [Order article via Infotrieve]
11. The fifth report of the Joint National Committee on detection, evaluation and treatment of high blood pressure (JNC V). Arch Intern Med. 1993; 153: 154–183.
12. WHO Study Group. Diabetes mellitus. World Health Organ Tech Rep Ser. 1985; 727: 7–98.
13. Stary HC, Chandler AB, Glagov S, et al. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler Thromb. 1994; 14: 840–856.
14. Stary HC, Chandler AB, Dinsmore RE, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis: a report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler Thromb Vasc Biol. 1995; 15: 1512–1531.
15. Naruko T, Ueda M, van der Wal AC, et al. C-type natriuretic peptide in human coronary atherosclerotic lesions. Circulation. 1996; 94: 3103–3108.
16. Letarte M, Vera S, Tran T, et al. Common acute lymphocytic leukemia antigen is identical to neutral endopeptidase. J Exp Med. 1988; 168: 1247–1253.
17. van der Loos CM, Becker AE, van den Oord JJ. Practical suggestions for successful immunoenzyme double-staining experiments. Histochem J. 1993; 25: 1–13.[CrossRef][Medline] [Order article via Infotrieve]
18. Sugiyama S, Okada Y, Sukhova GK, et al. Macrophage myeloperoxidase regulation by granulocyte macrophage colony-stimulating factor in human atherosclerosis and implications in acute coronary syndromes. Am J Pathol. 2001; 158: 879–891.
19. Mazzone A, De Servi S, Ricevuti G, et al. Increased expression of neutrophil and monocyte adhesion molecules in unstable coronary artery disease. Circulation. 1993; 88: 358–363.
20. Ueda M, Becker AE, Kasayuki N, et al. In situ detection of platelet-derived growth factor-A and B chain mRNA in human coronary arteries after percutaneous transluminal coronary angioplasty. Am J Pathol. 1996; 149: 831–843.[Abstract]
This article has been cited by other articles:
 |
|
 |
|
  J. Duchene, C. Cayla, S. Vessillier, R. Scotland, K. Yamashiro, F. Lecomte, I. Syed, P. Vo, A. Marrelli, C. Pitzalis, et al. Laminar Shear Stress Regulates Endothelial Kinin B1 Receptor Expression and Function: Potential Implication in Atherogenesis Arterioscler Thromb Vasc Biol, November 1, 2009; 29(11): 1757 - 1763. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Biasucci, G. Liuzzo, S. Giubilato, R. Della Bona, M. Leo, M. Pinnelli, A. Severino, M. Gabriele, S. Brugaletta, M. Piro, et al. Delayed neutrophil apoptosis in patients with unstable angina: relation to C-reactive protein and recurrence of instability Eur. Heart J., September 2, 2009; 30(18): 2220 - 2225. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Oh, E. R. Mohler III, A. Tian, T. Baumgart, and S. L. Diamond Membrane Cholesterol Is a Biomechanical Regulator of Neutrophil Adhesion Arterioscler Thromb Vasc Biol, September 1, 2009; 29(9): 1290 - 1297. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Yunoki, T. Naruko, R. Komatsu, S. Ehara, N. Shirai, K. Sugioka, M. Nakagawa, C. Kitabayashi, Y. Ikura, A. Itoh, et al. Enhanced expression of haemoglobin scavenger receptor in accumulated macrophages of culprit lesions in acute coronary syndromes Eur. Heart J., August 1, 2009; 30(15): 1844 - 1852. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Lavie and P. Lavie Molecular mechanisms of cardiovascular disease in OSAHS: the oxidative stress link Eur. Respir. J., June 1, 2009; 33(6): 1467 - 1484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kawai, K. Hisamatsu, H. Matsubara, K. Dan, S. Akagi, K. Miyaji, M. Munemasa, Y. Fujimoto, K. F. Kusano, and T. Ohe Intravenous administration of nicorandil immediately before percutaneous coronary intervention can prevent slow coronary flow phenomenon Eur. Heart J., April 1, 2009; 30(7): 765 - 772. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Patel, B. G. Drew, S. Nakhla, S. J. Duffy, A. J. Murphy, P. J. Barter, K.-A. Rye, J. Chin-Dusting, A. Hoang, D. Sviridov, et al. Reconstituted high-density lipoprotein increases plasma high-density lipoprotein anti-inflammatory properties and cholesterol efflux capacity in patients with type 2 diabetes. J. Am. Coll. Cardiol., March 17, 2009; 53(11): 962 - 971. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Singh, S. Devaraj, and I. Jialal C-Reactive Protein Stimulates Myeloperoxidase Release from Polymorphonuclear Cells and Monocytes: Implications for Acute Coronary Syndromes Clin. Chem., February 1, 2009; 55(2): 361 - 364. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 U. Ravnskov and K. S. McCully Vulnerable Plaque Formation from Obstruction of Vasa Vasorum by Homocysteinylated and Oxidized Lipoprotein Aggregates Complexed with Microbial Remnants and LDL Autoantibodies Ann. Clin. Lab. Sci., January 1, 2009; 39(1): 3 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. W. Hamm, H. Möllmann, J.-P. Bassand, and F. van de Werf CHAPTER 16 Acute Coronary Syndromes ESC Textbook of Cardiovascular Medicine, January 1, 2009; 2(1): med-9780199566990-chapter - med-9780199566990-chapter. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Quinn, M. Henriques, T. Parker, A. S. Slutsky, and H. Zhang Human neutrophil peptides: a novel potential mediator of inflammatory cardiovascular diseases Am J Physiol Heart Circ Physiol, November 1, 2008; 295(5): H1817 - H1824. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Aicher, O. Kollet, C. Heeschen, S. Liebner, C. Urbich, C. Ihling, A. Orlandi, T. Lapidot, A. M. Zeiher, and S. Dimmeler The Wnt Antagonist Dickkopf-1 Mobilizes Vasculogenic Progenitor Cells via Activation of the Bone Marrow Endosteal Stem Cell Niche Circ. Res., October 10, 2008; 103(8): 796 - 803. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Miyamoto, M Ueda, M Ikemoto, T Naruko, A Itoh, S Tamaki, R Nohara, F Terasaki, S Sasayama, and M Fujita Increased serum levels and expression of S100A8/A9 complex in infiltrated neutrophils in atherosclerotic plaque of unstable angina Heart, August 1, 2008; 94(8): 1002 - 1007. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Biasucci, M. Leo, and G. L. De Maria Local and Systemic Mechanisms of Plaque Rupture Angiology, August 1, 2008; 59(2_suppl): 73S - 76S. [Abstract] [PDF]
|
|
|
|
 |
|
 L. Dyugovskaya, A. Polyakov, P. Lavie, and L. Lavie Delayed Neutrophil Apoptosis in Patients with Sleep Apnea Am. J. Respir. Crit. Care Med., March 1, 2008; 177(5): 544 - 554. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R Tsuru, H Kondo, Y Hojo, M Gama, O Mizuno, T Katsuki, K Shimada, M Kikuchi, and T Yashiro Increased granzyme B production from peripheral blood mononuclear cells in patients with acute coronary syndrome Heart, March 1, 2008; 94(3): 305 - 310. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sainz and M. Sata Open Sesame!: CXCR4 Blockade Recruits Neutrophils Into the Plaque Circ. Res., February 1, 2008; 102(2): 154 - 156. [Full Text] [PDF]
|
|
|
|
|
|
A. Zernecke, I. Bot, Y. Djalali-Talab, E. Shagdarsuren, K. Bidzhekov, S. Meiler, R. Krohn, A. Schober, M. Sperandio, O. Soehnlein, et al. Protective Role of CXC Receptor 4/CXC Ligand 12 Unveils the Importance of Neutrophils in Atherosclerosis Circ. Res., February 1, 2008; 102(2): 209 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. van Leeuwen, M. J.J. Gijbels, A. Duijvestijn, M. Smook, M. J. van de Gaar, P. Heeringa, M. P.J. de Winther, and J. W. C. Tervaert Accumulation of Myeloperoxidase-Positive Neutrophils in Atherosclerotic Lesions in LDLR / Mice Arterioscler Thromb Vasc Biol, January 1, 2008; 28(1): 84 - 89. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Narducci, A. Grasselli, L. M. Biasucci, A. Farsetti, A. Mule, G. Liuzzo, G. La Torre, G. Niccoli, R. Mongiardo, A. Pontecorvi, et al. High Telomerase Activity in Neutrophils From Unstable Coronary Plaques J. Am. Coll. Cardiol., December 18, 2007; 50(25): 2369 - 2374. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Leclercq, X. Houard, M. Philippe, V. Ollivier, U. Sebbag, O. Meilhac, and J.-B. Michel Involvement of intraplaque hemorrhage in atherothrombosis evolution via neutrophil protease enrichment J. Leukoc. Biol., December 1, 2007; 82(6): 1420 - 1429. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T Adachi, T Naruko, A Itoh, R Komatsu, Y Abe, N Shirai, H Yamashita, S Ehara, M Nakagawa, C Kitabayashi, et al. Neopterin is associated with plaque inflammation and destabilisation in human coronary atherosclerotic lesions Heart, December 1, 2007; 93(12): 1537 - 1541. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Myoishi, H. Hao, T. Minamino, K. Watanabe, K. Nishihira, K. Hatakeyama, Y. Asada, K.-i. Okada, H. Ishibashi-Ueda, G. Gabbiani, et al. Increased Endoplasmic Reticulum Stress in Atherosclerotic Plaques Associated With Acute Coronary Syndrome Circulation, September 11, 2007; 116(11): 1226 - 1233. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. C. Raffel, G. J. Tearney, D. D. Gauthier, E. F. Halpern, B. E. Bouma, and I.-K. Jang Relationship Between a Systemic Inflammatory Marker, Plaque Inflammation, and Plaque Characteristics Determined by Intravascular Optical Coherence Tomography Arterioscler Thromb Vasc Biol, August 1, 2007; 27(8): 1820 - 1827. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Meuwese, E. S.G. Stroes, S. L. Hazen, J. N. van Miert, J. A. Kuivenhoven, R. G. Schaub, N. J. Wareham, R. Luben, J. J.P. Kastelein, K.-T. Khaw, et al. Serum Myeloperoxidase Levels Are Associated With the Future Risk of Coronary Artery Disease in Apparently Healthy Individuals: The EPIC-Norfolk Prospective Population Study J. Am. Coll. Cardiol., July 10, 2007; 50(2): 159 - 165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Q Khan, D. Kelly, P. Quinn, J. E Davies, and L. L Ng Myeloperoxidase aids prognostication together with N-terminal pro-B-type natriuretic peptide in high-risk patients with acute ST elevation myocardial infarction Heart, July 1, 2007; 93(7): 826 - 831. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. O. Angheloiu, J. T. Arendt, M. G. Muller, A. S. Haka, I. Georgakoudi, J. T. Motz, O. R. Scepanovic, B. D. Kuban, J. Myles, F. Miller, et al. Intrinsic Fluorescence and Diffuse Reflectance Spectroscopy Identify Superficial Foam Cells in Coronary Plaques Prone to Erosion Arterioscler Thromb Vasc Biol, July 1, 2006; 26(7): 1594 - 1600. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Exner, E. Minar, W. Mlekusch, S. Sabeti, J. Amighi, W. Lalouschek, G. Maurer, C. Bieglmayer, H. Kieweg, O. Wagner, et al. Myeloperoxidase Predicts Progression of Carotid Stenosis in States of Low High-Density Lipoprotein Cholesterol J. Am. Coll. Cardiol., June 6, 2006; 47(11): 2212 - 2218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Sasaki, M. Kuzuya, K. Nakamura, X. W. Cheng, T. Shibata, K. Sato, and A. Iguchi A Simple Method of Plaque Rupture Induction in Apolipoprotein E-Deficient Mice Arterioscler Thromb Vasc Biol, June 1, 2006; 26(6): 1304 - 1309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Falk Pathogenesis of atherosclerosis. J. Am. Coll. Cardiol., April 18, 2006; 47(8 Suppl): C7 - C12. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Tsimikas, J. T. Willerson, and P. M. Ridker C-reactive protein and other emerging blood biomarkers to optimize risk stratification of vulnerable patients. J. Am. Coll. Cardiol., April 18, 2006; 47(8 Suppl): C19 - C31. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Paumelle, C. Blanquart, O. Briand, O. Barbier, C. Duhem, G. Woerly, F. Percevault, J.-C. Fruchart, D. Dombrowicz, C. Glineur, et al. Acute Antiinflammatory Properties of Statins Involve Peroxisome Proliferator-Activated Receptor-{alpha} via Inhibition of the Protein Kinase C Signaling Pathway Circ. Res., February 17, 2006; 98(3): 361 - 369. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Pluskota, O. I. Stenina, I. Krukovets, D. Szpak, E. J. Topol, and E. F. Plow Mechanism and effect of thrombospondin-4 polymorphisms on neutrophil function Blood, December 1, 2005; 106(12): 3970 - 3978. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M Carter Inflammation, thrombosis and acute coronary syndromes Diabetes and Vascular Disease Research, October 1, 2005; 2(3): 113 - 121. [Abstract] [PDF]
|
|
|
|
|
|
T. Khreiss, L. Jozsef, L. A. Potempa, and J. G. Filep Loss of Pentameric Symmetry in C-Reactive Protein Induces Interleukin-8 Secretion Through Peroxynitrite Signaling in Human Neutrophils Circ. Res., September 30, 2005; 97(7): 690 - 697. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Garcia de Tena, I. Kriszbacher, M. Koppan, J. Bodis, and G. K. Hansson Inflammation, Atherosclerosis, and Coronary Artery Disease N. Engl. J. Med., July 28, 2005; 353(4): 429 - 430. [Full Text] [PDF]
|
|
|
|
 |
|
 M.-H. Fecteau, J.-C. Honore, M. Plante, J. Labonte, G. A. Rae, and P. D'Orleans-Juste Endothelin-1 (1-31) Is an Intermediate in the Production of Endothelin-1 After Big Endothelin-1 Administration In Vivo Hypertension, July 1, 2005; 46(1): 87 - 92. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. C. Kaski, P. Avanzas, R. Arroyo-Espliguero, and B. S. Coller Neutrophil Count and Complex Lesions in Patients With Coronary Artery Disease Arterioscler Thromb Vasc Biol, June 1, 2005; 25(6): e112 - e112. [Full Text] [PDF]
|
|
|
|
|
|
S. J. Nicholls and S. L. Hazen Myeloperoxidase and Cardiovascular Disease Arterioscler Thromb Vasc Biol, June 1, 2005; 25(6): 1102 - 1111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. D. Horne, J. L. Anderson, J. M. John, A. Weaver, T. L. Bair, K. R. Jensen, D. G. Renlund, J. B. Muhlestein, and Intermountain Heart Collaborative (IHC) Study Grou Which White Blood Cell Subtypes Predict Increased Cardiovascular Risk? J. Am. Coll. Cardiol., May 17, 2005; 45(10): 1638 - 1643. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Hakonarson, S. Thorvaldsson, A. Helgadottir, D. Gudbjartsson, F. Zink, M. Andresdottir, A. Manolescu, D. O. Arnar, K. Andersen, A. Sigurdsson, et al. Effects of a 5-Lipoxygenase-Activating Protein Inhibitor on Biomarkers Associated With Risk of Myocardial Infarction: A Randomized Trial JAMA, May 11, 2005; 293(18): 2245 - 2256. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. VanderLaan and C. A. Reardon Thematic review series: The Immune System and Atherogenesis. The unusual suspects:an overview of the minor leukocyte populations in atherosclerosis J. Lipid Res., May 1, 2005; 46(5): 829 - 838. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. S. Apple, A. H.B. Wu, J. Mair, J. Ravkilde, M. Panteghini, J. Tate, F. Pagani, R. H. Christenson, M. Mockel, O. Danne, et al. Future Biomarkers for Detection of Ischemia and Risk Stratification in Acute Coronary Syndrome Clin. Chem., May 1, 2005; 51(5): 810 - 824. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Madjid, I. Awan, J. T. Willerson, and S. W. Casscells Leukocyte count and coronary heart disease: Implications for risk assessment J. Am. Coll. Cardiol., November 16, 2004; 44(10): 1945 - 1956. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Madjid, A. Zarrabi, S. Litovsky, J. T. Willerson, and W. Casscells Finding Vulnerable Atherosclerotic Plaques: Is It Worth the Effort? Arterioscler Thromb Vasc Biol, October 1, 2004; 24(10): 1775 - 1782. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. P. Miller, W. Feng, D. Xing, N. M. Weathington, J. E. Blalock, Y.-F. Chen, and S. Oparil Estrogen Modulates Inflammatory Mediator Expression and Neutrophil Chemotaxis in Injured Arteries Circulation, September 21, 2004; 110(12): 1664 - 1669. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P Avanzas, R Arroyo-Espliguero, J Cosin-Sales, G Aldama, C Pizzi, J Quiles, and J C Kaski Markers of inflammation and multiple complex stenoses (pancoronary plaque vulnerability) in patients with non-ST segment elevation acute coronary syndromes Heart, August 1, 2004; 90(8): 847 - 852. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Lindstedt, M. J. Leskinen, and P. T. Kovanen Proteolysis of the Pericellular Matrix: A Novel Element Determining Cell Survival and Death in the Pathogenesis of Plaque Erosion and Rupture Arterioscler Thromb Vasc Biol, August 1, 2004; 24(8): 1350 - 1358. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Hazen Myeloperoxidase and Plaque Vulnerability Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1143 - 1146. [Full Text] [PDF]
|
|
|
|
|
|
S. Sugiyama, K. Kugiyama, M. Aikawa, S. Nakamura, H. Ogawa, and P. Libby Hypochlorous Acid, a Macrophage Product, Induces Endothelial Apoptosis and Tissue Factor Expression: Involvement of Myeloperoxidase-Mediated Oxidant in Plaque Erosion and Thrombogenesis Arterioscler Thromb Vasc Biol, July 1, 2004; 24(7): 1309 - 1314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. E. Wyche, S. S. Wang, K. K. Griendling, S. I. Dikalov, H. Austin, S. Rao, B. Fink, D. G. Harrison, and A. M. Zafari C242T CYBA Polymorphism of the NADPH Oxidase Is Associated With Reduced Respiratory Burst in Human Neutrophils Hypertension, June 1, 2004; 43(6): 1246 - 1251. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Skurk and K. Walsh Death Receptor Induced Apoptosis: A New Mechanism of Homocysteine-Mediated Endothelial Cell Cytotoxicity Hypertension, June 1, 2004; 43(6): 1168 - 1170. [Full Text] [PDF]
|
|
|
|
|
|
T. Suhara, K. Fukuo, O. Yasuda, M. Tsubakimoto, Y. Takemura, H. Kawamoto, T. Yokoi, M. Mogi, T. Kaimoto, and T. Ogihara Homocysteine Enhances Endothelial Apoptosis via Upregulation of Fas-Mediated Pathways Hypertension, June 1, 2004; 43(6): 1208 - 1213. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y Shimada, M Yoshiyama, Y Kobayashi, H Tanaka, S Jissho, H Iida, Y Nakamura, S Ehara, K Shimada, K Takeuchi, et al. Positive correlation between coronary arterial remodelling and prodromal angina in acute myocardial infarction Heart, April 1, 2004; 90(4): 444 - 445. [Full Text] [PDF]
|
|
|
|
|
|
J.-B. Michel Anoikis in the Cardiovascular System: Known and Unknown Extracellular Mediators Arterioscler Thromb Vasc Biol, December 1, 2003; 23(12): 2146 - 2154. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-L. Brennan, M. S. Penn, F. Van Lente, V. Nambi, M. H. Shishehbor, R. J. Aviles, M. Goormastic, M. L. Pepoy, E. S. McErlean, E. J. Topol, et al. Prognostic Value of Myeloperoxidase in Patients with Chest Pain N. Engl. J. Med., October 23, 2003; 349(17): 1595 - 1604. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Lafont Basic aspects of plaque vulnerability Heart, October 1, 2003; 89(10): 1262 - 1267. [Full Text] [PDF]
|
|
|
|
|
|
S. Baldus, C. Heeschen, T. Meinertz, A. M. Zeiher, J. P. Eiserich, T. Munzel, M. L. Simoons, C. W. Hamm, and on behalf of the CAPTURE Investigators Myeloperoxidase Serum Levels Predict Risk in Patients With Acute Coronary Syndromes Circulation, September 23, 2003; 108(12): 1440 - 1445. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||