(Circulation. 1995;92:1084-1088.)
© 1995 American Heart Association, Inc.
Articles |
Infiltrates of Activated Mast Cells at the Site of Coronary Atheromatous Erosion or Rupture in Myocardial Infarction
From the Wihuri Research Institute (P.T.K., M.K.) and the Department of Pathology, University of Helsinki (T.P.), Finland.
Correspondence to Petri T. Kovanen, MD, PhD, Wihuri Research Institute, Kalliolinnantie 4, 00140 Helsinki, Finland.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Erosion and rupture of coronary atheromas are the events preceding the vast majority of acute coronary syndromes. The shoulder regions of atheromas, the sites at which erosion or rupture is most likely to occur, are the sites at which mast cells accumulate. These cells are filled with neutral proteases capable of triggering extracellular matrix degradation via activation of matrix metalloproteinases. To obtain more direct evidence for the participation of mast cells in the acute coronary syndromes, we quantified the numbers of mast cells at eroded or ruptured sites of coronary atheromas in patients who died of myocardial infarction.
Methods and Results In specimens of coronary arteries from 20 patients who had died of acute myocardial infarction, the site of atheromatous erosion or rupture was identified. The specimens were stained with monoclonal antibodies against the two major proteases of mast cells, tryptase and chymase, and against macrophages, T lymphocytes, and smooth muscle cells. At the immediate site of erosion or rupture, mast cells amounted to 6% of all nucleated cells, in the adjacent atheromatous area to 1%, and in the unaffected intimal area to 0.1%. The proportions of these mast cells that were activated, ie, had been stimulated to degranulate and release some of their tryptase and chymase contents, were 86% at the site of erosion or rupture, 63% in the adjacent atheromatous area, and 27% in the unaffected intima. At the site of erosion or rupture, the numbers of macrophages and T lymphocytes were also increased, but the number of smooth muscle cells was decreased.
Conclusions The accumulation of activated mast cells (200-fold more than in the unaffected coronary intima) at the site of atheromatous erosion or rupture suggests that in thrombotic coronary occlusion the role played by mast cells is significant.
Key Words: atherosclerosis • chymase • tryptase • mast cells • atherosclerosis • myocardial infarction
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Myocardial infarction is usually a consequence of an eroded or ruptured coronary atheroma that leads to acute thrombotic coronary occlusion.1 2 There is growing evidence that inflammation plays an important role in these coronary events.3 Mast cells, an inflammatory cell type, were recently shown to accumulate in the shoulder region of human coronary atheromas, the predilection sites of atheromatous erosion/rupture.4 Coronary mast cells contain two neutral proteases (all contain tryptase and many also contain chymase) that are capable of triggering degradation of the extracellular matrix via activation of matrix metalloproteinases (MMPs).5 6 Indeed, the presence of mast cells in areas of excessive degradation of the extracellular matrix is well documented in diseases affecting the connective tissue.7 8 Thus, these cells could participate in the weakening of the fibrous cap and subsequent erosion or rupture of the coronary atheroma. In the present study, we measured the mast cell densities at and around the immediate sites of atheromatous erosion or rupture in coronary arteries obtained from patients who had died of myocardial infarction. We also determined the relative contribution of mast cells to the overall cellular composition at the erosion or rupture sites and the proportion of these mast cells that were activated, ie, had degranulated and secreted some of their neutral protease contents.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Autopsy Material and Treatment of Tissue
The autopsy series comprised coronary specimens of 26 patients who died of acute myocardial infarction. From this series, we selected 20 patients (12 men, 8 women) in whom we found a thrombosed coronary artery with local erosion or rupture. The ages of the patients ranged from 50 to 82 years (mean, 63 years). The time interval between the onset of cardiac symptoms and death varied from 3 hours to 7 days (mean interval, 2 days; in 15 patients within 2 days), and the autopsy material was obtained within 5 days of death (range, 0 to 5 days; mean, 2 days). Infarcted myocardium was identified at autopsy with nitro blue tetrazolium enzyme staining and confirmed by histology. The involved coronary artery was fixed in Carnoy's fluid (60% ethanol, 30% chloroform, and 10% glacial acetic acid) for 24 hours and then cut (unopened) into 2-mm pieces, which were embedded in paraffin, sectioned, and stained with elastica–van Gieson stain (for collagen and elastin) until the site of the erosion or rupture with the thrombus was found. In 13 patients an occlusive thrombus and in 7 a nonocclusive thrombus was found. Thrombolytic treatment had been given to 1 patient with an occlusive thrombus (death 1 day after treatment) and 1 with a nonocclusive thrombus (death 5 days after treatment).
Immunocytochemistry
For immunocytochemistry, fixed serial
sections (2 to 4 µm)
were dewaxed in xylene and rehydrated in a graded series of ethanol
solutions, and endogenous peroxide activity was inhibited
by incubation with 0.6% H2O2 in methanol. The
sections were then incubated with one of the following: anti-tryptase
monoclonal antibody G3 (1.5 µg/mL) for mast cells9 (kind
gift from Dr L.B. Schwartz, Medical College of Virginia, Richmond); HAM
56, a monoclonal antibody for macrophages (1:50); UCHL 1, a
monoclonal antibody for T lymphocytes (1:50) (both from Dakopatts); and
a monoclonal antibody for 
–smooth muscle actin against smooth
muscle cells (1:12 000) (Sigma Chemical Co). Mast cells and smooth
muscle cells were stained according to the indirect immunoperoxidase
method, and macrophages and T lymphocytes were stained by the
avidin-biotin complex method, as recently
described.4 10
Immunopositive mast cells, macrophages, T lymphocytes, and
smooth muscle cells were counted at a magnification of x100. Mast cell
degranulation, ie, activation, was detected by observing
extracellularly located mast cell granules at a magnification of
x1000.4
Statistical Analysis
Counts of various cell types were
examined with ANOVA, with the
cell count at the site of erosion or rupture as the explanatory
variable and with the F test for determination of the significance
of differences, which were considered to be statistically significant
when P<.05. The proportions of the various cell types in
relation to the total number of cells were analyzed with
logistic regression, with the proportion at the site of erosion or
rupture as the explanatory variable. Results are presented
as odds ratios (ORs), considering the result at the unaffected site as
the reference (OR=1). All ORs are reported with 95% CIs.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Of the 20 coronary atherosclerotic plaques underlying the coronary thromboses, 10 showed erosions (superficial ruptures) and 10 showed deep ruptures. Seven of the plaques had eroded or ruptured at the junction of the cap with the more normal intima (the shoulder region), and 6 had eroded or ruptured at more central areas of the cap. In the remaining 7 cases, the anatomic location (cap versus shoulder) of the erosion or rupture could not be unequivocally determined. With regard to mast cells, neither the type (erosion versus rupture) nor the location (shoulder versus more central area of the cap) at the lesion had a significant influence on the results. Therefore, the cytochemical results are presented without reference to the type of lesion or its location in the coronary atheroma ("erosion/rupture" in Tables 1, 2, and 3).
Fig 1
shows immunostaining of mast cells
(tryptase) in a highly atherosclerotic coronary artery. The
severely narrowed lumen was totally occluded with a thrombus, and the
endothelial layer was eroded. Accumulations of mast
cells (red-brown) can be clearly discerned. Numerous
macrophages and T lymphocytes had also accumulated in this area
(not shown).
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Fig 2 compares the densities of mast cells (ie,
tryptase-positive cells) in the 20 sections of coronary plaque
in which the erosion or rupture was identified. Three different areas
in each case were examined: the immediate site of erosion or rupture,
an adjacent area, and a more distant unaffected area. The average
density of mast cells was far higher (28-fold higher) at the sites of
erosion or rupture than in the unaffected areas. In the area adjacent
to the eroded or ruptured site, the densities of mast cells were
10-fold higher than in the unaffected area and were thus intermediate
between the affected and unaffected areas. Table 1 shows
numerical comparisons of the densities of mast cells (Fig 2),
macrophages, T lymphocytes, and smooth muscle cells in the
three areas examined. Like the average densities of mast cells, the
average densities of macrophages and T lymphocytes were higher
(by 4-fold and 3-fold, respectively) at the eroded or ruptured sites.
In sharp contrast, the average density of smooth muscle cells at the
eroded or ruptured sites was markedly decreased (4-fold).
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Table 2 shows the numbers of the individual cell types
as percentages of the total number of cells in the three intimal areas
considered. At the immediate site of erosion or rupture, mast cells
amounted to 6% of all nucleated cells, and in the adjacent
atheromatous area, they amounted to 1%. In the
unaffected intimal areas, the proportion of mast cells was very low
(0.1%). Notably, the predominant cell type at the erosion or rupture
site was macrophages, the second most frequent cell type being
the smooth muscle cells, and T lymphocytes equaling the mast cells in
number.
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Activated, ie, degranulated, mast cells were found in all the
areas studied (Table 3). Fig 3A shows a
degranulated mast cell with clearly visible extracellular granules. For
comparison, a resting mast cell is shown in Fig 3B. At the site
of
intimal erosion or rupture, the proportion of mast cells that were
activated was far higher (86%) than in the area adjacent to it
(63%) or in the unaffected area (27%) (Table 3). Taken
together,
Tables 2
and 3 reveal that the number of
activated mast cells
in relation to the total number of cells was 0.027% (0.001x0.27) in
the uninvolved area and 5.2% (0.06x0.86) at the erosion or rupture
site, ie, about 200-fold higher.
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All mast cells in the human arterial intima contain tryptase, and a fraction of them contain chymase as well.4 10 To determine the proportion of mast cells that contained chymase in addition to tryptase, adjacent sections were stained for tryptase and chymase. In the sections stained for chymase, the proportion of mast cells containing chymase averaged 37% (11% to 74%) at the sites of erosion or rupture, 42% (0% to 100%) in the adjacent areas, and 35% (0% to 100%) in the more distant unaffected areas. Some of the extruded granules also contained chymase; in the three areas compared above, the proportions of mast cells that had extruded such granules were 87%, 76%, and 38%.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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In the present study, we observed a striking increase (200-fold) in the number of activated mast cells at sites of thrombotic atheromatous erosion/rupture in coronary arteries of subjects who had died of myocardial infarction. Previously, in a medicolegal series, we found that mast cells in coronary atheromas were present both in the shoulder and in the more central areas of the cap, although preferentially in the shoulder region.4 This result agrees with the findings of Richardson et al11 that plaque ruptures occur both in the shoulder and in the more central areas of the cap, though preferentially in the shoulder region. In the present study plaque ruptures had also occurred in both the cap and shoulder regions. The distribution between these two locations could not be determined, however, since in seven cases the borders of the cap and the shoulder regions could not be identified unequivocally (see the severely narrowed coronary lumen in Fig 1
).
The important question arises of whether mast cells enter the lesion
before or after the plaque rupture. Circulating blood contains only
mast cell precursors, and these precursors take several days to weeks
to differentiate into morphologically identifiable mast cells filled
with cytoplasmic secretory granules.12 13 Since most
of
the patients had died within 2 days after the ischemic episode,
the mast cells must already have been present at the
erosion/rupture sites before the episode. In fact, the number of mast
cells was highest (158/mm2, Fig 2) in the patient
with the shortest interval between the onset of symptoms and death (3
hours). Macrophages, another blood-borne inflammatory cell
type, and T lymphocytes infiltrate not only the sites of
coronary arteries at which erosion or rupture has occurred
(with ensuing unstable angina14 or myocardial
infarction15 ) but also sites of coronary plaques
susceptible to erosion or rupture; ie, they invade before an actual
intimal event.4
We found that the degree of mast cell degranulation was much higher at the sites of erosion or rupture than in adjacent areas or in the more distant unaffected areas. To degranulate, the mast cells have to be stimulated. In addition to the classic IgE-mediated stimulation of mast cells,16 17 several "histamine-releasing factors" have been described. These factors are secreted by activated T lymphocytes18 and activated macrophages,19 two cell types that were also found at the erosion or rupture sites. Thus, several agents that stimulate mast cells appear to be present in the inflamed atherosclerotic lesions and could be responsible for the observed high proportion of degranulated mast cells.
Mast cells, when stimulated, degranulate and release their neutral proteases (tryptase and chymase) into the surrounding microenvironment. Every mast cell at the erosion or rupture site was found to contain tryptase, and a significant fraction of them also contained chymase. Moreover, the proportion of mast cells that had released at least some of their tryptase (and chymase) contents was highest at the site of erosion or rupture. Even though tryptase and chymase have limited activity against the various components of the extracellular matrix, they have both been shown to effectively activate the zymogen forms of metalloproteinases (the pro-MMPs), tryptase activating prostromelysin (pro-MMP-3)6 and chymase activating the zymogen form of interstitial collagenase (pro-MMP-1).5 Thus, rapidly increasing evidence suggests that when stimulated to release their neutral proteases, mast cells can activate various MMPs. Immunocytochemical and in situ hybridization studies of human atherosclerotic plaques have revealed active synthesis of MMP-1, MMP-3, and MMP-9 in macrophages and smooth muscle cells of the plaques.20 21 22 Interestingly, with the aid of zymographic techniques, Galis et al21 demonstrated that the plaques contain MMP-9 and MMP-3 in activated form. However, the mechanism of pro-MMP activation in vivo has remained unknown. Tryptase and chymase, the neutral proteases released from stimulated mast cells at the site of erosion or rupture, could be among the agents that activate these pro-MMPs.
In summary, the present observation of a dramatic increase in activated mast cells at the erosion or rupture sites of coronary atheromas, which are heavily populated with macrophages and T lymphocytes, provides evidence that mast cells are an integral component of the inflammatory infiltrate of the eroded or ruptured coronary plaques. Moreover, the ability of activated mast cells to initiate matrix degradation suggests that mast cells actively participate in the local weakening of inflamed atherosclerotic lesions that ultimately leads to erosion or rupture of the plaque. These considerations also lead us to suggest a new possibility for the prevention of myocardial infarction, namely, inhibition of mast cell degranulation in the unstable atherosclerotic plaques of coronary arteries.
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Acknowledgments |
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This study was supported by the Aarne Koskelo Foundation. The authors thank the staff of the Department of Forensic Medicine, University of Helsinki, for their excellent technical assistance.
Received April 17, 1995; revision received June 15, 1995; accepted June 17, 1995.
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References |
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TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes. N Engl J Med. 1992;326:242-250. [Medline] [Order article via Infotrieve]
2. Falk E. Why do plaques rupture? Circulation. 1992;86(suppl III):III-30-III-42.
3.
Buja LM, Willerson JT. Role of inflammation in
coronary plaque disruption.
Circulation. 1994;89:503-505.
4.
Kaartinen M, Penttilä A, Kovanen PT.
Accumulation of activated mast cells in the shoulder
region of human coronary atheroma, the predilection
site of atheromatous rupture.
Circulation. 1994;90:1669-1678.
5.
Saarinen J, Kalkkinen N, Welgus HG, Kovanen PT.
Activation of human interstitial
procollagenase through direct cleavage of the
Leu83-Thr84 bond by mast cell chymase.
J Biol Chem. 1994;269:18134-18140.
6. Gruber BL, Marchese MJ, Suzuki K, Schwartz LB, Okada Y, Nagase H, Ramamurthy NS. Synovial procollagenase activation by human mast cell tryptase: dependence upon matrix metalloproteinase 3 activation. J Clin Invest. 1989;84:1657-1662.
7.
Bromley M, Fisher WD, Woolley DE. Mast cells at
site of cartilage erosion in the rheumatoid joint. Ann
Rheum Dis. 1984;43:76-79.
8. Dabbous MK, Walker R, Haney L, Carter LM, Nicolson GL, Woolley DE. Mast cells and matrix degradation at sites of tumour invasion in rat mammary adenocarcinoma. Br J Cancer. 1986;54:459-465. [Medline] [Order article via Infotrieve]
9.
Irani A-M, Bradford TR, Kepley CL, Schechter NM,
Schwartz LB. Detection of MCT and MCTC
types of human mast cells by immunohistochemistry using new monoclonal
anti-tryptase and anti-chymase antibodies. J
Histochem Cytochem. 1989;37:1509-1515.
10.
Kaartinen M, Penttilä A, Kovanen PT. Mast
cells of two types differing in neutral protease composition in the
human aortic intima: demonstration of tryptase- and
tryptase/chymase-containing mast cells in normal intimas, fatty
streaks, and the shoulder regions of atheromas.
Arterioscler Thromb. 1994;14:966-972.
11. Richardson PD, Davies MJ, Born GVR. Influence of plaque configuration and stress distribution on fissuring of coronary atherosclerotic plaque. Lancet. 1989;2:941-944. [Medline] [Order article via Infotrieve]
12.
Irani AA, Nilsson G, Miettinen U, Craig SS, Ashman LK,
Ishizaka T, Zsebo KM, Schwartz LB. Recombinant human stem cell
factor stimulates differentiation of mast cells from dispersed human
fetal liver cells. Blood. 1992;80:3009-3021.
13.
Valent P, Spanblöchl E, Sperr WR, Sillaber C,
Zsebo KM, Strobl H, Geissler K, Bettelheim P, Lechner K.
Induction of differentiation of human mast cells from bone
marrow and peripheral blood mononuclear cells by
recombinant human stem cell factor (SCF)/kit ligand (KL) in long-term
culture. Blood. 1992;80:2237-2245.
14.
Moreno PR, Falk E, Palacios JF, Newell JB, Fuster V,
Fallon JT. Macrophage infiltration in acute
coronary syndromes: implications for plaque rupture.
Circulation. 1994;90:775-778.
15.
van der Wal AC, Becker AE, van der Loos CM, Das PK.
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.
16. Ishizaka T, Ishizaka K. Activation of mast cells for mediator release through IgE receptors. Prog Allergy. 1984;34:188-235. [Medline] [Order article via Infotrieve]
17. Sutton BJ, Gould HJ. The human IgE network. Nature. 1993;366:421-428. [Medline] [Order article via Infotrieve]
18. Sedgwick JD, Holt PG, Turner KJ. Production of a histamine-releasing lymphokine by antigen- or mitogen-stimulated human peripheral T cells. Clin Exp Immunol. 1981;45:409-418. [Medline] [Order article via Infotrieve]
19. Liu MC, Proud D, Lichtenstein LM, MacGlashan DW, Schleimer RP, Adkinson NF, Kagey-Sobotka A, Schulman ES, Plaut M. Human lung macrophage-derived histamine-releasing activity is due to IgE-dependent factors. J Immunol. 1986;136:2588-2595. [Abstract]
20.
Henney AM, Wakeley PR, Davies MJ, Foster K, Hembry R,
Murphy G, Humphries S. Localization of stromelysin gene
expression in atherosclerotic plaques by in situ hybridization.
Proc Natl Acad Sci U S A. 1991;88:8154-8158.
21. Galis ZS, Sukhova GK, Lark MW, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Invest. 1994;94:2493-2503.
22.
Brown DL, Hibbs MS, Kearney M, Loushin C, Isner JM.
Identification of 92-kD gelatinase in human coronary
atherosclerotic lesions: association of active enzyme synthesis with
unstable angina. Circulation. 1995;91:2125-2131.
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 O. Erdogan, C. Gul, A. Altun, and G. Ozbay Increased Immunoglobulin E Response in Acute Coronary Syndromes Angiology, January 1, 2003; 54(1): 73 - 79. [Abstract] [PDF]
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K. K. Koh, J. W. Son, J. Y. Ahn, D. K. Jin, H. S. Kim, Y. M. Choi, D. S. Kim, E.-M. Jeong, G. S. Park, I. S. Choi, et al. Comparative Effects of Diet and Statin on NO Bioactivity and Matrix Metalloproteinases in Hypercholesterolemic Patients With Coronary Artery Disease Arterioscler Thromb Vasc Biol, September 1, 2002; 22(9): e19 - 23. [Abstract] [Full Text] [PDF]
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 G. K. Hansson, P. Libby, U. Schonbeck, and Z.-Q. Yan Innate and Adaptive Immunity in the Pathogenesis of Atherosclerosis Circ. Res., August 23, 2002; 91(4): 281 - 291. [Abstract] [Full Text] [PDF]
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A. H Chester Mast cells feel the strain Cardiovasc Res, July 1, 2002; 55(1): 13 - 15. [Full Text] [PDF]
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M. Huang, X. Pang, R. Letourneau, W. Boucher, and T. C Theoharides Acute stress induces cardiac mast cell activation and histamine release, effects that are increased in Apolipoprotein E knockout mice Cardiovasc Res, July 1, 2002; 55(1): 150 - 160. [Abstract] [Full Text] [PDF]
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K. P. Metsarinne, P. Vehmaan-Kreula, P. T. Kovanen, O. Saijonmaa, M. Baumann, Y. Wang, T. Nyman, F. Y. Fyhrquist, and K. K. Eklund Activated Mast Cells Increase the Level of Endothelin-1 mRNA in Cocultured Endothelial Cells and Degrade the Secreted Peptide Arterioscler Thromb Vasc Biol, February 1, 2002; 22(2): 268 - 273. [Abstract] [Full Text] [PDF]
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G. K. Hansson Immune Mechanisms in Atherosclerosis Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 1876 - 1890. [Abstract] [Full Text] [PDF]
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Y. Wang, N. Shiota, M. J. Leskinen, K. A. Lindstedt, and P. T. Kovanen Mast Cell Chymase Inhibits Smooth Muscle Cell Growth and Collagen Expression In Vitro: Transforming Growth Factor-{beta}1-Dependent and -Independent Effects Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 1928 - 1933. [Abstract] [Full Text] [PDF]
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D. M. Wuttge, P. Eriksson, A. Sirsjo, G. K. Hansson, and S. Stemme Expression of Interleukin-15 in Mouse and Human Atherosclerotic Lesions Am. J. Pathol., August 1, 2001; 159(2): 417 - 423. [Abstract] [Full Text]
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 J.F. Bentzon and E. Falk Coronary plaques calling for action -- why, where and how many? Eur. Heart J. Suppl., August 1, 2001; 3(suppl_I): I3 - I9. [Abstract] [PDF]
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J.C. Kaski and E.G. Zouridakis Inflammation, infection and acute coronary plaque events Eur. Heart J. Suppl., August 1, 2001; 3(suppl_I): I10 - I15. [Abstract] [PDF]
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G.K. Hansson The stabilized plaque: will the dream come true? Eur. Heart J. Suppl., June 1, 2001; 3(suppl_C): C69 - C75. [PDF]
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M. Leskinen, Y. Wang, D. Leszczynski, K. A. Lindstedt, and P. T. Kovanen Mast Cell Chymase Induces Apoptosis of Vascular Smooth Muscle Cells Arterioscler Thromb Vasc Biol, April 1, 2001; 21(4): 516 - 522. [Abstract] [Full Text] [PDF]
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J. A. Goldstein, D. Demetriou, C. L. Grines, M. Pica, M. Shoukfeh, and W. W. O'Neill Multiple Complex Coronary Plaques in Patients with Acute Myocardial Infarction N. Engl. J. Med., September 28, 2000; 343(13): 915 - 922. [Abstract] [Full Text] [PDF]
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 M. Cusack, S. Redwood, and J. Coltart Recent advances in ischaemic heart disease Postgrad. Med. J., September 1, 2000; 76(899): 542 - 546. [Full Text]
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 A. Fischer, D. E Gutstein, Z. A Fayad, and V. Fuster Predicting plaque rupture: enhancing diagnosis and clinical decision-making in coronary artery disease Vascular Medicine, August 1, 2000; 5(3): 163 - 172. [Abstract] [PDF]
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G. Liuzzo, J. J. Goronzy, H. Yang, S. L. Kopecky, D. R. Holmes, R. L. Frye, and C. M. Weyand Monoclonal T-Cell Proliferation and Plaque Instability in Acute Coronary Syndromes Circulation, June 27, 2000; 101(25): 2883 - 2888. [Abstract] [Full Text] [PDF]
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A. Sabri, G. Muske, H. Zhang, E. Pak, A. Darrow, P. Andrade-Gordon, and S. F. Steinberg Signaling Properties and Functions of Two Distinct Cardiomyocyte Protease-Activated Receptors Circ. Res., May 26, 2000; 86(10): 1054 - 1061. [Abstract] [Full Text] [PDF]
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B. Schieffer, E. Schieffer, D. Hilfiker-Kleiner, A. Hilfiker, P. T. Kovanen, M. Kaartinen, J. Nussberger, W. Harringer, and H. Drexler Expression of Angiotensin II and Interleukin 6 in Human Coronary Atherosclerotic Plaques : Potential Implications for Inflammation and Plaque Instability Circulation, March 28, 2000; 101(12): 1372 - 1378. [Abstract] [Full Text] [PDF]
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 J. A. Cornicelli, D. Butteiger, D. L. Rateri, K. Welch, and A. Daugherty Interleukin-4 augments acetylated LDL-induced cholesterol esterification in macrophages J. Lipid Res., March 1, 2000; 41(3): 376 - 383. [Abstract] [Full Text]
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 S Kojima, H Nonogi, Y Miyao, S Miyazaki, Y Goto, A Itoh, S Daikoku, T Matsumoto, I Morii, and C Yutani Is preinfarction angina related to the presence or absence of coronary plaque rupture? Heart, January 1, 2000; 83(1): 64 - 68. [Abstract] [Full Text] [PDF]
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G. Liuzzo, S. L. Kopecky, R. L. Frye, W. M. O’ Fallon, A. Maseri, J. J. Goronzy, and C. M. Weyand Perturbation of the T-Cell Repertoire in Patients With Unstable Angina Circulation, November 23, 1999; 100(21): 2135 - 2139. [Abstract] [Full Text] [PDF]
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G. Liuzzo, L. M. Biasucci, J. R. Gallimore, G. Caligiuri, A. Buffon, A. G. Rebuzzi, M. B. Pepys, and A. Maseri Enhanced inflammatory response in patients with preinfarction unstable angina J. Am. Coll. Cardiol., November 15, 1999; 34(6): 1696 - 1703. [Abstract] [Full Text] [PDF]
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 H. HAMADA, M. TERAI, H. KIMURA, K. HIRANO, S. OANA, and H. NIIMI Increased Expression of Mast Cell Chymase in the Lungs of Patients with Congenital Heart Disease Associated with Early Pulmonary Vascular Disease Am. J. Respir. Crit. Care Med., October 1, 1999; 160(4): 1303 - 1308. [Abstract] [Full Text]
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M. C. Ignatescu, E. Gharehbaghi-Schnell, A. Hassan, S. Rezaie-Majd, I. Korschineck, R. R. Schleef, H. D. Glogar, and I. M. Lang Expression of the Angiogenic Protein, Platelet-Derived Endothelial Cell Growth Factor, in Coronary Atherosclerotic Plaques : In Vivo Correlation of Lesional Microvessel Density and Constrictive Vascular Remodeling Arterioscler Thromb Vasc Biol, October 1, 1999; 19(10): 2340 - 2347. [Abstract] [Full Text] [PDF]
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 D. Inui, M. Yoshizumi, N. Okishima, H. Houchi, K. Tsuchiya, H. Kido, and T. Tamaki Mechanism of endothelin-1-(1---31)-induced calcium signaling in human coronary artery smooth muscle cells Am J Physiol Endocrinol Metab, June 1, 1999; 276(6): E1067 - E1072. [Abstract] [Full Text] [PDF]
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M.-L. Kortelainen and T. Sarkioja Extent and Composition of Coronary Lesions in Relation to Fat Distribution in Women Younger Than 50 Years of Age Arterioscler Thromb Vasc Biol, March 1, 1999; 19(3): 695 - 699. [Abstract] [Full Text] [PDF]
|
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A. C. van der Wal and A. E. Becker Atherosclerotic plaque rupture - pathologic basis of plaque stability and instability Cardiovasc Res, February 1, 1999; 41(2): 334 - 344. [Full Text] [PDF]
|
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|
|
|
G. Bauriedel, R. Hutter, U. Welsch, R. Bach, H. Sievert, and B. Luderitz Role of smooth muscle cell death in advanced coronary primary lesions: implications for plaque instability Cardiovasc Res, February 1, 1999; 41(2): 480 - 488. [Abstract] [Full Text] [PDF]
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P. Laine, M. Kaartinen, A. Penttila, P. Panula, T. Paavonen, and P. T. Kovanen Association Between Myocardial Infarction and the Mast Cells in the Adventitia of the Infarct-Related Coronary Artery Circulation, January 26, 1999; 99(3): 361 - 369. [Abstract] [Full Text] [PDF]
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Y. Wang and P. T. Kovanen Heparin Proteoglycans Released From Rat Serosal Mast Cells Inhibit Proliferation of Rat Aortic Smooth Muscle Cells in Culture Circ. Res., January 22, 1999; 84(1): 74 - 83. [Abstract] [Full Text] [PDF]
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G. Caligiuri, G. Liuzzo, L. M. Biasucci, and A. Maseri Immune system activation follows inflammation in unstable angina: pathogenetic implications J. Am. Coll. Cardiol., November 1, 1998; 32(5): 1295 - 1304. [Abstract] [Full Text] [PDF]
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J. L. Johnson, C. L. Jackson, G. D. Angelini, and S. J. George Activation of Matrix-Degrading Metalloproteinases by Mast Cell Proteases in Atherosclerotic Plaques Arterioscler Thromb Vasc Biol, November 1, 1998; 18(11): 1707 - 1715. [Abstract] [Full Text] [PDF]
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 X. Pang, N. Alexacos, R. Letourneau, D. Seretakis, W. Gao, W. Boucher, D. E. Cochrane, and T. C. Theoharides A Neurotensin Receptor Antagonist Inhibits Acute Immobilization Stress-Induced Cardiac Mast Cell Degranulation, a Corticotropin-Releasing Hormone-Dependent Process J. Pharmacol. Exp. Ther., October 1, 1998; 287(1): 307 - 314. [Abstract] [Full Text]
|
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|
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|
M. Kaartinen, A. C. van der Wal, C. M. van der Loos, J. J. Piek, K. T. Koch, A. E. Becker, and P. T. Kovanen Mast cell infiltration in acute coronary syndromes: implications for plaque rupture J. Am. Coll. Cardiol., September 1, 1998; 32(3): 606 - 612. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. K Shah Role of inflammation and metalloproteinases in plaque disruption and thrombosis Vascular Medicine, August 1, 1998; 3(3): 199 - 206. [Abstract] [PDF]
|
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|
|
 |
|
 P. T. Kovanen, M. Manttari, T. Palosuo, V. Manninen, and K. Aho Prediction of Myocardial Infarction in Dyslipidemic Men by Elevated Levels of Immunoglobulin Classes A, E, and G, but Not M Arch Intern Med, July 13, 1998; 158(13): 1434 - 1439. [Abstract] [Full Text]
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A C van der Wal, J J Piek, O J de Boer, K T Koch, P Teeling, C M van der Loos, and A E Becker Recent activation of the plaque immune response in coronary lesions underlying acute coronary syndromes Heart, July 1, 1998; 80(1): 14 - 18. [Abstract] [Full Text]
|
|
|
|
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V. Patella, I. Marino, E. Arbustini, B. Lamparter-Schummert, L. Verga, M. Adt, and G. Marone Stem Cell Factor in Mast Cells and Increased Mast Cell Density in Idiopathic and Ischemic Cardiomyopathy Circulation, March 17, 1998; 97(10): 971 - 978. [Abstract] [Full Text] [PDF]
|
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R. Lassila, K. Lindstedt, and P. T. Kovanen Native Macromolecular Heparin Proteoglycans Exocytosed From Stimulated Rat Serosal Mast Cells Strongly Inhibit Platelet-Collagen Interactions Arterioscler Thromb Vasc Biol, December 1, 1997; 17(12): 3578 - 3587. [Abstract] [Full Text]
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K. Kaikita, H. Ogawa, H. Yasue, M. Takeya, K. Takahashi, T. Saito, K. Hayasaki, K. Horiuchi, A. Takizawa, Y. Kamikubo, et al. Tissue Factor Expression on Macrophages in Coronary Plaques in Patients with Unstable Angina Arterioscler Thromb Vasc Biol, October 1, 1997; 17(10): 2232 - 2237. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. Molino, M. J. Woolkalis, J. Reavey-Cantwell, D. Pratico, P. Andrade-Gordon, E. S. Barnathan, and L. F. Brass Endothelial Cell Thrombin Receptors and PAR-2. TWO PROTEASE-ACTIVATED RECEPTORS LOCATED IN A SINGLE CELLULAR ENVIRONMENT J. Biol. Chem., April 25, 1997; 272(17): 11133 - 11141. [Abstract] [Full Text] [PDF]
|
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|
|
|
|
M. Molino, E. S. Barnathan, R. Numerof, J. Clark, M. Dreyer, A. Cumashi, J. A. Hoxie, N. Schechter, M. Woolkalis, and L. F. Brass Interactions of Mast Cell Tryptase with Thrombin Receptors and PAR-2 J. Biol. Chem., February 14, 1997; 272(7): 4043 - 4049. [Abstract] [Full Text] [PDF]
|
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P. R. Moreno, V. H. Bernardi, J. Lopez-Cuellar, A. M. Murcia, I. F. Palacios, H. K. Gold, R. Mehran, S. K. Sharma, Y. Nemerson, V. Fuster, et al. Macrophages, Smooth Muscle Cells, and Tissue Factor in Unstable Angina: Implications for Cell-Mediated Thrombogenicity in Acute Coronary Syndromes Circulation, December 15, 1996; 94(12): 3090 - 3097. [Abstract] [Full Text]
|
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M. Kaartinen, A. Penttila, and P. T. Kovanen Mast Cells in Rupture-Prone Areas of Human Coronary Atheromas Produce and Store TNF-{alpha} Circulation, December 1, 1996; 94(11): 2787 - 2792. [Abstract] [Full Text]
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M. J. Davies Stability and Instability: Two Faces of Coronary Atherosclerosis: The Paul Dudley White Lecture 1995 Circulation, October 15, 1996; 94(8): 2013 - 2020. [Full Text]
|
|
|
|
|
|
R. Jaffe and D. Zahger The Domino Principle N. Engl. J. Med., August 1, 1996; 335(5): 340 - 341. [Full Text] [PDF]
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J. A. Ambrose and M. Weinrauch Thrombosis in Ischemic Heart Disease Arch Intern Med, July 8, 1996; 156(13): 1382 - 1394. [Abstract] [PDF]
|
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|
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|
|
P. Constantinides Infiltrates of Activated Mast Cells at the Site of Coronary Atheromatous Erosion or Rupture in Myocardial Infarction Circulation, September 1, 1995; 92(5): 1083 - 1083. [Full Text]
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|
|
|
 |
|
 A. L. Chancey, G. L. Brower, and J. S. Janicki Cardiac mast cell-mediated activation of gelatinase and alteration of ventricular diastolic function Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2152 - H2158. [Abstract] [Full Text] [PDF]
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