(Circulation. 1995;91:941-947.)
© 1995 American Heart Association, Inc.
Articles |
Tissue Endothelin-1 Immunoreactivity in the Active Coronary Atherosclerotic Plaque
A Clue to the Mechanism of Increased Vasoreactivity of the Culprit Lesion in Unstable Angina
From the Department of Internal Medicine III, Division of Cardiology (A.M.Z., H.G., V.S.), and the Department of Pathology (C.I.), University of Freiburg (Germany).
Correspondence to Andreas M. Zeiher, MD, Department of Internal Medicine III, Division of Cardiology, University of Freiburg, Hugstetterstr 55, D-79106 Freiburg, Germany.
Background The pathomorphological substrate of complicated coronary atherosclerotic lesions underlying unstable angina is characterized by a localized chronic inflammatory process. Functionally, coronary lesions associated with unstable angina demonstrate an enhanced vasoreactivity. Endothelin-1 is a potent vasoconstrictor peptide produced not only by endothelial cells but also by macrophages and polymorphonuclear leukocytes, the cell types characteristic of inflammation.
Methods and Results By use of immunohistochemical
techniques, we examined the presence of endothelin-1 in coronary
atherosclerotic plaque tissue obtained by directional coronary
atherectomy of primary lesions from 50 consecutive patients. The tissue
specimens of 43 of 50 patients (86%) demonstrated endothelin-1–like
immunoreactivity. Endothelin-1–like immunoreactivity preferentially
localized to macrophage-rich areas, to hypercellular regions rich in
microvessels, and to plaque areas with evidence of prior hemorrhage.
Double-immunolabeling revealed that both macrophages (HAM56 positive)
and intimal smooth muscle cells (
-actin positive) demonstrated
cytoplasmic immunostaining for endothelin-1. Semiquantitative
analysis of endothelin-1–like immunostaining revealed
significantly (P<.005) higher staining grades in active
(1.86±0.15, n=40) compared with nonactive lesions
(0.78±0.35, n=10):
endothelin-1 staining grades were significantly (P<.001)
lower in patients with stable angina (0.69±0.19, n=13) than in
patients with crescendo angina (1.82±0.30, n=11), with angina at
rest
(2.08±0.21, n=12), or with angina after myocardial infarction
(2.0±0.26, n=14).
Conclusions Endothelin-1 immunostaining of atherosclerotic tissue localizes predominantly with plaque components indicative of chronic inflammatory processes. The increased tissue endothelin-1–like immunoreactivity in active coronary atherosclerotic lesions may provide a clue to the mechanisms of increased vasoreactivity of the culprit lesion in acute ischemic syndromes, which is the clinical substrate of the active coronary atherosclerotic plaque.
Key Words: atherosclerosis • endothelin • angina • leukocytes • ischemia
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|
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|
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|
|
|
|
|
|
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|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
 |
|
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|
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|
|
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|
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|
|
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|
|
|
|
|
|
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