Circulation, Vol 84, 1984-1992, Copyright © 1991 by American Heart Association
AM Zeiher, H Drexler, H Wollschlager and H Just
BACKGROUND. The vascular endothelium is capable of regulating tissue
perfusion by the release of endothelium-derived relaxing factor to modulate
vasomotor tone of the resistance vasculature. METHODS AND RESULTS. To test
whether atherosclerosis is associated with a functional abnormality of
endothelium-mediated microvascular relaxation affecting coronary blood flow
regulation, we compared coronary blood flow responses with cold pressor
testing with the response of the coronary vasculature to acetylcholine (an
endothelium-dependent vasodilator) and to papaverin (a direct dilator of
vascular smooth muscle) in 12 normal control patients and in 19 patients
with non-flow- limiting epicardial atherosclerosis (CAD). The drugs were
subselectively infused into the left anterior descending coronary artery
via a Doppler catheter, and the response in coronary blood flow was
assessed by measuring intracoronary blood flow velocity and cross-
sectional arterial area (quantitative angiography). Coronary vascular
resistance decreased in all normal control patients by -24.1 +/- 5.5% (mean
+/- SD) during the cold pressor test, whereas the CAD patients demonstrated
a variable coronary vascular resistance response to cold pressor testing
despite comparable changes in the rate-pressure product. The slopes of the
acetylcholine dose-blood flow response (percent change in coronary blood
flow/dosage of acetylcholine) were significantly reduced in the CAD
patients with 38.5 +/- 24.8 compared with the normal patients (80.8 +/-
28.1; p less than 0.001). Although coronary blood flow responses to
papaverin were slightly but significantly (p less than 0.05) reduced in the
CAD patients, the response to the endothelium-dependent dilator
acetylcholine was considerably out of proportion to the papaverin response
in these patients compared with the normal patients. The capacity of the
coronary system to increase blood flow in response to acetylcholine
expressed as relative proportion of the maximal papaverin response was 52.5
+/- 18.2% in the normal control patients but only 33.6 +/- 23.6% in the CAD
patients (p less than 0.025 versus normals). There was a significant
negative correlation (r = -0.69; p less than 0.0001) between cold pressor
test-induced changes in coronary vascular resistance and the capacity of
the coronary system to increase blood flow in response to acetylcholine.
CONCLUSIONS. Early stages of epicardial atherosclerosis are associated with
an impairment in endothelium-dependent dilation of the coronary
microvasculature, indicating that the pathophysiological consequences of
atherosclerosis may extend into the human coronary microcirculation. The
correlation between cold pressor test-induced coronary vascular resistance
changes and the extent of endothelial dysfunction suggests a relation
between endothelial function of the microvasculature and coronary blood
flow regulation during sympathetic stimulation associated with increased
myocardial work.
ARTICLES
Endothelial dysfunction of the coronary microvasculature is associated with coronary blood flow regulation in patients with early atherosclerosis
Department of Cardiology, University of Freiburg, FRG.
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 S. Makita, M. Nakamura, A. Ohira, S. Ito, K. Yoshioka, A. Hirose, T. Nakajima, K. Komoda, K. Kawazoe, and K. Hiramori Impaired Peripheral Vasodilation in Ischemic and Nonischemic Limbs of Patients with Unilateral Arteriosclerosis Obliterans: Effect of Revascularization on Leg Hemodynamics Vascular and Endovascular Surgery, September 1, 1998; 32(5): 491 - 502. [Abstract] [PDF]
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 P. J. Pearson, P. R.B. Evora, B. Discigil, and H. V. Schaff Hypoxia Increases Vasodilator Release From Internal Mammary Artery and Saphenous Vein Grafts Ann. Thorac. Surg., May 1, 1998; 65(5): 1220 - 1225. [Abstract] [Full Text] [PDF]
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S. Husain, N. P. Andrews, D. Mulcahy, J. A. Panza, and A. A. Quyyumi Aspirin Improves Endothelial Dysfunction in Atherosclerosis Circulation, March 3, 1998; 97(8): 716 - 720. [Abstract] [Full Text] [PDF]
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G. Kojda, B. Husgen, A. Hacker, D. Perings, E. M. Schnaith, E. Kottenberg, and E. Noack Impairment of endothelium-dependent vasorelaxation in experimental atherosclerosis is dependent on gender Cardiovasc Res, March 1, 1998; 37(3): 738 - 747. [Abstract] [Full Text] [PDF]
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R. Elhage, F. Bayard, V. Richard, P. Holvoet, N. Duverger, C. Fievet, and J.-F. Arnal Prevention of Fatty Streak Formation of 17ß-Estradiol Is Not Mediated by the Production of Nitric Oxide in Apolipoprotein E– Deficient Mice Circulation, November 4, 1997; 96(9): 3048 - 3052. [Abstract] [Full Text]
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U. Solzbach, B. Hornig, M. Jeserich, and H. Just Vitamin C Improves Endothelial Dysfunction of Epicardial Coronary Arteries in Hypertensive Patients Circulation, September 2, 1997; 96(5): 1513 - 1519. [Abstract] [Full Text]
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P. Kessler, J. Bauersachs, R. Busse, and V. B. Schini-Kerth Inhibition of Inducible Nitric Oxide Synthase Restores Endothelium-Dependent Relaxations in Proinflammatory Mediator-Induced Blood Vessels Arterioscler Thromb Vasc Biol, September 1, 1997; 17(9): 1746 - 1755. [Abstract] [Full Text]
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G. Sambuceti, M. Marzilli, P. Marraccini, J. Schneider-Eicke, E. Gliozheni, O. Parodi, and A. L'Abbate Coronary Vasoconstriction During Myocardial Ischemia Induced by Rises in Metabolic Demand in Patients With Coronary Artery Disease Circulation, June 17, 1997; 95(12): 2652 - 2659. [Abstract] [Full Text]
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 M. F. Di Carli, M. C. Tobes, T. Mangner, A. B. Levine, O. Muzik, P. Chakroborty, and T. B. Levine Effects of Cardiac Sympathetic Innervation on Coronary Blood Flow N. Engl. J. Med., April 24, 1997; 336(17): 1208 - 1216. [Abstract] [Full Text] [PDF]
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I. Antony, G. Lerebours, and A. Nitenberg Angiotensin-Converting Enzyme Inhibition Restores Flow-Dependent and Cold Pressor Test–Induced Dilations in Coronary Arteries of Hypertensive Patients Circulation, December 15, 1996; 94(12): 3115 - 3122. [Abstract] [Full Text]
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 H. Engelberg State-of the-Art Review : Endogenous Heparin Activity Deficiency and Atherosclerosis Clinical and Applied Thrombosis/Hemostasis, April 1, 1996; 2(2): 83 - 93. [PDF]
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K. L. Gould, D. Ornish, L. Scherwitz, S. Brown, R. P. Edens, M. J. Hess, N. Mullani, L. Bolomey, F. Dobbs, W. T. Armstrong, et al. Changes in Myocardial Perfusion Abnormalities by Positron Emission Tomography After Long-term, Intense Risk Factor Modification JAMA, September 20, 1995; 274(11): 894 - 901. [Abstract] [PDF]
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A. A. Quyyumi, N. Dakak, N. P. Andrews, D. M. Gilligan, J. A. Panza, and R. O. Cannon III Contribution of Nitric Oxide to Metabolic Coronary Vasodilation in the Human Heart Circulation, August 1, 1995; 92(3): 320 - 326. [Abstract] [Full Text]
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J. Czernin, K. Sun, R. Brunken, M. Bottcher, M. Phelps, and H. Schelbert Effect of Acute and Long-term Smoking on Myocardial Blood Flow and Flow Reserve Circulation, June 15, 1995; 91(12): 2891 - 2897. [Abstract] [Full Text]
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A. M. Zeiher, T. Krause, V. Schachinger, J. Minners, and E. Moser Impaired Endothelium-Dependent Vasodilation of Coronary Resistance Vessels Is Associated With Exercise-Induced Myocardial Ischemia Circulation, May 1, 1995; 91(9): 2345 - 2352. [Abstract] [Full Text]
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M. Di Carli, J. Czernin, C. K. Hoh, V. H. Gerbaudo, R. C. Brunken, S.-C. Huang, M. E. Phelps, and H. R. Schelbert Relation Among Stenosis Severity, Myocardial Blood Flow, and Flow Reserve in Patients With Coronary Artery Disease Circulation, April 1, 1995; 91(7): 1944 - 1951. [Abstract] [Full Text]
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R. O. Cannon Chest Pain with Normal Coronary Angiograms N. Engl. J. Med., June 10, 1993; 328(23): 1706 - 1708. [Full Text]
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