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J Am Coll Cardiol, 2003; 42:1149-1160, doi:10.1016/S0735-1097(03)00994-X
© 2003 by the American College of Cardiology Foundation
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STATE-OF-ART PAPER

The clinical implications of endothelial dysfunction

Michael E. Widlansky, MD*, Noyan Gokce, MD, FACC*, John F. Keaney, Jr, MD, FACC* and Joseph A. Vita, MD, FACC*,*

* Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA

Manuscript received February 18, 2003; revised manuscript received April 27, 2003, accepted June 5, 2003.

* Reprint requests and correspondence: Dr. Joseph A. Vita, Section of Cardiology, Boston Medical Center, 88 East Newton Street, Boston, Massachusetts 02118, USA.
jvita{at}bu.edu

Defining new approaches for the prevention and treatment of atherosclerosis is an important priority. Recently, measurement of endothelial function in patients has emerged as a useful tool for atherosclerosis research. Risk factors are associated with impaired endothelial function, and clinical syndromes relate, in part, to a loss of endothelial control of vascular homeostasis. Recent studies have shown that the severity of endothelial dysfunction relates to cardiovascular risk. A growing number of interventions known to reduce cardiovascular risk have been shown to improve endothelial function. This work suggests that studies of endothelial function could be used in the care of patients and as a surrogate marker for the evaluation of new therapeutic strategies. This article will review this growing literature in an effort to evaluate the current clinical utility of endothelial dysfunction.

Abbreviations and Acronyms
  BP = blood pressure
  CAD = coronary artery disease
  CVD = cardiovascular disease
  FMD = flow-mediated dilation
  HRT = hormone replacement therapy
  ICAM = intercellular adhesion molecule
  NO = nitric oxide
  VCAM-1 = vascular cell adhesion molecule-1




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S. J. Duffy, E. S. Biegelsen, R. T. Eberhardt, D. F. Kahn, B. A. Kingwell, and J. A. Vita
Low-Renin Hypertension With Relative Aldosterone Excess Is Associated With Impaired NO-Mediated Vasodilation
Hypertension, October 1, 2005; 46(4): 707 - 713.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
S. Kathiresan, M. G. Larson, R. S. Vasan, C.-Y. Guo, J. A. Vita, G. F. Mitchell, M. J. Keyes, C. Newton-Cheh, S. L. Musone, A. L. Lochner, et al.
Common Genetic Variation at the Endothelial Nitric Oxide Synthase Locus and Relations to Brachial Artery Vasodilator Function in the Community
Circulation, September 6, 2005; 112(10): 1419 - 1427.
[Abstract] [Full Text] [PDF]

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 J. Appl. Physiol.Home page
D. Green
Point: Flow-mediated dilation does reflect nitric oxide-mediated endothelial function
J Appl Physiol, September 1, 2005; 99(3): 1233 - 1234.
[Full Text] [PDF]

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 J. Appl. Physiol.Home page
REBUTTAL FROM DR. GREEN
J Appl Physiol, September 1, 2005; 99(3): 1237 - 1237.
[Full Text] [PDF]

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 HeartHome page
A D Gavin and A D Struthers
Allopurinol reduces B-type natriuretic peptide concentrations and haemoglobin but does not alter exercise capacity in chronic heart failure
Heart, June 1, 2005; 91(6): 749 - 753.
[Abstract] [Full Text] [PDF]

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 J. Physiol.Home page
M. W. P. Bleeker, M. Kooijman, G. A. Rongen, M. T. E. Hopman, and P. Smits
Preserved contribution of nitric oxide to baseline vascular tone in deconditioned human skeletal muscle
J. Physiol., June 1, 2005; 565(2): 685 - 694.
[Abstract] [Full Text] [PDF]

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 Circ. Res.Home page
E. Anter, K. Chen, O. M. Shapira, R. H. Karas, and J. F. Keaney Jr
p38 Mitogen-Activated Protein Kinase Activates eNOS in Endothelial Cells by an Estrogen Receptor {alpha}-Dependent Pathway in Response to Black Tea Polyphenols
Circ. Res., May 27, 2005; 96(10): 1072 - 1078.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
J. Barnoya and S. A. Glantz
Cardiovascular Effects of Secondhand Smoke: Nearly as Large as Smoking
Circulation, May 24, 2005; 111(20): 2684 - 2698.
[Abstract] [Full Text] [PDF]

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 J Am Coll CardiolHome page
H. Koga, S. Sugiyama, K. Kugiyama, K. Watanabe, H. Fukushima, T. Tanaka, T. Sakamoto, M. Yoshimura, H. Jinnouchi, and H. Ogawa
Elevated Levels of VE-Cadherin-Positive Endothelial Microparticles in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease
J. Am. Coll. Cardiol., May 17, 2005; 45(10): 1622 - 1630.
[Abstract] [Full Text] [PDF]

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 J Am Coll CardiolHome page
T. H. Schindler, E. U. Nitzsche, H. R. Schelbert, M. Olschewski, J. Sayre, M. Mix, I. Brink, X.-L. Zhang, M. Kreissl, N. Magosaki, et al.
Positron Emission Tomography-Measured Abnormal Responses of Myocardial Blood Flow to Sympathetic Stimulation Are Associated With the Risk of Developing Cardiovascular Events
J. Am. Coll. Cardiol., May 3, 2005; 45(9): 1505 - 1512.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
P. H. Stone, D. M. Lloyd-Jones, S. Kinlay, B. Frei, W. Carlson, J. Rubenstein, T. C. Andrews, M. Johnstone, G. Sopko, H. Cole, et al.
Effect of Intensive Lipid Lowering, With or Without Antioxidant Vitamins, Compared With Moderate Lipid Lowering on Myocardial Ischemia in Patients With Stable Coronary Artery Disease: The Vascular Basis for the Treatment of Myocardial Ischemia Study
Circulation, April 12, 2005; 111(14): 1747 - 1755.
[Abstract] [Full Text] [PDF]

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 HeartHome page
D Tousoulis, C Antoniades, and C Stefanadis
Evaluating endothelial function in humans: a guide to invasive and non-invasive techniques
Heart, April 1, 2005; 91(4): 553 - 558.
[Full Text] [PDF]

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 Circ. Res.Home page
A. Huang, Y.-Y. Zhang, K. Chen, K. Hatakeyama, and J. F. Keaney Jr
Cytokine-Stimulated GTP Cyclohydrolase I Expression in Endothelial Cells Requires Coordinated Activation of Nuclear Factor-{kappa}B and Stat1/Stat3
Circ. Res., February 4, 2005; 96(2): 164 - 171.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
A. Lerman and A. M. Zeiher
Endothelial Function: Cardiac Events
Circulation, January 25, 2005; 111(3): 363 - 368.
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 CirculationHome page
G. Patti, V. Pasceri, R. Melfi, C. Goffredo, M. Chello, A. D'Ambrosio, R. Montesanti, and G. Di Sciascio
Impaired Flow-Mediated Dilation and Risk of Restenosis in Patients Undergoing Coronary Stent Implantation
Circulation, January 4, 2005; 111(1): 70 - 75.
[Abstract] [Full Text] [PDF]

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 Am. J. Clin. Nutr.Home page
J. A Vita
Polyphenols and cardiovascular disease: effects on endothelial and platelet function
Am. J. Clinical Nutrition, January 1, 2005; 81(1): 292S - 297S.
[Abstract] [Full Text] [PDF]

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 Postgrad. Med. J.Home page
M E Tushuizen, M Diamant, and R J Heine
Postprandial dysmetabolism and cardiovascular disease in type 2 diabetes
Postgrad. Med. J., January 1, 2005; 81(951): 1 - 6.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
J. A. Vita, J. F. Keaney Jr, M. G. Larson, M. J. Keyes, J. M. Massaro, I. Lipinska, B. T. Lehman, S. Fan, E. Osypiuk, P. W.F. Wilson, et al.
Brachial Artery Vasodilator Function and Systemic Inflammation in the Framingham Offspring Study
Circulation, December 7, 2004; 110(23): 3604 - 3609.
[Abstract] [Full Text] [PDF]

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 J. Physiol.Home page
D. J Green, A. Maiorana, G. O'Driscoll, and R. Taylor
Effect of exercise training on endothelium-derived nitric oxide function in humans
J. Physiol., November 15, 2004; 561(1): 1 - 25.
[Abstract] [Full Text] [PDF]

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 J. Biol. Chem.Home page
E. Anter, S. R. Thomas, E. Schulz, O. M. Shapira, J. A. Vita, and J. F. Keaney Jr.
Activation of Endothelial Nitric-oxide Synthase by the p38 MAPK in Response to Black Tea Polyphenols
J. Biol. Chem., November 5, 2004; 279(45): 46637 - 46643.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
H. S. Lim, G. Y. H. Lip, and A. D. Blann
Plasma von Willebrand Factor and the Development of the Metabolic Syndrome in Patients with Hypertension
J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5377 - 5381.
[Abstract] [Full Text] [PDF]

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 Eur Heart JHome page
S. Verma, C.-H. Wang, E. Lonn, F. Charbonneau, J. Buithieu, L. M. Title, M. Fung, S. Edworthy, A. C. Robertson, T. J. Anderson, et al.
Cross-sectional evaluation of brachial artery flow-mediated vasodilation and C-reactive protein in healthy individuals
Eur. Heart J., October 1, 2004; 25(19): 1754 - 1760.
[Abstract] [Full Text] [PDF]

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 HeartHome page
A. D Struthers
Aldosterone blockade in cardiovascular disease
Heart, October 1, 2004; 90(10): 1229 - 1234.
[Full Text] [PDF]

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 J. Nutr.Home page
H. L. Gornik and M. A. Creager
Arginine and Endothelial and Vascular Health
J. Nutr., October 1, 2004; 134(10): 2880S - 2887S.
[Abstract] [Full Text] [PDF]

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 J Am Coll CardiolHome page
J. M. Tsutsui, F. Xie, M. Cano, J. Chomas, P. Phillips, S. J. Radio, J. Lof, and T. R. Porter
Detection of retained microbubbles in carotid arteries with real-time low mechanical index imaging in the setting of endothelial dysfunction
J. Am. Coll. Cardiol., September 1, 2004; 44(5): 1036 - 1046.
[Abstract] [Full Text] [PDF]

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 CirculationHome page
J. A. Vita, M.-L. Brennan, N. Gokce, S. A. Mann, M. Goormastic, M. H. Shishehbor, M. S. Penn, J. F. Keaney Jr, and S. L. Hazen
Serum Myeloperoxidase Levels Independently Predict Endothelial Dysfunction in Humans
Circulation, August 31, 2004; 110(9): 1134 - 1139.
[Abstract] [Full Text] [PDF]

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 J. Appl. Physiol.Home page
D. J. Green, J. H. Walsh, A. Maiorana, V. Burke, R. R. Taylor, and J. G. O'Driscoll
Comparison of resistance and conduit vessel nitric oxide-mediated vascular function in vivo: effects of exercise training
J Appl Physiol, August 1, 2004; 97(2): 749 - 755.
[Abstract] [Full Text] [PDF]

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 Arterioscler. Thromb. Vasc. Bio.Home page
T. Kondo, M. Hayashi, K. Takeshita, Y. Numaguchi, K. Kobayashi, S. Iino, Y. Inden, and T. Murohara
Smoking Cessation Rapidly Increases Circulating Progenitor Cells in Peripheral Blood in Chronic Smokers
Arterioscler. Thromb. Vasc. Biol., August 1, 2004; 24(8): 1442 - 1447.
[Abstract] [Full Text] [PDF]

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 Circ. Res.Home page
J. A. Beckman, J. K. Liao, S. Hurley, L. A. Garrett, D. Chui, D. Mitra, and M. A. Creager
Atorvastatin Restores Endothelial Function in Normocholesterolemic Smokers Independent of Changes in Low-Density Lipoprotein
Circ. Res., July 23, 2004; 95(2): 217 - 223.
[Abstract] [Full Text] [PDF]

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 Biol Res NursHome page
T. R. Wessel, C. B. Arant, and C. J. Pepine
Commentary on "New and Emerging Theories of Cardiovascular Disease"
Biol Res Nurs, July 1, 2004; 6(1): 17 - 20.
[PDF]

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 J. Clin. Endocrinol. Metab.Home page
S. M. Grundy
Obesity, Metabolic Syndrome, and Cardiovascular Disease
J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2595 - 2600.
[Full Text] [PDF]

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 CirculationHome page
G. O. von Mering, C. B. Arant, T. R. Wessel, S. P. McGorray, C. N. Bairey Merz, B. L. Sharaf, K. M. Smith, M. B. Olson, B. D. Johnson, G. Sopko, et al.
Abnormal Coronary Vasomotion as a Prognostic Indicator of Cardiovascular Events in Women: Results From the National Heart, Lung, and Blood Institute-Sponsored Women's Ischemia Syndrome Evaluation (WISE)
Circulation, February 17, 2004; 109(6): 722 - 725.
[Abstract] [Full Text] [PDF]

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 Am. J. Respir. Crit. Care Med.Home page
P. Lavie
Pro: Sleep Apnea Causes Cardiovascular Disease
Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 147 - 148.
[Full Text] [PDF]

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 J Am Coll CardiolHome page
J. A. Vita and G. F. Mitchell
Effects of shear stress and flow pulsatility on endothelial function: Insights gleaned from external counterpulsation therapy
J. Am. Coll. Cardiol., December 17, 2003; 42(12): 2096 - 2098.
[Full Text] [PDF]


 
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