CLINICAL RESEARCH
Predictive value of noninvasivelydetermined endothelial dysfunction for long-term cardiovascular events inpatients with peripheral vascular disease
Noyan Gokce, MD, FACC*,
John F. Keaney, Jr, MD, FACC*,
Liza M. Hunter, ANP*,
Michael T. Watkins, MD ,
Zoran S. Nedeljkovic, MD*,
James O. Menzoian, MD and
Joseph A. Vita, MD, FACC*,*
* Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts, USA
Surgical Service, Massachusetts General Hospital, Boston, Massachusetts, USA
Department of Surgery, Boston University School of Medicine, Boston, Massachusetts, USA
Manuscript received October 22, 2002;
revised manuscript received January 2, 2003,
accepted February 13, 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
OBJECTIVES: The goal of this study was to prospectively examine the long-term predictive value of brachial-artery endothelial dysfunction for future cardiovascular events.
BACKGROUND: Brachial-artery endothelial function is impaired in individuals with atherosclerosis and coronary risk factors. The prospective relation between endothelial function determined by brachial-artery ultrasound and long-term cardiovascular risk is unknown.
METHODS: We examined brachial-artery endothelial function using ultrasound in 199 patients with peripheral arterial disease before elective vascular surgery. Patients were prospectively followed with an average follow-up of 1.2 years after surgery.
RESULTS: Thirty-five patients had an event during follow-up, including cardiac death (5 patients), myocardial infarction (17 patients), unstable angina (10 patients), or stroke (3 patients). Preoperative endothelium-dependent flow-mediated dilation (FMD) was significantly lower in patients with an event (4.4 ± 2.8%) compared with those without an event (7.0 ± 4.9%, p < 0.001), whereas endothelium-independent vasodilation to nitroglycerin was similar in both groups. In a Cox proportional-hazards model, independent predictors of events included age (p = 0.003), more invasive surgery (surgery other than carotid endarterectomy, p = 0.02), and impaired brachial-artery endothelial function (p = 0.002). Risk was approximately nine-fold higher in patients with FMD <8.1% (lower two tertiles) compared with those in the upper tertile (odds ratio 9.5; 95% confidence interval 2.3 to 40).
CONCLUSIONS: Impaired brachial-artery endothelial function independently predicts long-term cardiovascular events in patients with peripheral arterial disease. The findings suggest that noninvasive assessment of endothelial function using brachial-artery FMD may serve as a surrogate end point for cardiovascular risk.
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Abbreviations and Acronyms
| | CAD | | coronary artery disease | | FMD | | flow-mediated dilation | | MI | | myocardial infarction | | NTG | | nitroglycerin |
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D. W. Wray, A. Uberoi, L. Lawrenson, and R. S. Richardson
Heterogeneous limb vascular responsiveness to shear stimuli during dynamic exercise in humans
J Appl Physiol,
July 1, 2005;
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[Abstract]
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E. D. Beishuizen, J. T. Tamsma, J. W. Jukema, M. A. van de Ree, J. C. M. van der Vijver, A. E. Meinders, and M. V. Huisman
The Effect of Statin Therapy on Endothelial Function in Type 2 Diabetes Without Manifest Cardiovascular Disease
Diabetes Care,
July 1, 2005;
28(7):
1668 - 1674.
[Abstract]
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M. Rakobowchuk, C. L. McGowan, P. C. de Groot, J. W. Hartman, S. M. Phillips, and M. J. MacDonald
Endothelial function of young healthy males following whole body resistance training
J Appl Physiol,
June 1, 2005;
98(6):
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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]
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P. K. Witting, B. J. Wu, M. Raftery, P. Southwell-Keely, and R. Stocker
Probucol Protects against Hypochlorite-induced Endothelial Dysfunction: IDENTIFICATION OF A NOVEL PATHWAY OF PROBUCOL OXIDATION TO A BIOLOGICALLY ACTIVE INTERMEDIATE
J. Biol. Chem.,
April 22, 2005;
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[Abstract]
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J. A. Blumenthal, A. Sherwood, M. A. Babyak, L. L. Watkins, R. Waugh, A. Georgiades, S. L. Bacon, J. Hayano, R. E. Coleman, and A. Hinderliter
Effects of Exercise and Stress Management Training on Markers of Cardiovascular Risk in Patients With Ischemic Heart Disease: A Randomized Controlled Trial
JAMA,
April 6, 2005;
293(13):
1626 - 1634.
[Abstract]
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M. Charakida, A. E. Donald, M. Terese, S. Leary, J. P. Halcox, A. Ness, G. D. Smith, J. Golding, P. Friberg, N. J. Klein, et al.
Endothelial Dysfunction in Childhood Infection
Circulation,
April 5, 2005;
111(13):
1660 - 1665.
[Abstract]
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M. Terashima, C. H. Meyer, B. G. Keeffe, E. J. Putz, E. de la Pena-Almaguer, P. C. Yang, B. S. Hu, D. G. Nishimura, and M. V. McConnell
Noninvasive assessment of coronary vasodilation using magnetic resonance angiography
J. Am. Coll. Cardiol.,
January 4, 2005;
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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]
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D. Fischer, S. Rossa, U. Landmesser, S. Spiekermann, N. Engberding, B. Hornig, and H. Drexler
Endothelial dysfunction in patients with chronic heart failure is independently associated with increased incidence of hospitalization, cardiac transplantation, or death
Eur. Heart J.,
January 1, 2005;
26(1):
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[Abstract]
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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):
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A. T. Hirsch and A. R. Folsom
The Continuum of Risk: Vascular Pathophysiology, Function, and Structure
Circulation,
November 2, 2004;
110(18):
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R. Stocker, A. Huang, E. Jeranian, J. Y. Hou, T. T. Wu, S. R. Thomas, and J. F. Keaney Jr
Hypochlorous Acid Impairs Endothelium-Derived Nitric Oxide Bioactivity Through a Superoxide-Dependent Mechanism
Arterioscler Thromb Vasc Biol,
November 1, 2004;
24(11):
2028 - 2033.
[Abstract]
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S. Fazel, R. D. Weisel, and S. Verma
A novel technique to assess flow-mediated vasodilation
J. Am. Coll. Cardiol.,
October 6, 2004;
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R. Stocker and J. F. Keaney Jr.
Role of Oxidative Modifications in Atherosclerosis
Physiol Rev,
October 1, 2004;
84(4):
1381 - 1478.
[Abstract]
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D. H. Endemann and E. L. Schiffrin
Endothelial Dysfunction
J. Am. Soc. Nephrol.,
August 1, 2004;
15(8):
1983 - 1992.
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S. I. Sokol, E. L. Portnay, J. P. Curtis, M. A. Nelson, P. R. Hebert, J. F. Setaro, and J. M. Foody
Modulation of the renin-angiotensin-aldosterone system for the secondary prevention of stroke
Neurology,
July 27, 2004;
63(2):
208 - 213.
[Abstract]
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J. N. Cohn, A. A. Quyyumi, N. K. Hollenberg, and K. A. Jamerson
Surrogate Markers for Cardiovascular Disease: Functional Markers
Circulation,
June 29, 2004;
109(25_suppl_1):
IV-31 - IV-46.
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M. K. Nishizaka, M. A. Zaman, S. A. Green, K. Y. Renfroe, and D. A. Calhoun
Impaired Endothelium-Dependent Flow-Mediated Vasodilation in Hypertensive Subjects With Hyperaldosteronism
Circulation,
June 15, 2004;
109(23):
2857 - 2861.
[Abstract]
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M. E. Otto, A. Svatikova, R. B. d. M. Barretto, S. Santos, M. Hoffmann, B. Khandheria, and V. Somers
Early Morning Attenuation of Endothelial Function in Healthy Humans
Circulation,
June 1, 2004;
109(21):
2507 - 2510.
[Abstract]
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[PDF]
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S. Rajagopalan, E. C. Somers, R. D. Brook, C. Kehrer, D. Pfenninger, E. Lewis, A. Chakrabarti, B. C. Richardson, E. Shelden, W. J. McCune, et al.
Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity
Blood,
May 15, 2004;
103(10):
3677 - 3683.
[Abstract]
[Full Text]
[PDF]
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J. P. Cooke
Asymmetrical Dimethylarginine: The Uber Marker?
Circulation,
April 20, 2004;
109(15):
1813 - 1818.
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M. Xaymardan, J. Zheng, I. Duignan, A. Chin, J. M. Holm, V. L.T. Ballard, and J. M. Edelberg
Senescent Impairment in Synergistic Cytokine Pathways That Provide Rapid Cardioprotection in the Rat Heart
J. Exp. Med.,
March 15, 2004;
199(6):
797 - 804.
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G. B. J. Mancini
Vascular structure versus function: is endothelial dysfunction of independent prognostic importance or not?
J. Am. Coll. Cardiol.,
February 18, 2004;
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A. N. DeMaria, O. Ben-Yehuda, D. Berman, G. K. Feld, B. H. Greenberg, J. D. Knoke, K. U. Knowlton, W. Y. W. Lew, and S. Tsimikas
Highlights of the year in JACC 2003
J. Am. Coll. Cardiol.,
December 17, 2003;
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P. Ganz and J. A. Vita
Testing Endothelial Vasomotor Function: Nitric Oxide, a Multipotent Molecule
Circulation,
October 28, 2003;
108(17):
2049 - 2053.
[Full Text]
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G. Brevetti, A. Silvestro, V. Schiano, and M. Chiariello
Endothelial Dysfunction and Cardiovascular Risk Prediction in Peripheral Arterial Disease: Additive Value of Flow-Mediated Dilation to Ankle-Brachial Pressure Index
Circulation,
October 28, 2003;
108(17):
2093 - 2098.
[Abstract]
[Full Text]
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M. E. Widlansky, N. Gokce, J. F. Keaney Jr, and J. A. Vita
The clinical implications of endothelial dysfunction
J. Am. Coll. Cardiol.,
October 1, 2003;
42(7):
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M. E. Widlansky, D. T. Price, N. Gokce, R. T. Eberhardt, S. J. Duffy, M. Holbrook, C. Maxwell, J. Palmisano, J. F. Keaney Jr, J. D. Morrow, et al.
Short- and Long-Term COX-2 Inhibition Reverses Endothelial Dysfunction in Patients With Hypertension
Hypertension,
September 1, 2003;
42(3):
310 - 315.
[Abstract]
[Full Text]
[PDF]
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