This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Vita, J. A. Articles by Keaney, J. F. Search for Related Content PubMed PubMed Citation Articles by Vita, J. A. Articles by Keaney, J. F., Jr Related Collections Chronic ischemic heart disease Epidemiology Coronary circulation Endothelium/vascular type/nitric oxide

(Circulation. 2002;106:640.)
© 2002 American Heart Association, Inc.

Editorial

Endothelial Function

A Barometer for Cardiovascular Risk?

Joseph A. Vita, MD; John F. Keaney, Jr, MD

From Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Mass.

Correspondence to Joseph A. Vita, MD, Section of Cardiology, Boston Medical Center, 88 East Newton St, Boston, MA 02118. E-mail jvita{at}bu.edu

Key Words: Editorials • endothelium • risk factors • coronary disease

The endothelium regulates vascular homeostasis by elaborating a variety of paracrine factors that act locally in the blood vessel wall and lumen.¹ Under normal conditions, the sum total effect of these endothelial factors is to maintain normal vascular tone, blood fluidity, and limit vascular inflammation and smooth muscle cell proliferation. However, when coronary risk factors are present, the endothelium may adopt a phenotype that facilitates inflammation, thrombosis, vasoconstriction, and atherosclerotic lesion formation.² In human subjects, this maladaptive endothelial phenotype manifests itself prior to the development of frank atherosclerosis and is associated with traditional risk factors such as hypercholesterolemia, hypertension, and diabetes mellitus and with emerging risk factors such as hyperhomocystinemia, obesity, and systemic inflammation.¹

See p 653

In addition to its role in early atherosclerosis, there is growing recognition that endothelial dysfunction also contributes to the later stages of the disease when patients develop clinical symptoms. Cross-sectional studies have demonstrated the most severe impairment of endothelial function in arteries containing a culprit lesion that precipitates unstable angina or myocardial infarction.^3,4 Furthermore, endothelial dysfunction promotes pathological vasoconstrictor responses in situations known to provoke ischemia, including physical and emotional stress.⁵ Another line of evidence supporting the pathophysiological role of endothelial dysfunction is provided by intervention studies.⁶ The ability to improve endothelial function is a common feature of many otherwise diverse interventions proven to reduce cardiovascular risk. For example, lipid-lowering therapy, angiotensin-converting enzyme inhibitors, smoking cessation, and physical exercise have all been shown to reduce cardiovascular risk and to improve endothelium-dependent vasodilation in the coronary and peripheral circulations.¹

In the past, most of the evidence suggesting a causal relation between endothelial dysfunction and clinical events from atherosclerosis was circumstantial. Recently, this evidence has been strengthened by a series of outcome studies showing that endothelial dysfunction predicts future events. For example, Suwaidi and colleagues⁷ examined 157 patients with mild coronary disease and demonstrated a greater incidence of cardiovascular events during 2.3 year follow-up in patients with impaired endothelium-dependent vasodilation of coronary resistance and conduit arteries. A similar study by Schachinger and colleagues⁸ examined coronary artery vasomotor responses to acetylcholine and nitroglycerin infusions, increased flow, and the cold pressor test in 147 patients with coronary artery disease and then followed them for a median of 7.7 years. Patients with more severe impairment of endothelium-dependent and endothelium-independent vasodilator function were more likely to suffer an event. Those two studies are limited by the relatively small number of clinical events (6 and 16, respectively) and the inclusion of coronary revascularization procedures as events. Nevertheless, they are quite important because they provided the first evidence that endothelial dysfunction has prognostic value.

In the present issue of Circulation, Halcox and colleagues⁹ provide additional information about the predictive value of coronary endothelial dysfunction. In the largest study of this type to date, they examined the coronary blood flow and epicardial coronary diameter responses to endothelium-dependent and endothelium-independent vasodilators in 308 patients undergoing cardiac catheterization. During an average 46-month follow-up period, they observed a total of 35 ischemic cardiovascular events, including sudden cardiac death, acute myocardial infarction, unstable angina, and stroke. These events were independently associated with impaired endothelium-dependent dilation of both coronary microvessels and epicardial arteries, even after controlling for other clinical variables such as the presence of coronary disease and traditional risk factors. In contrast, vasodilator responses to the endothelium-independent vasodilators sodium nitroprusside and adenosine did not predict events, providing evidence for a specific relation with endothelial dysfunction. The results were similar when an additional 21 patients who required a coronary revascularization procedure were also categorized as having an event. Very interestingly, impaired endothelium-dependent vasodilation predicted cardiovascular events even in patients with angiographically normal coronary arteries.

Thus, the study by Halcox and colleagues⁹ makes an important contribution to the literature on endothelial function. Together with the prior studies by Suwaidi⁷ and Schachinger,⁸ it makes a very strong case that impaired vascular function in the coronary circulation relates to the pathogenesis of cardiovascular disease. The strengths of the study include its large sample size, the well-developed methodology for study of coronary endothelial function, and the focus on spontaneously occurring cardiovascular disease events. The study by Halcox and colleagues has several limitations, as acknowledged by the authors.⁹ For example, the study was retrospective in nature. The investigators apparently contacted and obtained clinical information from patients who had undergone study of coronary vascular function for other reasons in their laboratory over recent years. The study also excluded patients with relatively severe coronary disease, and thus is not applicable to all patients.

Although assessment of coronary endothelial function is clearly germane for coronary artery disease events, this methodology is limited by the risk and expense of coronary angiography and selective intracoronary agonist infusion. As a consequence, there has been considerable interest in the study of endothelial vasomotor function in more accessible vascular beds, such as the brachial circulation. Many investigators have used venous occlusion plethysmography to examine vasomotor responses of forearm resistance vessels during brachial artery infusion of acetylcholine and other endothelium-dependent vasodilators.¹⁰ This approach affords several advantages including the ability to examine dose-response relations and use specific agonists and antagonists. However, these studies are limited by the requirement for arterial catheterization that renders them less well suited for large-scale and intervention studies. An alternative approach involves vascular ultrasound to examine endothelium-dependent flow-mediated dilation of the conduit brachial artery.¹¹ This noninvasive technique has gained popularity as an assessment of endothelial function that can safely be applied to large and varied groups of patients that may involve repeated measurement of vascular function over time. Similar to the coronary circulation, endothelial function in the brachial circulation is impaired in the setting of traditional and novel risk factors and responds to interventions known to reduce cardiovascular disease risk.¹

The relevance of the brachial circulation to coronary and carotid artery events is not obvious. However, the systemic nature of many risk factors makes it plausible that they might affect central and peripheral arteries in a parallel manner. Indeed, studies suggest that endothelial dysfunction detected noninvasively in the arm correlates with coronary endothelial dysfunction.¹² Despite these findings, it is well recognized that physiological mechanisms differ importantly according to vascular bed. Although the brachial artery does develop atherosclerosis,¹³ it is clinically different from the obstructive disease that affects the coronary circulation. For these reasons, there has been a need for outcome studies demonstrating the clinical relevance of endothelial dysfunction in brachial circulation.

Several recent studies have examined this question using both the invasive and noninvasive approaches. Perticone and colleagues¹⁴ observed that an impaired forearm blood flow response to acetylcholine predicted future cardiovascular events in patients with hypertension. Heitzer and colleagues¹⁵ observed a similar relationship in patients with coronary artery disease. In regard to ultrasound-detected flow-mediated dilation, Neunteufl and colleagues¹⁶ observed a relation between endothelial dysfunction and need for a revascularization procedure, although their study had a relatively small number of subjects and the relation between endothelial dysfunction and events was lost after controlling for extent of coronary disease. A very recent prospective study from our laboratory demonstrated that impaired brachial artery flow-mediated dilation is an independent predictor of short-term events in high-risk patients undergoing surgery for vascular disease.¹⁷

Thus, assessment of endothelial function in both the coronary and peripheral circulation of patients with cardiovascular disease and coronary risk factors provides prognostic information about future cardiovascular disease events. This body of clinical evidence fits well with current paradigms depicting the endothelium as an organ that integrates signals between the milieu of the vascular wall and the vessel lumen. In this context, endothelial function should represent an excellent "barometer" of underlying vascular health as it represents an orchestrated response to the many known and unknown processes that contribute to the development, progression, and clinical expression of atherosclerosis. Indeed, it is plausible that endothelial resistance to the adverse effects of risk factors might be determined by genetic or environmental factors that are currently difficult to quantify using traditional risk assessment models.

Although the present body of knowledge supports the notion that endothelial function has prognostic value for cardiovascular risk, several important issues remain unaddressed. Most of the published data involves selected patient populations referred for evaluation of cardiovascular disease or with established risk factors for the disease. Thus, the extent to which these data are applicable to the general population remains to be determined. Moreover, clinical studies to date have been largely retrospective and applied a variety of methods to assess endothelial function, thereby precluding consensus estimates for positive and negative predictive value. These issues are critical for any future plans to use endothelial function as a surrogate marker for cardiovascular risk to effectively target individuals for intensive primary prevention and assess potential new therapies. Further prospective studies involving large numbers of patients will be required to resolve these issues and determine the most clinically useful vascular bed and methodology for assessment of endothelial function.

Acknowledgments

Drs Vita and Keaney and their work on endothelial function are supported in part by a Program Project Grant from the National Institutes of Health (PO1HL60886) and by NIH grants P50 HL55993 (J.A.V.), HL/AI64753 (J.A.V., J.F.K.), and HL60040 (J.A.V., J.F.K.).

Footnotes

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

References

1. Gokce N, Keaney JF Jr, Vita JA. Endotheliopathies: clinical manifestations of endothelial dysfunction. In: Loscalzo J, Shafer AI, eds. Thrombosis and Hemorrhage. Baltimore, Md: Williams and Wilkins; 1998: 901–924.
   
2. Levine GN, Keaney JF Jr, Vita JA. Cholesterol reduction in cardiovascular disease: clinical benefits and possible mechanisms. N Engl J Med. 1995; 332: 512–521.[Free Full Text]
   
3. Okumura K, Yasue H, Matsuyama K, et al. Effect of acetylcholine on the highly stenotic coronary artery: difference between the constrictor response of the infarct-related coronary artery and that of the noninfarct-related artery. J Am Coll Cardiol. 1992; 19: 752–758.[Abstract]
   
4. Bogaty P, Hackett D, Davies G, et al. Vasoreactivity of the culprit lesion in unstable angina. Circulation. 1994; 90: 5–11.[Abstract/Free Full Text]
   
5. Yeung AC, Vekshtein VI, Krantz DS, et al. The effect of atherosclerosis on the vasomotor response of coronary arteries to mental stress. N Engl J Med. 1991; 325: 1551–1556.[Abstract]
   
6. Vita JA, Keaney JF Jr. Exercise: toning up the endothelium? N Engl J Med. 2000; 342: 503–505.[Free Full Text]
   
7. Suwaidi JA, Hamasaki S, Higano ST, et al. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation. 2000; 101: 948–954.[Abstract/Free Full Text]
   
8. Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long- term outcome of coronary heart disease. Circulation. 2000; 101: 1899–1906.[Abstract/Free Full Text]
   
9. Halcox JPJ, Schenke WH, Zalos G, et al. Prognostic value of coronary vascular endothelial function. 2002; 106: 653–658.
   
10. Creager MA, Cooke JP, Mendelsohn ME, et al. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Invest. 1990; 86: 228–234.[Medline] [Order article via Infotrieve]
    
11. Corretti MC, Anderson TJ, Benjamin EJ, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002; 39: 257–265.[Abstract/Free Full Text]
    
12. Anderson TJ, Uehata A, Gerhard MD, et al. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol. 1995; 26: 1235–1241.[Abstract]
    
13. Sorensen KE, Kristensen IB, Celermajer DS. Atherosclerosis in the human brachial artery. J Am Coll Cardiol. 1997; 29: 318–322.[Abstract]
    
14. Perticone F, Ceravolo R, Pujia A, et al. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation. 2001; 104: 191–196.[Abstract/Free Full Text]
    
15. Heitzer T, Schlinzig T, Krohn K, et al. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation. 2001; 104: 2673–2678.[Abstract/Free Full Text]
    
16. Neunteufl T, Heher S, Katzenschlager R, et al. Late prognostic value of flow-mediated dilation in the brachial artery of patients with chest pain. Am J Cardiol. 2000; 86: 207–210.[CrossRef][Medline] [Order article via Infotrieve]
    
17. Gokce N, Keaney JF Jr, Menzoian JO, et al. Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function. Circulation. 2002; 105: 1567–1572.[Abstract/Free Full Text]
    

This article has been cited by other articles:

				M. A. Black, D. J. Green, and N. T. Cable Exercise prevents age-related decline in nitric-oxide-mediated vasodilator function in cutaneous microvessels J. Physiol., July 15, 2008; 586(14): 3511 - 3524. [Abstract] [Full Text] [PDF]

				M. S. K. Wong, R. Delansorne, R. Y. K. Man, and P. M. Vanhoutte Vitamin D derivatives acutely reduce endothelium-dependent contractions in the aorta of the spontaneously hypertensive rat Am J Physiol Heart Circ Physiol, July 1, 2008; 295(1): H289 - H296. [Abstract] [Full Text] [PDF]

				D. H. J. Thijssen, M. Kooijman, P. C. E. de Groot, M. W. P. Bleeker, P. Smits, D. J. Green, and M. T. E. Hopman Endothelium-dependent and -independent vasodilation of the superficial femoral artery in spinal cord-injured subjects J Appl Physiol, May 1, 2008; 104(5): 1387 - 1393. [Abstract] [Full Text] [PDF]

				E. Linden, W. Cai, J. C. He, C. Xue, Z. Li, J. Winston, H. Vlassara, and J. Uribarri Endothelial Dysfunction in Patients with Chronic Kidney Disease Results from Advanced Glycation End Products (AGE)-Mediated Inhibition of Endothelial Nitric Oxide Synthase through RAGE Activation Clin. J. Am. Soc. Nephrol., May 1, 2008; 3(3): 691 - 698. [Abstract] [Full Text] [PDF]

				M. H. Laughlin, S. C. Newcomer, and S. B. Bender Importance of hemodynamic forces as signals for exercise-induced changes in endothelial cell phenotype J Appl Physiol, March 1, 2008; 104(3): 588 - 600. [Abstract] [Full Text] [PDF]

				C. Heiss, R. E. Sievers, N. Amabile, T. Y. Momma, Q. Chen, S. Natarajan, Y. Yeghiazarians, and M. L. Springer In vivo measurement of flow-mediated vasodilation in living rats using high-resolution ultrasound Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H1086 - H1093. [Abstract] [Full Text] [PDF]

				R. M. McAllister, S. C. Newcomer, E. R. Pope, J. R. Turk, and M. H. Laughlin Effects of chronic nitric oxide synthase inhibition on responses to acute exercise in swine J Appl Physiol, January 1, 2008; 104(1): 186 - 197. [Abstract] [Full Text] [PDF]

				S. M. Shenouda and J. A. Vita Effects of Flavonoid-Containing Beverages and EGCG on Endothelial Function J. Am. Coll. Nutr., August 1, 2007; 26(4): 366S - 372S. [Abstract] [Full Text] [PDF]

				V. G. Barauna, K. T. Rosa, M. C. Irigoyen, and E. M. de Oliveira Effects of Resistance Training on Ventricular Function and Hypertrophy in a Rat Model Clin. Med. Res., June 1, 2007; 5(2): 114 - 120. [Abstract] [Full Text] [PDF]

				D. G. Ingram, S. C. Newcomer, E. M. Price, K. E. Eklund, R. M. McAllister, and M. H. Laughlin Chronic nitric oxide synthase inhibition blunts endothelium-dependent function of conduit coronary arteries, not arterioles Am J Physiol Heart Circ Physiol, June 1, 2007; 292(6): H2798 - H2808. [Abstract] [Full Text] [PDF]

				J. Yeboah, J. R. Crouse, F.-C. Hsu, G. L. Burke, and D. M. Herrington Brachial Flow-Mediated Dilation Predicts Incident Cardiovascular Events in Older Adults: The Cardiovascular Health Study Circulation, May 8, 2007; 115(18): 2390 - 2397. [Abstract] [Full Text] [PDF]

				M. E. Widlansky, N. M. Hamburg, E. Anter, M. Holbrook, D. F. Kahn, J. G. Elliott, J. F. Keaney Jr., and J. A. Vita Acute EGCG Supplementation Reverses Endothelial Dysfunction in Patients with Coronary Artery Disease J. Am. Coll. Nutr., April 1, 2007; 26(2): 95 - 102. [Abstract] [Full Text] [PDF]

				J. E. Deanfield, J. P. Halcox, and T. J. Rabelink Endothelial Function and Dysfunction: Testing and Clinical Relevance Circulation, March 13, 2007; 115(10): 1285 - 1295. [Full Text] [PDF]

				K. F. Hoth, D. F. Tate, A. Poppas, D. E. Forman, J. Gunstad, D. J. Moser, R. H. Paul, A. L. Jefferson, A. P. Haley, and R. A. Cohen Endothelial Function and White Matter Hyperintensities in Older Adults With Cardiovascular Disease Stroke, February 1, 2007; 38(2): 308 - 312. [Abstract] [Full Text] [PDF]

				K. Hirata, A. Kadirvelu, M. Di Tullio, S. Homma, A. M. Choy, and C. C. Lang Coronary Vasomotor Function Is Abnormal in First-Degree Relatives of Patients With Type 2 Diabetes Diabetes Care, January 1, 2007; 30(1): 150 - 153. [Full Text] [PDF]

				S. Jadhav, W. Ferrell, I. A. Greer, J. R. Petrie, S. M. Cobbe, and N. Sattar Effects of Metformin on Microvascular Function and Exercise Tolerance in Women With Angina and Normal Coronary Arteries: A Randomized, Double-Blind, Placebo-Controlled Study J. Am. Coll. Cardiol., September 5, 2006; 48(5): 956 - 963. [Abstract] [Full Text] [PDF]

				F. Bitar, A. Lerman, M. W. Akhter, P. Hatamizadeh, M. Janmohamed, S. Khan, and U. Elkayam Variable response of conductance and resistance coronary arteries to endothelial stimulation in patients with heart failure due to nonischemic dilated cardiomyopathy. Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2006; 11(3): 197 - 202. [Abstract] [PDF]

				D. J. Green, A. J. Maiorana, M. E. Tschakovsky, K. E. Pyke, C. J. Weisbrod, and G. O'Driscoll Relationship between changes in brachial artery flow-mediated dilation and basal release of nitric oxide in subjects with Type 2 diabetes Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1193 - H1199. [Abstract] [Full Text] [PDF]

				R. A Harris, J. Padilla, L. D Rink, and J. P Wallace Variability of flow-mediated dilation measurements with repetitive reactive hyperemia Vascular Medicine, February 1, 2006; 11(1): 1 - 6. [Abstract] [PDF]

				P. Y. Hsue and D. D. Waters What a Cardiologist Needs to Know About Patients With Human Immunodeficiency Virus Infection Circulation, December 20, 2005; 112(25): 3947 - 3957. [Abstract] [Full Text] [PDF]

				C. R. Woodman, M. A. Thompson, J. R. Turk, and M. H. Laughlin Endurance exercise training improves endothelium-dependent relaxation in brachial arteries from hypercholesterolemic male pigs J Appl Physiol, October 1, 2005; 99(4): 1412 - 1421. [Abstract] [Full Text] [PDF]

				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]

				A. Sherwood, A. L. Hinderliter, L. L. Watkins, R. A. Waugh, and J. A. Blumenthal Impaired Endothelial Function in Coronary Heart Disease Patients With Depressive Symptomatology J. Am. Coll. Cardiol., August 16, 2005; 46(4): 656 - 659. [Abstract] [Full Text] [PDF]

				M. S. O'Neill, A. Veves, A. Zanobetti, J. A. Sarnat, D. R. Gold, P. A. Economides, E. S. Horton, and J. Schwartz Diabetes Enhances Vulnerability to Particulate Air Pollution-Associated Impairment in Vascular Reactivity and Endothelial Function Circulation, June 7, 2005; 111(22): 2913 - 2920. [Abstract] [Full Text] [PDF]

				A. L. Moens, I. Goovaerts, M. J. Claeys, and C. J. Vrints Flow-Mediated Vasodilation: A Diagnostic Instrument, or an Experimental Tool? Chest, June 1, 2005; 127(6): 2254 - 2263. [Abstract] [Full Text] [PDF]

				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]

				M. S. Goligorsky Endothelial cell dysfunction: can't live with it, how to live without it Am J Physiol Renal Physiol, May 1, 2005; 288(5): F871 - F880. [Abstract] [Full Text] [PDF]

				M. D. Iafrati, O. Vitseva, K. Tanriverdi, P. Blair, S. Rex, S. Chakrabarti, S. Varghese, and J. E. Freedman Compensatory mechanisms influence hemostasis in setting of eNOS deficiency Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1627 - H1632. [Abstract] [Full Text] [PDF]

				M. I. Yilmaz, A. Sonmez, S. Kilic, T. Celik, N. Bingol, M. Pinar, T. Mumcuoglu, and M. Ozata The association of plasma adiponectin levels with hypertensive retinopathy Eur. J. Endocrinol., February 1, 2005; 152(2): 233 - 240. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				S. Fazel, R. D. Weisel, and S. Verma A novel technique to assess flow-mediated vasodilation J. Am. Coll. Cardiol., October 6, 2004; 44(7): 1478 - 1480. [Full Text] [PDF]

				K. K. Henderson, J. R. Turk, J. W. E. Rush, and M. H. Laughlin Endothelial function in coronary arterioles from pigs with early-stage coronary disease induced by high-fat, high-cholesterol diet: effect of exercise J Appl Physiol, September 1, 2004; 97(3): 1159 - 1168. [Abstract] [Full Text] [PDF]

				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]

				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]

				G. F. Mitchell, H. Parise, J. A. Vita, M. G. Larson, E. Warner, J. F. Keaney Jr, M. J. Keyes, D. Levy, R. S. Vasan, and E. J. Benjamin Local Shear Stress and Brachial Artery Flow-Mediated Dilation: The Framingham Heart Study Hypertension, August 1, 2004; 44(2): 134 - 139. [Abstract] [Full Text] [PDF]

				N. C. Ward, J. Rivera, J. Hodgson, I. B. Puddey, L. J. Beilin, J. R. Falck, and K. D. Croft Urinary 20-Hydroxyeicosatetraenoic Acid Is Associated With Endothelial Dysfunction in Humans Circulation, July 27, 2004; 110(4): 438 - 443. [Abstract] [Full Text] [PDF]

				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]

				S. J. Moat, S. N. Doshi, D. Lang, I. F. W. McDowell, M. J. Lewis, and J. Goodfellow Treatment of coronary heart disease with folic acid: is there a future? Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H1 - H7. [Full Text] [PDF]

				S. L. Hazen Myeloperoxidase and Plaque Vulnerability Arterioscler. Thromb. Vasc. Biol., July 1, 2004; 24(7): 1143 - 1146. [Full Text] [PDF]

				J E Macdonald, N Kennedy, and A D Struthers Effects of spironolactone on endothelial function, vascular angiotensin converting enzyme activity, and other prognostic markers in patients with mild heart failure already taking optimal treatment Heart, July 1, 2004; 90(7): 765 - 770. [Abstract] [Full Text] [PDF]

				Y. Iwashima, T. Katsuya, K. Ishikawa, N. Ouchi, M. Ohishi, K. Sugimoto, Y. Fu, M. Motone, K. Yamamoto, A. Matsuo, et al. Hypoadiponectinemia Is an Independent Risk Factor for Hypertension Hypertension, June 1, 2004; 43(6): 1318 - 1323. [Abstract] [Full Text] [PDF]

				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] [Full Text] [PDF]

				K. Watts, P. Beye, A. Siafarikas, E. A. Davis, T. W. Jones, G. O'Driscoll, and D. J. Green Exercise training normalizes vascular dysfunction and improves central adiposity in obese adolescents J. Am. Coll. Cardiol., May 19, 2004; 43(10): 1823 - 1827. [Abstract] [Full Text] [PDF]

				G. F. Watts and B. Staels Regulation of Endothelial Nitric Oxide Synthase by PPAR Agonists: Molecular and Clinical Perspectives Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 619 - 621. [Full Text] [PDF]