doi: 10.1161/01.CIR.0000089191.72957.ED
(Circulation. 2003;108:2054.)
© 2003 American Heart Association, Inc.
Mini-Review: Expert Opinions |
Endothelial Function Testing as a Biomarker of Vascular Disease
From the Department of Cardiac Surgery, University of Toronto, Toronto, Ontario, and Department of Pharmacology and Therapeutics, University of Calgary, Calgary, Alberta, Canada (S.V.); the Department of Pathology and Molecular Science, McMaster University, Health Sciences Centre, Hamilton, Ontario, Canada (M.B.); and the Department of Medicine, University of Calgary, Calgary, Alberta, Canada (T.J.A.).
Correspondence to Subodh Verma, MD, PhD, Division of Cardiac Surgery, 14EN-215, 200 Elizabeth St, Toronto General Hospital, Toronto, Ontario, Canada M5G 2C4. E-mail Subodh.Verma{at}Sympatico.ca
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Introduction |
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 Top Introduction Assessment of Endothelial...SummaryReferences |
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The endothelium is the monolayer of endothelial cells lining the lumen of all blood vessels. These cells function as a protective biocompatible barrier between all tissues and the circulating blood. Endothelial cells also function as a selective sieve to facilitate bidirectional passage of macromolecules and blood gases to and from tissues and blood. The strategic location of the endothelium allows it to "sense" changes in hemodynamic forces and blood-borne signals and "respond" by releasing a number of autocrine and paracrine substances. A balanced release of these bioactive factors facilitates vascular homeostasis. Endothelial cell dysfunction disrupts this balance, thereby predisposing the vessel wall to vasoconstriction, leukocyte adherence, platelet activation, mitogenesis, pro-oxidation, thrombosis, impaired coagulation, vascular inflammation, and atherosclerosis.1 Our understanding of these endothelial cell responses has led to the development of tests that are believed to reflect endothelial cell dysfunction or integrity in vivo. Given the central role of the endothelium in the development and clinical course of atherosclerosis, endothelial function testing may serve as a useful biomarker of atherosclerosis.
Nitric oxide (NO) is the key endothelium-derived relaxing factor that plays a pivotal role in the maintenance of vascular tone and reactivity.2 In addition to being the main determinant of basal vascular smooth muscle tone, NO acts to negate the actions of potent endothelium-derived contracting factors such as angiotensin II and endothelin-1. In addition, NO serves to inhibit platelet and white cell activation and to maintain the vascular smooth muscle in a nonproliferative state. NO is synthesized from L-arginine under the influence of the enzyme NO synthase (NOS). NOS requires a critical cofactor, tetrahydrobiopterin, to facilitate NO production. Tetrahydrobiopterin deficiency leads to an "uncoupling" of NOS that results in the formation of untoward oxidants such as superoxide and hydrogen peroxide (versus NO) with resultant impairment in endothelial function.3 Superoxide inactivates NO to peroxynitrite, which further decreases NO activity in this uncoupled state. Cardiac risk factors in general lead to an increase in oxidative stress, attenuating net NO bioactivity.
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Assessment of Endothelial Function |
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TopIntroductionAssessment of Endothelial...SummaryReferences |
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Assessment of endothelial cell function refers to a measure of endothelial cell response to stimulation—for example, by vasoactive substances released by or those that interact with the vascular endothelium. Endothelium-dependent vasodilation can be assessed in the coronary and peripheral circulations in humans. In addition, measures of platelet function and inflammation/leukocyte activation (such as C-reactive protein [CRP]) are other measures of endothelial health. Figure 1 shows methods of assessing endothelium-dependent vasomotion.
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Coronary Circulation
Quantitative coronary angiography has been used to examine the changes in vascular diameter in response to an infusion of an endothelium-dependent vasodilator such as acetylcholine (Ach), bradykinin, substance P, or serotonin.4 In healthy vessels, Ach evokes a NO-mediated vasodilatory response; however, in patients with endothelial dysfunction, this effect is blunted or paradoxical vasoconstriction may occur.5 Endothelial function of the coronary microvasculature (resistance vessels) has been assessed by using intracoronary Doppler techniques to measure coronary blood flow in response to pharmacological or physiological stimuli.6 Although considered by many to be the best assessment of endothelial function, this technique is limited by its invasive nature, expense, and relative inaccessibility.
Peripheral Circulation
Brachial artery ultrasound is a widely used, noninvasive measure of endothelial cell function.7,8 The forearm blood flow is occluded for 5 minutes using a blood pressure cuff maintained at a standard pressure. When the pressure is released, reactive hyperemia occurs. This results in shear stress-induced NO release and subsequent vasodilatation (flow-mediated vasodilatation). This technique has the advantage of being noninvasive and can readily identify populations with attenuated endothelial function. The major limitations of this technique are the need for ultrasonographic expertise and a significant day-to-day variability (about 25%) due to biological circadian rhythms. Nonetheless, at present, this approach is widely used to assess vasomotion function.
Resistance vessel function in the forearm is assessed by strain-gauge venous impedance plethysmography. This methodology examines the change in forearm blood flow in response to direct intraarterial (brachial artery) administration of agonists. This technique is excellent for acute interventions with repeated measurements.9,10 The major drawbacks, again, are reproducibility and the technique’s more invasive nature compared with ultrasound. Noninvasive measures of arterial compliance and waveform morphology also provide a marker of vascular health that may in part be endothelium dependent.
Inflammatory Markers
Over the past few years, we have witnessed a paradigm shift in our understanding of the underlying principles of atherosclerosis. This new view supports the concept that vascular inflammation is a central orchestrator of atherosclerotic lesion formation, progression, and eventual rupture.11 Chronic inflammation results in endothelial dysfunction and facilitates the interactions among modified lipoproteins, monocyte-derived macrophages, T cells, and normal cellular elements of the arterial wall, thus inciting early and late atherosclerotic processes. This paradigm has fueled interest in evaluating inflammatory markers of atherosclerosis, of which high-sensitivity CRP has emerged as one of the most important. As such, CRP is a powerful independent predictor of myocardial infarction, stroke, and vascular death in a variety of settings and appears to be a better prognosticator of cardiovascular events than LDL cholesterol.12–14 Over the past year, much interest has been generated into unraveling the mechanistic basis of the CRP-atherosclerosis connection (Figure 2). Indeed, recent studies, including work from our laboratory, suggest that CRP is not only a predictor but also a mediator of lesion formation.15–25 CRP, at concentrations known to predict vascular disease, has a direct effect to stimulate diverse early atherosclerotic processes, including the expression of endothelial cell adhesion molecules, the production of chemoattractant chemokines, and macrophage LDL uptake. In addition, CRP directly modulates the production of endothelium-derived vasoactive factors, including downregulating endothelial NOS (eNOS)-derived NO while augmenting production of the potent endothelium-derived vasoconstrictor endothelin-1. Additionally, CRP facilitates endothelial cell apoptosis and attenuates angiogenesis, which is an important compensatory mechanism in ischemia. More recently, CRP has also been demonstrated to promote the release of plasminogen activator inhibitor-1 from endothelial cells,25 upregulate angiotensin-mediated neointimal formation,20 and alter endothelial progenitor cell survival and differentiation.22
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B signaling in endothelial cells while attenuating endothelial progenitor cell survival and differentiation (Verma et al, unpublished observations, 2003). Also, the proatherogenic effects of CRP are augmented in the hyperglycemic milieu.Thus, CRP is not only an inflammatory marker of atherosclerosis/coronary events but is also a mediator of the disease because it contributes to the pathogenesis of lesion formation, plaque rupture, and coronary thrombosis by interacting with and altering the endothelial cell phenotype. CRP should be regarded as an indirect, albeit important, measure of endothelial function. The major advantage of biochemical measures of endothelial function is that they are inexpensive and offer excellent reproducibility. However, it is not yet clear what the relationship is between these markers, measures of endothelium-dependent vasodilation, and cardiovascular outcomes, and it is an area that is currently being investigated. Preliminary studies suggest that patients with elevated levels of CRP have impaired endothelium-dependent vasodilatation, which suggests that CRP may be a useful clinical tool for endothelial vasomotion.26
Endothelial Function as a Biomarker of Atherosclerosis
Dysfunction of endothelial cells is probably the earliest event in the process of lesion formation—hence, the concept that assessment of endothelial function may be a useful prognostic tool for coronary artery disease. Heterogeneity of vascular dysfunction must be appreciated. Nonetheless, coronary endothelial cell perturbations often are reflected in peripheral vasodilator abnormalities, thereby allowing the assessment of peripheral endothelial function as a measure of coronary vasomotion.27 Recent studies also suggest that there is a correlation between endothelium-dependent vasodilation and CRP levels.26 Thus, endothelial dysfunction may be reflected systemically, thereby allowing for a less invasive approach to the assessment of overall endothelial cell biocompatibility.
The rationale for why endothelial function testing, either directly or indirectly, may serve as an indicator of vascular damage or disease is as follows: (1) The healthy endothelium is nonthrombogenic; (2) endothelial dysfunction occurs in response to vascular risk factors and is an early event in atherosclerosis; (3) endothelial dysfunction precedes structural atherosclerosis; (4) interventions that improve endothelial function also decrease cardiovascular events in patients with stable coronary disease; (5) reproducible, noninvasive assessments of endothelial function exist; and (6) endothelial function testing fulfills the criteria for an acceptable biomarker. Because risk factors, even those not yet identified, target the endothelium, it is a logical "window" of future atherosclerotic outcomes.
Prognostic Relevance of Endothelial Function
The clinical manifestations of coronary artery disease depend on a multitude of interrelated pathophysiological processes, of which endothelial dysfunction is only one.
Studies of Vasomotion
We demonstrated that endothelial dysfunction was associated with the development of transplantation atherosclerosis as assessed by intravascular ultrasound.28 Those subjects with normal vasodilator responses to Ach immediately after transplantation developed atherosclerosis at a rate one third that of those with endothelial dysfunction during the first year of follow-up. Three retrospective trials have assessed the relationship between Ach-mediated coronary endothelial function and clinical events (Table). Subjects with vasoconstrictor responses to Ach were more likely to develop adverse cardiovascular events during follow-up of 5 to 10 years despite having minimal coronary disease at baseline. Although important, these observations are diminished by the relative low frequency of end point events.29,30 A recently published trial of 308 subjects who underwent coronary endothelial function testing revealed improved survival in those subjects with better conduit and resistance vessel responses to Ach. Endothelial function was a predictor of outcome in a multivariate analysis.31
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Perticone and colleagues32 studied 225 hypertensive subjects who underwent Ach testing in the forearm with plethysmography. After correcting for blood pressure, subjects with the lowest tertile of endothelial function had an increase in cardiovascular events over a 3-year follow-up. The most robust of the prognostic studies was reported by Heitzer et al,33 who studied 281 subjects with coronary disease undergoing forearm Ach studies. Two key observations were made. First, subjects with attenuated responses had more events. Second, subjects with a greater acute improvement of endothelial function with vitamin C (suggesting more oxidative stress) had a worse outcome.
Small studies have also suggested a prognostic role for the brachial ultrasound assessment of endothelial function.34 A recently reported prospective study demonstrated that abnormalities of flow-mediated dilation were predictive of postoperative complications in patients undergoing noncardiac vascular surgery.35
All the studies done to date are too small to be definitive. Studies with thousands of subjects are underway36 with brachial ultrasound to determine if a single measure of vasoreactivity in an individual patient predicts the development of atherosclerosis or its complications (J. Vita, MD, personal communication, 2002).
Studies of Inflammatory Markers
Studies by Ridker37 have demonstrated a relationship of cardiovascular outcomes with interleukin-6, tumor necrosis factor-
, soluble P selectin, and soluble intercellular adhesion molecule-1.38 However, high-sensitivity CRP has emerged as the most powerful predictor of future cardiovascular events.12–14
In both healthy men and women, CRP levels in the upper quartile increase risk of adverse clinical events by 2- to 4-fold and are at least as prognostic as lipid parameters. Of great interest is the fact that subjects with elevated levels of CRP seem to gain more benefit from pharmacological therapies such as aspirin or statin therapy. Given the direct effects of CRP to destabilize eNOS mRNA in endothelial cells,16 it is logical to propose that CRP is a sensitive marker of endothelial dysfunction; it remains to be determined whether the predictive value of endothelial vasomotion assessments will be independent of CRP levels.
An alternative approach to measuring endothelial cell function in response to assorted agonists is to measure changes in endothelial cell biocompatibility. In support of this possibility, Brister et al38 found that the lipoxygenase pathway-derived monohydroxide, 13-hydroxyoctadecadienoic acid (13-HODE) decreases with age in patients with coronary artery disease undergoing coronary artery bypass grafting and that this decrease is associated with increased endothelial cell thrombogenicity.38 More recently, 13-HODE plasma levels have been shown to dramatically increase in patients with confirmed atherosclerosis and were higher in coronary artery bypass grafting patients who suffered a cardiovascular event during the 2-year follow-up.39
Several other surrogate markers of endothelial cell activation and inflammation are being investigated, including lipoprotein-associated phospholipase A2,40 CD40 receptor/CD40-ligand interaction, 41 LOX-1,42 and measurement of circulating endothelial progenitor cells.43,44
Implications for Practice
Atherosclerotic vascular disease remains the leading cause of morbidity and mortality among adults in developed countries and is increasing at an alarming rate in developing nations. The concept of risk introduced by the Framingham Heart Study more than 50 years ago serves as the "gold standard" in risk assessment.45 Enthusiasm for risk assessment46 and prevention are based on the demonstration that aggressive medical therapy reduces the likelihood of recurrent coronary events in patients with established coronary heart disease. A similar potential exists for primary prevention.
Patients at high risk (those with diabetes, other vascular disease, or multiple risk factors) clearly benefit from pharmacological therapy. In addition, patients without traditional risk factors are at low risk of events over both the short and long term. It is estimated however, that 40% to 50% of adults fall into the intermediate risk group according to National Health and Examination Survey (NHANES) III data. Patients in this intermediate risk group do not currently qualify for the most intensive risk factor interventions. The problem with this approach is that the treatment algorithms take into account short-term (10 years) rather than long-term risk (30 years), and there is a wide range of risk within this large group. It is this group that could potentially benefit from further risk stratification with endothelial function testing. If prospective studies confirm the predictive nature of endothelial markers for cardiovascular outcomes, then incorporation of these measures into risk factor models would lead to more effective prevention. A positive test in a subject at low to moderate risk would identify an individual whose risk would warrant pharmacological treatment.47 Other proposed markers of risk, including coronary calcium score (electron beam computed tomography), carotid intimal-medial thickness, ankle-brachial index, and stress testing, are also being evaluated carefully. The optimal diagnostic/therapeutic approach is not known at this time but will be better defined in the next decade. These data will come from ongoing prospective studies of endothelial function and the National Institutes of Health-sponsored MESA study (Multi-Ethnic Study of Atherosclerosis). Given the increasing atherosclerosis pandemic, advances in diagnostic modalities, and health economics issues, the time is right to define the most effective prevention strategy for subjects at risk of atherosclerotic events.48
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Summary |
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TopIntroductionAssessment of Endothelial...SummaryReferences |
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At the present time, measures of endothelial cell function and biocompatibility have advanced our understanding of the pathophysiology of atherosclerosis and its treatment. They are quickly becoming well-established surrogates of disease activity; however, the ideal test(s) of endothelial function have yet to be established. As we incorporate new biomarkers into global risk assessment, the endothelium is the logical target of study, given its unique position as both a sensor and participant in the atherosclerosis process. Recent evidence suggests that the mechanistic basis for the powerful predictive value of inflammatory biomarkers such as CRP may also reside at the level of the endothelium.16 Although endothelial function testing remains a research tool at the present time, it is our contention that this technology will figure prominently in risk assessment strategies in the future.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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References |
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1. Verma S, Anderson TJ. Fundamentals of endothelial function for the clinical cardiologist. Circulation. 2002; 105: 546–549.
2. Furchgott RF, Zawadski JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980; 288: 373–376.[CrossRef][Medline] [Order article via Infotrieve]
3. Verma S, Maitland A, Weisel RD, et al. Novel cardioprotective effects of tetrahydrobiopterin after anoxia and reoxygenation: identifying cellular targets for pharmacologic manipulation. J Thorac Cardiovasc Surg. 2002; 123: 1074–1083.
4. Aymong ED, Curtis MJ, Youssef M, et al. Abciximab attenuates coronary microvascular endothelial dysfunction after coronary stenting. Circulation. 2002; 105: 2981–2985.
5. Ludmer PL, Selwyn AP, Shook TL, et al. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med. 1986; 315: 1046–1051.[Abstract]
6. Zeiher AM, Drexler H, Wollschlaeger H, et al. Endothelial dysfunction of the coronary microvasculature is associated with impaired coronary blood flow regulation in patients with early atherosclerosis. Circulation. 1991; 84: 1984–1992.
7. Anderson TJ, Elstein E, Haber H, et al. Comparative study of ACE-inhibition, angiotensin II antagonism, and calcium channel blockade on flow-mediated vasodilation in patients with coronary disease (BANFF study). J Am Coll Cardiol. 2000; 35: 60–66.
8. 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.
9. Verma S, Raj SR, Shewchuk L, et al. Cyclooxygenase-2 blockade does not impair endothelial vasodilator function in healthy volunteers: randomized evaluation of rofecoxib versus naproxen on endothelium-dependent vasodilatation. Circulation. 2001; 104: 2879–2882.
10. Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol. 2001; 37: 1344–1350.
11. Libby P. Inflammation in atherosclerosis. Nature. 2002; 420: 868–874.[CrossRef][Medline] [Order article via Infotrieve]
12. Ridker PM, Rifai N, Rose L, et al. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002; 347: 1557–1565.
13. Ridker PM, Hennekens CH, Buring JE, et al. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000; 342: 836–843.
14. Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation. 2003; 107: 363–369.
15. Verma S, Li SH, Badiwala MV, et al. Endothelin antagonism and interleukin-6 inhibition attenuate the proatherogenic effects of C-reactive protein. Circulation. 2002; 105: 1890–1896.
16. Verma S, Wang CH, Li SH, et al. A self-fulfilling prophecy: C-reactive protein attenuates nitric oxide production and inhibits angiogenesis. Circulation. 2002; 106: 913–919.
17. Pasceri V, Chang J, Willerson JT, et al. Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation. 2001; 103: 2531–2534.
18. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation. 2000; 102: 2165–2168.
19. Zwaka TP, Hombach V, Torzewski J. C-reactive protein-mediated low-density lipoprotein uptake by macrophages: implications for atherosclerosis. Circulation. 2001; 103: 1194–1197.
20. Wang CH, Li SH, Weisel RD, et al. C-reactive protein upregulates angiotensin type 1 receptors in vascular smooth muscle. Circulation. 2003; 107: 1783–1790.
21. Verma S, Li SH, Wang CH, et al. Hyperglycemia potentiates the proatherogenic effects of C-reactive protein: reversal with rosiglitazone. J Mol Cell Cardiol. 2003; 35: 417–419.[CrossRef][Medline] [Order article via Infotrieve]
22. Verma S, Kuliszewski MA, Mickle DAG, et al. C-reactive protein attenuates endothelial progenitor cell survival and differentiation. Can J Cardiol. 2002; 18 (suppl B): 325.
23. Yeh ET, Willerson JT. Coming of age of C-reactive protein: using inflammation markers in cardiology. Circulation. 2003; 107: 370–371.
24. Venugopal SK, Devaraj S, Yuhanna I, et al. Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation. 2002; 106: 1439–1441.
25. Devaraj S, Xu DY, Jialal I. C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothelial cells: implications for the metabolic syndrome and atherothrombosis. Circulation. 2003; 107: 398–404.
26. Fichtlscherer S, Rosenberger G, Walter DH, et al. Elevated C-reactive protein levels and impaired endothelial vasoreactivity in patients with coronary artery disease. Circulation. 2000; 102: 1000–1006.
27. 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]
28. Davis SF, Yeung AC, Meredith IT, et al. Early endothelial dysfunction predicts the development of transplant coronary artery disease at 1 year posttransplant. Circulation. 1996; 93: 457–462.
29. Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000; 101: I899–1906.
30. 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.
31. Halcox JPJ, Schenke WH, Zalos G, et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation. 2002; 106: 653–658.
32. Perticone F, Ceravolo R, Pujia A, et al. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation. 2001; 104: 191–196.
33. 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.
34. 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]
35. Gokce N, Keaney JF Jr, Hunter LM, et al. Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: a prospective study. Circulation. 2002; 105: 1567–1572.
36. Anderson TJ, Robertson A, Hildebrand K, et al. The FATE of endothelial function testing: rational and design of the Firefighters And Their Endothelium (FATE) study. Can J Cardiol. 2003; 19: 61–66.[Medline] [Order article via Infotrieve]
37. Ridker PM, Stampfer MJ, Rifai N. Novel risk factors for systemic atherosclerosis. JAMA. 2001; 285: 2481–2485.
38. Brister SJ, Buchanan MR. Effects of linoleic acid and/or marine fish oil supplements on vessel wall thromboresistance in patients undergoing cardiac surgery. Adv Exp Med Biol. 1997; 423: 275–278.
39. Varghese R, Brister SJ, Buchanan MR. Plasma 13-HODE levels, cardiovascular disease (CAD) severity and thrombotic risk in patients undergoing coronary artery bypass grafting (CABG). Can J Cardiol. 2001; 17 (suppl C): 435.
40. Dada N, Kim NW, Wolfert RL. Lp-PLA2: an emerging biomarker of coronary artery disease. Expert Rev Mol Diagn. 2002; 2: 17–22.[CrossRef][Medline] [Order article via Infotrieve]
41. Schonbeck U, Libby P. CD40 signaling and plaque instability. Circ Res. 2001; 89: 1092–1103.
42. Mehta JL, Li D. Identification, regulation and function of a novel lectin-like oxidized low-density lipoprotein receptor. J Am Coll Cardiol. 2002; 39: 1429–1435.
43. Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003; 348: 593–600.
44. Szmitko PE, Fedak PWM, Weisel RD, et al. Endothelial progenitor cells: new hope for a broken heart. Circulation. 2003; 107: 3093–3100.
45. Wilson PWF, D’Agostino RB, Levy D, et al. Prediction of coronary heart disease using risk factor categories. Circulation. 1998; 97: 1837–1847.
46. Pearson TA, Mensah GA, Alexander RW, et al. Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation. 2003; 107: 499–511.
47. Greenland P, Smith SC Jr, Grundy SM. Improving coronary heart disease risk assessment in asymptomatic people: role of traditional risk factors and noninvasive cardiovascular tests. Circulation. 2001; 104: 1863–1867.
48. Bhatt DL, Topol EJ. Need to test the arterial inflammation hypothesis. Circulation. 2002; 106: 136–140.
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 M. Oroszlan, E. Herczenik, S. Rugonfalvi-Kiss, A. Roos, A. J Nauta, M. R Daha, I. Gombos, I. Karadi, L. Romics, Z. Prohaszka, et al. Proinflammatory changes in human umbilical cord vein endothelial cells can be induced neither by native nor by modified CRP Int. Immunol., June 1, 2006; 18(6): 871 - 878. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Vasan Biomarkers of Cardiovascular Disease: Molecular Basis and Practical Considerations Circulation, May 16, 2006; 113(19): 2335 - 2362. [Full Text] [PDF]
|
|
|
|
|
|
B. M. Scirica, D. A. Morrow, S. Verma, S. Devaraj, I. Jialal, B. M. Scirica, D. A. Morrow, S. Verma, S. Devaraj, and I. Jialal The Verdict Is Still Out Circulation, May 2, 2006; 113(17): 2128 - 2151. [Full Text] [PDF]
|
|
|
|
 |
|
 L. M Yunker, J. S Parboosingh, H. E Conradson, P. Faris, P. J Bridge, J. Buithieu, L. M Title, F. Charbonneau, S. Verma, E. M Lonn, et al. The effect of iron status on vascular health Vascular Medicine, May 1, 2006; 11(2): 85 - 91. [Abstract] [PDF]
|
|
|
|
 |
|
 A. Zambon, P. Gervois, P. Pauletto, J.-C. Fruchart, and B. Staels Modulation of Hepatic Inflammatory Risk Markers of Cardiovascular Diseases by PPAR-{alpha} Activators: Clinical and Experimental Evidence Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 977 - 986. [Abstract] [Full Text] [PDF]
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|
|
 |
|
 D. A. Smirnov, B. W. Foulk, G. V. Doyle, M. C. Connelly, L. W.M.M. Terstappen, and S. M. O'Hara Global gene expression profiling of circulating endothelial cells in patients with metastatic carcinomas. Cancer Res., March 15, 2006; 66(6): 2918 - 2922. [Abstract] [Full Text] [PDF]
|
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|
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|
M. Shimabukuro, N. Higa, I. Chinen, K. Yamakawa, and N. Takasu Effects of a Single Administration of Acarbose on Postprandial Glucose Excursion and Endothelial Dysfunction in Type 2 Diabetic Patients: A Randomized Crossover Study J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 837 - 842. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kathiresan, P. Gona, M. G. Larson, J. A. Vita, G. F. Mitchell, G. H. Tofler, D. Levy, C. Newton-Cheh, T. J. Wang, E. J. Benjamin, et al. Cross-Sectional Relations of Multiple Biomarkers From Distinct Biological Pathways to Brachial Artery Endothelial Function Circulation, February 21, 2006; 113(7): 938 - 945. [Abstract] [Full Text] [PDF]
|
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A. A. Quyyumi Women and Ischemic Heart Disease: Pathophysiologic Implications From the Women's Ischemia Syndrome Evaluation (WISE) Study and Future Research Steps J. Am. Coll. Cardiol., February 7, 2006; 47(3_Suppl_S): S66 - S71. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. G. Howarth, W. B. Wiehler, M. Pannirselvam, Y. Jiang, J. P. Berger, D. Severson, T. J. Anderson, and C. R. Triggle A Nonthiazolidinedione Peroxisome Proliferator-Activated Receptor {gamma} Agonist Reverses Endothelial Dysfunction in Diabetic (db/db-/-) Mice J. Pharmacol. Exp. Ther., January 1, 2006; 316(1): 364 - 370. [Abstract] [Full Text] [PDF]
|
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|
|
|
T. Weber, J. Auer, M. F. O'Rourke, E. Kvas, E. Lassnig, G. Lamm, N. Stark, M. Rammer, and B. Eber Increased arterial wave reflections predict severe cardiovascular events in patients undergoing percutaneous coronary interventions Eur. Heart J., December 2, 2005; 26(24): 2657 - 2663. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Nanami, T. Ookawara, Y. Otaki, K. Ito, R. Moriguchi, K. Miyagawa, Y. Hasuike, M. Izumi, H. Eguchi, K. Suzuki, et al. Tumor Necrosis Factor-{alpha}-Induced Iron Sequestration and Oxidative Stress in Human Endothelial Cells Arterioscler. Thromb. Vasc. Biol., December 1, 2005; 25(12): 2495 - 2501. [Abstract] [Full Text] [PDF]
|
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|
|
 |
|
 S. M. Wildhirt, C. Schulze, N. Conrad, R. Bauernschmitt, R. Lange, and W. von Scheidt Persistently increased systemic, but not cardiac-specific, adhesion molecule expression and coronary endothelial dysfunction in human cardiac allografts J. Thorac. Cardiovasc. Surg., October 1, 2005; 130(4): 1175 - 1175. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hetzel, B. Balletshofer, K. Rittig, D. Walcher, W. Kratzer, V. Hombach, H.-U. Haring, W. Koenig, and N. Marx Rapid Effects of Rosiglitazone Treatment on Endothelial Function and Inflammatory Biomarkers Arterioscler. Thromb. Vasc. Biol., September 1, 2005; 25(9): 1804 - 1809. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Verma and P. A. Marsden Nitric Oxide-Eluting Polyurethanes -- Vascular Grafts of the Future? N. Engl. J. Med., August 18, 2005; 353(7): 730 - 731. [Full Text] [PDF]
|
|
|
|
|
|
H. Zheng, R. Cable, B. Spencer, N. Votto, and S. D. Katz Iron Stores and Vascular Function in Voluntary Blood Donors Arterioscler. Thromb. Vasc. Biol., August 1, 2005; 25(8): 1577 - 1583. [Abstract] [Full Text] [PDF]
|
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|
|
 |
|
 I. Tarkun, B. Cetinarslan, E. Turemen, T. Sahin, Z. Canturk, and B. Komsuoglu Effect of rosiglitazone on insulin resistance, C-reactive protein and endothelial function in non-obese young women with polycystic ovary syndrome Eur. J. Endocrinol., July 1, 2005; 153(1): 115 - 121. [Abstract] [Full Text] [PDF]
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H. Ding, A. G. Howarth, M. Pannirselvam, T. J. Anderson, D. L. Severson, W. B. Wiehler, C. R. Triggle, and B. S. Tuana Endothelial dysfunction in Type 2 diabetes correlates with deregulated expression of the tail-anchored membrane protein SLMAP Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H206 - H211. [Abstract] [Full Text] [PDF]
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S. C. Newcomer, U. A. Leuenberger, C. S. Hogeman, and D. N. Proctor Heterogeneous vasodilator responses of human limbs: influence of age and habitual endurance training Am J Physiol Heart Circ Physiol, July 1, 2005; 289(1): H308 - H315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Lerman and A. M. Zeiher Endothelial Function: Cardiac Events Circulation, January 25, 2005; 111(3): 363 - 368. [Full Text] [PDF]
|
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|
|
|
|
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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|
 M-H Gaugler A unifying system: does the vascular endothelium have a role to play in multi-organ failure following radiation exposure? Br. J. Radiol., January 1, 2005; Supplement 27(1): 100 - 105. [Abstract] [Full Text] [PDF]
|
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I. Tarkun, B. C. Arslan, Z. Canturk, E. Turemen, T. Sahin, and C. Duman Endothelial Dysfunction in Young Women with Polycystic Ovary Syndrome: Relationship with Insulin Resistance and Low-Grade Chronic Inflammation J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5592 - 5596. [Abstract] [Full Text] [PDF]
|
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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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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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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. [Full Text] [PDF]
|
|
|
|
|
|
J. T. Willerson and D. J. Kereiakes Endothelial Dysfunction Circulation, October 28, 2003; 108(17): 2060 - 2061. [Full Text] [PDF]
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