Developed in 1992, the flow-mediated dilation test is now the most commonly used noninvasive assessment of vascular endothelial function in humans. Since its inception, scientists have refined their understanding of the physiology, analysis, and interpretation of this measurement. Recently, a significant growth of knowledge has added to our understanding and implementation of this clinically relevant research methodology. Therefore, this tutorial provides timely insight into recent advances and practical information related to the ultrasonic assessment of vascular endothelial function in humans.
|Publication status||Published - 29 Mar 2010|
Bibliographical noteReference text: 1. Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, Lloyd JK, Deanfield JE. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340:1111–1115.
2. Uehata A, Lieberman EH, Gerhard MD, Anderson TJ, Ganz P, Polak JF, Creager MA, Yeung AC. Noninvasive assessment of endotheliumdependent flow-mediated dilation of the brachial artery. Vasc Med. 1997; 2:87–92.
3. Anderson TJ, Uehata A, Gerhard MD. Close relationship of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol. 1995;26:1235–1241.
4. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gehard-Herman M, Herrington D, Vallance P, Vita J, Vogel R. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery.
J Am Coll Cardiol. 2002;39:257–265.
5. Bots ML, Westerink J, Rabelink TJ, de Koning EJ. Assessment of flow-mediated vasodilatation (FMD) of the brachial artery: effects of technical aspects of the FMD measurement on the FMD response. Eur Heart J. 2005;26:363–368.
6. Deanfield J, Donald A, Ferri C, Giannattasio C, Halcox J, Halligan S, Lerman A, Mancia G, Oliver JJ, Pessina AC, Rizzoni D, Rossi GP, Salvetti A, Schiffrin EL, Taddei S, Webb DJ. Endothelial function and dysfunction: part I–methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension. J Hypertens. 2005;23:7–17.
7. Pyke KE, Tschakovsky ME. The relationship between shear stress and flow-mediated dilatation: implications for the assessment of endothelial function. J Physiol. 2005;568:357–369.
8. Celermajer D. Endothelial dysfunction: does it matter? Is it reversible? J Am Coll Cardiol. 1997;30:325–333.
9. Rubanyi GM. The role of endothelium in cardiovascular homeostasis and disease. J Cardiovasc Pharmacol. 1993;22:S1–S14.
10. Vane JR, Anggard EE, Botting RM. Regulatory functions of the vascular enodothelium. N Engl J Med. 1990;323:27–36.
11. Singel DJ, Stamler JS. Chemical physiology of blood flow regulation by red blood cells: the role of nitric oxide and S-nitrosohemoglobin. Annu Rev Physiol. 2005;67:99 –145.
12. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288: 373–376.
13. Green D. Point: flow-mediated dilation does reflect nitric oxide-mediated endothelial function. J Appl Physiol. 2005;99:1233–1234; discussion 1237–1238.
14. Verma S, Buchanan MR, Anderson TJ. Endothelial function testing as a biomarker of vascular disease. Circulation. 2003;108:2054 –2059.
15. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340:115–126.
16. Niebauer J, Cooke JP. Cardiovascular effects of exercise: role of endothelial shear stress. J Am Coll Cardiol. 1996;28:1652–1660.
17. Sessa WC. eNOS at a glance. J Cell Sci. 2004;117:2427–2429.
18. Shimokawa H, Yasutake H, Fujii K, Owada MK, Nakaike R, Fukumoto Y, Takayanagi T, Nagao T, Egashira K, Fujishima M, Takeshita A. The
importance of the hyperpolarizing mechanism increases as the vessel size decreases in endothelium-dependent relaxations in rat mesenteric circulation. J Cardiovasc Pharmacol. 1996;28:703–711.
19. Doshi SN, Naka KK, Payne N, Jones CJ, Ashton M, Lewis MJ, Goodfellow J. Flow-mediated dilatation following wrist and upper arm occlusion in humans: the contribution of nitric oxide. Clin Sci (Lond). 2001;101:629–635.
20. Mullen MJ, Kharbanda RK, Cross J, Donald AE, Taylor M, Vallance P, Deanfield JE, MacAllister RJ. Heterogenous nature of flow-mediated dilatation in human conduit arteries in vivo: relevance to endothelial dysfunction in hypercholesterolemia. Circ Res. 2001;88:145–151.
21. Tschakovsky ME, Pyke KE. Counterpoint: flow-mediated dilation does not reflect nitric oxide-mediated endothelial function. J Appl Physiol. 2005;99:1235–1237.
22. Pyke K, Green DJ, Weisbrod C, Best M, Dembo L, O’Driscoll G, Tschakovsky M. Nitric oxide is not obligatory for radial artery flowmediated dilation following release of 5 or 10 min distal occlusion. Am J Physiol. 2010;298:H119–H126.
23. Mitchell GF, Parise H, Vita JA, Larson MG, Warner E, Keaney JF Jr, Keyes MJ, Levy D, Vasan RS, Benjamin EJ. Local shear stress and brachial artery flow-mediated dilation: the Framingham Heart Study. Hypertension. 2004;44:134 –139.
24. Harris RA, Padilla J, Rink LD, Wallace JP. Variability of flow-mediated dilation measurements with repetitive reactive hyperemia. Vasc Med. 2006;11:1– 6.
25. Harris RA, Padilla J, Hanlon KP, Rink LD, Wallace JP. The flowmediated dilation response to acute exercise in overweight active and inactive men. Obesity (Silver Spring). 2008;16:578 –584.
26. Wright SA, O’Prey FM, Rea DJ, Plumb RD, Gamble AJ, Leahey WJ, Devine AB, McGivern RC, Johnston DG, Finch MB, Bell AL, McVeigh GE. Microcirculatory hemodynamics and endothelial dysfunction in systemic lupus erythematosus. Arterioscler Thromb Vasc Biol. 2006;26: 2281–2287.
27. Jogestrand T, von Arbin M, Bergqvist D, Lilja A, Lindqvist M, Matzsch T, Norrving B, Nowak J, Troeng T, Wahlgren NG. Recommendations by the Swedish Quality Board for Carotid Surgery: ultrasound good preoperative method for evaluating degree of carotid stenosis [in Swedish].
28. Logason K, Barlin T, Jonsson ML, Bostrom A, Hardemark HG, Karacagil S. The importance of Doppler angle of insonation on differentiation between 50–69% and 70–99% carotid artery stenosis. Eur J Vasc Endovasc Surg. 2001;21:311–313.
29. Rizzo RJ, Sandager G, Astleford P, Payne K, Peterson-Kennedy L, Flinn WR, Yao JS. Mesenteric flow velocity variations as a function of angle of insonation. J Vasc Surg. 1990;11:688–694.
30. Radegran G, Saltin B. Nitric oxide in the regulation of vasomotor tone in human skeletal muscle. Am J Physiol. 1999;276:H1951–H1960.
31. Harris RA, Nishiyama SK, Wray DW, Tedjasaputra V, Bailey DM, Richardson RS. The effect of oral antioxidants on brachial artery flowmediated dilation following 5 and 10 min of ischemia. Eur J Appl Physiol. 2009;107:445– 453.
32. Wray DW, Uberoi A, Lawrenson L, Richardson RS. Evidence of preserved endothelial function and vascular plasticity with age. Am J Physiol. 2006;290:H1271–H1277.
33. Richardson RS, Donato AJ, Uberoi A, Wray DW, Lawrenson L, Nishiyama S, Bailey DM. Exercise-induced brachial artery vasodilation: role of free radicals. Am J Physiol. 2007;292:H1516–H1522.
34. Wray DW, Uberoi A, Lawrenson L, Bailey DM, Richardson RS. Oral antioxidants and cardiovascular health in the exercise-trained and untrained elderly: a radically different outcome. Clin Sci (Lond). 2009; 116:433– 441.
35. Eskurza I, Monahan KD, Robinson JA, Seals DR. Effect of acute and chronic ascorbic acid on flow-mediated dilatation with sedentary and physically active human ageing. J Physiol. 2004;556:315–324.
36. Franzoni F, Ghiadoni L, Galetta F, Plantinga Y, Lubrano V, Huang Y, Salvetti G, Regoli F, Taddei S, Santoro G, Salvetti A. Physical activity, plasma antioxidant capacity, and endothelium-dependent vasodilation in young and older men. Am J Hypertens. 2005;18:510 –516.
37. Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C, Thomas O, Robinson J, Deanfield JE. Cigarette smoking is associated with dose- 1084 Hypertension May 2010 related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation. 1993;88:2149 –2155.
38. Kato T, Inoue T, Morooka T, Yoshimoto N, Node K. Short-term passive smoking causes endothelial dysfunction via oxidative stress in nonsmokers. Can J Physiol Pharmacol. 2006;84:523–529.
39. Strinden ST, Stellwagen RH. Inhibition of guanylate cyclases by methylxanthines and papaverine. Biochem Biophys Res Commun. 1984;123: 1194–1200.
40. Papamichael CM, Aznaouridis KA, Karatzis EN, Karatzi KN, Stamatelopoulos KS, Vamvakou G, Lekakis JP, Mavrikakis ME. Effect of coffee on endothelial function in healthy subjects: the role of caffeine. Clin Sci (Lond). 2005;109:55– 60.
41. Hayashi T, Yamada K, Esaki T, Kuzuya M, Satake S, Ishikawa T, Hidaka H, Iguchi A. Estrogen increases endothelial nitric oxide by a receptormediated system. Biochem Biophys Res Commun. 1995;214:847– 855. 42. Mendelsohn ME, Karas RH. The protective effects of estrogen on the
cardiovascular system. N Engl J Med. 1999;340:1801–1811.
43. Hashimoto M, Akishita M, Eto M, Ishikawa M, Kozaki K, Toba K, Sagara Y, Taketani Y, Orimo H, Ouchi Y. Modulation of endotheliumdependent flow-mediated dilatation of the brachial artery by sex and menstrual cycle. Circulation. 1995;92:3431–3435.
44. Clarkson P, Montgomery HE, Mullen MJ, Donald AE, Powe AJ, Bull T, Jubb M, World M, Deanfield JE. Exercise training enhances endothelial function in young men. J Am Coll Cardiol. 1999;33:1379 –1385.
45. Harvey PJ, Morris BL, Kubo T, Picton PE, Su WS, Notarius CF, Floras JS. Hemodynamic after-effects of acute dynamic exercise in sedentary normotensive postmenopausal women. Hypertension. 2005;23:285–292.
46. Padilla J, Harris RA, Fly AD, Rink LD, Wallace JP. The effect of acute exercise on endothelial function following a high-fat meal. Eur J Appl Physiol. 2006;98:256 –262.
47. Vogel RA, Corretti MC, Plotnick GD. Effect of a single high-fat meal on enothelial function in healthy subjects. Am Heart Hosp J. 1997;79: 350–354.
48. Ceriello A, Cavarape A, Martinelli L, Da Ros R, Marra G, Quagliaro L, Piconi L, Assaloni R, Motz E. The post-prandial state in type 2 diabetes and endothelial dysfunction: effects of insulin aspart. Diabet Med. 2004; 21:171–175.
49. Jarvisalo MJ, Jartti L, Marniemi J, Ronnemaa T, Viikari JS, Lehtimaki T, Raitakari OT. Determinants of short-term variation in arterial flowmediated dilatation in healthy young men. Clin Sci (Lond). 2006;110: 475–482.
50. Thijssen DH, van Bemmel MM, Bullens LM, Dawson EA, Hopkins ND, Tinken TM, Black MA, Hopman MT, Cable NT, Green DJ. The impact of baseline diameter on flow-mediated dilation differs in young and older humans. Am J Physiol. 2008;295:H1594–H1598.
51. Corretti MC, Plotnick GD, Vogel RA. Technical aspects of evaluating brachial artery vasodilatation using high-frequency ultrasound. Am J Physiol. 1995;268:H1397–H1404.
52. Thijssen DH, Dawson EA, Black MA, Hopman MT, Cable NT, Green DJ. Heterogeneity in conduit artery function in humans: impact of arterial size. Am J Physiol. 2008;295:H1927–H1934.
53. Pyke KE, Tschakovsky ME. Peak vs. total reactive hyperemia: which determines the magnitude of flow-mediated dilation? J Appl Physiol. 2007;102:1510 –1519.
54. Gill RW. Measurement of blood flow by ultrasound: accuracy and sources of error. Ultrasound Med Biol. 1985;11:625– 641.
55. Betik AC, Luckham VB, Hughson RL. Flow-mediated dilation in human brachial artery after different circulatory occlusion conditions. Am J Physiol. 2004;286:H442–H448.
56. Berry KL, Skyrme-Jones RA, Meredith IT. Occlusion cuff position is an important determinant of the time course and magnitude of human brachial artery flow-mediated dilation. Clin Sci (Lond). 2000;99: 261–267.
57. Kooijman M, Thijssen DHJ, de Groot PCE, Bleeker MWP, van Kuppevelt HJM, Green DJ, Rongen GA, Smits P, Hopman MTE. Flowmediated dilatation in the superficial femoral artery is nitric oxide mediated in humans. J Physiol. 2008;586:1137–1145.
58. Black MA, Cable NT, Thijssen DH, Green DJ. Importance of measuring the time course of flow-mediated dilatation in humans. Hypertension. 2008;51:203–210.
59. Mancini GB, Yeoh E, Abbott D, Chan S. Validation of an automated method for assessing brachial artery endothelial dysfunction. Can J Cardiol. 2002;18:259 –262.
60. Eskurza I, Monahan KD, Robinson JA, Seals DR. Ascorbic acid does not affect large elastic artery compliance or central blood pressure in young and older men. Am J Physiol. 2004;286:H1528–H1534.
61. Eskurza I, Myerburgh LA, Kahn ZD, Seals DR. Tetrahydrobiopterin augments endothelium-dependent dilatation in sedentary but not in habitually exercising older adults. J Physiol. 2005;568:1057–1065.
62. Padilla J, Johnson BD, Newcomer SC, Wilhite DP, Mickleborough TD, Fly AD, Mather KJ, Wallace JP. Normalization of flow-mediated dilationto shear stress area under the curve eliminates the impact of variable hyperemic stimulus. Cardiovasc Ultrasound. 2008;6:44.
63. Nishiyama SK, Wray DW, Berkstresser K, Ramaswamy M, Richardson RS. Limb-specific differences in flow-mediated dilation: the role of shear rate. J Appl Physiol. 2007;103:843– 851.
64. Thijssen DH, Bullens LM, van Bemmel MM, Dawson EA, Hopkins N, Tinken TM, Black MA, Hopman MT, Cable NT, Green DJ. Does arterial shear explain the magnitude of flow-mediated dilation?: a comparison between young and older humans. Am J Physiol. 2009;296:H57–H64.
65. Huang AL, Silver AE, Shvenke E, Schopfer DW, Jahangir E, Titas MA, Shpilman A, Menzoian JO, Watkins MT, Raffetto JD, Gibbons G, Woodson J, Shaw PM, Dhadly M, Eberhardt RT, Keaney JF Jr, Gokce N, Vita JA. Predictive value of reactive hyperemia for cardiovascular events in patients with peripheral arterial disease undergoing vascular surgery. Arterioscler Thromb Vasc Biol. 2007;27:2113–2119.
66. Harris RA, Padilla J. Proper “normalization” of flow-mediated dilation for shear. J Appl Physiol. 2007;103:1108; author reply 1109.
- endothelial function
- reactive hyperemia
- shear stress