Abstract
Endothelium plays a primary role in the control of vascular function and structure by protective properties of nitric oxide, which have stimulated the development of methods to assess of endothelial function. Flow-mediated dilation is the most widely used method to test endothelial function since it is non-invasive, and measures by ultrasounds the response to increased shear stress, commonly in the brachial artery. This review focuses on available evidence on FMD, which has been tested for the association with risk factors, target organ damage and the predictive value for future cardiovascular events. FMD has been studied widely in clinical research as it enables serial evaluation, also testing the effect of lifestyle and pharmacological interventions on endothelial function at an early preclinical stage, when the disease process is most likely to be reversible. Despite these advantages, endothelial tests, including FMD, are not yet recommended by guidelines for cardiovascular prevention, for the absence of clear additional prognostic value and particularly the poorly standardized non-invasive methodology. However, recent multicenter studies suggest that accurate methodology ensures reproducible FMD measurements, which can be used in future clinical research to test whether interventions ameliorating FMD function are associated to better cardiovascular prognosis.
Similar content being viewed by others
References
Luscher TF, Barton M. Biology of the endothelium. Clin Cardiol. 1997;20(11 suppl 2):II-3–-10.
Deanfield J, Donald A, Ferri C, Giannattasio C, Halcox J, Halligan S, et al. 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(1):7–17.
Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007;115(10):1285–95.
Flammer AJ, Anderson T, Celermajer DS, Creager MA, Deanfield J, Ganz P, et al. The assessment of endothelial function: from research into clinical practice. Circulation. 2012;126(6):753–67.
Celermajer DS, Sorensen KE, Gooch VM, Spiegelhalter DJ, Miller OI, Sullivan ID, et al. Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis. Lancet. 1992;340(8828):1111–5.
Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, 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(2):257–65.
Ghiadoni L, Versari D, Magagna A, Kardasz I, Plantinga Y, Giannarelli C, et al. Ramipril dose-dependently increases nitric oxide availability in the radial artery of essential hypertension patients. J Hypertens. 2007;25(2):361–6.
Charakida M, Masi S, Luscher TF, Kastelein JJ, Deanfield JE. Assessment of atherosclerosis: the role of flow-mediated dilatation. Eur Heart J. 2010;31(23):2854–61.
Ghiadoni L, Donald AE, Cropley M, Mullen MJ, Oakley G, Taylor M, et al. Mental stress induces transient endothelial dysfunction in humans. Circulation. 2000;102(20):2473–8.
Thijssen DH, Black MA, Pyke KE, Padilla J, Atkinson G, Harris RA, et al. Assessment of flow-mediated dilation in humans: a methodological and physiological guideline. Am J Physiol Heart Circ Physiol. 2011;300(1):H2–12.
Anderson TJ, Charbonneau F, Title LM, Buithieu J, Rose MS, Conradson H, et al. Microvascular function predicts cardiovascular events in primary prevention: long-term results from the Firefighters and Their Endothelium (FATE) study. Circulation. 2011;123(2):163–9.
Donald AE, Halcox JP, Charakida M, Storry C, Wallace SM, Cole TJ, et al. Methodological approaches to optimize reproducibility and power in clinical studies of flow-mediated dilation. J Am Coll Cardiol. 2008;51(20):1959–64.
Gemignani V, Faita F, Ghiadoni L, Poggianti E, Demi M. A system for real-time measurement of the brachial artery diameter in B-mode ultrasound images. IEEE Trans Med Imaging. 2007;26(3):393–404.
Gemignani V, Bianchini E, Faita F, Giannarelli C, Plantinga Y, Ghiadoni L, et al. Ultrasound measurement of the brachial artery flow-mediated dilation without ECG gating. Ultrasound Med Biol. 2008;34(3):385–91.
Ghiadoni L, Faita F, Salvetti M, Cordiano C, Biggi A, Puato M, et al. Assessment of flow-mediated dilation reproducibility: a nationwide multicenter study. J Hypertens. 2012;30(7):1399–405.
Charakida M, de Groot E, Loukogeorgakis SP, Khan T, Luscher T, Kastelein JJ, et al. Variability and reproducibility of flow-mediated dilatation in a multicentre clinical trial. Eur Heart J. 2013;34(45):3501–7.
Luscher TF, Taddei S, Kaski JC, Jukema JW, Kallend D, Munzel T, et al. Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-Vessel randomized clinical trial. Eur Heart J. 2012;33(7):857–65.
Faita F, Masi S, Loukogeorgakis S, Gemignani V, Okorie M, Bianchini E, et al. Comparison of two automatic methods for the assessment of brachial artery flow-mediated dilation. J Hypertens. 2011;29(1):85–90.
Mitchell GF, Vita JA, Larson MG, Parise H, Keyes MJ, Warner E, et al. Cross-sectional relations of peripheral microvascular function, cardiovascular disease risk factors, and aortic stiffness: the Framingham Heart Study. Circulation. 2005;112(24):3722–8 Epub 2005 Dec 5.
Atkinson G, Batterham AM. Allometric scaling of diameter change in the original flow-mediated dilation protocol. Atherosclerosis. 2013;226(2):425–7.
Cipollone F, Muiesan ML. Flow-mediated vasodilation: improving specificity for endothelial function evaluation. J Hypertens. 2013;31(2):253–5.
Gori T, Dragoni S, Lisi M, Di Stolfo G, Sonnati S, Fineschi M, et al. Conduit artery constriction mediated by low flow a novel noninvasive method for the assessment of vascular function. J Am Coll Cardiol. 2008;51(20):1953–8.
Ghiadoni L, Huang Y, Magagna A, Buralli S, Taddei S, Salvetti A. Effect of acute blood pressure reduction on endothelial function in the brachial artery of patients with essential hypertension. J Hypertens. 2001;19(3 Pt 2):547–51.
Kuvin JT, Patel AR, Sliney KA, Pandian NG, Sheffy J, Schnall RP, et al. Assessment of peripheral vascular endothelial function with finger arterial pulse wave amplitude. Am Heart J. 2003;146(1):168–74.
Nohria A, Gerhard-Herman M, Creager MA, Hurley S, Mitra D, Ganz P. Role of nitric oxide in the regulation of digital pulse volume amplitude in humans. J Appl Physiol. 2006;101(2):545–8.
Hamburg NM, Keyes MJ, Larson MG, Vasan RS, Schnabel R, Pryde MM, et al. Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation. 2008;117(19):2467–74.
Schnabel RB, Schulz A, Wild PS, Sinning CR, Wilde S, Eleftheriadis M, et al. Noninvasive vascular function measurement in the community: cross-sectional relations and comparison of methods. Circ Cardiovasc Imaging. 2011;4(4):371–80.
Hashimoto M, Eto M, Akishita M, Kozaki K, Ako J, Iijima K, et al. Correlation between flow-mediated vasodilatation of the brachial artery and intima-media thickness in the carotid artery in men. Arterioscler Thromb Vasc Biol. 1999;19(11):2795–800.
Juonala M, Viikari JS, Laitinen T, Marniemi J, Helenius H, Ronnemaa T, et al. Interrelations between brachial endothelial function and carotid intima-media thickness in young adults: the cardiovascular risk in young Finns study. Circulation. 2004;110(18):2918–23.
Yan RT, Anderson TJ, Charbonneau F, Title L, Verma S, Lonn E. Relationship between carotid artery intima-media thickness and brachial artery flow-mediated dilation in middle-aged healthy men. J Am Coll Cardiol. 2005;45(12):1980–6.
Halcox JP, Donald AE, Ellins E, Witte DR, Shipley MJ, Brunner EJ, et al. Endothelial function predicts progression of carotid intima-media thickness. Circulation. 2009;119(7):1005–12.
Rossi R, Nuzzo A, Olaru AI, Origliani G, Modena MG. Endothelial function affects early carotid atherosclerosis progression in hypertensive postmenopausal women. J Hypertens. 2011;29(6):1136–44.
Ercan E, Tengiz I, Ercan HE, Nalbantgil I. Left ventricular hypertrophy and endothelial functions in patients with essential hypertension. Coron Artery Dis. 2003;14(8):541–4.
Muiesan ML, Salvetti M, Monteduro C, Corbellini C, Guelfi D, Rizzoni D, et al. Flow-mediated dilatation of the brachial artery and left ventricular geometry in hypertensive patients. J Hypertens. 2001;19(3 Pt 2):641–7.
Ochodnicky P, Henning RH, van Dokkum RP, de Zeeuw D. Microalbuminuria and endothelial dysfunction: emerging targets for primary prevention of end-organ damage. J Cardiovasc Pharmacol. 2006;47(Suppl 2):S151–62 (discussion S72–6).
Diercks GF, Stroes ES, van Boven AJ, van Roon AM, Hillege HL, de Jong PE, et al. Urinary albumin excretion is related to cardiovascular risk indicators, not to flow-mediated vasodilation, in apparently healthy subjects. Atherosclerosis. 2002;163(1):121–6.
Ghiadoni L, Cupisti A, Huang Y, Mattei P, Cardinal H, Favilla S, et al. Endothelial dysfunction and oxidative stress in chronic renal failure. J Nephrol. 2004;17(4):512–9.
Patti G, Pasceri V, Melfi R, Goffredo C, Chello M, D’Ambrosio A, et al. Impaired flow-mediated dilation and risk of restenosis in patients undergoing coronary stent implantation. Circulation. 2005;111(1):70–5.
Gokce N, Keaney JF Jr, Hunter LM, Watkins MT, Menzoian JO, Vita JA. Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: a prospective study. Circulation. 2002;105(13):1567–72.
Neunteufl T, Heher S, Katzenschlager R, Wolfl G, Kostner K, Maurer G, et al. Late prognostic value of flow-mediated dilation in the brachial artery of patients with chest pain. Am J Cardiol. 2000;86(2):207–10.
Yeboah J, Crouse JR, Hsu FC, Burke GL, Herrington DM. Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health Study. Circulation. 2007;115(18):2390–7.
Yeboah J, Folsom AR, Burke GL, Johnson C, Polak JF, Post W, et al. Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: the multi-ethnic study of atherosclerosis. Circulation. 2009;120(6):502–9.
Rossi R, Nuzzo A, Origliani G, Modena MG. Prognostic role of flow-mediated dilation and cardiac risk factors in post-menopausal women. J Am Coll Cardiol. 2008;51(10):997–1002.
Muiesan ML, Salvetti M, Paini A, Monteduro C, Galbassini G, Poisa P, et al. Prognostic role of flow-mediated dilatation of the brachial artery in hypertensive patients. J Hypertens. 2008;26(8):1612–8.
Inaba Y, Chen JA, Bergmann SR. Prediction of future cardiovascular outcomes by flow-mediated vasodilatation of brachial artery: a meta-analysis. Int J Cardiovasc Imaging. 2010;26(6):631–40.
Modena MG, Bonetti L, Coppi F, Bursi F, Rossi R. Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women. J Am Coll Cardiol. 2002;40(3):505–10.
Kitta Y, Obata JE, Nakamura T, Hirano M, Kodama Y, Fujioka D, et al. Persistent impairment of endothelial vasomotor function has a negative impact on outcome in patients with coronary artery disease. J Am Coll Cardiol. 2009;53(4):323–30.
Ghiadoni L, Taddei S, Virdis A. Hypertension and endothelial dysfunction: therapeutic approach. Curr Vasc Pharmacol. 2012;10(1):42–60.
Ghiadoni L, Magagna A, Versari D, Kardasz I, Huang Y, Taddei S, et al. Different effect of antihypertensive drugs on conduit artery endothelial function. Hypertension. 2003;41(6):1281–6.
Tzemos N, Lim PO, MacDonald TM. Valsartan improves endothelial dysfunction in hypertension: a randomized, double-blind study. Cardiovasc Ther. 2009 Fall;27(3):151–8.
Tzemos N, Lim PO, MacDonald TM. Nebivolol reverses endothelial dysfunction in essential hypertension: a randomized, double-blind, crossover study. Circulation. 2001;104(5):511–4.
Plantinga Y, Ghiadoni L, Magagna A, Giannarelli C, Franzoni F, Taddei S, et al. Supplementation with vitamins C and e improves arterial stiffness and endothelial function in essential hypertensive patients. Am J Hypertens. 2007;20(4):392–7.
Grassi D, Necozione S, Lippi C, Croce G, Valeri L, Pasqualetti P, et al. Cocoa reduces blood pressure and insulin resistance and improves endothelium-dependent vasodilation in hypertensives. Hypertension. 2005;46(2):398–405.
Grassi D, Mulder TP, Draijer R, Desideri G, Molhuizen HO, Ferri C. Black tea consumption dose-dependently improves flow-mediated dilation in healthy males. J Hypertens. 2009;27(4):774–81.
DeSouza CA, Shapiro LF, Clevenger CM, Dinenno FA, Monahan KD, Tanaka H, et al. Regular aerobic exercise prevents and restores age-related declines in endothelium-dependent vasodilation in healthy men. Circulation. 2000;102(12):1351–7.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ghiadoni, L., Salvetti, M., Muiesan, M.L. et al. Evaluation of Endothelial Function by Flow Mediated Dilation: Methodological Issues and Clinical Importance. High Blood Press Cardiovasc Prev 22, 17–22 (2015). https://doi.org/10.1007/s40292-014-0047-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40292-014-0047-2