Skip to main content
SpringerLink
Log in

Endothelial Dysfunction: Its Clinical Value and Methods of Assessment

  • Cardiovascular Disease and Stroke (P Perrone-Filardi and S. Agewall, Section Editors)
  • Published:
Current Atherosclerosis Reports Aims and scope Submit manuscript

Abstract

Endothelial dysfunction (ED) is a systemic disorder characterized by reduced production of nitric oxide. This pathologic condition, which impairs vascular homeostasis, leads to the loss of protective properties of endothelial cells and is related to the pathogenesis of cardiovascular diseases. ED may affect every vascular bed, accounting for several clinical implications, particularly when the coronary bed is affected. Although the reliability of ED as a cardiovascular disease surrogate is still debated, many methods for its assessment have been proposed. In this review, we underline the clinical value of ED in the cardiovascular field and summarize the principal methods currently available for its assessment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci U S A. 1987;84(24):9265–9.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Drexler H. Nitric oxide and coronary endothelial dysfunction in humans. Cardiovasc Res. 1999;43(3):572–9.

    Article  CAS  PubMed  Google Scholar 

  3. Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A. 1991;88(11):4651–5.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Michelson AD, Benoit SE, Furman MI, Breckwoldt WL, Rohrer MJ, Barnard MR, et al. Effects of nitric oxide/EDRF on platelet surface glycoproteins. Am J Physiol. 1996;270(5 Pt 2):H1640–8.

    CAS  PubMed  Google Scholar 

  5. Stamler JS, Lamas S, Fang FC. Nitrosylation. The prototypic redox-based signaling mechanism. Cell. 2001;106(6):675–8.

    Article  CAS  PubMed  Google Scholar 

  6. Radomski MW, Palmer RM, Moncada S. Comparative pharmacology of endothelium-derived relaxing factor, nitric oxide and prostacyclin in platelets. Br J Pharmacol. 1987;92(1):181–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288(5789):373–6.

    Article  CAS  PubMed  Google Scholar 

  8. Heistad DD, Armstrong ML, Marcus ML, Piegors DJ, Mark AL. Augmented responses to vasoconstrictor stimuli in hypercholesterolemic and atherosclerotic monkeys. Circ Res. 1984;54(6):711–8.

    Article  CAS  PubMed  Google Scholar 

  9. Barbato E, Piscione F, Bartunek J, Galasso G, Cirillo P, De Luca G, et al. Role of beta2 adrenergic receptors in human atherosclerotic coronary arteries. Circulation. 2005;111(3):288–94.

    Article  CAS  PubMed  Google Scholar 

  10. Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109(23 Suppl 1):III27–32.

    PubMed  Google Scholar 

  11. Zeiher AM, Drexler H, Wollschläger H, Just H. Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation. 1991;83(2):391–401.

    Article  CAS  PubMed  Google Scholar 

  12. Gargiulo P, Marciano C, Savarese G, D'Amore C, Paolillo S, Esposito G, et al. Endothelial dysfunction in type 2 diabetic patients with normal coronary arteries: a digital reactive hyperemia study. Int J Cardiol. 2013;165(1):67–71. This study demonstrated that diabetes could impair coronary endothelial dysfunction before atherosclerosis development and progression. These results have been obtained trough the EndoPAT method.

    Article  PubMed  Google Scholar 

  13. Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med. 2007;356(8):830–40.

    Article  CAS  PubMed  Google Scholar 

  14. Ong P, Athanasiadis A, Borgulya G, Mahrholdt H, Kaski JC, Sechtem U. High prevalence of a pathological response to acetylcholine testing in patients with stable angina pectoris and unobstructed coronary arteries. The ACOVA Study (Abnormal COronary VAsomotion in patients with stable angina and unobstructed coronary arteries). J Am Coll Cardiol. 2012;59:655–62.

    Article  CAS  PubMed  Google Scholar 

  15. Lamendola P, Lanza GA, Spinelli A, Sgueglia GA, Di Monaco A, Barone L, et al. Long-term prognosis of patients with cardiac syndrome X. Int J Cardiol. 2010;140(2):197–9.

    Article  PubMed  Google Scholar 

  16. Crea F, Camici PG, Bairey Merz CN. Coronary microvascular dysfunction: an update. Eur Heart J. 2013 Dec 23. This review widely considers all types of endothelial dysfunction and its underlying mechanisms.

  17. Lerman A, Zeiher AM. Endothelial function: cardiac events. Circulation. 2005;111(3):363–8.

    Article  PubMed  Google Scholar 

  18. Galasso G, Schiekofer S, D'Anna C, Gioia GD, Piccolo R, Niglio T, et al. No-reflow phenomenon: pathophysiology, diagnosis, prevention, and treatment. A review of the current literature and future perspectives. Angiology. 2014;65(3):180–9.

    Article  PubMed  Google Scholar 

  19. Muller O, Hamilos M, Bartunek J, Ulrichts H, Mangiacapra F, Holz JB, et al. Relation of endothelial function to residual platelet reactivity after clopidogrel in patients with stable angina pectoris undergoing percutaneous coronary intervention. Am J Cardiol. 2010;105(3):333–8.

    Article  CAS  PubMed  Google Scholar 

  20. 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.

    Article  PubMed  Google Scholar 

  21. Hamilos M, Sarma J, Ostojic M, Cuisset T, Sarno G, Melikian N, et al. Interference of drug-eluting stents with endothelium-dependent coronary vasomotion: evidence for device-specific responses. Circ Cardiovasc Interv. 2008;1(3):193–200.

    Article  PubMed  Google Scholar 

  22. Galasso G, De Rosa R, Ciccarelli M, Sorriento D, Del Giudice C, Strisciuglio T, et al. β2-Adrenergic receptor stimulation improves endothelial progenitor cell-mediated ischemic neoangiogenesis. Circ Res. 2013;112(7):1026–34. This article provides new insights of the biology and functions of EPCs.

    Article  CAS  PubMed  Google Scholar 

  23. Wilkinson IB, Webb DJ. Venous occlusion plethysmography in cardiovascular research: methodology and clinical applications. Br J Clin Pharmacol. 2001;52(6):631–46.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Schindler TH, Schelbert HR, Quercioli A, Dilsizian V. Cardiac PET imaging for the detection and monitoring of coronary artery disease and microvascular health. J Am Coll Cardiol. 2010;3:623–40.

    Article  Google Scholar 

  25. Hamada S, Nishiue T, Nakamura S, Sugiura T, Kamihata H, Miyoshi H, et al. TIMI frame count immediately after primary coronary angioplasty as a predictor of functional recovery in patients with TIMI 3 reperfused acute myocardial infarction. J Am Coll Cardiol. 2001;38(3):666–71.

    Article  CAS  PubMed  Google Scholar 

  26. Henriques JP, Zijlstra F, van’t Hof AW, de Boer MJ, Dambrink JH, Gosselink M, et al. Angiographic assessment of reperfusion in acute myocardial infarction by myocardial blush grade. Circulation. 2003;107(16):2115–9.

    Article  PubMed  Google Scholar 

  27. Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Cahrbonneam F, Creager MA, et al. International Brachial Artery Reactivity Task Force. 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.

    Article  PubMed  Google Scholar 

  28. Pellegrino T, Storto G, Filardi PP, Sorrentino AR, Silvestro A, Petretta M, et al. Relationship between brachial artery flow-mediated dilation and coronary flow reserve in patients with peripheral artery disease. J Nucl Med. 2005;46(12):1997–2002.

    PubMed  Google Scholar 

  29. Brevetti G, Silvestro A, Schiano V, Chiariello M. Endothelial dysfunction and cardiovascular risk prediction in peripheral arterial disease: additive value of flow-mediated dilation to ankle-brachial pressure index. Circulation. 2003;108(17):2093–8.

    Article  PubMed  Google Scholar 

  30. Perrone-Filardi P, Cuocolo A, Brevetti G, Silvestro A, Storto G, Dellegrottaglie S, et al. Relation of brachial artery flow-mediated vasodilation to significant coronary artery disease in patients with peripheral arterial disease. Am J Cardiol. 2005;96(9):1337–41.

    Article  PubMed  Google Scholar 

  31. Hashimoto M, Akishita M, Eto M, Ishikawa M, Kozaki K, Toba K, et al. Modulation of endothelium-dependent flow-mediated dilatation of the brachial artery by sex and menstrual cycle. Circulation. 1995;92(12):3431–5.

    Article  CAS  PubMed  Google Scholar 

  32. 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(4):363–8.

    Article  PubMed  Google Scholar 

  33. Hijmering ML, Stroes ES, Olijhoek J, Hutten BA, Blankestijn PJ, Rabelink TJ. Sympathetic activation markedly reduces endothelium-dependent, flow-mediated vasodilation. J Am Coll Cardiol. 2002;39(4):683–8.

    Article  PubMed  Google Scholar 

  34. McVeigh GE, Bratteli CW, Morgan DJ, et al. Age-related abnormalities in arterial compliance identified by pressure pulse contour analysis. Hypertension. 1999;33:1392–8.

    Article  CAS  PubMed  Google Scholar 

  35. McVeigh GE, Brennan G, Hayes R, Cohn J, Finklestein S, Johnston D. Vascular abnormalities in non-insulin dependent diabetes mellitus identified by arterial waveform analysis. Am J Med. 1993;95:424–30.

    Article  CAS  PubMed  Google Scholar 

  36. Celermajer DS. Reliable endothelial function testing: at our fingertips? Circulation. 2008;117(19):2428–30.

    Article  PubMed  Google Scholar 

  37. 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.

    Article  CAS  PubMed  Google Scholar 

  38. 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.

    Article  PubMed Central  PubMed  Google Scholar 

  39. Bonetti PO, Pumper GM, Higano ST, Holmes Jr DR, Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol. 2004;44(11):2137–41.

    Article  PubMed  Google Scholar 

  40. Rubinshtein R, Kuvin JT, Soffler M, Lennon RJ, Lavi S, Nelson RE, et al. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J. 2010;31(9):1142–8.

    Article  PubMed  Google Scholar 

  41. Moerland M, Kales AJ, Schrier L, van Dongen MG, Bradnock D, Burggraaf J. Evaluation of the EndoPAT as a Tool to Assess Endothelial Function. Int J Vasc Med. 2012;2012:904141.

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Noble MI, Drake-Holland AJ, Vink H. Hypothesis: arterial glycocalyx dysfunction is the first step in the atherothrombotic process. QJM. 2008;101(7):513–8.

    Article  CAS  PubMed  Google Scholar 

  43. Constantinescu AA, Vink H, Spaan JA. Endothelial cell glycocalyx modulates immobilization of leukocytes at the endothelial surface. Arterioscler Thromb Vasc Biol. 2003;23:1541–7.

    Article  CAS  PubMed  Google Scholar 

  44. Vink H, Constantinescu AA, Spaan JA. Oxidized lipoproteins degrade the endothelial surface layer. Circulation. 2000;101:1500–5.

    Article  CAS  PubMed  Google Scholar 

  45. Koo A, Dewey Jr CF, García-Cardeña G. Hemodynamic shear stress characteristic of atherosclerosis-resistant regions promotes glycocalyx formation in cultured endothelial cells. Am J Physiol Cell Physiol. 2013;304(2):C137–46.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Puri R, Leong DP, Nicholls SJ, Liew GY, Nelson AJ, Carbone A, et al. Coronary artery wall shear stress is associated with endothelial dysfunction and expansive arterial remodelling in patients with coronary artery disease. EuroIntervention. 2014 Jan 15.

  47. Nieuwdorp M, van Haeften TW, Gouverneur MC, Mooij HL, van Lieshout MH, Levi M, et al. Loss of endothelial glycocalyx during acute hyperglycemia coincides with endothelial dysfunction and coagulation activation in vivo. Diabetes. 2006;55(2):480–6.

    Article  CAS  PubMed  Google Scholar 

  48. Bulut D, Maier K, Bulut-Streich N, Börgel J, Hanefeld C, Mügge A. Circulating endothelial microparticles correlate inversely with endothelial function in patients with ischemic left ventricular dysfunction. J Card Fail. 2008;14(4):336–40.

    Article  CAS  PubMed  Google Scholar 

  49. Bernal-Mizrachi L, Jy W, Jimenez JJ, Pastor J, Mauro LM, Horstman LL, et al. High levels of circulating endothelial microparticles in patients with acute coronary syndromes. Am Heart J. 2003;145(6):962–70.

    Article  PubMed  Google Scholar 

  50. Feng B, Chen Y, Luo Y, Chen M, Li X, Ni Y. Circulating level of microparticles and their correlation with arterial elasticity and endothelium-dependent dilation in patients with type 2 diabetes mellitus. Atherosclerosis. 2010;208(1):264–9.

    Article  CAS  PubMed  Google Scholar 

  51. Bulut D, Tüns H, Mügge A. CD31+/Annexin V + microparticles in healthy offsprings of patients with coronary artery disease. Eur J Clin Invest. 2009;39(1):17–22.

    Article  CAS  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

Teresa Strisciuglio, Stefania De Luca, Ernesto Capuano, Rossella Luciano, Tullio Niglio, Bruno Trimarco, and Gennaro Galasso declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Department of Advanced Biomedical Sciences, University of Naples Federico II, Via S. Pansini 5, Naples, Italy

    Teresa Strisciuglio, Stefania De Luca, Ernesto Capuano, Rossella Luciano, Tullio Niglio, Bruno Trimarco & Gennaro Galasso

Authors
  1. Teresa Strisciuglio
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Stefania De Luca
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ernesto Capuano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rossella Luciano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tullio Niglio
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bruno Trimarco
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gennaro Galasso
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gennaro Galasso.

Additional information

This article is part of the Topical Collection on Cardiovascular Disease and Stroke

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Strisciuglio, T., De Luca, S., Capuano, E. et al. Endothelial Dysfunction: Its Clinical Value and Methods of Assessment. Curr Atheroscler Rep 16, 417 (2014). https://doi.org/10.1007/s11883-014-0417-1

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11883-014-0417-1

Keywords

Search

Navigation