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Endothelial Dysfunction in Early Phases of Hypertension

  • Stefano Taddei
  • Rosa Maria Bruno
  • Stefano Masi
Chapter
Part of the Updates in Hypertension and Cardiovascular Protection book series (UHCP)

Abstract

Endothelial dysfunction can be considered the first, asymptomatic step of the atherosclerotic process. It is characterised by an imbalance between substances with vasodilating, antimitogenic and anti-thrombogenic properties (first of all nitric oxide, NO) and substances with vasoconstricting, prothrombotic and proliferative characteristics (also known with the generic term endothelium-derived contracting factors, EDCFs).

Endothelial dysfunction, involving both micro- and macrocirculation of cardiac and peripheral districts, is a common trait of essentially all cardiovascular risk factors, including essential hypertension. In hypertensive patients, reactive oxygen species are the main cause of reduced NO availability. However, current evidence suggest that endothelial dysfunction is not a direct consequence of high blood pressure values. Indeed, impaired endothelium-dependent vasodilation is observed in young offspring of hypertensive subjects despite the presence of normal blood pressure values, as well as in individuals with prehypertension. In prehypertensive individuals, a reduced NO availability, as well as an increased vasoconstriction in response to endothelin and an impaired endothelial repair capacity, are present.

Keywords

Endothelium Endothelial dysfunction Nitric oxide Endothelium-derived contracting factors Prehypertension Essential hypertension 

Notes

Acknowledgments

Disclosures: ST received research grants from Novartis, Servier, Recordati, Menarini and Boehringer and is on the speaker’s bureau for Servier, Recordati, Novartis and Boehringer.

References

  1. 1.
    Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980;288:373–6.CrossRefGoogle Scholar
  2. 2.
    Bruno RM, Taddei S. Nitric Oxide. In: Mooren FC, Skinner JS, editors. Encyclopedia of exercise medicine in health and disease. Berlin Heidelberg: Springer-Verlag; 2011.Google Scholar
  3. 3.
    Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999;340:115–26.CrossRefGoogle Scholar
  4. 4.
    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.CrossRefGoogle Scholar
  5. 5.
    Ludmer PL, Selwyn AP, Shook TL, Wayne RR, Mudge GH, Alexander RW, Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med. 1986;315:1046–51.CrossRefGoogle Scholar
  6. 6.
    Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med. 2007;356:830–40.CrossRefGoogle Scholar
  7. 7.
    Gibson CM, Cannon CP, Daley WL, Dodge JT Jr, Alexander B Jr, Marble SJ, McCabe CH, Raymond L, Fortin T, Poole WK, Braunwald E. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation. 1996;93:879–88.CrossRefGoogle Scholar
  8. 8.
    Leung DY, Leung M. Non-invasive/invasive imaging: significance and assessment of coronary microvascular dysfunction. Heart. 2011;97:587–95.CrossRefGoogle Scholar
  9. 9.
    Taddei S, Virdis A, Ghiadoni L, Magagna A, Salvetti A. Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension. Circulation. 1998;97:2222–9.CrossRefGoogle Scholar
  10. 10.
    Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange D, Lieberman EH, Ganz P, Creager MA, Yeung AC, et al. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol. 1995;26:1235–41.CrossRefGoogle Scholar
  11. 11.
    Virdis A, Savoia C, Grassi G, Lembo G, Vecchione C, Seravalle G, Taddei S, Volpe M, Rosei EA, Rizzoni D. Evaluation of microvascular structure in humans: a ‘state-of-the-art’ document of the Working Group on Macrovascular and Microvascular Alterations of the Italian Society of Arterial Hypertension. J Hypertens. 2014;32:2120–9. discussion 2129CrossRefGoogle Scholar
  12. 12.
    Bruno RM, Duranti E, Ippolito C, Segnani C, Bernardini N, Di Candio G, Chiarugi M, Taddei S, Virdis A. Different impact of essential hypertension on structural and functional age-related vascular changes. Hypertension. 2017;69:71–8.CrossRefGoogle Scholar
  13. 13.
    Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr, Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol. 2004;44:2137–41.CrossRefGoogle Scholar
  14. 14.
    Takase B, Uehata A, Akima T, Nagai T, Nishioka T, Hamabe A, Satomura K, Ohsuzu F, Kurita A. Endothelium-dependent flow-mediated vasodilation in coronary and brachial arteries in suspected coronary artery disease. Am J Cardiol. 1998;82:1535–9. A7-8CrossRefGoogle Scholar
  15. 15.
    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;340:1111–5.CrossRefGoogle Scholar
  16. 16.
    Matsuzawa Y, Kwon TG, Lennon RJ, Lerman LO, Lerman A. Prognostic value of flow-mediated vasodilation in brachial artery and fingertip artery for cardiovascular events: a systematic review and meta-analysis. J Am Heart Assoc. 2015;4:e002270.CrossRefGoogle Scholar
  17. 17.
    Reriani MK, Lerman LO, Lerman A. Endothelial function as a functional expression of cardiovascular risk factors. Biomark Med. 2010;4:351–60.CrossRefGoogle Scholar
  18. 18.
    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;101:545–8.CrossRefGoogle Scholar
  19. 19.
    Bruno RM, Gori T, Ghiadoni L. Endothelial function testing and cardiovascular disease: focus on peripheral arterial tonometry. Vasc Health Risk Manag. 2014;10:577–84.Google Scholar
  20. 20.
    Brunner H, Cockcroft JR, Deanfield J, Donald A, Ferrannini E, Halcox J, Kiowski W, Luscher TF, Mancia G, Natali A, Oliver JJ, Pessina AC, Rizzoni D, Rossi GP, Salvetti A, Spieker LE, Taddei S, Webb DJ. Endothelial function and dysfunction. Part II: association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension. J Hypertens. 2005;23:233–46.CrossRefGoogle Scholar
  21. 21.
    Witte DR, Westerink J, de Koning EJ, van der Graaf Y, Grobbee DE, Bots ML. Is the association between flow-mediated dilation and cardiovascular risk limited to low-risk populations? J Am Coll Cardiol. 2005;45:1987–93.CrossRefGoogle Scholar
  22. 22.
    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;45:1980–6.CrossRefGoogle Scholar
  23. 23.
    Halcox JP, Donald AE, Ellins E, Witte DR, Shipley MJ, Brunner EJ, Marmot MG, Deanfield JE. Endothelial function predicts progression of carotid intima-media thickness. Circulation. 2009;119:1005–12.CrossRefGoogle Scholar
  24. 24.
    Rossi R, Nuzzo A, Olaru AI, Origliani G, Modena MG. Endothelial function affects early carotid atherosclerosis progression in hypertensive postmenopausal women. J Hypertens. 2011;29:1136–44.CrossRefGoogle Scholar
  25. 25.
    Koivistoinen T, Virtanen M, Hutri-Kahonen N, Lehtimaki T, Jula A, Juonala M, Moilanen L, Aatola H, Hyttinen J, Viikari JS, Raitakari OT, Kahonen M. Arterial pulse wave velocity in relation to carotid intima-media thickness, brachial flow-mediated dilation and carotid artery distensibility: The Cardiovascular Risk in Young Finns Study and the Health 2000 Survey. Atherosclerosis. 2012;220:387–93.CrossRefGoogle Scholar
  26. 26.
    Bruno RM, Penno G, Daniele G, Pucci L, Lucchesi D, Stea F, Landini L, Cartoni G, Taddei S, Ghiadoni L, Del Prato S. Type 2 diabetes mellitus worsens arterial stiffness in hypertensive patients through endothelial dysfunction. Diabetologia. 2012;56:1847–55.CrossRefGoogle Scholar
  27. 27.
    Lerman A, Zeiher AM. Endothelial function: cardiac events. Circulation. 2005;111:363–8.CrossRefGoogle Scholar
  28. 28.
    Inaba Y, Chen JA, Bergmann SR. Prediction of future cardiovascular outcomes by flow-mediated vasodilatation of brachial artery: a meta-analysis. Int J Card Imaging. 2010;26:631–40.CrossRefGoogle Scholar
  29. 29.
    Ras RT, Streppel MT, Draijer R, Zock PL. Flow-mediated dilation and cardiovascular risk prediction: a systematic review with meta-analysis. Int J Cardiol. 2013;168:344–51.CrossRefGoogle Scholar
  30. 30.
    Xu Y, Arora RC, Hiebert BM, Lerner B, Szwajcer A, McDonald K, Rigatto C, Komenda P, Sood MM, Tangri N. Non-invasive endothelial function testing and the risk of adverse outcomes: a systematic review and meta-analysis. Eur Heart J Cardiovasc Imaging. 2014;15:736–46.CrossRefGoogle Scholar
  31. 31.
    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;51:997–1002.CrossRefGoogle Scholar
  32. 32.
    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;115:2390–7.CrossRefGoogle Scholar
  33. 33.
    Shechter M, Issachar A, Marai I, Koren-Morag N, Freinark D, Shahar Y, Shechter A, Feinberg MS. Long-term association of brachial artery flow-mediated vasodilation and cardiovascular events in middle-aged subjects with no apparent heart disease. Int J Cardiol. 2009;134:52–8.CrossRefGoogle Scholar
  34. 34.
    Neunteufl T, Heher S, Katzenschlager R, Wolfl G, Kostner K, Maurer G, Weidinger F. Late prognostic value of flow-mediated dilation in the brachial artery of patients with chest pain. Am J Cardiol. 2000;86:207–10.CrossRefGoogle Scholar
  35. 35.
    Hirsch L, Shechter A, Feinberg MS, Koren-Morag N, Shechter M. The impact of early compared to late morning hours on brachial endothelial function and long-term cardiovascular events in healthy subjects with no apparent coronary heart disease. Int J Cardiol. 2011;151:342–7.CrossRefGoogle Scholar
  36. 36.
    Shimbo D, Grahame-Clarke C, Miyake Y, Rodriguez C, Sciacca R, Di Tullio M, Boden-Albala B, Sacco R, Homma S. The association between endothelial dysfunction and cardiovascular outcomes in a population-based multi-ethnic cohort. Atherosclerosis. 2007;192:197–203.CrossRefGoogle Scholar
  37. 37.
    Yeboah J, Folsom AR, Burke GL, Johnson C, Polak JF, Post W, Lima JA, Crouse JR, Herrington DM. Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: the multi-ethnic study of atherosclerosis. Circulation. 2009;120:502–9.CrossRefGoogle Scholar
  38. 38.
    Philpott AC, Lonn E, Title LM, Verma S, Buithieu J, Charbonneau F, Anderson TJ. Comparison of new measures of vascular function to flow mediated dilatation as a measure of cardiovascular risk factors. Am J Cardiol. 2009;103:1610–5.CrossRefGoogle Scholar
  39. 39.
    Anderson TJ, Charbonneau F, Title LM, Buithieu J, Rose MS, Conradson H, Hildebrand K, Fung M, Verma S, Lonn EM. Microvascular function predicts cardiovascular events in primary prevention: long-term results from the Firefighters and Their Endothelium (FATE) study. Circulation. 2011;123:163–9.CrossRefGoogle Scholar
  40. 40.
    Lind L, Berglund L, Larsson A, Sundstrom J. Endothelial function in resistance and conduit arteries and 5-year risk of cardiovascular disease. Circulation. 2011;123:1545–51.CrossRefGoogle Scholar
  41. 41.
    Rubinshtein R, Kuvin JT, Soffler M, Lennon RJ, Lavi S, Nelson RE, Pumper GM, Lerman LO, Lerman A. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J. 2010;31:1142–8.CrossRefGoogle Scholar
  42. 42.
    Graham I, Atar D, Borch-Johnsen K, Boysen G, Burell G, Cifkova R, Dallongeville J, De Backer G, Ebrahim S, Gjelsvik B, Herrmann-Lingen C, Hoes A, Humphries S, Knapton M, Perk J, Priori SG, Pyorala K, Reiner Z, Ruilope L, Sans-Menendez S, Op Reimer WS, Weissberg P, Wood D, Yarnell J, Zamorano JL, Walma E, Fitzgerald T, Cooney MT, Dudina A, Vahanian A, Camm J, De Caterina R, Dean V, Dickstein K, Funck-Brentano C, Filippatos G, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Altiner A, Bonora E, Durrington PN, Fagard R, Giampaoli S, Hemingway H, Hakansson J, Kjeldsen SE, Larsen L, Mancia G, Manolis AJ, Orth-Gomer K, Pedersen T, Rayner M, Ryden L, Sammut M, Schneiderman N, Stalenhoef AF, Tokgozoglu L, Wiklund O, Zampelas A. European guidelines on cardiovascular disease prevention in clinical practice: full text. Fourth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts). Eur J Cardiovasc Prev Rehabil. 2007;14(Suppl 2):S1–113.CrossRefGoogle Scholar
  43. 43.
    Greenland P, Alpert JS, Beller GA, Benjamin EJ, Budoff MJ, Fayad ZA, Foster E, Hlatky MA, Hodgson JM, Kushner FG, Lauer MS, Shaw LJ, Smith SC Jr, Taylor AJ, Weintraub WS, Wenger NK, Jacobs AK, Anderson JL, Albert N, Buller CE, Creager MA, Ettinger SM, Guyton RA, Halperin JL, Hochman JS, Nishimura R, Ohman EM, Page RL, Stevenson WG, Tarkington LG, Yancy CW. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2010;56:e50–103.CrossRefGoogle Scholar
  44. 44.
    Mordi I, Mordi N, Delles C, Tzemos N. Endothelial dysfunction in human essential hypertension. J Hypertens. 2016;34:1464–72.CrossRefGoogle Scholar
  45. 45.
    Taddei S, Bruno RM. Endothelial dysfunction in hypertension: achievements and open questions. J Hypertens. 2016;34:1492–3.CrossRefGoogle Scholar
  46. 46.
    Taddei S, Virdis A, Mattei P, Ghiadoni L, Sudano I, Salvetti A. Defective L-arginine-nitric oxide pathway in offspring of essential hypertensive patients. Circulation. 1996;94:1298–303.CrossRefGoogle Scholar
  47. 47.
    John S, Schmieder RE. Impaired endothelial function in arterial hypertension and hypercholesterolemia: potential mechanisms and differences. J Hypertens. 2000;18:363–74.CrossRefGoogle Scholar
  48. 48.
    Benjamin EJ, Larson MG, Keyes MJ, Mitchell GF, Vasan RS, Keaney JF Jr, Lehman BT, Fan S, Osypiuk E, Vita JA. Clinical correlates and heritability of flow-mediated dilation in the community: the Framingham Heart Study. Circulation. 2004;109:613–9.CrossRefGoogle Scholar
  49. 49.
    Ghiadoni L, Magagna A, Versari D, Kardasz I, Huang Y, Taddei S, Salvetti A. Different effect of antihypertensive drugs on conduit artery endothelial function. Hypertension. 2003;41(6):1281.CrossRefGoogle Scholar
  50. 50.
    Ried K, Sullivan TR, Fakler P, Frank OR, Stocks NP. Effect of cocoa on blood pressure. Cochrane Database Syst Rev. 2012;8:CD008893.Google Scholar
  51. 51.
    Munzel T, Gori T, Bruno RM, Taddei S. Is oxidative stress a therapeutic target in cardiovascular disease? Eur Heart J. 2010;31:2741–8.CrossRefGoogle Scholar
  52. 52.
    Taddei S, Versari D, Cipriano A, Ghiadoni L, Galetta F, Franzoni F, Magagna A, Virdis A, Salvetti A. Identification of a cytochrome P450 2C9-derived endothelium-derived hyperpolarizing factor in essential hypertensive patients. J Am Coll Cardiol. 2006;48:508–15.CrossRefGoogle Scholar
  53. 53.
    Luscher TF. Imbalance of endothelium-derived relaxing and contracting factors. A new concept in hypertension? Am J Hypertens. 1990;3:317–30.CrossRefGoogle Scholar
  54. 54.
    Taddei S, Virdis A, Ghiadoni L, Sudano I, Magagna A, Salvetti A. Role of endothelin in the control of peripheral vascular tone in human hypertension. Heart Fail Rev. 2001;6:277–85.CrossRefGoogle Scholar
  55. 55.
    Virdis A, Bacca A, Colucci R, Duranti E, Fornai M, Materazzi G, Ippolito C, Bernardini N, Blandizzi C, Bernini G, Taddei S. Endothelial dysfunction in small arteries of essential hypertensive patients: role of cyclooxygenase-2 in oxidative stress generation. Hypertension. 2013;62:337–44.CrossRefGoogle Scholar
  56. 56.
    Taddei S, Virdis A, Ghiadoni L, Salvetti A. Vascular effects of endothelin-1 in essential hypertension: relationship with cyclooxygenase-derived endothelium-dependent contracting factors and nitric oxide. J Cardiovasc Pharmacol. 2000;35:S37–40.CrossRefGoogle Scholar
  57. 57.
    Vanhoutte PM, Feletou M, Taddei S. Endothelium-dependent contractions in hypertension. Br J Pharmacol. 2005;144:449–58.CrossRefGoogle Scholar
  58. 58.
    Yang D, Feletou M, Boulanger CM, Wu HF, Levens N, Zhang JN, Vanhoutte PM. Oxygen-derived free radicals mediate endothelium-dependent contractions to acetylcholine in aortas from spontaneously hypertensive rats. Br J Pharmacol. 2002;136:104–10.CrossRefGoogle Scholar
  59. 59.
    Virdis A, Colucci R, Fornai M, Duranti E, Giannarelli C, Bernardini N, Segnani C, Ippolito C, Antonioli L, Blandizzi C, Taddei S, Salvetti A, Del Tacca M. Cyclooxygenase-1 is involved in endothelial dysfunction of mesenteric small arteries from angiotensin II-infused mice. Hypertension. 2007;49:679–86.CrossRefGoogle Scholar
  60. 60.
    Taddei S, Virdis A, Ghiadoni L, Magagna A, Salvetti A. Cyclooxygenase inhibition restores nitric oxide activity in essential hypertension. Hypertension. 1997;29:274–9.CrossRefGoogle Scholar
  61. 61.
    Taddei S, Virdis A, Mattei P, Salvetti A. Vasodilation to acetylcholine in primary and secondary forms of human hypertension. Hypertension. 1993;21:929–33.CrossRefGoogle Scholar
  62. 62.
    Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev. 2004;56:387–437.CrossRefGoogle Scholar
  63. 63.
    Feletou M, Huang Y, Vanhoutte PM. Endothelium-mediated control of vascular tone: COX-1 and COX-2 products. Br J Pharmacol. 2011;164:894–912.CrossRefGoogle Scholar
  64. 64.
    Taddei S, Virdis A, Ghiadoni L, Salvetti G, Bernini G, Magagna A, Salvetti A. Age-related reduction of NO availability and oxidative stress in humans. Hypertension. 2001;38:274–9.CrossRefGoogle Scholar
  65. 65.
    Taddei S, Virdis A, Mattei P, Ghiadoni L, Gennari A, Fasolo CB, Sudano I, Salvetti A. Aging and endothelial function in normotensive subjects and patients with essential hypertension. Circulation. 1995;91(7):1981.CrossRefGoogle Scholar
  66. 66.
    Weil BR, Stauffer BL, Greiner JJ, DeSouza CA. Prehypertension is associated with impaired nitric oxide-mediated endothelium-dependent vasodilation in sedentary adults. Am J Hypertens. 2011;24:976–81.CrossRefGoogle Scholar
  67. 67.
    Giannotti G, Doerries C, Mocharla PS, Mueller MF, Bahlmann FH, Horvath T, Jiang H, Sorrentino SA, Steenken N, Manes C, Marzilli M, Rudolph KL, Luscher TF, Drexler H, Landmesser U. Impaired endothelial repair capacity of early endothelial progenitor cells in prehypertension: relation to endothelial dysfunction. Hypertension. 2010;55:1389–97.CrossRefGoogle Scholar
  68. 68.
    Zhen Y, Xiao S, Ren Z, Shen HW, Su H, Tang YB, Zeng H. Increased endothelial progenitor cells and nitric oxide in young prehypertensive women. J Clin Hypertens (Greenwich). 2015;17:298–305.CrossRefGoogle Scholar
  69. 69.
    Virdis A, Ghiadoni L, Sudano I, Buralli S, Salvetti G, Taddei S, Salvetti A. Endothelial function in hypertension: role of gender. J Hypertens Suppl. 2002;20:S11–6.CrossRefGoogle Scholar
  70. 70.
    Weil BR, Westby CM, Greiner JJ, Stauffer BL, DeSouza CA. Elevated endothelin-1 vasoconstrictor tone in prehypertensive adults. Can J Cardiol. 2012;28:347–53.CrossRefGoogle Scholar
  71. 71.
    Flammer AJ, Anderson T, Celermajer DS, Creager MA, Deanfield J, Ganz P, Hamburg NM, Luscher TF, Shechter M, Taddei S, Vita JA, Lerman A. The assessment of endothelial function: from research into clinical practice. Circulation. 2012;126:753–67.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  • Stefano Taddei
    • 1
  • Rosa Maria Bruno
    • 1
  • Stefano Masi
    • 1
  1. 1.Department of Internal MedicineUniversity of PisaPisaItaly

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