Endotheliale Dysfunktion: Pathophysiologie, Diagnostik und prognostische Bedeutung

 

 Buy Article Permissions and Reprints

Zusammenfassung

Die endotheliale Dysfunktion ist das erste klinisch fassbare Substrat für die Entwicklung einer Atherosklerose. Sie kann invasiv im Koronarkreislauf mit Hilfe der intrakoronaren Acetylcholininfusion, aber auch peripher, nicht invasiv, beispielsweise mit Hilfe der Ultraschall-gesteuerten Bestimmung der flussabhängigen Dilatation der Arteria brachialis bestimmt werden. Neuere Methoden, die aktuell in der Testphase sind, sind die Fingerpulsplethysmografie sowie die Pulswellenreflektion als Marker der vaskulären Steifigkeit (Stiffness), Parameter die entscheidend durch den funktionellen Zustand des Endothels bestimmt werden. Zu kardiovaskulären Risikofaktoren, die zur Ausbildung einer endothelialen Dysfunktion führen, zählen arterielle Hypertonie, Diabetes mellitus, Hypercholesterinämie, chronisches Rauchen, und familiäre Disposition. Die akute intraarterielle oder orale Gabe einer hohen Vitamin C-Dosis ist in der Lage, die endotheliale Dysfunktion zu korrigieren, was als Nachweis für die herausragende Rolle von reaktiven Sauerstoffspezies als Verursacher der endothelialen Dysfunktion gewertet wird. Enzymatische Quellen der vermehrten Radikalbildung sind Enzyme wie die vaskuläre NADPH-Oxidase, eine dysfunktionelle, entkoppelte endotheliale NO-Synthase, mitochondriale Atmungskettenenzyme, die Cyclooxygenase und die Xanthinoxidase.

Neuere Untersuchungen belegen, dass die endotheliale Dysfunktion in koronaren und peripheren Leitungs- und Widerstandsgefäßen bei Patienten mit einer bekannten koronaren Herzerkrankung, mit einer arteriellen Hypertonie oder mit einer peripheren arteriellen Verschlusserkrankung eine prognostische Bedeutung besitzt. Die Bedeutung der endothelialen Dysfunktion im Bereich der Primärprävention ist unklar. Sie wird in der zurzeit laufenden Gutenberg-Herzstudie untersucht.

Summary

The endothelium plays a crucial role in the regulation of vascular tone. Recent studies have indicated that endothelial dysfunction develops in the presence of cardiovascular risk factors such as hypertension, diabetes mellitus, hypercholesterolemia and in chronic smokers, as well as in patients with a family history of cardiovascular disease. It has now been established that endothelial dysfunction represents the first indicator of vascular damage. Endothelial function can be assessed in coronary and peripheral conductance and resistance vessels by means of invasive and noninvasive (ultrasound-guided) methods such as intracoronary infusion of acetylcholine, the endothelium-dependent vasodilator. It is interesting that endothelial dysfunction in the presence of cardiovascular risk factors can be almost completely corrected by the acute administration of antioxidants such as vitamin C, pointing to a crucial role of reactive oxygen species in mediating this phenomenon. Superoxide producing enzymes involved in the increased production of reactive oxygen species include NADPH oxidase, nitric oxide synthase in the uncoupled state, mitochondrial superoxide sources, cyclooxygenase and xanthine oxidase. Recent studies indicate that the endothelial dysfunction found in coronary and peripheral conductance and resistance vessels provide prognostic information about future cardiovascular events. The role of endothelial dysfunction in the setting of primary prevention is not yet clear, but is being investigated in the current Gutenberg Heart Study.

Literatur

• 1 Anderson T J. et al . Close relation of endothelial function in the human coronary and peripheral circulations.  J Am Coll Cardiol. 1995;  26 1235-1241
  Google Scholar
• 2 Bonetti P O, Pumper G M, Higano S T. et al . Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia.  J Am Coll Cardiol. 2004;  44 2137-2141
  Google Scholar
• 3 Calver A, Collier J, Vallance P. Inhibition and stimulation of nitric oxide synthesis in the human forearm arterial bed of patients with insulin-dependent diabetes.  J Clin Invest. 1992;  90 2548-2554
  Google Scholar
• 4 Celermajer D S. et al . Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults.  Circulation. 1993;  88 2149-2155
  Google Scholar
• 5 Celermajer D S. et al . Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction.  J Am Coll Cardiol. 1994;  24 1468-1474
  Google Scholar
• 6 Celermajer D S, Sorensen K E, Gooch V M. et al . Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis.  Lancet. 1992;  340 1111-1115
  Google Scholar
• 7 Deanfield J E, Halcox J P, Rabelink T J. Endothelial function and dysfunction: testing and clinical relevance.  Circulation. 2007;  115 1285-1295
  Google Scholar
• 8 Eiserich J P, Baldus S, Brennan M L. et al . Myeloperoxidase, a leukocyte-derived vascular NO oxidase.  Science (New York, NY). 2002;  296 2391-2394
  Google Scholar
• 9 Forstermann U, Munzel T. Endothelial nitric oxide synthase in vascular disease: from marvel to menace.  Circulation. 2006;  113 1708-1714
  Google Scholar
• 10 Gokce N, Keaney Jr J F, Hunter L M. et al . Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease.  J Am Coll Cardiol. 2003;  41 1769-1775
  Google Scholar
• 11 Gokce N, Keaney Jr J F, Hunter L M. et al . Risk stratification for postoperative cardiovascular events via noninvasive assessment of endothelial function: a prospective study.  Circulation. 2002;  105 1567-1572
  Google Scholar
• 12 Harrison D G. Cellular and molecular mechanisms of endothelial cell dysfunction.  J Clin Invest. 1997;  100 2153-2157
  Google Scholar
• 13 Heitzer T, Yla-Herttuala S, Luoma J. et al . Cigarette smoking potentiates endothelial dysfunction of forearm resistance vessels in patients with hypercholesterolemia. Role of oxidized LDL.  Circulation. 1996;  93 1346-1353
  Google Scholar
• 14 Heitzer T, Just H, Munzel T. Antioxidant vitamin C improves endothelial dysfunction in chronic smokers.  Circulation. 1996;  94 6-9
  Google Scholar
• 15 Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease.  Circulation. 2001;  104 2673-2678
  Google Scholar
• 16 Heitzer T, Baldus S, Kodolitsch Y von, Rudolph V, Meinertz T. Systemic endothelial dysfunction as an early predictor of adverse outcome in heart failure.  Arterioscler Thromb Vasc Biol. 2005;  25 1174-1179
  Google Scholar
• 17 Hornig B. et al . Vitamin C improves endothelial function of conduit arteries in patients with chronic heart failure.  Circulation. 1998;  97 363-368
  Google Scholar
• 18 Landmesser U, Dikalov S, Price S R. et al . Oxidation of tetrahydrobiopterin leads to uncoupling of endothelial cell nitric oxide synthase in hypertension.  J Clin Invest. 2003;  111 1201-1209
  Google Scholar
• 19 Ludmer P L, Selwyn A P, Shook T L. et al . Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries.  N Engl J Med. 1986;  315 1046-1051
  Google Scholar
• 20 Munzel T, Daiber A, Ullrich V, Mulsch A. Vascular consequences of endothelial nitric oxide synthase uncoupling for the activity and expression of the soluble guanylyl cyclase and the cGMP-dependent protein kinase.  Arterioscler Thromb Vasc Biol. 2005;  25 1551-1557
  Google Scholar
• 21 Panza J A, Quyyumi A A, Brush Jr J E, Epstein S E. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension.  N Engl J Med. 1990;  323 22-27
  Google Scholar
• 22 Perticone F, Ceravolo R, Maio R. et al . Effects of atorvastatin and vitamin C on endothelial function of hypercholesterolemic patients.  Atherosclerosis. 2000;  152 511-518
  Google Scholar
• 23 Perticone F, Ceravolo R, Pujia A. et al . Prognostic significance of endothelial dysfunction in hypertensive patients.  Circulation. 2001;  104 191-196
  Google Scholar
• 24 Schachinger V, Britten M B, Zeiher A M. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease.  Circulation. 2000;  101 1899-1906
  Google Scholar
• 25 Schmidt-Lucke C, Rossig L, Fichtlscherer S. et al . Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair.  Circulation. 2005;  111 2981-2987
  Google Scholar
• 26 Suwaidi J A, Hamasaki S, Higano S T. et al . Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction.  Circulation. 2000;  101 948-954
  Google Scholar
• 27 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 2222-2229
  Google Scholar
• 28 Timimi F K, Ting H H, Haley E A. et al . Vitamin C improves endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus.  J Am Coll Cardiol. 1998;  31 552-557
  Google Scholar
• 29 Ting H H, Timimi F K, Boles K S. et al . Vitamin C improves endothelium-dependent vasodilation in patients with non-insulin-dependent diabetes mellitus.  J Clin Invest. 1996;  97 22-28
  Google Scholar
• 30 Vita J A, Treasure C B, Nabel E G. et al . Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease.  Circulation. 1990;  81 491-497
  Google Scholar
• 31 Werner N, Kosiol S, Schiegl T. et al . Circulating endothelial progenitor cells and cardiovascular outcomes.  N Engl J Med. 2005;  353 999-1007
  Google Scholar
• 32 Wilkinson I B, Webb D J. Venous occlusion plethysmography in cardiovascular research: methodology and clinical applications.  British journal of clinical pharmacology. 2001;  52 631-646
  Google Scholar

Prof. Dr. T. Münzel

II. Medizinische Klinik, Johannes Gutenberg Universität Mainz

Langenbeckstrasse 1

55131 Mainz

Phone: 06131/17-7250

Fax: 06131/17-6615

Email: tmuenzel@uni-mainz.de