Der Klinikarzt 2004; 33(3): 58-61
DOI: 10.1055/s-2004-823139
In diesem Monat

© Georg Thieme Verlag Stuttgart · New York

Altbewährtes neu entdeckt - Aldosteronantagonisten und chronische Herzinsuffizienz

Well Tried but Newly Discovered - Aldosterone-Antagonists and Chronic Heart FailureA. Römer1 , H. Sievert1 , H.-J. Gilfrich1
  • 1CardioVasculäres Centrum Frankfurt, Innere Medizin I (Kardiologie/Angiologie/Intensivmedizin), Sankt Katharinen Krankenhaus, Frankfurt/Main (Leiter: Prof. Dr. H. Sievert)
Further Information

Publication History

Publication Date:
15 April 2004 (online)

Zusammenfassung

In der neurohormonalen Theorie der Herzinsuffizienz spielt Aldosteron eine bedeutsame Rolle, durch seine Effekte auf die Endothelfunktion, auf die glatte Gefäßmuskulatur, auf die Adventitia, auf den PAI-1 (Plasminogen-Aktivator-Inhibitor-1) und auf die Fibrosierung des Myokards. Der therapeutische Ansatz mit Aldosteronantagonisten konnte sowohl tierexperimentell als auch in klinischen Studien (RALES, EPHESUS) eine günstige Wirkung auf die Herzinsuffizienzentwicklung zeigen sowie die Mortalität signifikant verbessern, wobei auf eine Niereninsuffizienz und engmaschige Kaliumkontrollen besonders geachtet werden muss.

Summary

Aldosterone has an important role in the neurohumoral pathophysiology of heart failure. This is caused by aldosterone effects on endothelium, smooth muscle cells, adventitia, PAI-1 and fibrosis of the myocardium. Experimental studies with aldosterone-antagonists were able to show a positive effect on the development of heart failure and large clinical trials could prove a significant reduction of mortality in patients with left ventricular dysfunction (RALES, EPHESUS). Close monitoring of potassium and renal failure is crucial for safe therapy with aldosterone-receptor-antagonists.

Literatur

  • 1 Andreis PG, Tortorella C, Malendowicz LK. et al. . Endothelins stimulate aldosterone secretion from dispersed rat adrenal zona glomerulosa cells, acting through ETB receptors coupled with the phospholipase C-dependent signalling pathway.  Peptides. 2001;  22 117-122
  • 2 Blacher J, Amah G, Girerd X. et al. . Association between increased plasma levels of aldosterone and decreased systemic arterial compliance in subjects with essential hypertension.  Am J Hypertens. 1997;  10 1326-1334
  • 3 Brown NJ, Abbas A, Byrne D. et al. . Comparative effects of estrogen and angiotensin-converting enzyme inhibition on plasminogen activator inhibitor-1 in healthy postmenopausal women.  Circulation. 2002;  105 304-309
  • 4 Brown NJ, Agirbasli MA, Williams GH. et al. . Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1.  Hypertension. 1998;  32 965-971
  • 5 Brown NJ, Kim KS, Chen YQ. et al. . Synergistic effect of adrenal steroids and angiotensin II on plasminogen activator inhibitor-1 production.  J Clin Endocrinol Metab. 2000;  85 336-344
  • 6 Duprez DA, De ML Buyzere, Rietzschel ER. et al. . Inverse relationship between aldosterone and large artery compliance in chronically treated heart failure patients [Comments].  Eur Heart J. 1998;  19 1371-1376
  • 7 Farquharson CA, Struthers AD. Spironolactone increases nitric oxide bioactivity, improves endothelial vasodilator dysfunction, and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure.  Circulation. 2000;  101 594-597
  • 8 Funder JW. Aldosterone, salt and cardiac fibrosis.  Clin Exp Hypertens. 1997;  19 885-899
  • 9 Funder JW. Glucocorticoid and mineralocorticoid receptors: biology and clinical relevance.  Annu Rev Med. 1997;  48 231-240
  • 10 Hatakeyama H, Miyamori I, Fujita T. et al. . Vascular aldosterone. Biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells.  J Biol Chem. 1994;  269 24316-24320
  • 11 Hinson JP, Kapas S. The role of endothelial cell products in the regulation of adrenocortical function: actions of endothelin, nitric oxide, adrenomedullin and PAMP.  Horm Metab Res. 1998;  30 334-340
  • 12 Klein KHW. Klinisch-experimentelle Untersuchungen über den Einfluss von Aldosteron auf Hämodynamik und Gerinnung.  Z Kreisl Forsch. 1963;  52 40-53
  • 13 Lombes M, Oblin ME, Gasc JM. et al. . Immunohistochemical and biochemical evidence for a cardiovascular mineralocorticoid receptor.  Circ Res. 1992;  71 503-510
  • 14 Luttun A, Dewerchin M, Collen D. et al. . The role of proteinases in angiogenesis, heart development, restenosis, atherosclerosis, myocardial ischemia, and stroke: insights from genetic studies.  Current Atherosclerosis Reports. 2000;  2 407-416
  • 15 MacFadyen RJ, Barr CS, Struthers AD. Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients.  Cardiovasc Res. 1997;  35 30-34
  • 16 McKelvie RS, Yusuf S, Pericak D. et al. . Comparison of candesartan, enalapril, and their combination in congestive heart failure: randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study.  The RESOLVD Pilot Study Investigators [Comments]. Circulation. 1999;  100 1056-1064
  • 17 Modena MG, Aveta P, Menozzi A. et al. . Aldosterone inhibition limits collagen synthesis and progressive left ventricular enlargement after anterior myocardial infarction.  Am Heart J. 2001;  141 41-46
  • 18 Natarajan R, Lanting L, Bai W. et al. . The role of nitric oxide in the regulation of aldosterone synthesis by adrenal glomerulosa cells.  J Steroid Biochem Mol Biol. 1997;  61 47-53
  • 19 Oelkers W. Drospirenone - a new progestogen with antimineralocorticoid activity, resembling natural progesterone.  Eur J Contracept Reprod Health Care. 2000;  5 17-24
  • 20 Pitt B. Escape of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: implications for therapy.  Cardiovasc Drugs Ther. 1995;  9 145-149
  • 21 Pitt B, Remme W, Zannad F. et al. . Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction.  N Engl J Med. 2003;  348 1309-1321
  • 22 Pitt B, Zannad F, Remme W. et al. . The effect of spironolactone on morbidity and mortality in patients with severe heart failure.  N Engl J Med. 1999;  341 709-717
  • 23 Quinn S, Williams G. Regulation of aldosterone secretion.  Annu Rev Physiol. 1988;  50 409-426
  • 24 Rajagopalan S, Duquaine D, King S. et al. . Mineralocorticoid receptor antagonism in experimental atherosclerosis.  Circulation. 2002;  105 2212-2216
  • 25 Rajagopalan S, Pitt B. Aldosterone antagonists in the treatment of hypertension and target organ damage.  Curr Hypertension Repts. 2001;  3 240-248
  • 26 Safar ME. Epidemiological findings imply that goals for drug treatment of hypertension need to be revised.  Circulation. 2001;  103 1188-1190
  • 27 Safar ME. Mechanical factors predicting cardiovascular risk and drug treatment of hypertension.  J Hypertens. 2002;  20 349-352
  • 28 Safar ME. Systolic blood pressure, pulse pressure and arterial stiffness as cardiovascular risk factors.  Curr Opin Nephrol Hypertens. 2001;  10 257-261
  • 29 Schepkens H, Vanholder R, Billiouw JM. et al. . Life-threatening hyperkalemia during combined therapy with angiotensin-converting enzyme inhibitors and spironolactone: an analysis of 25 cases.  Am J Med. 2001;  110 438-441
  • 30 Silvestre JS, Robert V, Heymes C. et al. . Myocardial production of aldosterone and corticosterone in the rat. Physiological regulation.  J Biol Chem. 1998;  273 4883-4891
  • 31 Slight SH, Ganjam VK, Gomez-Sanchez CE. et al. . High affinity NAD(+)-dependent 11 beta-hydroxysteroid dehydrogenase in the human heart.  J Mol Cell Cardiol. 1996;  28 781-787
  • 32 Somers MJ, Mavromatis K, Galis ZS. et al. . Vascular superoxide production and vasomotor function in hypertension induced by deoxycorticosterone acetate-salt.  Circulation. 2000;  101 1722-1728
  • 33 Staessen J, Lijnen P, Fagard R. et al. . Rise in plasma concentration of aldosterone during long-term angiotensin II suppression.  J Endocrinol. 1981;  91 457-465
  • 34 Sun Y, Ratajska A, Zhou G. et al. . Angiotensin-converting enzyme and myocardial fibrosis in the rat receiving angiotensin II or aldosterone.  J Lab Clin Med. 1993;  122 395-403
  • 35 Taddei S, Virdis A, Mattei P. et al. . Vasodilation to acetylcholine in primary and secondary forms of human hypertension.  Hypertension. 1993;  21 929-933
  • 36 Takeda Y, Yoneda T, Demura M. et al. . Sodium-induced cardiac aldosterone synthesis causes cardiac hypertrophy.  Endocrinology. 2000;  141 1901-1904
  • 37 Van Belle E, Bauters C, Wernert N. et al. . Neointimal thickening after balloon denudation is enhanced by aldosterone and inhibited by spironolactone, and aldosterone antagonist.  Cardiovasc Res. 1995;  29 27-32
  • 38 Weber KT. et al. . Mechanisms of disease: aldosterone in congestive heart failure.  N Engl J Med. 2001;  345 1689-1697
  • 39 Wehling M, Neylon CB, Fullerton M. et al. . Nongenomic effects of aldosterone on intracellular Ca2+ in vascular smooth muscle cells.  Circ Res. 1995;  76 973-979
  • 40 Wehling M, Ulsenheimer A, Schneider M. et al. . Rapid effects of aldosterone on free intracellular calcium in vascular smooth muscle and endothelial cells: subcellular localization of calcium elevations by single cell imaging.  Biochem Biophys Res Commun. 1994;  204 475-481
  • 41 Xiao F, Puddefoot JR, Vinson GP. Aldosterone mediates angiotensin II-stimulated rat vascular smooth muscle cell proliferation.  J Endocrinol. 2000;  165 533-536
  • 42 Yee KM, Pringle SD, Struthers AD. Circadian variation in the effects of aldosterone blockade on heart rate variability and QT dispersion in congestive heart failure.  J Am Coll Cardiol. 2001;  37 1800-1807
  • 43 Zannad F, Alla F, Dousset B. et al. . Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the Randomized Aldactone Evaluation Study (RALES).  Circulation. 2000;  102 2700-2706
  • 44 Zhou G, Kandala JC, Tyagi SC. et al. . Effects of angiotensin II and aldosterone on collagen gene expression and protein turnover in cardiac fibroblasts.  Mol Cell Biochem. 1996;  154 171-178

1 randomized evaluation of strategies for left ventricular dysfunction

2 randomized aldactone evaluation study

3 eplerenone post-acute myocardial infarction heart failure efficacy and survival trial

Anschrift für die Verfasser

Dr. A. Römer

CardioVasculäres Centrum Frankfurt

Innere Medizin I, Sankt Katharinen Krankenhaus

Seckbacher Landstr. 65

60389 Frankfurt