Review Article Korean Circulation J 2000;30 8 : 심부전증의최신개념과치료 김재중 New Concepts and Treatment of Heart Failure Modulation of Neurohormonal Syst

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1 Review Article Korean Circulation J 2000;308: 심부전증의최신개념과치료 김재중 New Concepts and Treatment of Heart Failure Modulation of Neurohormonal System Jae-Joong Kim, MD, PhD Asan Medical Center, College of Medicine, University of Ulsan, Seoul, Korea Activation of Neurohormnal Systems in Heart Failure 1045

2 Fig. 1. Activation of neurohormonal system in heart failure. Renin-Angiotensin-Aldosterone System (RAAS) Table 1. Adverse effects of angiotensin in congestive heart failure Left ventricular structural and functional effects Increased transmural wall stress Dilation caused by increase of end-diastolic and endsystolic volumes Decreased coronary flow in epicardial and transmural vessels Hemodynamic effects Increased vascular resistance Positive Inotropic stimulation Neurohormonal and paracrine effects Increased tissue effects of angiotensin Stimulation of aldosterone production, with sodium and volume retention Increase of circulatory catecholamines, impaired baroreceptor function, and abnormal Sympathetic-parasympathetic balance Increased bradykinin degradation Stimulate the secretion of arginine vasopressin Mitogenic and growth effects Myocardial hypertrophy Vascular smooth muscle hypertrophy Cell protein enhancement Angiotensin con-verting enzyme (ACE) inhibitor 1046 Korean Circulation J 2000;308:

3 Table 2. Effects of Ace inhibitors in patients with congestive heart failure Study No. Age CAD EF Class Drugs F/U Mortality reduction CONSENSUS % N/A Enalapril 1 88 days 27%p0.003 V-HeFT % 29%, Enalapril 2.5 years 28%p0.002 SOLVD treat % 25%, Enalapril 41.1 mos. 16%p0.004 SOLVD prev % 28%, Enalapril 37.4 mos. 8%p0.30 Evaluation of ACE inhibitor dose in CHF Angiotensin Ⅱ receptor blocker 1047

4 Fig. 2. Cascades of RAS and mechanism of action of ACE inhibitors and AT1 receptor antagonists. ATAngiotensin receptorst-patissue plasminogen activatorsnssympathetic nervous systemgrowth Fgrowth factorspaiplasminogen activator inhibitor. Table 3. Angiotensin receptor subtypeeffect Angiotesin R subtype Angiotensin R subtype Fibrosis Vasoconstriction Matrix growth PA-I synthesis Endothelial dysfunction 1048 Nitric oxide release Antiproliferative effect Apoptosis Korean Circulation J 2000;308:

5 Fig. 3. Stimuli generating aldosterone. Aldosterone antagonist Fig. 4. The results of RALES. 1049

6 Fig. 5. Harmful effect of prolonged sympathetic stimulation on cardiac myocytes Sympathetic System Harmful effect of prolonged sympathetic stimulation in heart failure Effects of β-blockers in heart failure Korean Circulation J 2000;308:

7 Clinical use of β-blocker in heart failure 1051

8 Endothelin System Fig. 6. -Blocker Effects on Mortality in CHF. Fig. 8. -blocker Effects on Combination in CHF. Fig. 7. -blocker Effects on Hospitalization in CHF. Fig. 9. Generation of endothelin Korean Circulation J 2000;308:

9 REFERENCES 1) Elsner D. Changes in neurohumoral systems during the development of congestive heart failure: Impact on cardiovascular and renal function. Eur Heart J 1995;16suppl N: ) Colucci WS. Molecular and cellular mechanisms of myocardial failure. Am J Cardiol 1997;8011A:15L-25L. 3) Bayliss J, Norell M, Canepa-Anson R, Sutton G, Poole- Wilson P. Untreated heart failure: Clinical and neuroendocrine effects of introducing diuretics. Br Heart J 1987; 57: ) Rocca HPBL, Vaddadi G, Elser MD. Recent insight into therapy of congestive heart failure: Focus on ACE inhibition and angiotensin- antagonism. J Am Coll Cardiol 1999;33: ) Zusman RM. Effects of converting-enzyme inhibitors on the renin-angiotensin-aldosterone, bradykinin, and arachidonic acid-prostaglandin systems: Correlation of chemical structure and biologic activity. Am J Kidney Dis 1987; 10: ) Barbe F, Su JB, Guyen T, Crozatier B, Menard J, Hittinger L. Bradykinin pathway is involved in the acute hemodynamic effects of enalaprilat in dogs with heart failure. Am J Physiol 1996;270:H1985-H92. 7) The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure: Results of the Cooperative North Scandinavian Enalapril Survival Study CON-SENSUS. N Engl J Med 1987;316: ) The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;35: ) Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325: ) Garg R, Yufuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. JAMA 1995;273: ) The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992;327: ) Packer M, Poole-Wilson PA, Armstron PW, Cleland JGF, Horowitz JD, Massie BM, et al. Comparative effect of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. Circulation 1999;100: ) Pitt B, Segal R, Martinez FA, Meurers G, Cowley AJ, Thomas I, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure Evaluation of Losartan in the Elderly Study, ELITE. Lancet 1997; 349: ) Hamroff G, Katz SD, Mancini D, Blaufarb I, Bijou R, Patet R, et al. Addition of angiotensin receptor blockade to maximal angiotensin-converting enzyme inhibition improves exercise capacity in patients with severe congestive heart failure. Circulation 1999;99: ) Pitt B. Escape of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: Implication for therapy. Cardiovasc Drugs Ther 1995;9: ) Young M, Fullerton M, Dilley R, Funder J. Mineralocorticoids, hypertension, and cardiac fibrosis. J Clin Invest 1994;93: ) Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341: ) Daly PA, Sole MJ. Myocardial catecholamine and the pathophysiology of heart failure. Circulation 1990;82: ) Bristow MR, Hershberger RE, Port JD, et al. -Adrenergic pathways in nonfailing and failing human ventricular myocardium. Circulation 1990;82:I-12-I ) Ungerer M, Parruti G, Bohm M, et al. Expression of - arrestins and -adrenergic receptor kinases in the human heart. Cir Res 1994;74: ) Mann DL, Kent RL, Parsons B, Cooper G. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation 1992;85: ) Bristow MR. Mechanism of action of beta-blocking agents in heart failure. Am J Cardiol 1997;80suppl L:26L-40L. 23) Bristow MR, Larrabee P, Muller-Beckmann B, et al. Ef- 1053

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$(Microsoft PowerPoint - S13-3_\261\350\273\363\307\366 [\310\243\310\257 \270\360\265\345])$ Cardiovascular Disease in Metabolic Syndrome 김상현 보라매병원내과 서울대학교의과대학내과학교실 Contents Metabolic syndrome and Cardiovascular system CVD Mortality Coronary artery disease Heart failure Atrial fibrillation Management