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Neurohumoral blockade in CHF management

Franz-Volhard-Klinik, Charité, Humboldt-University of Berlin, Berlin, Germany, willenbrock{at}fvk-berlin.de

Sebastian Philipp

Franz-Volhard-Klinik, Charité, Humboldt-University of Berlin, Berlin, Germany

Veslin Mitrovic

Max-Planck-Institute and Kerckhoff-Klinik, Bad Nauheim, Germany

Rainer Dietz

Franz-Volhard-Klinik, Charité, Humboldt-University of Berlin, Berlin, Germany

Is heart failure an endocrine disease? Historically, congestive heart failure (CHF) has often been regarded as a mechanical and haemodynamic condition. However, there is now strong evidence that the activation of neuroendocrine systems, like the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, as well as the activation of natriuretic peptides, endothelin and vasopressin, play key roles in the progression of CHF. In this context, agents targeting neurohormones offer a highly rational approach to CHF management, with ACE inhibitors, aldosterone antagonists and beta-adrenergic blockade improving the prognosis for many patients. Although relevant improvements in clinical status and survival can be achieved with these drug classes, mortality rates for patients with CHF are still very high. Moreover, most patients do not receive these proven life-prolonging drugs, partially due to fear of adverse events, such as hypotension (with ACE inhibitors), gynaecomastia (with spironolactone) and fatigue (with beta-blockers).

New agents that combine efficacy with better tolerability are therefore needed. The angiotensin II type 1 (AT₁)-receptor blockers have the potential to fulfil both these requirements, by blocking the deleterious cardiovascular and haemodynamic effects of angiotensin II while offering placebo-like tolerability. As shown with candesartan, AT₁-receptor blockers also modulate the levels of other neurohormones, including aldosterone and atrial natriuretic peptide (ANP). Combined with its tight, long-lasting binding to AT₁-receptors, this characteristic gives candesartan the potential for complete blockade of the RAAS-neurohormonal axis, along with the great potential to improve clinical outcomes.

Key Words: congestive heart failure • renin-angiotensin-aldosterone system • neurohormones • angiotensin II receptor

References

• Willenbrock R., Pagel I., Krause E.-G, Scheuermann M., Dietz R.Acute hemodynamic and renal effects of adrenomedullin in aortocaval shunted rats. Eur J Pharmacol 1999;369:195-203.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Urata H., Boehm KD, Phillip A. et al. Cellular localisation and regional distribution of an angiotensin II-forming chymase in the heart. J Clin Invest 1993;91:1269-81.[Web of Science][Medline] [Order article via Infotrieve]
• Timmermans PB,Wong PC, Chiu AT, Herblin WF, Smith RD New perspectives in angiotensin system control. J Hum Hypertens 1993;7 Suppl 2:S19-31.[Web of Science][Medline] [Order article via Infotrieve]
• Gallinat S., Busche S., Raizada MK, Sumners C. The angiotensin II type 2 receptor: an enigma with multiple variations. Am J Physiol Endocrinol Metab 2000;278:E357-E374.[Abstract/Free Full Text]
• Unger T. The angiotensin type 2 receptor: variations on an enigmatic theme. J Hypertens 1999;17 (12 Part 2):1775-86.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet 1999; 353:2001-7.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• CIBIS-II Investigators and Committees. The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomised trial. Lancet 1999;353:9-13.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Piano MR, Bondmass M., Schwertz DW The molecular and cellular pathophysiology of heart failure. Heart Lung 1998;27:3-19.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Kato M., Kinugawa T., Omodani H. et al. Responses of plasma norepinephrine and renin-angiotensin-aldosterone system to dynamic exercise in patients with congestive heart failure. J Card Fail 1996;2:103-10.[CrossRef][Medline] [Order article via Infotrieve]
• Dutka DP, Olivotto I.,Ward S. et al. Plasma neuro-endocrine activity in very elderly subjects and patients with and without heart failure. Eur Heart J 1995;16:1223-30.[Abstract/Free Full Text]
• Eriksson SV, Eneroth P., Kjekshus J., Offstad J., Swedberg K. Neuroendocrine activation in relation to left ventricular function in chronic severe congestive heart failure: a subgroup analysis from the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). Clin Cardiol 1994;17:603-6.[Web of Science][Medline] [Order article via Infotrieve]
• Sigurdsson A.,Amtorp O., Gundersen T., Nilsson B., Remes J., Swedberg K. Neurohormonal activation in patients with mild or moderately severe congestive heart failure and effects of ramipril. The Ramipril Trial Study Group. Br Heart J 1994;72:422-7.[Abstract/Free Full Text]
• Langenickel T., Pagel I., Höhnel K., Dietz R., Willenbrock R. Differential regulation of cardiac ANP and BNP mRNA in different stages of experimental heart failure. Am J Physiol Heart Circ Physiol 2000;278:H1500-H1506.[Abstract/Free Full Text]
• Dutka DP, Olivotto I., Ward S., Oakley CM, Impallomeni M., Cleland JG Effects of aging on neuroendocrine activation in subjects and patients in the presence and absence of heart failure with left ventricular systolic dysfunction. Am J Cardiol 1996;77:1197-201.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Featherstone JA, Veith RC, Flatness D., Murburg MM, Villacres EC, Halter JB Age and alpha-2 adrenergic regulation of plasma norepinephrine kinetics in humans. J Gerontol 1987;42:271-6.[Abstract/Free Full Text]
• Remme WJ Effect of ACE inhibition on neurohormones. Eur Heart J 1998;19 Suppl J:J16-23.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Sigurdsson A. Neurohormonal activation in patients with acute myocardial infarction or chronic congestive heart failure. With special reference to treatment with angiotensin converting enzyme inhibitors. Blood Press Suppl 1995;1:1-45.[Medline] [Order article via Infotrieve]
• The CONSENSUS trial study group. Effects of enalapril on mortality in severe congestive heart failure: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS).NEnglJMed 1987;316:1429-35.[Abstract]
• Rucinska EJ Enalapril in the treatment of congestive heart failure: effects on signs, symptoms and mortality. Acta Cardiol 1991;46:231-46.[Medline] [Order article via Infotrieve]
• Greenberg B., Quinones MA, Koilpillai C. et al., for the SOLVD Investigators. Effects of long-term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Results of the SOLVD Echocardiography Substudy. Circulation 1995;91:2573-81.[Abstract/Free Full Text]
• Konstam MA, Rousseau MF, Kronenberg MW et al., for the SOLVD Investigators. Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dysfunction in patients with heart failure. Circulation 1992;86:431-8.[Abstract/Free Full Text]
• 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;325:293-302.[Abstract]
• 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;327:685-91.[Abstract]
• The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators: Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821-8.[Web of Science][Medline] [Order article via Infotrieve]
• Pfeffer MA, Braunwald E., Moye LA et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the Survival and Ventricular Enlargement Trial.The SAVE Investigators. N Engl J Med 1992;327:669-77.[Abstract]
• Rydén L. Results of the ATLAS study. Int J Clin Pract Suppl 1999;100:17-18.[Medline] [Order article via Infotrieve]
• Barr CS, Lang CC, Hanson J., Arnott M., Kennedy N., Struthers AD Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol 1995;76:1259-65.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Pitt B. ACE inhibitor co-therapy in patients with heart failure: rationale for the Randomized Aldactone Evaluation Study (RALES). Eur Heart J 1995;16 Suppl N:107-10.[Abstract]
• Pitt B., Zannad F., Remme WJ et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-17.[Abstract/Free Full Text]
• 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;101:594-7.[Abstract/Free Full Text]
• Elmfeldt D., George M., Hübner R., Olofsson B. Candesartan cilexetil, a new generation angiotensin II antagonist, provides dose dependent antihypertensive effect. J Hum Hypertens 1997;11 Suppl 2:S49-53.[Web of Science][Medline] [Order article via Infotrieve]
• Sever PS Key features of candesartan cilexetil and a comparison with other angiotensin II receptor antagonists. J Hum Hypertens 1999;13 Suppl 1:S3-S10.
• Lacourcière Y., Asmar R., for the Candesartan/Losartan study investigators.A comparison of the efficacy and duration of action of candesartan cilexetil and losartan as assessed by clinic and ambulatory blood pressure after a missed dose, in truly hypertensive patients. A placebo-controlled, forced titration study. Am J Hypertens 1999;12:1181-7.
• Pitt B., Segal R., Martinez FA 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;349:747-52.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
• Witte K., Thackray S., Banerjee T., Clark AL, Cleland JGF. Update of ELITE-II, BEST, CHAMP,and IMPRESS clinical trials in heart failure. Eur J Heart Fail 2000;2:107-12.[Abstract/Free Full Text]
• 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. Circulation 1999;100:1056-64.[Abstract/Free Full Text]
• Willenbrock R., Scheuermann M., Thibault G. et al. Angiotensin inhibition and atrial natriuretic peptide release after acute volume expansion in rats with aortocaval shunt. Cardiovasc Res 1999;42:733-42.[Abstract/Free Full Text]
• Granger CB, Ertl G., Kuch J. et al. Randomized trial of candesartan cilexetil in the treatment of patients with congestive heart failure and a history of intolerance to angiotensin-converting enzyme inhibitors. Am Heart J 2000;139:609-17.[Web of Science][Medline] [Order article via Infotrieve]
• Mitrovic, V. Acute and long-term haemodynamic and neurohormonal effects of candesartan cilexitil in patients with congestive heart failure J Am Coll Cardiol 35:206A (Abstract).
• Swedberg K., Pfeffer M., Granger C. et al. Candesartan in Heart Failure - Assessment of Reduction in Mortality and Morbidity (CHARM): rationale and design. J Card Fail 1999;5:276-82.[CrossRef][Medline] [Order article via Infotrieve]

Journal of Renin-Angiotensin-Aldosterone System, Vol. 1, No. 1 suppl, 24-30 (2000)
DOI: 10.3317/jraas.2000.030


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