Neurohormonal Inhibition in Heart Failure: Insights from Recent Clinical Trials

Neurohormonal Inhibition in Heart Failure: Insights from Recent Clinical Trials Mihai Gheorghiade, MD,a,* Leonardo De Luca, MD,b and Robert O. Bonow, MDa Heart failure (HF) is a clinical syndrome characterized by chronic, persistent activation of the neuroendocrine system, which has been assumed to be linked to disease progression and adverse outcomes. Clinical trials have shown that adrenergic modulators, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone blockers, and ␤-blockers, improve long-term outcomes in patients with HF. These findings have led to the hypothesis that inhibition of a single neurohormonal or cytokine pathway may continue to provide incremental benefits. However, the results of recent clinical trials, using centrally acting agents— endopeptidase inhibitors or endothelin and cytokine antagonists—suggest that selective inhibition of neurohormonal systems may not be advantageous and actually may have serious adverse effects. The reasons for this lack of benefit may be ascribed to the fact that long-term mortality benefits in patients with chronic HF are primarily the result of treatment of the diseases that have caused HF in the first place rather than treatment of neurohormonal abnormalities. © 2005 Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96[suppl]:3L–9L)

Heart failure (HF) is a clinical syndrome characterized by excessive, persistent activation of the renin-angiotensinaldosterone axis and the sympathetic nervous system.1 In patients with HF, homeostatic mechanisms appear activated in response to a relative reduction in cardiac output. The resultant effect is the development of a vicious circle characterized by excessive neurohormonal stimulation that is responsible not only for the chronic expression of adverse hemodynamic abnormalities but also for myocardial and vascular remodeling, a hallmark of progressive HF.2

Neurohormonal Hypothesis Neurohormonal abnormalities in HF may increase oxygen consumption, accelerate left ventricular (LV) remodeling, worsen myocardial function (necrosis or apoptosis), and lower the threshold for life-threatening arrhythmias.3–5 Contemporary management of HF relies on different antiadrenergic strategies, predicated on the hypothesis that reducing the harmful effects of excessive and continuous increased neuroendocrine drive on the myocardium will improve both symptoms and prognosis. In patients with HF, angiotensin-converting enzyme (ACE) inhibition has been found to reduce enhanced peripheral sympathetic nerve impulse traffic6 and cardiac ad-

a Division of Cardiology, Northwestern University, Feinberg School of Medicine, Chicago, Illinois, USA; and bDepartment of Cardiovascular and Respiratory Sciences, La Sapienza University, Rome, Italy. *Address for reprints: Mihai Gheorghiade, MD, Galter 10-240, 201 East Huron Street, Chicago, Illinois 60611. E-mail address: [email protected].

0002-9149/05/$ – see front matter © 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2005.09.059

renergic drive.7 The beneficial effects of ACE inhibitors and angiotensin receptor blockers are especially prominent in patients with increased adrenergic activation.8,9 Conversely, a series of placebo-controlled trials has demonstrated the hemodynamic and mortality benefits of ␤-blockers that reduce the harmful increased adrenergic drive on the myocardium10,11 and the secretion of renin, thereby reducing the levels of angiotensin and aldosterone.12 Aldosterone antagonists have improved survival in patients with current or recent symptoms at rest and in those with low ejection fraction and HF symptoms after acute myocardial infarction.13,14 After success with adrenergic blockade and inhibition of the renin-angiotensin-aldosterone axis, it has been postulated that selective blockade of other neurohormonal systems or cytokine pathways may continue to provide incremental benefits to patients with HF.15

Recent Clinical Trials on Neurohormonal Inhibition Centrally acting agents: As an alternative to blocking the peripheral effects of norepinephrine, inhibiting central sympathetic outflow may represent a useful means to interfere generally with the adverse effects of elevated catecholamines on cardiac function.16 Moxonidine is a novel imidazoline ligand that acts specifically on central nervous system receptors to decrease sympathetic nervous system tone.17,18 The multicenter Moxonidine Safety and Efficacy (MOXE) trial randomized 268 patients with chronic New York Heart Association (NYHA) functional class II to IV HF receiving optimal standard therapy to placebo or 1 of 5 doses of moxonidine.19 Plasma norepinephrine was greatly reduced in a dose-related manner by moxonidine, acwww.AJConline.org

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companied by evidence of reverse remodeling. However, these apparently “beneficial” changes were associated with an increase in adverse clinical events.19 In the subsequent Moxonidine Congestive Heart Failure (MOXCON) trial, not yet published, patients with NYHA class II to IV HF and left ventricular ejection fraction (LVEF) ⱕ0.35 were randomly assigned to placebo or 1.5 mg moxonidine twice daily.20 With only 1,993 of the anticipated 4,533 patients recruited, the trial was terminated prematurely on the recommendation of the Data Safety Monitoring Board. There was an excess of deaths in the active treatment group (54 vs 32, p ⫽ 0.005).20 Endothelin antagonists: Apart from activation of the sympathetic nervous and renin-angiotensin systems,21 increased endothelin (ET)-1 production contributes to neurohormonal activation in chronic HF. An elevated plasma level of ET-1 is a strong independent predictor of death.22,23 Although previous studies with nonselective ET blockade in patients with HF demonstrated an improvement in pulmonary and systemic hemodynamics,24,25 results of clinical trials were discouraging (Table 1).26 –32 Two nonselective ET receptor antagonists, enrasentan and bosentan, both failed to demonstrate a significant benefit in optimally treated systolic HF.2 In particular, the Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure (ENABLE) trial evaluated ⬎1,600 patients with severe systolic HF and demonstrated the lack of efficacy of bosentan on all-cause mortality and HF hospitalizations. In the 419 patients evaluated in the Enrasentan Cooperative Randomized (ENCOR) study, fewer patients treated with enrasentan improved compared with those treated with placebo, and conditions in more enrasentantreated patients were judged to worsen.26 The REACH-1 study (Research on Endothelin Antagonism in Chronic Heart Failure) evaluated 370 patients with NYHA class III to IV and an ejection fraction less than 35% while receiving diuretics and ACE inhibitors.26 The primary end point was change in clinical status from baseline after 6 months of treatment defined as worse, improved, or unchanged. The study was prematurely terminated following the recommendation of the Data Safety Monitoring Board as a result of a concern over the incidence of asymptomatic elevations in liver enzymes, which was 15.6% in the bosentan group. There was no significant difference in clinical status between the 2 groups at the time of study termination.26 The nonselective ET receptor antagonist tezosentan was studied in the Randomized Intravenous Tezosentan (RITZ) trials, which consisted of 4 phase 3 studies enrolling patients with acute HF requiring hospitalization. In the RITZ-1 trial, 669 patients receiving standard therapy for acute HF were randomized to placebo versus tezosentan 25 mg/hr intravenously for 1 hour, followed by uptitration to 50 mg/hr intravenously for 24 to 72 hours.27 There was no improvement in the primary end point (patient assessment of dys-

pnea at 24 hours) or secondary end points of time to death or worsening symptoms of HF in the first 24 hours. Notably, the 50-mg/hr dose of tezosentan was associated with an excess of hypotension, dizziness, and renal failure, suggesting that the dose may have been excessive.27 In the RITZ-4 trial, the effect of tezosentan in patients with acute decompensated HF associated with acute coronary syndromes was evaluated.28 In this multicenter, randomized, double-blind trial, 193 patients were randomized to receive placebo or intravenous tezosentan 25 mg/hr for the first hour, and then 50 mg/hr up to 48 hours. The primary end point was a composite of death, worsening HF, recurrent ischemia, and recurrent or new myocardial infarction (MI) within 72 hours. No significant difference was observed in the composite primary end point between the group receiving tezosentan and the group receiving placebo. Symptomatic hypotension occurred more often in the tezosentan-treated group.28 The RITZ-5 trial evaluated the addition of intravenous tezosentan (50 or 100 mg/hr for up to 24 hours) to standard therapy in 84 patients presenting with acute pulmonary edema.29 There was no significant difference in the primary end point, which was the change in arterial oxygen saturation from baseline. The incidence of death, recurrent pulmonary edema, mechanical ventilation, and MI was also similar in the first 24 hours of treatment.29 Recently, data from the Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Studies (VERITAS) have also been presented.30 The VERITAS program consisted of 2 parallel trials, VERITAS 1 and VERITAS 2, evaluating death or worsening HF within 7 days after study drug initiation and improvement in dyspnea as co-primary clinical end points in 1,435 patients with acute decompensated HF receiving standard care and either therapy with tezosentan (1 mg/hr for 23 to 72 hours) or placebo (for 24 to 72 hours). Although hemodynamic effects were observed in the treatment arm and were consistent with previous studies, there was no significant efficacy of treatment within the defined period, and the trials were discontinued in November 2004 following recommendations made by the steering committee and the independent Data Safety Monitoring Board.30 The Heart Failure ETA Receptor Blockade Trial (HEAT) randomized 157 patients with chronic HF to double-blind treatment with placebo or darusentan (30, 100, or 300 mg/ day) in addition to standard therapy.31 Short-term administration of darusentan increased cardiac index, but this did not reach statistical significance when compared with placebo. Higher dosages were associated with a trend toward more adverse events, including death, and early exacerbation of chronic HF without further benefit from hemodynamics versus moderate dosages.31 Moreover, in the Endothelin A Receptor Antagonist Trial in Heart Failure (EARTH), darusentan (10, 25, 50, 100, or 300 mg/day for 24 weeks) failed to affect cardiac remodeling (as assessed

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Table 1 Randomized clinical trials with endothelin receptor blockers Study

Patients (N)

Treatment

Outcomes

Comments

Tezosentan associated with excess of hypotension and renal failure No serious adverse events

Acute HF RITZ-127

669

Tezosentan 25 mg/hr IV for 1 hr, titrated to 50 mg/hr for 24–72 hr vs placebo

No difference in all end points

RITZ-226

215

Tezosentan 50 mg or 100 mg/hr IV vs placebo

RITZ-428

193

RITZ-529

84

Tezosentan 25 mg/hr IV for 1 hr, then 50 mg/ hr for ⱕ48 hr vs placebo Tezosentan 50 or 100 mg/hr IV for ⱕ24 hr

Both doses produced similar increase in cardiac index and decreases in PCWP No difference in all end points No improvement in end points No improvement in coprimary end points

VERITAS 1/230 Chronic HF REACH-126

1,435

Bosentan 250 mg bid vs placebo

No improvement in end points

1,613

Bosentan 125 mg bid vs placebo for 9 mo

HEAT31

157

Darusentan 3 dosages vs placebo for 3 wk

EARTH32

642

Darusentan 5 dosages vs placebo for 24 wk

No improvement in end points Improvement in cardiac index No improvement in end points

ENABLE I/II26

370

Tezosentan 1 mg/hr IV for 23–72 hr vs placebo for 24–72 hr

Patients with recent acute MI Higher dose had worse effects Patients with advanced acute HF Terminated early as a result of excessive increase in LFTs Worsening HF early in bosentan group Increased adverse events at higher doses Cardiac remodeling assessed by MRI

EARTH ⫽ Endothelin A Receptor antagonist Trial in Heart Failure; ENABLE I/II ⫽ Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure; HEAT ⫽ Heart Failure ETA Receptor Blockade Trial; HF ⫽ heart failure; IV ⫽ intravenously; LFTs ⫽ liver function tests; MI ⫽ myocardial infarction; MRI ⫽ magnetic resonance imaging; PCWP ⫽ pulmonary capillary wedge pressure; REACH-1 ⫽ Reinforcing Education About Cholesterol; RITZ ⫽ Randomized Intravenous Tezosentan; VERITAS ⫽ Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Studies.

by cardiac magnetic resonance imaging) or to improve clinical symptoms or outcomes in 642 patients with chronic HF receiving ACE inhibitors, ␤-blockers, and aldosterone antagonists.32 In the last few years, some potential reasons for the lack of beneficial effects of long-term treatment with ET antagonists in patients with HF have been proposed.33,34 Recently, Schirger and associates35 demonstrated in a canine model with progressive LV dysfunction that ET-A receptor antagonism further activates the renin-angiotensin system without improving sodium excretion, suggesting a potential mechanism for lack of benefit of ET receptor antagonists in virtually all clinical trials. Cytokine antagonists: The finding of elevated levels of tumor necrosis factor (TNF) in patients with chronic HF suggested that inflammatory mediators may play a role in the pathophysiology of this syndrome.36,37 This hypothesis was strengthened by the finding that exogenous administration and transgenic overexpression of proinflammatory cytokines can mimic many aspects of the HF phenotype, including LV remodeling, and reduce survival in experimental animals.38 – 40 Etanercept is a recombinant human TNF receptor that binds to circulating TNF and functionally inactivates TNF by preventing it from binding to its receptors on the surface of cell membranes. Phase 1 safety studies showed that a single intravenous infusion of etanercept was safe

and well tolerated, and led to an improvement in the functional status of patients with HF.41 In a subsequent study, biweekly injections of etanercept for 3 months resulted in a significant increase in LVEF and a significant decrease in LV volume.42 On the basis of preclinical and clinical studies, patients with NYHA class II to IV chronic HF and LVEF ⱕ0.30 were enrolled in 2 clinical trials that differed only in the doses of etanercept. In the Research Into Etanercept: Cytokine Antagonism in Ventricular Dysfunction trial (RECOVER), patients received placebo (n ⫽ 373) or subcutaneous etanercept in doses of 25 mg/wk (n ⫽ 375) or 25 mg twice per week (n ⫽ 375). In the Randomized Etanercept North American Strategy to Study Antagonism of Cytokines (RENAISSANCE), patients received placebo (n ⫽ 309), etanercept 25 mg twice per week (n ⫽ 308), or etanercept 25 mg 3 times per week (n ⫽ 308). The primary end point of each individual trial was clinical status at 24 weeks. Analysis of the effect of the 2 higher doses of etanercept on the combined outcome of death or hospitalization due to chronic HF from the 2 studies also was planned (the Randomized Etanercept Worldwide Evaluation [RENEWAL]).43 Following the prespecified stopping rules, both trials were terminated prematurely owing to lack of benefit. Etanercept had no effect on clinical status in the RENAISSANCE trial (p ⫽ 0.17) or RECOVER (p ⫽ 0.34) and had no effect on end points of death or hospi-

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Table 2 Randomized clinical trials with cytokine antagonists Study

Patient Status

RECOVER43

NYHA class II–IV, LVEF ⬍0.30 (n ⫽ NYHA class II–IV, LVEF ⬍0.30 (n ⫽ NYHA class II–IV, LVEF ⬍0.30 (n ⫽ NYHA class III–IV, LVEF ⬍0.35 (n ⫽

RENAISSANCE43 RENEWAL (RECOVER ⫹ RENAISSANCE)43 ATTACH44

1,123)

Treatment

Outcomes

Etanercept 25 mg once or twice weekly vs placebo Etanercept 25 mg 2 or 3 times weekly vs placebo

No improvement in clinical status at 24 wk No improvement in clinical status at 24 wk No difference in death or rehospitalization No improvement in clinical status at 14 wk

925) Etanercept 25 mg 2 or 3 times weekly vs placebo 1,365) Infliximab 5–10 mg/kg for 6 wk 150)

ATTACH ⫽ Anti-TNF Therapy Against Congestive Heart failure; LVEF ⫽ left ventricular ejection fraction; NYHA ⫽ New York Heart Association; RECOVER ⫽ Research Into Etanercept: Cytokine Antagonism in Ventricular Dysfunction; RENAISSANCE ⫽ Randomized Etanercept North American Strategy to Study Antagonism of Cytokines; RENEWAL ⫽ Randomized Etanercept Worldwide Evaluation.

talization for chronic HF in RENEWAL (etanercept to placebo: relative risk, 1.1; 95% confidence interval [CI], 0.91 to 1.33; p ⫽ 0.33) (Table 2).43,44 By contrast, the Anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial evaluated the efficacy and safety of infliximab, a chimeric monoclonal antibody to TNF-␣, in patients with moderate-to-severe HF.43 One hundred fifty patients with stable NYHA class III to IV HF and LVEF ⱕ0.35 were randomly assigned to receive placebo (n ⫽ 49), infliximab 5 mg/kg (n ⫽ 50), or infliximab 10 mg/kg (n ⫽ 51) at 0, 2, and 6 weeks after randomization and were followed prospectively for 28 weeks.44 Neither dose of infliximab improved clinical status at 14 weeks, the primary end point of the study, and the combined risk of death from any cause or hospitalization for HF through 28 weeks was increased in patients randomized to 10 mg/kg of infliximab (hazard ratio [HR], 2.84; 95% CI, 1.01 to 7.97; nominal p ⫽ 0.043) (Table 2).44 Endopeptidase inhibitors: Recent studies have shown that several endogenous peptides (ie, natriuretic peptides, bradykinin, and adrenomedullin) can attenuate vasoconstriction and sodium retention as well as retard cardiac and vascular hypertrophy and remodeling, thus acting to ameliorate many of the pathophysiologic abnormalities of HF.45– 47 This observation has led to the hypothesis that enhancing the effects of these endogenous vasodilators by blocking neutral endopeptidase, 1 of the key enzymes responsible for the breakdown of these peptides, may have favorable effects in treating this disorder.48,49 Simultaneous inhibition of both ACE and neutral endopeptidase produces greater short- and long-term benefits in experimental models of HF than does ACE inhibition alone.50,51 Single molecules, such as omapatrilat, that inhibit both the ACE and neutral endopeptidase (vasopeptidase inhibitors) have been developed in recent years.52 In patients with HF, omapatrilat was reported in early experience to reduce the risk of death or hospitalization to a greater degree than ACE inhibition alone,53 but this effect was based on a small number of clinical events observed in patients who were treated for only 6 months. In the Omapatrilat Versus Enalapril Randomized Trial of

Utility in Reducing Events (OVERTURE), 5,770 patients with NYHA class II to IV HF were randomly assigned to double-blind treatment with either the ACE inhibitor enalapril (10 mg twice daily, n ⫽ 2,884) or to omapatrilat (40 mg once daily, n ⫽ 2,886) for a mean of 14.5 months.54 The primary end point, the combined risk of death or hospitalization for HF requiring intravenous treatment, was achieved in 973 patients in the enalapril group and in 914 patients in the omapatrilat group (HR, 0.94; 95% CI, 0.86 to 1.03; p ⫽ 0.187).54 Therefore, omapatrilat appears to reduce the risk of death and hospitalization in patients with chronic HF but is not more effective than ACE inhibition alone in reducing the risk of a primary clinical event.

Why Are the Established Therapies Beneficial? The aggregate data across trials involving neurohormonal modulators, such as ACE inhibitors, angiotensin receptor blockers, ␤-blockers, and aldosterone blockers, fail to support variability in clinical benefit across various stages of disease. Moreover, the impact of these therapies on plasma norepinephrine concentrations and other vasoconstrictor neurotransmitters co-released by noradrenergic nerves is relatively modest,55,56 suggesting that their mortality benefit accrues primarily through nonadrenergic mechanisms. It has been postulated that survival benefits of these nonselective sympathetic modulators may primarily be correlated with their effects on different diseases underlying HF (eg, hypertension, atrial fibrillation, renal dysfunction, diabetes mellitus, or coronary artery disease [CAD]), which should be considered comorbidities that continuously contribute to HF morbidity and mortality (Figure 1). In fact, most patients with HF have these comorbidities. In the Acute Decompensated Heart Failure National Registry (ADHERE)57 that enrolled ⬎100,000 consecutive patients admitted with worsening HF, the population was elderly (mean age, 75 years), 75% had a prior history of HF, ⬎50% were women, and hypertension (72%) and CAD (57%) were prevalent. In addition, approximately 40% had a normal ejection fraction, atrial fibrillation, diastolic HF, diabetes, or any com-

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Figure 1. The pathophysiologic cascade leading to heart failure (HF) morbidity and mortality. Underlying diseases lead to LV dysfunction and continue to contribute to HF progression. AF ⫽ atrial fibrillation; CAD ⫽ coronary artery disease; LV ⫽ left ventricle; NH ⫽ neurohormons; RAS ⫽ renin-angiotensin system; SNS ⫽ sympathetic nervous system.

Figure 2. Saturation of benefits with incremental and selective neurohormonal blockade in patients with heart failure. ACE-I ⫽ angiotensin-converting enzyme inhibitor. (Adapted from J Am Coll Cardiol.2)

bination of these. Also, in another recent study of older Americans admitted to the hospital with HF, diabetes (38%), chronic lung disease (33%), atrial fibrillation (30%), and prior stroke (18%) were remarkably common.58

Conclusion In summary, recent data suggest that selective neurohormonal blockade may actually be deleterious (Figure 2). Isolated or selected neurohormonal modulation with centrally acting agents, endopeptidase inhibitors or ET, and cytokine antago-

nists, has not resulted in improved outcomes. In contrast, therapies such as ␤-blockers, ACE inhibitors, angiotensin receptor blockers, and aldosterone-blocking agents, used to treat the underlying diseases (CAD, hypertension, diabetes, atrial fibrillation) that have caused HF and that continue to contribute to its progression, have proved to be life-saving. Further clinical trials with different dosages and new study designs are required to better understand why this all-encompassing strategy has led to disappointing results. 1. Francis GS. Pathophysiology of chronic heart failure. Am J Med 2001;110(suppl 7A):37S– 46S.

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2. Mehra MR, Uber PA, Francis GS. Heart failure therapy at a crossroad: are there limits to the neurohormonal model? J Am Coll Cardiol 2003;41:1606 –1610. 3. Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, Simon AB, Rector T. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984; 311:819 – 824. 4. Floras JS. Clinical aspects of sympathetic activation and parasympathetic withdrawal in heart failure. J Am Coll Cardiol 1993;22(suppl): 72A– 84A. 5. Kaye DM, Lefkovits J, Jennings GL, Bergin P, Broughton A, Esler MD. Adverse consequences of high sympathetic nervous activity in the failing human heart. J Am Coll Cardiol 1995;26:1257–1263. 6. Grassi G, Cattaneo BM, Seravalle G, Lanfranchi A, Pozzi M, Morganti A, Carugo S, Manci G. Effects of chronic ACE inhibition on sympathetic nerve traffic and baroreflex control of circulation in heart failure. Circulation 1997;96:1173–1179. 7. Gilbert EM, Sandoval A, Larrabee P, Renlund DG, O’Connell JB, Bristow MR. Lisinopril lowers cardiac adrenergic drive and increases ␤-receptor density in the failing human heart. Circulation 1993;88: 472– 480. 8. MacFadyen RJ, Barr CS, Struthers AD. Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability, and reduces early morning rise in heart failure patients. Cardiovasc Res 1997;35:30–34. 9. Burnier M. Angiotensin II type 1 receptor blockers. Circulation 2001; 103:904 –912. 10. Gheorghiade M, Goldstein S. ␤-Blockers in the post–myocardial infarction patient. Circulation 2002;106:394 –396. 11. Gheorghiade M, Colucci W, Swedberg K. ␤-blockers in chronic heart failure. Circulation 2003;107:1570 –1575. 12. Francis GS. The relationship of the sympathetic nervous system and the renin-angiotensin system in congestive heart failure. Am Heart J 1989;118:642– 648. 13. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J, for the Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709 –717. 14. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, Bittman R, Hurley S, Kleiman J, Gatlin M. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309 –1321. 15. Gottlieb SS. The neurohormonal paradigm: have we gone too far? J Am Coll Cardiol 2003;41:1458 –1459. 16. Buccafusco JJ, Lapp CA, Westbrooks KL, Ernsberger P. Role of medullary I1-imidazoline and ␣2-adrenergic receptors in the antihypertensive responses evoked by central administration of clonidine analogs in conscious spontaneously hypertensive rats. J Pharmacol Exp Ther 1995;273:1162–1171. 17. Swedberg K, Bergh CH, Dickstein K, McNay J, Steinberg M. The effects of moxonidine, a novel imidazoline, on plasma norepinephrine in patients with congestive heart failure. J Am Coll Cardiol 2000;35: 398 – 404. 18. Ernsberger PR, Westbrooks KL, Christen MO, Schafer S. A second generation of centrally acting antihypertensive agents act on putative 1-imidazoline receptors. J Cardiovasc Pharmacol 1992;20(suppl):S1– S10. 19. Swedberg K, Bristow MR, Cohn JN, Dargie H, Straub M, Wiltsie C, Wright TJ, for the Moxonidine Safety and Efficacy (MOXSE) Investigators. Effects of sustained-release moxonidine, an imidazoline agonist, on plasma norepinephrine in patients with chronic heart failure. Circulation 2002;105:1797–1803. 20. Floras JS. The “unsympathetic” nervous system of heart failure. Circulation 2002;105:1753–1755. 21. Levine TB, Francis GS, Goldsmith SR, Simon AB, Cohn JN. Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relation to hemodynamic

22.

23. 24.

25.

26. 27.

28.

29.

30.

31.

32.

33. 34. 35.

36.

37.

38.

abnormalities in congestive heart failure. Am J Cardiol 1982;49:1659 –1666. Stewart DJ, Cernacek P, Costello KB, Rouleau JL. Elevated endothelin-1 in heart failure and loss of normal response to postural change. Circulation 1992;85:510 –517. McMurray JJ, Ray SG, Abdullah I, Dargie HJ, Morton JJ. Plasma endothelin in chronic heart failure. Circulation 1992;85:1374 –1379. Kiowski W, Sütsch G, Hunziker P, Muller P, Kim J, Oechslin E, Schmitt R, Jones R, Bertel O. Evidence for endothelin-1 mediated vasoconstriction in severe chronic heart failure. Lancet 1995;346:732– 736. Sütsch G, Kiowski W, Yan XW, Hünziker P, Christen S, Strobel W, Kim JH, Rickenbacher P, Bertel O. Short-term oral endothelin-receptor antagonist therapy in conventionally treated patients with symptomatic severe chronic heart failure. Circulation 1998;98:2262–2268. Rich S. Endothelin receptor blockers in cardiovascular disease. Circulation 2003;108:2184 –2190. Coletta AP, Cleland JG. Clinical trials update: highlights of the Scientific Sessions of the XXIII Congress of the European Society of Cardiology—WARIS II, ESCAMI, PAFAC, RITZ-1 and TIME. Eur J Heart Failure 2001;3:747–750. O’Connor CM, Gattis WA, Adams KF, Hasselblad V, Chandler B, Frey A, Kobrin I, Rainisio M, Shah MR, Teerlink J, Gheorghiade M, for the Randomized Intravenous Tezosentan Study-4 Investigators. Tezosentan in patients with acute heart failure and acute coronary syndromes. J Am Coll Cardiol 2003;41:1452–1457. Kaluski E, Kobrin I, Zimlichman R, Marmor A, Krakov O, Milo O, Frey A, Kaplan S, Krakover R, Caspi A, et al. RITZ-5: randomized intravenous tezosentan (an endothelin-A/B antagonist) for the treatment of pulmonary edema. J Am Coll Cardiol 2003;41:204 –210. Teerlink JR, McMurray JJV. VERITAS: Value of Endothelin Receptor Inhibition with Tezosentan in Acute Heart Failure Studies. Presented at 2005 Annual Meeting of the American College of Cardiology; March 6 –9, 2005; Orlando, Florida. Lüscher TF, Enseleit F, Pacher R, Mitrovic V, Schulze MR, Willenbrock R, Dietz R, Rousson V, Hurlimann D, Philipp S, et al. Hemodynamic and neurohumoral effects of selective endothelin A (ETA) receptor blockade in chronic heart failure: the Heart Failure ETA Receptor Blockade Trial (HEAT). Circulation 2002;106:2666 –2672. Anand I, McMurray J, Cohn JN, Konstam MA, Netter T, Quitzau K, Ruschitzka F, Lüscher TF, for the EARTH Investigators. Long-term effects of darusentan on left-ventricular remodelling and clinical outcomes in the Endothelin A Receptor antagonist Trial in Heart failure (EARTH): randomised, double-blind, placebo-controlled trial. Lancet 2004;364:347–354. Kaddoura S, Poole-Wilson PA. Endothelin-1 in heart failure: a new therapeutic target? Lancet 1996;348:418 – 419. Ertl G, Bauersachs J. Endothelin receptor antagonists in heart failure: current status and future directions. Drugs 2004;64:1029 –1040. Schirger JA, Chen HH, Jougasaki M, Lisy O, Boerrigter G, Cataliotti A, Burnett JC Jr. Endothelin A receptor antagonism in experimental congestive heart failure results in augmentation of the renin-angiotensin system and sustained sodium retention. Circulation 2004;109:249 – 254. Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990;223:236 –241. Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann DL. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 1996;27:1201– 1206. Bozkurt B, Kribbs S, Clubb FJ Jr, Michael LH, Didenko VV, Hornsby PJ, Seta Y, Oral H, Spinale FG, Mann DL. Pathophysiologically relevant concentrations of tumor necrosis factor-␣ promote progressive left ventricular dysfunction and remodeling in rats. Circulation 1998;97:1382–1391.

Gheorghiade et al/Neurohormonal Inhibition in Heart Failure 39. Kubota T, McTiernan CF, Frye CS, Slawson SE, Lemster BH, Koretsky AP, Demetris AJ, Feldman AM. Dilated cardiomyopathy in transgenic mice with cardiac specific overexpression of tumor necrosis factor-␣. Circ Res 1997;81:627– 635. 40. Sivasubramanian N, Coker ML, Kurrelmeyer KM, MacLellan WR, DeMayo FJ, Spinale FG, Mann DL. Left ventricular remodeling in transgenic mice with cardiac restricted overexpression of tumor necrosis factor. Circulation 2001;104:826 – 831. 41. Deswal A, Bozkurt B, Seta Y, Parilti-Eiswirth S, Hays FA, Blosch C, Mann DL. A phase I trial of tumor necrosis factor receptor fusion protein (TNFR:Fc) in patients with advanced heart failure. Circulation 1999;99:3224 –3226. 42. Bozkurt B, Torre-Amione G, Warren MS, Whitmore J, Soran OZ, Feldman AM, Mann DL. Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure. Circulation 2001;103:1044 –1047. 43. Mann DL, McMurray JJV, Packer M, et al. Targeted anticytokine therapy in patients with chronic heart failure: results of the Randomized Etanercept Worldwide Evaluation (RENEWAL). Circulation 2004;109:1594 –1602. 44. Chung ES, Packer M, Hung Lo K, Fasmanade AA, Willerson JT. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-␣, in patients with moderate-to-severe heart failure: results of the Anti-TNF Therapy Against Congestive Heart failure (ATTACH) trial. Circulation 2003;107:3133–3140. 45. Brandt RR, Wright RS, Redfield MM, Burnett JC. Atrial natriuretic peptide in heart failure. J Am Coll Cardiol 1993;22(suppl):86A–92A. 46. Cheng CP, Onishi K, Ohte N, Suzuki M, Little WC. Functional effects of endogenous bradykinin in congestive heart failure. J Am Coll Cardiol 1998;31:1679 –1686. 47. Petrie MC, McClure SJ, Love MP, McMurray JJ. Novel neuropeptides in the pathophysiology of heart failure: adrenomedullin and endothelin-1. Eur J Heart Fail 1999;1:25–29. 48. Newby DE, McDonagh T, Currie PF, Northridge DB, Boon NA, Dargie HJ. Candoxatril improves exercise capacity in patients with chronic heart failure receiving angiotensin converting enzyme inhibition. Eur Heart J 1998;19:1808 –1813. 49. Munzel T, Kurz S, Holtz J, Busse R, Steinhauer H, Just H, Drexler H. Neurohormonal inhibition and hemodynamic unloading during prolonged inhibition of ANF degradation in patients with severe chronic heart failure. Circulation 1992;86:1089 –1098.

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50. Rademaker MT, Charles CJ, Espiner EA, Nicholls MG, Richards AM, Kosoglou T. Combined neutral endo-peptidase and angiotensin-converting enzyme inhibition in heart failure: role of natriuretic peptides and angiotensin II. J Cardiovasc Pharmacol 1998;31:116 –125. 51. Trippodo NC, Fox M, Monticello TM, Panchal BC, Asaad MM. Vasopeptidase inhibition with omapatrilat improves cardiac geometry and survival in cardiomyopathic hamsters more than does ACE inhibition with captopril. J Cardiovasc Pharmacol 1999;34:782–790. 52. Fournie-Zaluski MC, Coric P, Turcaud S, Rousselet N, Gonzales W, Barbe B, Pham I, Julian N, Michel JB, Roques BP. New dual inhibitors of neutral endopeptidase and angiotensin-converting enzyme: rational design, bioavailability, and pharmacological responses in experimental hypertension. J Med Chem 1994;37:1070 –1083. 53. Rouleau JL, Pfeffer MA, Stewart DJ, Isaac D, Sestier I, Kerut EK, Porter CB, Proulx G, Qian C, Block AJ. Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial. Lancet 2000;356:615– 620. 54. Packer M, Califf RM, Konstam MA, Krum H, McMurray JJ, Rouleau JL, Swedberg K. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation 2002;106:920 –926. 55. Benedict CR, Francis GS, Shelton B, Johnstone DE, Kubo SH, Kirlin P, Nicklas J, Liang CS, Konstam MA, Greenberg B, et al. Effect of long-term enalapril therapy on neurohormones in patients with left ventricular dysfunction: SOLVD Investigators. Am J Cardiol 1995;75:1151–1157. 56. Swedberg K, Eneroth P, Kjekshus J, Wilhelmsen L. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality: CONSENSUS trial study group. Circulation 1990;82:1730 –1736. 57. Fonarow GC, for the ADHERE Scientific Advisory Committee. The Acute Decompensated Heart Failure National Registry (ADHERE): opportunities to improve care of patients hospitalized with acute decompensated heart failure. Rev Cardiovasc Med 2003;4(suppl 7):S21– S30. 58. Havranek EP, Masoudi FA, Westfall KA, et al. Spectrum of heart failure in older patients: results from the national heart failure project. Am Heart J 2002;143:412– 417.