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Circulation. 2004;109:143-145
doi: 10.1161/01.CIR.0000110644.92116.91
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(Circulation. 2004;109:143-145.)
© 2004 American Heart Association, Inc.

Focused Perspectives

Endothelin Expression and the Progression of Heart Failure

Exemplifying the Vagaries of Therapeutic Development

Marvin A. Konstam, MD; David DeNofrio, MD

From the Division of Cardiology, Department of Medicine, Tufts-New England Medical Center and Tufts University School of Medicine, Boston, Mass.

Correspondence to Marvin A. Konstam, MD, Division of Cardiology, Box 108, Tufts-New England Medical Center, 750 Washington St, Boston, MA. E-mail mkonstam{at}tufts-nemc.org


Key Words: Focused Perspectives • heart failure • endothelin • renin • angiotensin

Increased expression of endothelin (ET)–1 has been well described in heart failure and has been thought to potentiate the progression of this disorder through hemodynamic effects as well as vascular and cardiac remodeling.1,2 Investigations of heart failure animal models3,4 as well as early clinical studies5–7 supported a potential beneficial effect of ET-1 blockade in heart failure. On the basis of these observations, it is surprising that larger-scale clinical trials failed to support the value of chronic endothelin receptor blockade in reducing symptoms or adverse clinical outcomes for patients with heart failure.8,9 In fact, there was evidence for harm, in part mediated through increased fluid retention. The study by Schirger et al10 in this issue provides us with important new insights into the role of ET-1 in the progression of cardiovascular remodeling to clinical heart failure. This study also reminds us of the caution required in navigating the complex road from a partial understanding of pathophysiology to achieving clinical benefit through pharmacological intervention.

See p 249

Schirger et al10 observe, first, that during a phase of "transition" from experimental ventricular remodeling and dysfunction to the earliest signs of sodium retention, ET-1 expression is upregulated, without evidence of either systemic or tissue activation of the renin-angiotensin system (RAS). Second, they find that blockade of the ETA receptor in the presence of experimental heart failure produced no improvement in sodium excretion but increased plasma renin activity (PRA) and further increased plasma ET-1. In adding to our understanding of the complexity of interactions between endothelin and other neurohormonal systems in mediating structural and functional manifestations of progressive heart failure, the authors demonstrate the difficulty in applying our always-limited understanding of pathophysiological mechanisms to anticipating the clinical impact of a particular drug. Critical differences between early and late stages of disease, the multiplicity of effects of a particular agent, and the presence of concomitant treatments all can impact importantly on the physiological and clinical consequences of a particular treatment.

Based on existing data, there has been little justification for differential drug therapy during different phases in the progression of cardiac dysfunction and clinical heart failure. Data regarding the RAS, from this perspective, are mixed. The absence of RAS activation early in the expression of clinical heart failure is consistent with observations from the Studies of Left Ventricular Dysfunction (SOLVD) that minimally symptomatic patients within the Prevention trial manifest minimal elevations in PRA, and the degree of PRA expression that was observed might be explainable on the basis of diuretic administration.11 Schirger et al10 cite the absence of significant survival benefit among patients randomized to enalapril within SOLVD Prevention as further evidence for the relative unimportance of RAS activation early in the course of heart failure.12 However, enalapril induced a significant reduction in the frequency of heart failure hospitalizations within this study. Furthermore, we observed a significant beneficial effect of enalapril on ventricular remodeling within a substudy of SOLVD Prevention.13 It is therefore likely that the positive survival trend observed in this trial would have reached statistical significance with a larger number of events.

In contrast to the RAS, sympathetic activation more clearly occurs early in the course of ventricular remodeling and clinical heart failure.11 Clinical trial data support a role for ß-blockers across the spectrum of disease from asymptomatic ventricular dilatation and dysfunction, to patients with symptoms at rest.14–16 More recently, aldosterone antagonists have been shown to improve survival in the following 2 distinct populations of patients: those with current or recent symptoms at rest and those with low ejection fraction and symptoms of heart failure after acute myocardial infarction.17,18 The consistency of findings across these 2 populations suggests (although it does not prove) that aldosterone antagonism will be beneficial across a broad spectrum of patients with ventricular remodeling and clinical heart failure. Thus, the aggregate data across trials involving angiotensin-converting enzyme (ACE) inhibitors, ß-blockers, and aldosterone blockers fail to support variability in clinical benefit across various stages of disease.

However, these findings do not dispel the possibility that drugs that have failed to improve clinical outcomes for patients with heart failure—inotropic agents and tumor necrosis factor-{alpha} antagonists, for example—might have fared better if they had been studied within a more circumscribed population. The findings of Schirger et al10 support such a possibility with regard to ET-1 blockers. The Figure presents a mechanistic hypothesis, suggested by these findings, by which ET-1 expression might drive different responses through alternate hemodynamic effects at different stages of disease. During a stage of early cardiac remodeling, before substantial hemodynamic derangement, ET-1–induced vasoconstriction might be expected to raise blood pressure and downregulate both sympathetic tone and the RAS, in part via baroreceptor mechanisms. Under these conditions, ET-1 receptor antagonism might activate the RAS, as was observed by Schirger et al.10 In contrast, during more advanced stages of heart failure, ET-1 contribution to increased vascular tone would tend to depress cardiac output and contribute to a vicious cycle of events, including further activation of the adrenergic nervous system and RAS. ET-1 blockade might then be expected to mitigate against these events and dampen adrenergic and RAS activation.



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  		Postulated hemodynamic and neurohormonal response to ET-1 expression during the transition from ventricular remodeling and dysfunction to heart failure (A) and in the presence of established clinical heart failure (B). SNS indicates sympathetic nervous system.

A detailed understanding of the impact of ET-1 expression at various stages of heart failure, as Schirger et al10 have begun to elucidate, does not assure accurate prediction of the clinical effects of ET-1 blockade, in part because of the potential impact of concomitant medications. The authors propose that combining ET-1 blockade with ACE inhibition might improve clinical responses by mitigating against an RAS potentiating effect of ET-1 blockade during early stages of the transition to heart failure. However, in trials already performed, effects of ET-1 blocking agents were examined in the presence of ACE inhibitors. The confounding influence of concomitant therapy on a drug’s effect is multifactorial and difficult to anticipate. It is possible, for example, that in later stages of disease, when ET-1 blockade might be expected to exert a salutary effect, there might tend to be overlap between effects of an ACE inhibitor and those of an ET-1 blocker, the effects of which are in part mediated through RAS downregulation. The overlapping mechanisms of action might mitigate against added benefit from added therapy, and "side" effects such as fluid retention might assume a more prominent role in driving the observed net clinical effects.

Each of these factors—variability of action at various stages of disease, the role of concomitant medications, and collateral actions of the proposed therapeutic agent—render projection of an agent’s clinical actions exceedingly difficult. Examination of the effects of an agent on the process of ventricular remodeling remains an attractive tool for predicting the agent’s impact on clinical outcomes. However, animal investigations of remodeling effects may be of limited value, because the model used may not accurately represent the spectrum of disease that exists within the target human population. Furthermore, the clinical use of concomitant medications renders extrapolation from animal to human investigation even more difficult. Animal investigations had demonstrated prevention or reversal of ventricular remodeling by ET-1 blockade within heart failure models.3,19 In contrast, we have recently shown absence of a significant benefit by ET-1 blockade on the remodeling process, using MRI in patients with clinical heart failure and ventricular dilatation (I.S. Anand, MD, et al, unpublished data, 2002).

The work of Schirger et al10 further confirms a role for ET-1 in the pathogenesis of heart failure and, at the same time, provides important insight into the complexity of this role—including interaction with other neurohormonal systems—during various stages of the disease. Findings to date with ET-1 blockers represent a prime example of how challenging it is to translate basic observations from animal models into anticipated clinical benefit. The increasingly complex medical regimens used in patients with heart failure will mandate development of more sophisticated approaches to developing new therapeutic modalities in this condition.


*    Footnotes
 
The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.


*    References
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 *References
 

  1. Margulies K, Hidebrand FLJ, Lerman A, et al. Increased endothelin in experimental heart failure. Circulation. 1990; 82: 2226–2230.[Abstract/Free Full Text]
  2. Wei C, Lerman A, Rodeheffer R, et al. Endothelin in human congestive heart failure. Circulation. 1994; 89: 1580–1586.[Abstract/Free Full Text]
  3. Spinale FG, Walker JD, Mukherjee R, et al. Concomitant endothelin receptor subtype-A blockade during progression of pacing induced congestive heart failure in rabbits. Circulation. 1997; 95: 1918–1929.[Abstract/Free Full Text]
  4. Borgeson DD, Grantham JA, Williamson EE, et al. Chronic oral endothelin type A receptor antagonism in experimental heart failure. Hypertension. 1998; 31: 776–770.
  5. Love MP, Haynes WG, Gray GA, et al. Vasodilator effects of endothelin-converting enzyme inhibition and endothelin ETA receptor blockade in chronic heart failure patients treated with ACE inhibitors. Circulation. 1996; 94: 2131–2137.[Abstract/Free Full Text]
  6. Mulder P, Richard V, Derumeaux G, et al. Role of endogenous endothelin in chronic heart failure: effect of long-term treatment with an endothelin receptor antagonist on survival, hemodynamics, and cardiac remodeling. Circulation. 1997; 96: 1976–1982.[Abstract/Free Full Text]
  7. Sutsch G, Kiowski W, Yan X, et al. Short-term oral endothelin-receptor antagonist therapy in conventionally treated patients with symptomatic severe chronic heart failure. Circulation. 1998; 98: 2262–2268.[Abstract/Free Full Text]
  8. Luscher TF, Enseleit F, Pacher R, et al. Hemodynamic and neurohumoral effects of selective endothelin A (ETA) receptor blockade in chronic heart failure: the Heart Failure ET(A) Receptor Blockade Trial (HEAT). Circulation. 2002; 106: 2666–2672.[Abstract/Free Full Text]
  9. Kalra PR, Moon JC, Coats AJ. Do results of the ENABLE (Endothelin Antagonist Bosentan for Lowering Cardiac Events in Heart Failure) study spell the end for non-selective endothelin antagonism in heart failure. Int J Cardiol. 2002; 85: 195–197.[CrossRef][Medline] [Order article via Infotrieve]
  10. Schirger JA, Chen HH, Jougasaki M, et al. ET-A receptor antagonism in experimental congestive heart failure results in augmentation of the renin-angiotensin system and sustained sodium retention. Circulation. 2003; 109: 249–254.[Medline] [Order article via Infotrieve]
  11. Francis GS, Benedict C, Johnstone DE, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure: a substudy of the Studies Of Left Ventricular Dysfunction (SOLVD). Circulation. 1990; 82: 1724–1729.[Abstract/Free Full Text]
  12. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fraction. N Engl J Med. 1992; 327: 685–691.[Abstract]
  13. Konstam MA, Kronenberg MW, Rousseau MF, et al. SOLVD (Studies Of Left Ventricular Dysfunction) investigators. Effects of the angiotensin converting enzyme inhibitor enalapril on the long-term progression of left ventricular dilatation in patients with asymptomatic systolic dysfunction. Circulation. 1993; 88: 2277–2283.[Abstract/Free Full Text]
  14. The CAPRICORN Investigators. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet. 2001; 357: 1385–1390.[CrossRef][Medline] [Order article via Infotrieve]
  15. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). Lancet. 1999; 353: 2001–2007.[CrossRef][Medline] [Order article via Infotrieve]
  16. Packer M, Fowler MB, Roecker EB, et al. The effect of carvedilol on morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation. 2002; 106: 2194–2199.[Abstract/Free Full Text]
  17. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999; 341: 709–717.[Abstract/Free Full Text]
  18. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003; 348: 1309–1321.[Abstract/Free Full Text]
  19. Sakai S, Miyauchi T, Kobayashi M, et al. Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. Nature. 1996; 384: 353–355.[CrossRef][Medline] [Order article via Infotrieve]




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