European Heart Journal Advance Access originally published online on September 28, 2007
European Heart Journal 2007 28(21):2561-2562; doi:10.1093/eurheartj/ehm413
Exploring new drugs for heart failure: the case of urocortin
Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA
* Corresponding author. Tel: +1 216 444-3410; fax: +1 216 636-0063. E-mail address: francig{at}ccf.org
This editorial refers to ‘Urocortin 2 infusion in human heart failure’ by M.E. Davis et al., on page 2589
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
Over the past decade, clinical development of natriuretic peptide analogues as drug therapy for acute heart failure has sparked a wide range of interests to seek other endogenous vasoactive peptide systems that are operative as adaptive responders in human heart failure. With rapid advances in the molecular understanding of heart failure pathogenesis, several novel neurohormonal systems have been identified and more are under study. Bringing a potential therapeutic concept from bench to bedside today often involves a prerequisite set of animal and human studies. However, much of the attention in recent years has focused on identifying what the best clinical end-points should be or what the sample size should be in order to power statistical significance. Sometimes the fundamental mechanisms of action are overlooked with the rush to clinical implications. Opportunities to refine our thinking in the exploitation of such neurohormonal agonists/antagonists can be easily missed.
Davis and colleagues have extended our understanding of a new neurohormone and its pathophysiological role in heart failure1. Urocortin is actually a group of peptides belonging to the corticotrophin-releasing factor (CRF) family, with other members including urocortin 1, urocortin 2, and urocortin 3. It is interesting to point out that the urocortin system has been conserved throughout evolution in vertebrates all the way back to the amphibian sauvagine.2 Such evolutionary conservation usually suggests that the peptide subserves an important adaptive role. This system appears to release corticosteroids in response to stress, at the same time contributing to some ‘cardioprotective’ properties. Other neurohormones such as angiotensin II, arginine vasopressin, natriuretic peptides, and norepinephrine similarly share >600 million years of history and serve important adaptive responses to protect the heart and circulation, thus ensuring survival. The urocortins act on specific G-protein-coupled receptors that subserve important homeostatic physiological functions: urocortin 1 acts on both CRF1 receptors in the central nervous system and CRF2 receptors in the myocardium, whereas urocortin 2 and urocortin 3 act selectively for specific CRF2 receptors found in the myocardium and arteriolar vessels. CRF2-deficient mice demonstrate elevated blood pressure.3 Reports to date suggest that urocortin has a complex role in volume and pressure homeostasis. Based on existing data, these peptides are still considered primarily as vasodilators. Neurohormones such as urocortin stabilize haemodynamic alterations in heart failure and hypertension, and are attractive pathways to drug development. However, there are several fundamental gaps that have to be filled.
First and foremost, is there a direct association between the neurohormonal system and the disease state? Identification of CRF2 receptors in the myocardium and certain blood vessels provides the first evidence of their involvement in cardiac diseases, with urocortin 2 and urocortin 3 expression abundant in the myocardium.2 In animal experiments, the expression of endogenous cardiac urocortin is increased in response to ischaemia–reperfusion damage, and the addition of exogenous urocortin is associated with reduction of myocardial cell death during ischaemia–reperfusion damage.2 Furthermore, gene expression of urocortin has been demonstrated in human myocytes derived from both dilated and hypertrophic cardiomyopathy,4 and elevated levels of circulating urocortin can be found in patients with heart failure. Taken together, the role of urocortin in heart failure pathophysiology appears convincing.
Secondly, does modification of an observed pathophysiological mechanism directly relate to improvement in disease? If improvement is determined by resolution of haemodynamic alterations, the answer is affirmative. The group from Christchurch in particular has systematically studied all three urocortin infusions in normal and experimental heart failure animal models, normal humans, and now humans with heart failure. Consistently, they all produce substantial and prolonged cardiac vasodilatory and inotropic effects,5–8 and the reverse effects were seen when receptors were competitively antagonized.9 However, short-term administration of urocortin 1 did not show any significant haemodynamic or neurohormonal effects either in normal subjects or in patients with heart failure.10,11 In contrast to the report of Davis and colleagues1, short-term urocortin 2 infusion caused flushing in all eight male patients with stable heart failure, consistent with its vasodilatory properties. Overall, cardiac output improved with urocortin 2 infusion in the setting of an increase in heart rate and decrease in blood pressure, while estimated cardiac work was decreased.1 All changes were observed to occur in a dose-dependent manner. In addition, several neurohormones, including plasma renin activity, angiotensin II, arginine vasopressin, aldosterone, and norepinephrine, were largely unchanged. There is, therefore, modification of a mechanism, but we do not yet know if the disease process is favourably affected.
Thirdly, does the intended therapeutic intervention have incremental benefit over existing therapies? From the report of Davis and colleagues, there are several unanswered questions regarding the potential risks of urocortin 2 infusion. For example, the lack of effect on neurohormones is somewhat surprising, given the marked suppression seen in experimental heart failure.7 Although natriuretic peptide levels were unchanged with urocortin 2 infusion in normal humans,12 plasma natriuretic peptide levels were augmented in the setting of haemodynamic improvement with urocortin 2 infusion. The implications of this finding are not clear, but activation of the CRF2 receptor with urocortin can induce the production of atrial and B-type natriuretic peptide in cultured neonatal rat cardiomyocytes, at least in part via the cAMP-dependent protein kinase A pathway during cardiac hypertrophy.13 In contrast, long-term infusion of urocortin 1 in animal models can result in late reduction of natriuretic peptide levels,8 and short-term human infusion did not lead to any significant changes.6 Hence, the observed surge in plasma natriuretic peptide levels needs to be confirmed and the underlying mechanisms further explored. Another observation unique to urocortin 2 infusion is the noticeable increase in heart rate with urocortin 2 infusion in animal models,14 in normal humans,12 and in patients with a failing heart.1 This was not observed with urocortin 1 infusions, and therefore begs the question as to whether long-term effects of urocortin 2 may interact with the autonomic system and be potentially detrimental. Furthermore, the observed increase in serum creatinine in the combined analysis of the urocortin 2-treated group vs. the controls coupled with the relatively lower urine output is not reassuring, and is consistent with a previous report on urocortin 2 infusion in normal humans.12 Taken together, the safety profile of this therapeutic approach remains to be verified.
The lack of internal consistency between animal and human data suggests that the fundamental understanding of urocortins and their receptors in the pathophysiology of heart failure is incomplete. The bigger question is at what stage of heart failure is urocortin 2 likely to be most beneficial. Our view is that it may be more likely to benefit patients in the earlier stages. There are recent reports suggesting that urocortin may have a greater impact in attenuation of disease progression during the earlier stages of experimental heart failure than late salvage of decompensated states15. While Davis and colleagues have given urocortin 2 as a short-term infusion to demonstrate its vasodilatory effects, the peptide should not be pigeon-holed as a therapy only useful in the acute stages. Elegant studies such as this, coupled with a wide range of molecular and physiological investigations, will probably provide greater insight.
Conflict of interest: G.S.F. and W.H.W.T. have previously served as paid consultants to Neurocrine Biosciences Inc.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehm340 
References
- Davis ME, Pemberton CJ, Yandle TG, Fisher SF, Lainchbury JG, Frampton CM, Rademaker MT, Richards M. Urocortin 2 infusion in human heart failure. Eur Heart J (2007) 28:2589–2597. First Published on August 25, 2007, doi:10.1093/eurheartj/ehm340.
[Abstract/Free Full Text] - Coste SC, Quintos RF, Stenzel-Poore MP. Corticotropin-releasing hormone-related peptides and receptors: emergent regulators of cardiovascular adaptations to stress. Trends Cardiovasc Med (2002) 12:176–182.[CrossRef][Web of Science][Medline]
- Bale TL, Contarino A, Smith GW, Chan R, Gold LH, Sawchenko PE, Koob GF, Vale WW, Lee KF. Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress. Nat Genet (2000) 24:410–414.[CrossRef][Web of Science][Medline]
- Ikeda K, Tojo K, Tokudome G, Ohta M, Sugimoto K, Tamura T, Tajima N, Mochizuki S, Kawakami M, Hosoya T. Cardiac expression of urocortin (Ucn) in diseased heart; preliminary results on possible involvement of Ucn in pathophysiology of cardiac diseases. Mol Cell Biochem (2003) 252:25–32.[CrossRef][Web of Science][Medline]
- Rademaker MT, Cameron VA, Charles CJ, Richards AM. Urocortin 3: haemodynamic, hormonal, and renal effects in experimental heart failure. Eur Heart J (2006) 27:2088–2098.
[Abstract/Free Full Text] - Rademaker MT, Charles CJ, Espiner EA, Fisher S, Frampton CM, Kirkpatrick CM, Lainchbury JG, Nicholls MG, Richards AM, Vale WW. Beneficial hemodynamic, endocrine, and renal effects of urocortin in experimental heart failure: comparison with normal sheep. J Am Coll Cardiol (2002) 40:1495–1505.
[Abstract/Free Full Text] - Rademaker MT, Cameron VA, Charles CJ, Richards AM. Integrated hemodynamic, hormonal, and renal actions of urocortin 2 in normal and paced sheep: beneficial effects in heart failure. Circulation (2005) 112:3624–3632.
[Abstract/Free Full Text] - Rademaker MT, Charles CJ, Espiner EA, Frampton CM, Lainchbury JG, Richards AM. Four-day urocortin-I administration has sustained beneficial haemodynamic, hormonal, and renal effects in experimental heart failure. Eur Heart J (2005) 26:2055–2062.
[Abstract/Free Full Text] - Rademaker MT, Charles CJ, Espiner EA, Frampton CM, Lainchbury JG, Richards AM. Endogenous urocortins reduce vascular tone and renin–aldosterone/endothelin activity in experimental heart failure. Eur Heart J (2005) 26:2046–2054.
[Abstract/Free Full Text] - Davis ME, Pemberton CJ, Yandle TG, Lainchbury JG, Rademaker MT, Nicholls MG, Frampton CM, Richards AM. Effect of urocortin 1 infusion in humans with stable congestive cardiac failure. Clin Sci (Lond) (2005) 109:381–388.[Medline]
- Davis ME, Pemberton CJ, Yandle TG, Lainchbury JG, Rademaker MT, Nicholls MG, Frampton CM, Richards AM. Urocortin-1 infusion in normal humans. J Clin Endocrinol Metab (2004) 89:1402–1409.
[Abstract/Free Full Text] - Davis ME, Pemberton CJ, Yandle TG, Fisher SF, Lainchbury JG, Frampton CM, Rademaker MT, Richards AM. Urocortin 2 infusion in healthy humans: hemodynamic, neurohormonal, and renal responses. J Am Coll Cardiol (2007) 49:461–471.
[Abstract/Free Full Text] - Ikeda K, Tojo K, Sato S, Ebisawa T, Tokudome G, Hosoya T, Harada M, Nakagawa O, Nakao K. Urocortin, a newly identified corticotropin-releasing factor-related mammalian peptide, stimulates atrial natriuretic peptide and brain natriuretic peptide secretions from neonatal rat cardiomyocytes. Biochem Biophys Res Commun (1998) 250:298–304.[CrossRef][Web of Science][Medline]
- Bale TL, Hoshijima M, Gu Y, Dalton N, Anderson KR, Lee KF, Rivier J, Chien KR, Vale WW, Peterson KL. The cardiovascular physiologic actions of urocortin II: acute effects in murine heart failure. Proc Natl Acad Sci USA (2004) 101:3697–3702.
[Abstract/Free Full Text] - Rademaker MT, Charles CJ, Richards AM. Urocortin 1 administration from the onset of rapid left ventricular pacing represses progression to overt heart failure. Am J Physiol Heart Circ Physiol (2007) Accessed at http://ajpheart.physiology.org/cgi/reprint/00377.2007v1 (00316 May 2007).
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Related articles in EHJ:
- Urocortin 2 infusion in human heart failure
- Mark E. Davis, Christopher J. Pemberton, Timothy G. Yandle, Steve F. Fisher, John G. Lainchbury, Christopher M. Frampton, Miriam T. Rademaker, and Mark Richards
EHJ 2007 28: 2589-2597.[Abstract] [FREE Full Text]
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