Serelaxin: A novel therapy for acute heart failure with a range of hemodynamic and non-hemodynamic actions

American Journal of Cardiovascular Drugs

Volumn 14, Issue 4, 2014, Pages 275-285

  Díez, Javier ^a,b,c  

^a UNIVERSITY OF NAVARRA   (Spain)

^b UNIVERSITY OF NAVARRA   (Spain)

^c UNIVERSITY CLINIC OF NAVARRA   (Spain)

Author keywords

[No Author keywords available]

Indexed keywords

RECOMBINANT PROTEIN; RELAXIN; SERELAXIN PROTEIN, HUMAN; TROPONIN T;

ACUTE DISEASE; BIOSYNTHESIS; DRUG EFFECTS; ENDOMYOCARDIAL FIBROSIS; HEART FAILURE; HEART MUSCLE CELL; HEMODYNAMICS; HUMAN; METABOLISM; RENAL INSUFFICIENCY;

ACUTE DISEASE; ENDOMYOCARDIAL FIBROSIS; HEART FAILURE; HEMODYNAMICS; HUMANS; MYOCYTES, CARDIAC; RECOMBINANT PROTEINS; RELAXIN; RENAL INSUFFICIENCY; TROPONIN T;

EID: 84905919333     PISSN: 11753277     EISSN: 1179187X     Source Type: Journal    
DOI: 10.1007/s40256-014-0069-0     Document Type: Review

References (101)

1. Dickstein K, Cohen-Solal A, Filippatos G, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM). Eur Heart J. 2008;29:2388-442.
2. Go AS, Mozaffarian D, Roger VL, et al. Executive summary: heart disease and stroke statistics-2013 update: a report from the American Heart Association. Circulation. 2013;127:143-52.
3. Grady KL. Quality of life in patients with chronic heart failure. Crit Care Nurs Clin North Am. 1993;5:661-70.
4. Heidenreich PA, Albert NM, Allen LA, et al. Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association. Circ Heart Fail. 2013;6:606-19.
5. Ng TM, Dasta JF, Durtschi AJ, McLaughlin TP, Feldman DS. Characteristics, drug therapy, and outcomes from a database of 500,000 hospitalized patients with a discharge diagnosis of heart failure. Congest Heart Fail. 2008;14:202-10.
6. Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol. 2009;53:557-73.
7. Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53:e1-90.
8. Harjola VP, Follath F, Nieminen MS, et al. Characteristics, outcomes, and predictors of mortality at 3 months and 1 year in patients hospitalized for acute heart failure. Eur J Heart Fail. 2010;12:239-48.
9. Siirilä-Waris K, Lassus J, Melin J, et al. Characteristics, outcomes, and predictors of 1-year mortality in patients hospitalized for acute heart failure. Eur Heart J. 2006;27:3011-7. (Pubitemid 44950446)
10. Felker GM, Pang PS, Adams KF, et al. Clinical trials of pharmacological therapies in acute heart failure syndromes: lessons learned and directions forward. Circ Heart Fail. 2010;3:314-25.
11. Cotter G, Felker GM, Adams KF, Milo-Cotter O, O'Connor CM. The pathophysiology of acute heart failure - is it all about fluid accumulation? Am Heart J. 2008;155:9-18. (Pubitemid 350234787)
12. Cotter G, Metra M, Milo-Cotter O, Dittrich HC, Gheorghiade M. Fluid overload in acute heart failure - re-distribution and other mechanisms beyond fluid accumulation. Eur J Heart Fail. 2008;10:165-9. (Pubitemid 351222743)
13. Cotter G, Milo O, Davison BA. Increased mortality after an acute heart failure episode: new pathophysiological insights from the RELAX-AHF study and beyond. Curr Heart Fail Rep. 2014;11:19-30.
14. Metra M, Cotter G, Davison BA, et al. Effect of serelaxin on cardiac, renal, and hepatic biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) development program: correlation with outcomes. J Am Coll Cardiol. 2013;61:196-206.
15. Kociol RD, Pang PS, Gheorghiade M, Fonarow GC, O'Connor CM, Felker GM. Troponin elevation in heart failure: prevalence, mechanisms, and clinical implications. J Am Coll Cardiol. 2010;56:1071-8.
16. Metra M, Bettari L, Pagani F, et al. Troponin T levels in patients with acute heart failure: clinical and prognostic significance of their detection and release during hospitalisation. Clin Res Cardiol. 2012;101:663-72.
17. Peacock WF 4th, De Marco T, Fonarow GC, et al. Cardiac troponin and outcome in acute heart failure. N Engl J Med. 2008;358:2117-26. (Pubitemid 351679598)
18. Del Carlo CH, Pereira-Barretto AC, Cassaro-Strunz C, Latorre Mdo R, Ramires JA. Serial measure of cardiac troponin T levels for prediction of clinical events in decompensated heart failure. J Card Fail. 2004;10:43-8. (Pubitemid 38880891)
19. La Vecchia L, Mezzena G, Zanolla L, et al. Cardiac troponin I as diagnostic and prognostic marker in severe heart failure. J Heart Lung Transpl. 2000;19:644-52. (Pubitemid 30621676)
20. Parenti N, Bartolacci S, Carle F, Angelo F. Cardiac troponin I as prognostic marker in heart failure patients discharged from emergency department. Intern Emerg Med. 2008;3:43-7.
21. You JJ, Austin PC, Alter DA, Ko DT, Tu JV. Relation between cardiac troponin I and mortality in acute decompensated heart failure. Am Heart J. 2007;153:462-70. (Pubitemid 46440690)
22. Felker GM, Hasselblad V, Tang WH, et al. Troponin I in acute decompensated heart failure: insights from the ASCEND-HF study. Eur J Heart Fail. 2012;14:1257-64.
23. Braga JR, Tu JV, Austin PC, et al. Outcomes and care of patients with acute heart failure syndromes and cardiac troponin elevation. Circ Heart Fail. 2013;6:193-202.
24. Perna ER, Macín SM, Cimbaro Canella JP, et al. Minor myocardial damage detected by troponin T is a powerful predictor of long-term prognosis in patients with acute decompensated heart failure. Int J Cardiol. 2005;99:253-61. (Pubitemid 40320798)
25. Perna ER, Aspromonte N, Cimbaro Canella JP, et al. Minor myocardial damage is a prevalent condition in patients with acute heart failure syndromes and preserved systolic function with long-term prognostic implications: a report from the CI-AST- HF (Collaborative Italo-Argentinean Study on cardiac Troponin T in Heart Failure) study. J Card Fail. 2012;18:822-30.
26. Metra M, Cotter G, Gheorghiade M, Dei Cas L, Voors AA. The role of the kidney in heart failure. Eur Heart J. 2012;33: 2135-42.
27. Maisel AS, Choudhary R. Biomarkers in acute heart failure - state of the art. Nat Rev Cardiol. 2012;9:478-90.
28. Maisel AS, Mueller C, Fitzgerald R, et al. Prognostic utility of plasma neutrophil gelatinase-associated lipocalin in patients with acute heart failure: the NGAL EvaLuation Along with B-type NaTriuretic Peptide in acutely decompensated heart failure (GALLANT) trial. Eur J Heart Fail. 2011;13:846-51.
29. Damman K, Van Veldhuisen DJ, Navis G, et al. Tubular damage in chronic systolic heart failure is associated with reduced survival independent of glomerular filtration rate. Heart. 2010;96:1297-302.
30. Ambrosy AP, Vaduganathan M, Huffman MD, et al. Clinical course and predictive value of liver function tests in patients hospitalized for worsening heart failure with reduced ejection fraction: an analysis of the EVEREST trial. Eur J Heart Fail. 2012;14:302-11.
31. Bathgate RAD, Halls ML, van der Westhuizen ET, Callander GE, Kocan M, Summers RJ. Relaxin family peptides and their receptors. Physiol Rev. 2013;93:405-80.
32. Teichman SL, Unemori E, Dschietzig T, et al. Relaxin, a pleiotropic vasodilator for the treatment of heart failure. Heart Fail Rev. 2009;14:321-9.
33. Du XJ, Bathgate RA, Samuel CS, Dart AM, Summers RJ. Cardiovascular effects of relaxin: from basic science to clinical therapy. Nat Rev Cardiol. 2010;7:48-58.
34. Teichman SL, Unemori E, Teerlink JR, Cotter G, Metra M. Relaxin: review of biology and potential role in treating heart failure. Curr Heart Fail Rep. 2010;7:75-82.
35. Bennett RG. Relaxin and its role in the development and treatment of fibrosis. Transl Res. 2009;154:1-6.
36. Teerlink JR, Cotter G, Davison BA, et al. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet. 2013;381:29-39.
37. Ponikowski P, Metra M, Teerlink JR, et al. Design of the RELAX in in acute heart failure study. Am Heart J. 2012;163:149-55.
38. Teerlink JR, Metra M, Felker GM, et al. Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study. Lancet. 2009;373:1429-39.
39. Metra M, Ponikowski P, Cotter G, et al. Effects of serelaxin in subgroups of patients with acute heart failure: results from RELAX-AHF. Eur Heart J. 2013;34:3128-36.
40. Filippatos G, Teerlink JR, Farmakis D, et al. Serelaxin in acute heart failure patients with preserved left ventricular ejection fraction: results from the RELAX-AHF trial. Eur Heart J. 2013 (Epub ahead of print).
41. Dschietzig T, Teichman S, Unemori E, et al. First clinical experience with intravenous recombinant human relaxin in compensated heart failure. Ann N Y Acad Sci. 2009;1160: 387-92.
42. Dschietzig T, Teichman S, Unemori E, et al. Intravenous recombinant human relaxin in compensated heart failure: a safety, tolerability, and pharmacodynamic trial. J Card Fail. 2009;15:182-90.
43. Ponikowski P, Mitrovic V, Ruda M, et al. A randomized, double- blind, placebo-controlled, multicentre study to assess haemodynamic effects of serelaxin in patients with acute heart failure. Eur Heart J. 2014;35:431-41.
44. Danielson LA, Kercher LJ, Conrad KP. Impact of gender and endothelin on renal vasodilation and hyperfiltration induced by relaxin in conscious rats. Am J Physiol Regul Integr Comp Physiol. 2000;279:R1298-304.
45. Smith MC, Danielson LA, Conrad KP, Davison JM. Influence of recombinant human relaxin on renal hemodynamics in healthy volunteers. J Am Soc Nephrol. 2006;17:3192-7. (Pubitemid 44707780)
46. Conrad KP. Unveiling the vasodilatory actions and mechanisms of relaxin. Hypertension. 2010;56:2-9.
47. McGuane JT, Danielson LA, Debrah JE, Rubin JP, Novak J, Conrad KP. Angiogenic growth factors are new and essential players in the sustained relaxin vasodilatory pathway in rodents and humans. Hypertension. 2011;57:1151-60.
48. Debrah DO, Conrad KP, Danielson LA, Shroff SG. Effects of relaxin on systemic arterial hemodynamics and mechanical properties in conscious rats: sex dependency and dose response. J Appl Physiol. 2005;98:1013-20. (Pubitemid 40283683)
49. Bani D. Relaxin as a natural agent for vascular health. Vasc Health Risk Manag. 2008;4:515-24. (Pubitemid 352037913)
50. Missouris CG, Grouzmann E, Buckley MG, Barron J, MacGregor GA, Singer DR. How does treatment influence endocrine mechanisms in acute severe heart failure? Effects on cardiac natriuretic peptides, the renin system, neuropeptide Y and catecholamines. Clin Sci (Lond). 1998;94:591-9. (Pubitemid 28269058)
51. Lazzarini V, Felker GM. Management of the cardiorenal syndrome in acute heart failure. Curr Treat Options Cardiovasc Med. 2012;14:342-55.
52. Broqvist M, Dahlström U, Karlberg BE, Karlsson E, Marklund T. Neuroendocrine response in acute heart failure and the influence of treatment. Eur Heart J. 1989;10:1075-83. (Pubitemid 20031948)
53. Danielson LA, Sherwood OD, Conrad KP. Relaxin is a potent renal vasodilator in conscious rats. J Clin Invest. 1999;103:525-33. (Pubitemid 29094053)
54. Sasser JM, Molnar M, Baylis C. Relaxin ameliorates hypertension and increases nitric oxide metabolite excretion in angiotensin II but not N(ω)-nitro-L-arginine methyl ester hypertensive rats. Hypertension. 2011;58:197-204.
55. Debrah DO, Conrad KP, Jeyabalan A, Danielson LA, Shroff SG. Relaxin increases cardiac output and reduces systemic arterial load in hypertensive rats. Hypertension. 2005;46:745-50. (Pubitemid 43186748)
56. Jelinic M, Leo CH, Uiterweer ED, et al. Localization of relaxin receptors in arteries and veins, and region-specific increases in compliance and bradykinin-mediated relaxation after in vivo serelaxin treatment. FASEB J. 2014;28:275-87.
57. Fallick C, Sobotka PA, Dunlap ME. Sympathetically mediated changes in capacitance: redistribution of the venous reservoir as a cause of decompensation. Circ Heart Fail. 2011;4:669-75.
58. Perna AM, Masini E, Nistri S, et al. Novel drug development opportunity for relaxin in acute myocardial infarction: evidences from a swine model. FASEB J. 2005;19:1525-7. (Pubitemid 41279019)
59. Nistri S, Pini A, Sassoli C, et al. Relaxin promotes growth and maturation of mouse neonatal cardiomyocytes in vitro: clues for cardiac regeneration. J Cell Mol Med. 2012;16:507-19.
60. Perna AM, Masini E, Nistri S, Bani Sacchi T, Bigazzi M, Bani D. Human recombinant relaxin reduces heart injury and improves ventricular performance in a swine model of acute myocardial infarction. Ann N Y Acad Sci. 2005;1041:431-3. (Pubitemid 41132281)
61. Málek F, Ošťádal P, Pařenica J, et al. Uric acid, allopurinol therapy, and mortality in patients with acute heart failure - results of the Acute HEart FAilure Database registry. J Crit Care. 2012;27:737.e11-24.
62. Alimonda AL, Núñez J, Núñez E, et al. Hyperuricemia in acute heart failure. More than a simple spectator? Eur J Intern Med. 2009;20:74-9.
63. Collino M, Rogazzo M, Pini A, et al. Acute treatment with relaxin protects the kidney against ischaemia/reperfusion injury. J Cell Mol Med. 2013;17:1494-505.
64. Boehnert MU, Armbruster FP, Hilbig H. Relaxin as a protective substance in the preserving solution for liver transplantation: spectrophotometric in vivo imaging of local oxygen supply in an isolated perfused rat liver model. Ann N Y Acad Sci. 2009;1160:320-1.
65. Boehnert MU, Hilbig H, Armbruster FP. Relaxin as an additional protective substance in preserving and reperfusion solution for liver transplantation, shown in a model of isolated perfused rat liver. Ann N Y Acad Sci. 2005;1041:434-40. (Pubitemid 41132282)
66. Samuel CS, Unemori EN, Mookerjee I, et al. Relaxin modulates cardiac fibroblast proliferation, differentiation, and collagen production and reverses cardiac fibrosis in vivo. Endocrinology. 2004;145:4125-33. (Pubitemid 39120561)
67. Conrad KP, Schroff SG. Effects of relaxin on arterial dilation, remodeling, and mechanical properties. Curr Hypertens Rep. 2011;13:409-20.
68. Mookerjee I, Unemori EN, Du XJ, Tregear GW, Samuel CS. Relaxin modulates fibroblast function, collagen production, and matrix metalloproteinase-2 expression by cardiac fibroblasts. Ann N Y Acad Sci. 2005;1041:190-3. (Pubitemid 41132246)
69. Samuel CS, Zhao C, Bathgate RA, et al. The relaxin geneknockout mouse: a model of progressive fibrosis. Ann N Y Acad Sci. 2005;1041:173-81. (Pubitemid 41132243)
70. Samuel CS, Cendrawan S, Gao XM, et al. Relaxin remodels fibrotic healing following myocardial infarction. Lab Invest. 2011;91:675-90.
71. Du XJ, Xu Q, Lekgabe E, et al. Reversal of cardiac fibrosis and related dysfunction by relaxin. Ann N Y Acad Sci. 2009;1160: 278-84.
72. Sassoli C, Chellini F, Pini A, et al. Relaxin prevents cardiac fibroblast-myofibroblast transition via notch-1-mediated inhibition of TGF-b/Smad3 signaling. PLoS One. 2013;8:e63896.
73. Chow BS, Chew EG, Zhao C, Bathgate RA, Hewitson TD, Samuel CS. Relaxin signals through a RXFP1-pERK-nNOS-NO- cGMP-dependent pathway to up-regulate matrix metalloproteinases: the additional involvement of iNOS. PLoS One. 2012;7:e42714.
74. Parikh A, Patel D, McTiernan CF, et al. Relaxin suppresses atrial fibrillation by reversing fibrosis andmyocyte hypertrophy and increasing conduction velocity and sodium current in spontaneously hypertensive rat hearts. Circ Res. 2013;113:313-21.
75. Fallowfield J, Hayden A, Snowdon V, et al. Relaxin modulates human and rat hepatic myofibroblast function and ameliorates portal hypertension in vivo. Hepatology. 2013 (Epub ahead of print).
76. Bennett RG, Kharbanda KK, Tuma DJ. Inhibition of markers of hepatic stellate cell activation by the hormone relaxin. Biochem Pharmacol. 2003;66:867-74. (Pubitemid 37011425)
77. Bennett RG, Heimann DG, Tuma DJ. Relaxin reduces fibrosis in models of progressive and established hepatic fibrosis. Ann N Y Acad Sci. 2009;1160:348-9.
78. Bennett RG, Heimann DG, Singh S, Simpson RL, Tuma DJ. Relaxin decreases the severity of established hepatic fibrosis in mice. Liver Int. 2013 (Epub ahead of print).
79. Gukathasan N, Mehran R. Acute coronary syndromes: advances in antithrombotics. Curr Atheroscler Rep. 2013;15:318.
80. Chen SA, Perlman AJ, Spanski N, et al. The pharmacokinetics of recombinant human relaxin in nonpregnant women after intravenous, intravaginal, and intracervical administration. Pharm Res. 1993;10:834-8. (Pubitemid 23167564)
81. Stough WG, O'Connor CM, Gheorghiade M. Overview of current noninodilator therapies for acute heart failure syndromes. Am J Cardiol. 2005;96(6A):41G-6G. (Pubitemid 41338073)
82. Metra M, Teerlink JR, Voors AA, et al. Vasodilators in the treatment of acute heart failure: what we know, what we don't. Heart Fail Rev. 2009;14:299-307.
83. Moore XL, Tan SL, Lo CY, et al. Relaxin antagonizes hypertrophy and apoptosis in neonatal rat cardiomyocytes. Endocrinology. 2007;148:1582-9.
84. Mookerjee I, Hewitson TD, Halls ML, et al. Relaxin inhibits renal myofibroblast differentiation via RXFP1, the nitric oxide pathway, and Smad2. FASEB J. 2009;23:1219-29.
85. Wilson BC, Rappaport R. An in vitro study of the protective effect of relaxin on brain tissue under ischemic stress. Ann N Y Acad Sci. 2009;1160:265-8.
86. Heeg MH, Koziolek MJ, Vasko R, et al. The antifibrotic effects of relaxin in human renal fibroblasts are mediated in part by inhibition of the Smad2 pathway. Kidney Int. 2005;68:96-109. (Pubitemid 43181367)
87. Brecht A, Bartsch C, Baumann G, Stangl K, Dschietzig T. Relaxin inhibits early steps in vascular inflammation. Regul Pept. 2011;166:76-82.
88. Armbruster FP, Grön HJ, Maier I, et al. A sensitive homologous radioimmunoassay for human relaxin-2 (h-RLX-2) based on antibodies characterized by epitope mapping studies. Eur J Med Res. 2001;6:1-9.
89. Fisher C, Berry C, Blue L, Morton JJ, McMurray J. N-terminal pro B type natriuretic peptide, but not the new putative cardiac hormone relaxin, predicts prognosis in patients with chronic heart failure. Heart. 2003;89:879-81. (Pubitemid 36920811)
90. Dschietzig T, Richter C, Bartsch C, et al. The pregnancy hormone relaxin is a player in human heart failure. FASEB J. 2001;15:2187-95. (Pubitemid 32927936)
91. Kupari M, Mikkola TS, Turto H, Lommi J. Is the pregnancy hormone relaxin an important player in human heart failure? Eur J Heart Fail. 2005;7:195-8. (Pubitemid 40215612)
92. Callander GE, Thomas WG, Bathgate RA. Prolonged RXFP1 and RXFP2 signaling can be explained by poor internalization and a lack of beta-arrestin recruitment. Am J Physiol Cell Physiol. 2009;296:C1058-66.
93. 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.
94. Hjalmarson A, Goldstein S, Fagerberg B, et al. Effects of controlled- release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/ XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). MERIT-HF Study Group. JAMA. 2000;283: 1295-302. (Pubitemid 30129796)
95. Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362: 772-6. (Pubitemid 37093917)
96. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11-21.
97. Krumholz HM, Lin Z, Keenan PS, et al. Relationship between hospital readmission and mortality rates for patients hospitalized with acute myocardial infarction, heart failure, or pneumonia. JAMA. 2013;309:587-93.
98. Vaduganathan M, Bonow RO, Gheorghiade M. Thirty-day readmissions: the clock is ticking. JAMA. 2013;309:345-6.
99. Gorodeski EZ, Starling RC, Blackstone EH. Are all readmissions bad readmissions? N Engl J Med. 2010;363:297-8.
100. Gheorghiade M, Vaduganathan M, Fonarow GC, Bonow RO. Rehospitalization for heart failure: problems and perspectives. J Am Coll Cardiol. 2013;61:391-403.
101. Clinicaltrials.gov identifier NCT01870778. http://clinicaltrials. gov/ct2/show/NCT01870778. Accessed January 2014.