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Current Molecular Medicine

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ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

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Review Article

Relaxin and the Cardiovascular System: from Basic Science to Clinical Practice

Author(s): Rafael Clara Martins, Mariana Pintalhão, Adelino Leite-Moreira and Paulo Castro-Chaves*

Volume 20, Issue 3, 2020

Page: [167 - 184] Pages: 18

DOI: 10.2174/1566524019666191023121607

Price: $65

Abstract

The peptide hormone relaxin was originally linked to reproductive physiology, where it is believed to mediate systemic and renal hemodynamic adjustments to pregnancy. Recently, its broad range of effects in the cardiovascular system has been the focus of intensive research regarding its implications under pathological conditions and potential therapeutic potential. An understanding of the multitude of cardioprotective actions prompted the study of serelaxin, recombinant human relaxin-2, for the treatment of acute heart failure. Despite early promising results from phase II studies, recently revealed RELAX-AHF-2 outcomes were rather disappointing and the treatment for acute heart failure remains an unmet medical need. This article reviews the physiologic actions of relaxin on the cardiovascular system and its relevance in the pathophysiology of cardiovascular disease. We summarize the most updated clinical data and discuss future directions of serelaxin for the treatment of acute heart failure. This should encourage additional work to determine how can relaxin's beneficial effects be exploited for the treatment of cardiovascular disease.

Keywords: Relaxin, cardiovascular system, biomarker, acute heart failure, cardiovascular drugs, vasodilator

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[1]
Grossman J, Frishman WH. Relaxin: a new approach for the treatment of acute congestive heart failure. Cardiol Rev 2010; 18(6): 305-12.
[http://dx.doi.org/10.1097/CRD.0b013e3181f493e3] [PMID: 20926940]
[2]
Haugaard-Kedström LM, Hossain MA, Daly NL, et al. Solution structure, aggregation behavior, and flexibility of human relaxin-2. ACS Chem Biol 2015; 10(3): 891-900.
[http://dx.doi.org/10.1021/cb500918v] [PMID: 25547165]
[3]
Baccari MC, Bani D. Relaxin and nitric oxide signalling. Curr Protein Pept Sci 2008; 9(6): 638-45.
[http://dx.doi.org/10.2174/138920308786733921] [PMID: 19075752]
[4]
Cernaro V, Lacquaniti A, Lupica R, et al. Relaxin: new pathophysiological aspects and pharmacological perspectives for an old protein. Med Res Rev 2014; 34(1): 77-105.
[http://dx.doi.org/10.1002/med.21277] [PMID: 23401142]
[5]
Pintalhao M, Castro-Chaves P, Vasques-Novoa F, et al. Relaxin serum levels in acute heart failure are associated with pulmonary hypertension and right heart overload. Eur J Heart Fail 2017; 19(2): 218-25.
[http://dx.doi.org/10.1002/ejhf.611] [PMID: 27488261]
[6]
McGuane JT, Debrah JE, Debrah DO, et al. Role of relaxin in maternal systemic and renal vascular adaptations during gestation. Ann N Y Acad Sci 2009; 1160: 304-12.
[http://dx.doi.org/10.1111/j.1749-6632.2009.03829.x] [PMID: 19416209]
[7]
Samuel CS, Parry LJ, Summers RJ. Physiological or pathological--a role for relaxin in the cardiovascular system? Curr Opin Pharmacol 2003; 3(2): 152-8.
[http://dx.doi.org/10.1016/S1471-4892(03)00011-0] [PMID: 12681237]
[8]
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(1): 48-58.
[http://dx.doi.org/10.1038/nrcardio.2009.198] [PMID: 19935741]
[9]
Ratner M. Odds still favor Novartis heart failure drug Serelaxin. Nat Biotechnol 2014; 32(7): 602-3.
[http://dx.doi.org/10.1038/nbt0714-602] [PMID: 25004210]
[10]
van der Westhuizen ET, Halls ML, Samuel CS, et al. Relaxin family peptide receptors--from orphans to therapeutic targets. Drug Discov Today 2008; 13(15-16): 640-51.
[http://dx.doi.org/10.1016/j.drudis.2008.04.002] [PMID: 18675759]
[11]
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 2014; 35(16): 1041-50.
[http://dx.doi.org/10.1093/eurheartj/eht497] [PMID: 24316514]
[12]
Teerlink JR, Kumbhani DJ. RELAXin in Acute Heart Failure-2 - RELAX-AHF-2 2017 [24 October 2017] 2017. Available from: http://www.acc.org/latest-in-cardiology/clinical-trials/2017/05/07/16/09/relax-ahf-2
[13]
Bathgate RA, Halls ML, van der Westhuizen ET, Callander GE, Kocan M, Summers RJ. Relaxin family peptides and their receptors. Physiol Rev 2013; 93(1): 405-80.
[http://dx.doi.org/10.1152/physrev.00001.2012] [PMID: 23303914]
[14]
Feijóo-Bandín S, Aragón-Herrera A, Rodríguez-Penas D, et al. Relaxin-2 in cardiometabolic diseases: mechanisms of action and future perspectives. Front Physiol 2017; 8: 599.
[http://dx.doi.org/10.3389/fphys.2017.00599] [PMID: 28868039]
[15]
Conrad KP, Shroff SG. Effects of relaxin on arterial dilation, remodeling, and mechanical properties. Curr Hypertens Rep 2011; 13(6): 409-20.
[http://dx.doi.org/10.1007/s11906-011-0231-x] [PMID: 21971830]
[16]
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(5): C1058-66.
[http://dx.doi.org/10.1152/ajpcell.00581.2008] [PMID: 19279230]
[17]
Abstracts of the Heart Failure 2017 and the 4th World Congress on Acute Heart Failure, Paris, France. Eur J Heart Failure 2017; May; 29 April - 2 May 2017
[18]
McGuane JT, Debrah JE, Sautina L, et al. Relaxin induces rapid dilation of rodent small renal and human subcutaneous arteries via PI3 kinase and nitric oxide. Endocrinology 2011; 152(7): 2786-96.
[http://dx.doi.org/10.1210/en.2010-1126] [PMID: 21558316]
[19]
Sarwar M, Samuel CS, Bathgate RA, Stewart DR, Summers RJ. Serelaxin-mediated signal transduction in human vascular cells: bell-shaped concentration-response curves reflect differential coupling to G proteins. Br J Pharmacol 2015; 172(4): 1005-19.
[http://dx.doi.org/10.1111/bph.12964] [PMID: 25297987]
[20]
Dschietzig T, Alexiou K, Kinkel HT, Baumann G, Matschke K, Stangl K. The positive inotropic effect of relaxin-2 in human atrial myocardium is preserved in end-stage heart failure: role of G(i)-phosphoinositide-3 kinase signaling. J Card Fail 2011; 17(2): 158-66.
[http://dx.doi.org/10.1016/j.cardfail.2010.08.011] [PMID: 21300306]
[21]
Halls ML, Bathgate RA, Summers RJ. Relaxin family peptide receptors RXFP1 and RXFP2 modulate cAMP signaling by distinct mechanisms. Mol Pharmacol 2006; 70(1): 214-26.
[http://dx.doi.org/10.1124/mol.105.021691] [PMID: 16569707]
[22]
Nguyen BT, Dessauer CW. Relaxin stimulates protein kinase C zeta translocation: requirement for cyclic adenosine 3′,5′-monophosphate production. Mol Endocrinol 2005; 19(4): 1012-23.
[http://dx.doi.org/10.1210/me.2004-0279] [PMID: 15604116]
[23]
Nguyen BT, Yang L, Sanborn BM, Dessauer CW. Phosphoinositide 3-kinase activity is required for biphasic stimulation of cyclic adenosine 3′,5′-monophosphate by relaxin. Mol Endocrinol 2003; 17(6): 1075-84.
[http://dx.doi.org/10.1210/me.2002-0284] [PMID: 12595573]
[24]
Zhang Q, Liu SH, Erikson M, Lewis M, Unemori E. Relaxin activates the MAP kinase pathway in human endometrial stromal cells. J Cell Biochem 2002; 85(3): 536-44.
[http://dx.doi.org/10.1002/jcb.10150] [PMID: 11967993]
[25]
Jeyabalan A, Kerchner LJ, Fisher MC, et al. Matrix metalloproteinase-2 activity, protein, mRNA, and tissue inhibitors in small arteries from pregnant and relaxin-treated nonpregnant rats. Journal of applied physiology (Bethesda, Md : 1985 2006; 100(6): 1955-63.
[http://dx.doi.org/10.1152/japplphysiol.01330.2005]
[26]
Jeyabalan A, Novak J, Doty KD, et al. Vascular matrix metalloproteinase-9 mediates the inhibition of myogenic reactivity in small arteries isolated from rats after short-term administration of relaxin. Endocrinology 2007; 148(1): 189-97.
[http://dx.doi.org/10.1210/en.2006-0989] [PMID: 17053025]
[27]
Palejwala S, Stein DE, Weiss G, Monia BP, Tortoriello D, Goldsmith LT. Relaxin positively regulates matrix metalloproteinase expression in human lower uterine segment fibroblasts using a tyrosine kinase signaling pathway. Endocrinology 2001; 142(8): 3405-13.
[http://dx.doi.org/10.1210/endo.142.8.8295] [PMID: 11459784]
[28]
Unemori EN, Erikson ME, Rocco SE, et al. Relaxin stimulates expression of vascular endothelial growth factor in normal human endometrial cells in vitro and is associated with menometrorrhagia in women. Hum Reprod 1999; 14(3): 800-6.
[http://dx.doi.org/10.1093/humrep/14.3.800] [PMID: 10221717]
[29]
Unemori EN, Lewis M, Constant J, et al. Relaxin induces vascular endothelial growth factor expression and angiogenesis selectively at wound sites. Wound repair and regeneration: official publication of the Wound Healing Society [and] the European Tissue Repair Society 2000; 8(5): 361-70.
[http://dx.doi.org/10.1111/j.1524-475X.2000.00361.x]
[30]
Dschietzig T, Richter C, Bartsch C, et al. The pregnancy hormone relaxin is a player in human heart failure. FASEB J 2001; 15(12): 2187-95.
[http://dx.doi.org/10.1096/fj.01-0070com] [PMID: 11641245]
[31]
Danielson LA, Sherwood OD, Conrad KP. Relaxin is a potent renal vasodilator in conscious rats. J Clin Invest 1999; 103(4): 525-33.
[http://dx.doi.org/10.1172/JCI5630] [PMID: 10021461]
[32]
McGuane JT, Danielson LA, Debrah JE, et al. Angiogenic growth factors are new and essential players in the sustained relaxin vasodilatory pathway in rodents and humans. Hypertension (Dallas, Tex: 1979) 2011; 57(6): 1151-60.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.110.165027]
[33]
Failli P, Nistri S, Quattrone S, et al. Relaxin up-regulates inducible nitric oxide synthase expression and nitric oxide generation in rat coronary endothelial cells. FASEB J 2002; 16(2): 252-4.
[http://dx.doi.org/10.1096/fj.01-0569fje] [PMID: 11744624]
[34]
Dschietzig T, Bartsch C, Richter C, Laule M, Baumann G, Stangl K. Relaxin, a pregnancy hormone, is a functional endothelin-1 antagonist: attenuation of endothelin-1-mediated vasoconstriction by stimulation of endothelin type-B receptor expression via ERK-1/2 and nuclear factor-kappaB. Circ Res 2003; 92(1): 32-40.
[http://dx.doi.org/10.1161/01.RES.0000051884.27117.7E] [PMID: 12522118]
[35]
Dschietzig T, Bartsch C, Stangl V, Baumann G, Stangl K. Identification of the pregnancy hormone relaxin as glucocorticoid receptor agonist. FASEB J 2004; 18(13): 1536-8.
[http://dx.doi.org/10.1096/fj.03-1120fje] [PMID: 15289446]
[36]
Halls ML, Bathgate RA, Summers RJ. Comparison of signaling pathways activated by the relaxin family peptide receptors, RXFP1 and RXFP2, using reporter genes. J Pharmacol Exp Ther 2007; 320(1): 281-90.
[http://dx.doi.org/10.1124/jpet.106.113225] [PMID: 17065365]
[37]
Neverova N, Teerlink JR. Serelaxin: a potential new drug for the treatment of acute heart failure. Expert Opin Investig Drugs 2014; 23(7): 1017-26.
[http://dx.doi.org/10.1517/13543784.2014.924504] [PMID: 24865798]
[38]
Marshall SA, Senadheera SN, Parry LJ, Girling JE. The role of relaxin in normal and abnormal uterine function during the menstrual cycle and early pregnancy. Reprod Sci 2017; 24(3): 342-54.
[http://dx.doi.org/10.1177/1933719116657189] [PMID: 27365367]
[39]
Parry LJ, Vodstrcil LA. Relaxin physiology in the female reproductive tract during pregnancy. Adv Exp Med Biol 2007; 612: 34-48.
[http://dx.doi.org/10.1007/978-0-387-74672-2_4] [PMID: 18161480]
[40]
Vannuccini S, Bocchi C, Severi FM, Challis JR, Petraglia F. Endocrinology of human parturition. Ann Endocrinol (Paris) 2016; 77(2): 105-13.
[http://dx.doi.org/10.1016/j.ando.2016.04.025] [PMID: 27155774]
[41]
Teichman SL, Unemori E, Dschietzig T, et al. Relaxin, a pleiotropic vasodilator for the treatment of heart failure. Heart Fail Rev 2009; 14(4): 321-9.
[http://dx.doi.org/10.1007/s10741-008-9129-3] [PMID: 19101795]
[42]
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(7): 431-41.
[http://dx.doi.org/10.1093/eurheartj/eht459] [PMID: 24255129]
[43]
Fisher C, MacLean M, Morecroft I, et al. Is the pregnancy hormone relaxin also a vasodilator peptide secreted by the heart? Circulation 2002; 106(3): 292-5.
[http://dx.doi.org/10.1161/01.CIR.0000025630.05387.45] [PMID: 12119241]
[44]
Petersen LK, Svane D, Uldbjerg N, Forman A. Effects of human relaxin on isolated rat and human myometrium and uteroplacental arteries. Obstet Gynecol 1991; 78(5 Pt 1): 757-62.
[PMID: 1923192]
[45]
Dombrowski MP, Savoy-Moore RT, Swartz K, et al. Effect of porcine relaxin on the human umbilical artery. J Reprod Med 1986; 31(6): 467-72.
[PMID: 3525833]
[46]
Marshall SA, Leo CH, Girling JE, et al. Relaxin treatment reduces angiotensin II-induced vasoconstriction in pregnancy and protects against endothelial dysfunction. Biol Reprod 2017; 96(4): 895-906.
[http://dx.doi.org/10.1093/biolre/iox023] [PMID: 28379296]
[47]
Kompa AR, Samuel CS, Summers RJ. Inotropic responses to human gene 2 (B29) relaxin in a rat model of myocardial infarction (MI): effect of pertussis toxin. Br J Pharmacol 2002; 137(5): 710-8.
[http://dx.doi.org/10.1038/sj.bjp.0704922] [PMID: 12381685]
[48]
Osheroff PL, Ho WH. Expression of relaxin mRNA and relaxin receptors in postnatal and adult rat brains and hearts. Localization and developmental patterns. J Biol Chem 1993; 268(20): 15193-9.
[PMID: 8392068]
[49]
Toth M, Taskinen P, Ruskoaho H. Relaxin stimulates atrial natriuretic peptide secretion in perfused rat heart. J Endocrinol 1996; 150(3): 487-95.
[http://dx.doi.org/10.1677/joe.0.1500487] [PMID: 8882168]
[50]
Shaw EE, Wood P, Kulpa J, Yang FH, Summerlee AJ, Pyle WG. Relaxin alters cardiac myofilament function through a PKC-dependent pathway. Am J Physiol Heart Circ Physiol 2009; 297(1): H29-36.
[http://dx.doi.org/10.1152/ajpheart.00482.2008] [PMID: 19429819]
[51]
Masini E, Bani D, Bello MG, Bigazzi M, Mannaioni PF, Sacchi TB. Relaxin counteracts myocardial damage induced by ischemia-reperfusion in isolated guinea pig hearts: evidence for an involvement of nitric oxide. Endocrinology 1997; 138(11): 4713-20.
[http://dx.doi.org/10.1210/endo.138.11.5520] [PMID: 9348198]
[52]
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.
[http://dx.doi.org/10.1196/annals.1282.064] [PMID: 15956741]
[53]
Bani D, Masini E, Bello MG, Bigazzi M, Sacchi TB. Relaxin protects against myocardial injury caused by ischemia and reperfusion in rat heart. Am J Pathol 1998; 152(5): 1367-76.
[PMID: 9588905]
[54]
Beiert T, Tiyerili V, Knappe V, et al. Relaxin reduces susceptibility to post-infarct atrial fibrillation in mice due to anti-fibrotic and anti-inflammatory properties. Biochem Biophys Res Commun 2017; 490(3): 643-9.
[http://dx.doi.org/10.1016/j.bbrc.2017.06.091] [PMID: 28634079]
[55]
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(9): 4125-33.
[http://dx.doi.org/10.1210/en.2004-0209] [PMID: 15155573]
[56]
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.
[http://dx.doi.org/10.1196/annals.1282.028] [PMID: 15956706]
[57]
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(3): 182-90.
[http://dx.doi.org/10.1016/j.cardfail.2009.01.008] [PMID: 19327619]
[58]
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(11): 3192-7.
[http://dx.doi.org/10.1681/ASN.2005090950] [PMID: 17035617]
[59]
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(2): 75-82.
[http://dx.doi.org/10.1007/s11897-010-0010-z] [PMID: 20424993]
[60]
Teerlink JR, Saini R, Gullestad L, et al. RELAX-REPEAT: A multicenter, prospective, randomized, double-blind study evaluating the safety and tolerability of repeat doses of serelaxin in patients with chronic heart failure. J Card Fail 2016; 22: S14.
[http://dx.doi.org/10.1016/j.cardfail.2016.06.051]
[61]
Voors AA, Dahlke M, Meyer S, et al. Renal hemodynamic effects of serelaxin in patients with chronic heart failure: a randomized, placebo-controlled study. Circ Heart Fail 2014; 7(6): 994-1002.
[http://dx.doi.org/10.1161/CIRCHEARTFAILURE.114.001536] [PMID: 25286914]
[62]
Sato N, Takahashi W, Hirayama A, et al. Multicenter, randomized, double-blinded, placebo-controlled phase II study of serelaxin in japanese patients with acute heart failure. Circulation J 2015; 79(6): 1237-47.
[63]
Teerlink JR, Cotter G, Davison BA, et al. RELAXin in Acute Heart Failure (RELAX-AHF) Investigators. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Lancet 2013; 381(9860): 29-39.
[http://dx.doi.org/10.1016/S0140-6736(12)61855-8] [PMID: 23141816]
[64]
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(9673): 1429-39.
[http://dx.doi.org/10.1016/S0140-6736(09)60622-X] [PMID: 19329178]
[65]
Dahlke M, Ng D, Yamaguchi M, et al. Safety and tolerability of serelaxin, a recombinant human relaxin-2 in development for the treatment of acute heart failure, in healthy Japanese volunteers and a comparison of pharmacokinetics and pharmacodynamics in healthy Japanese and Caucasian populations. J Clin Pharmacol 2015; 55(4): 415-22.
[http://dx.doi.org/10.1002/jcph.433] [PMID: 25408331]
[66]
Khanna D, Clements PJ, Furst DE, et al. Relaxin investigators and the scleroderma clinical trials consortium. recombinant human relaxin in the treatment of systemic sclerosis with diffuse cutaneous involvement: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2009; 60(4): 1102-11.
[http://dx.doi.org/10.1002/art.24380] [PMID: 19333948]
[67]
Conrad KP, Gandley RE, Ogawa T, Nakanishi S, Danielson LA. Endothelin mediates renal vasodilation and hyperfiltration during pregnancy in chronically instrumented conscious rats. Am J Physiol 1999; 276(5): F767-76.
[PMID: 10330059]
[68]
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(4): R1298-304.
[http://dx.doi.org/10.1152/ajpregu.2000.279.4.R1298] [PMID: 11003996]
[69]
Gellai M, De Wolf R, Fletcher T, Nambi P. Contribution of endogenous endothelin-1 to the maintenance of vascular tone: role of nitric oxide. Pharmacology 1997; 55(6): 299-308.
[http://dx.doi.org/10.1159/000139542] [PMID: 9413859]
[70]
Nose-Ogura S, Yoshino O, Yamada-Nomoto K, et al. Oral contraceptive therapy reduces serum relaxin-2 in elite female athletes. J Obstet Gynaecol Res 2017; 43(3): 530-5.
[http://dx.doi.org/10.1111/jog.13226] [PMID: 28026087]
[71]
Ng TM, Goland S, Elkayam U. Relaxin for the treatment of acute decompensated heart failure: pharmacology, mechanisms of action, and clinical evidence. Cardiol Rev 2016; 24(4): 194-204.
[http://dx.doi.org/10.1097/CRD.0000000000000089] [PMID: 26331289]
[72]
Wolf JM, Cameron KL, Clifton KB, Owens BD. Serum relaxin levels in young athletic men are comparable with those in women. Orthopedics 2013; 36(2): 128-31.
[http://dx.doi.org/10.3928/01477447-20130122-06] [PMID: 23379736]
[73]
Dragoo JL, Castillo TN, Korotkova TA, Kennedy AC, Kim HJ, Stewart DR. Trends in serum relaxin concentration among elite collegiate female athletes. Int J Womens Health 2011; 3: 19-24.
[PMID: 21339934]
[74]
Lafayette RA, Hladunewich MA, Derby G, Blouch K, Druzin ML, Myers BD. Serum relaxin levels and kidney function in late pregnancy with or without preeclampsia. Clin Nephrol 2011; 75(3): 226-32.
[http://dx.doi.org/10.5414/CNP75226] [PMID: 21329633]
[75]
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(8): 879-81.
[http://dx.doi.org/10.1136/heart.89.8.879] [PMID: 12860863]
[76]
Heringlake M, Kox T, Poeling J, et al. The effects of physical exercise on plasma levels of relaxin, NTproANP, and NTproBNP in patients with ischemic heart disease. Eur J Med Res 2009; 14(3): 106-12.
[http://dx.doi.org/10.1186/2047-783X-14-3-106] [PMID: 19380280]
[77]
Fisher C, Al-Benna S, Kirk A, Morton JJ, McMurray JJ. Transcardiac and transpulmonary gradients in the putative new cardiovascular hormone relaxin. Heart 2003; 89(7): 789-90.
[http://dx.doi.org/10.1136/heart.89.7.789] [PMID: 12807861]
[78]
Kupari M, Turto H, Lommi J, Mäkijärvi M, Parikka H. Transcardiac gradients of N-terminal B-type natriuretic peptide in aortic valve stenosis. Eur J Heart Fail 2005; 7(5): 809-14.
[http://dx.doi.org/10.1016/j.ejheart.2004.10.011] [PMID: 16087135]
[79]
Kapelouzou A, Tsourelis L, Kaklamanis L, Degiannis D, Kogerakis N, Cokkinos DV. Serum and tissue biomarkers in aortic stenosis. Glob Cardiol Sci Pract 2015; 2015(4): 49.
[http://dx.doi.org/10.5339/gcsp.2015.49] [PMID: 26779524]
[80]
Krüger S, Graf J, Merx MW, et al. Relaxin kinetics during dynamic exercise in patients with chronic heart failure. Eur J Intern Med 2004; 15(1): 54-6.
[http://dx.doi.org/10.1016/j.ejim.2003.11.009] [PMID: 15066650]
[81]
Mazurek JA, Horne BD, Kelesidis I, Salamon JN, Zolty R. Relaxin levels in pulmonary hypertension: a comparison between pulmonary arterial hypertension and diastolic heart failure-induced pulmonary hypertension. The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 2013; 32(3): 371-4.
[http://dx.doi.org/10.1016/j.healun.2012.11.030]
[82]
Damp J, Givertz MM, Semigran M, et al. Relaxin-2 and Soluble Flt1 Levels in Peripartum Cardiomyopathy: Results of the Multicenter IPAC Study. JACC Heart Fail 2016; 4(5): 380-8.
[http://dx.doi.org/10.1016/j.jchf.2016.01.004] [PMID: 26970832]
[83]
Emmens JE, Ter Maaten JM, Voors AA. Are circulating relaxin levels related to pulmonary hypertension in patients with heart failure? Eur J Heart Fail 2017; 19(7): 958-60.
[http://dx.doi.org/10.1002/ejhf.791] [PMID: 28244195]
[84]
Gedikli O, Yilmaz H, Kiris A, et al. Circulating levels of relaxin and its relation to cardiovascular function in patients with hypertension. Blood Press 2009; 18(1-2): 68-73.
[http://dx.doi.org/10.1080/08037050902864086] [PMID: 19353414]
[85]
Papadopoulos DP, Mourouzis I, Faselis C, et al. Masked hypertension and atherogenesis: the impact of apelin and relaxin plasma levels. J Clin Hypertens (Greenwich) 2013; 15(5): 333-6.
[http://dx.doi.org/10.1111/jch.12075] [PMID: 23614848]
[86]
Papadopoulos DP, Makris T, Perrea D, et al. Apelin and relaxin plasma levels in young healthy offspring of patients with essential hypertension. J Clin Hypertens (Greenwich) 2014; 16(3): 198-201.
[http://dx.doi.org/10.1111/jch.12260] [PMID: 24708381]
[87]
Zhou H, Qu X, Gao Z, et al. Relaxin Level in Patients With Atrial Fibrillation and Association with Heart Failure Occurrence: A STROBE Compliant Article. Medicine (Baltimore) 2016; 95(21) e3664
[http://dx.doi.org/10.1097/MD.0000000000003664] [PMID: 27227926]
[88]
Miro O, Herrero-Puente P, Prieto B, et al. The subset of patients with acute heart failure able to secrete relaxin-2 at pregnancy concentrations could have a longer survival: a pilot study. Biomarkers: biochemical indicators of exposure, response, and susceptibility to chemicals 2018; 23 6(573): 9-188.
[http://dx.doi.org/10.1080/1354750X.2018.1463564]
[89]
Pintalhao M, Castro-Chaves P, Bettencourt P. Reply. Eur J Heart Fail 2017; 19(7): 961.
[http://dx.doi.org/10.1002/ejhf.836] [PMID: 28474436]
[90]
Teerlink JR. The role of endothelin in the pathogenesis of heart failure. Curr Cardiol Rep 2002; 4(3): 206-12.
[http://dx.doi.org/10.1007/s11886-002-0052-2] [PMID: 11960589]
[91]
Simon J, Nemeth E, Nemes A, et al. Circulating relaxin-1 level is a surrogate marker of myocardial fibrosis in HFrEF. Front Physiol 2019; 10: 690.
[http://dx.doi.org/10.3389/fphys.2019.00690] [PMID: 31231242]
[92]
Tan AY, Zimetbaum P. Atrial fibrillation and atrial fibrosis. J Cardiovasc Pharmacol 2011; 57(6): 625-9.
[http://dx.doi.org/10.1097/FJC.0b013e3182073c78] [PMID: 21633248]
[93]
Henry BL, Gabris B, Li Q, et al. Relaxin suppresses atrial fibrillation in aged rats by reversing fibrosis and upregulating Na+ channels. Heart Rhythm 2016; 13(4): 983-91.
[http://dx.doi.org/10.1016/j.hrthm.2015.12.030] [PMID: 26711798]
[94]
Parikh A, Patel D, McTiernan CF, et al. Relaxin suppresses atrial fibrillation by reversing fibrosis and myocyte hypertrophy and increasing conduction velocity and sodium current in spontaneously hypertensive rat hearts. Circ Res 2013; 113(3): 313-21.
[http://dx.doi.org/10.1161/CIRCRESAHA.113.301646] [PMID: 23748429]
[95]
Luetkens JA, Wolpers AC, Beiert T, et al. Cardiac magnetic resonance using late gadolinium enhancement and atrial T1 mapping predicts poor outcome in patients with atrial fibrillation after catheter ablation therapy. Sci Rep 2018; 8(1): 13618.
[http://dx.doi.org/10.1038/s41598-018-31916-2] [PMID: 30206274]
[96]
Qu X, Chen L, Sun L, et al. Serum relaxin level predicts recurrence of atrial fibrillation after radiofrequency catheter ablation. Heart Vessels 2019; 34(9): 1543-51.
[http://dx.doi.org/10.1007/s00380-019-01386-1] [PMID: 30937522]
[97]
Zhang X, Zhu M, Zhao M, et al. The plasma levels of relaxin-2 and relaxin-3 in patients with diabetes. Clin Biochem 2013; 46(16-17): 1713-6.
[http://dx.doi.org/10.1016/j.clinbiochem.2013.08.007] [PMID: 23994775]
[98]
Szepietowska B, Gorska M, Szelachowska M. Plasma relaxin concentration is related to beta-cell function and insulin sensitivity in women with type 2 diabetes mellitus. Diabetes Res Clin Pract 2008; 79(3): e1-3.
[http://dx.doi.org/10.1016/j.diabres.2007.10.017] [PMID: 18035445]
[99]
Hocher B, Ziebig R, Krause R, et al. Relaxin is an independent risk factor predicting death in male patients with end-stage kidney disease. Circulation 2004; 109(19): 2266-8.
[http://dx.doi.org/10.1161/01.CIR.0000128598.72920.B5] [PMID: 15136497]
[100]
Binder C, Simon A, Binder L, et al. Elevated concentrations of serum relaxin are associated with metastatic disease in breast cancer patients. Breast Cancer Res Treat 2004; 87(2): 157-66.
[http://dx.doi.org/10.1023/B:BREA.0000041622.30169.16] [PMID: 15377840]
[101]
Ren P, Yu ZT, Xiu L, Wang M, Liu HM. Elevated serum levels of human relaxin-2 in patients with esophageal squamous cell carcinoma. World J Gastroenterol 2013; 19(15): 2412-8.
[http://dx.doi.org/10.3748/wjg.v19.i15.2412] [PMID: 23613637]
[102]
Dragoo JL, Castillo TN, Braun HJ, Ridley BA, Kennedy AC, Golish SR. Prospective correlation between serum relaxin concentration and anterior cruciate ligament tears among elite collegiate female athletes. Am J Sports Med 2011; 39(10): 2175-80.
[http://dx.doi.org/10.1177/0363546511413378] [PMID: 21737831]
[103]
Owens BD, Cameron KL, Clifton KB, Svoboda SJ, Wolf JM. Association between serum relaxin and subsequent shoulder instability. Orthopedics 2016; 39(4): e724-8.
[http://dx.doi.org/10.3928/01477447-20160421-01] [PMID: 27111077]
[104]
Garvin R, Burns A. Serum relaxin levels in subjects with multiple sclerosis. Italian journal of anatomy and embryology = Archivio italiano di anatomia ed embriologia 2016; 121(1): 51-9.
[105]
Giordano N, Papakostas P, Lucani B, et al. Serum relaxin in systemic sclerosis. J Rheumatol 2005; 32(11): 2164-6.
[PMID: 16265695]
[106]
Vogel I, Glavind-Kristensen M, Thorsen P, Armbruster FP, Uldbjerg N. S-relaxin as a predictor of preterm delivery in women with symptoms of preterm labour. BJOG 2002; 109(9): 977-82.
[http://dx.doi.org/10.1111/j.1471-0528.2002.01187.x] [PMID: 12269692]
[107]
Vogel I, Goepfert AR, Møller HJ, Cliver S, Thorsen P, Andrews WW. Early mid-trimester serum relaxin, soluble CD163, and cervical length in women at high risk for preterm delivery. Am J Obstet Gynecol 2006; 195(1): 208-14.
[http://dx.doi.org/10.1016/j.ajog.2005.12.009] [PMID: 16600167]
[108]
Bramham K, Seed PT, Lightstone L, et al. Diagnostic and predictive biomarkers for pre-eclampsia in patients with established hypertension and chronic kidney disease. Kidney Int 2016; 89(4): 874-85.
[http://dx.doi.org/10.1016/j.kint.2015.10.012] [PMID: 26924064]
[109]
Weiss G, Teichman S, Stewart D, et al. Recombinant human relaxin versus placebo for cervical ripening: a double-blind randomised trial in pregnant women scheduled for induction of labour. BMC Pregnancy Childbirth 2016; 16: 260.
[http://dx.doi.org/10.1186/s12884-016-1046-1] [PMID: 27596360]
[110]
Samuel CS, Royce SG, Hewitson TD, Denton KM, Cooney TE, Bennett RG. Anti-fibrotic actions of relaxin. Br J Pharmacol 2017; 174(10): 962-76.
[http://dx.doi.org/10.1111/bph.13529] [PMID: 27250825]
[111]
Ponikowski P, Metra M, Teerlink JR, et al. Design of the RELAXin in acute heart failure study. Am Heart J 2012; 163(2): 149-55.e1.
[http://dx.doi.org/10.1016/j.ahj.2011.10.009] [PMID: 22305830]
[112]
Metra M, Cotter G, Davison BA, et al. RELAX-AHF Investigators. 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(2): 196-206.
[http://dx.doi.org/10.1016/j.jacc.2012.11.005] [PMID: 23273292]
[113]
ClinicalTrials.gov. Safety of repeat doses of IV serelaxin in subjects with chronic heart failure (RELAX-REPEAT) 2013 [25 October 2017] 2013. Available from:. https://clinicaltrials.gov/ct2/show/NCT01982292
[114]
Teerlink JR, Voors AA, Ponikowski P, et al. Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX-AHF-2 study. Eur J Heart Fail 2017; 19(6): 800-9.
[http://dx.doi.org/10.1002/ejhf.830] [PMID: 28452195]
[115]
Teerlink JR. RELAX-AHF-2: Serelaxin does not reduce risk for CV death worsening HF 2017.
[116]
Sato N, Lam CSP, Teerlink JR, et al. The efficacy, safety, and tolerability of additional serelaxin administration to standard therapy in asian patients with acute heart failure: The RELAX-AHF-ASIA trial. J Card Fail 2018; 24(11): 812.
[http://dx.doi.org/10.1016/j.cardfail.2018.11.007]
[117]
Maggioni AP, López-Sendón J, Nielsen OW, et al. Efficacy and safety of serelaxin when added to standard of care in patients with acute heart failure: results from a PROBE study, RELAX-AHF-EU. Eur J Heart Fail 2019; 21(3): 322-33.
[http://dx.doi.org/10.1002/ejhf.1368] [PMID: 30604559]
[118]
Felker GM, Teerlink JR, Butler J, et al. Effect of serelaxin on mode of death in acute heart failure: results from the RELAX-AHF study. J Am Coll Cardiol 2014; 64(15): 1591-8.
[http://dx.doi.org/10.1016/j.jacc.2014.05.071] [PMID: 25301463]
[119]
Liu LC, Voors AA, Teerlink JR, et al. Effects of serelaxin in acute heart failure patients with renal impairment: results from RELAX-AHF. Clin Res Cardiol 2016; 105(9): 727-37.
[http://dx.doi.org/10.1007/s00392-016-0979-8] [PMID: 27017514]
[120]
Hollenberg SM. Vasodilators in acute heart failure. Heart Fail Rev 2007; 12(2): 143-7.
[http://dx.doi.org/10.1007/s10741-007-9017-2] [PMID: 17447137]
[121]
Pang PS, Teerlink JR, Voors AA, et al. Use of high-sensitivity troponin t to identify patients with acute heart failure at lower risk for adverse outcomes: An exploratory analysis From the RELAX-AHF Trial. JACC Heart Fail 2016; 4(7): 591-9.
[http://dx.doi.org/10.1016/j.jchf.2016.02.009] [PMID: 27039129]
[122]
Wang D, Zhu H, Yang Q, Sun Y. Effects of relaxin on cardiac fibrosis, apoptosis, and tachyarrhythmia in rats with myocardial infarction. Biomed Pharmacother Biomed Pharmacother 2016; 84: 348-55.
[http://dx.doi.org/10.1016/j.biopha.2016.09.054]
[123]
Zhang J, Qi YF, Geng B, et al. Effect of relaxin on myocardial ischemia injury induced by isoproterenol. Peptides 2005; 26(9): 1632-9.
[http://dx.doi.org/10.1016/j.peptides.2005.02.008] [PMID: 16112403]
[124]
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(11): 1525-7.
[http://dx.doi.org/10.1096/fj.04-3664fje] [PMID: 16009702]
[125]
Felker GM, Mentz RJ, Teerlink JR, et al. Serial high sensitivity cardiac troponin T measurement in acute heart failure: insights from the RELAX-AHF study. Eur J Heart Fail 2015; 17(12): 1262-70.
[http://dx.doi.org/10.1002/ejhf.341] [PMID: 26333655]
[126]
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(40): 3128-36.
[http://dx.doi.org/10.1093/eurheartj/eht371] [PMID: 23999454]
[127]
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(1): 19-30.
[http://dx.doi.org/10.1007/s11897-013-0180-6] [PMID: 24363020]
[128]
Hernandez AV. Serelaxin: insights into its haemodynamic, biochemical, and clinical effects in acute heart failure. Eur Heart J 2014; 35(7): 410-2.
[http://dx.doi.org/10.1093/eurheartj/eht477] [PMID: 24277752]
[129]
Alexander P, Alkhawam L, Curry J, et al. Lack of evidence for intravenous vasodilators in ED patients with acute heart failure: a systematic review. Am J Emerg Med 2015; 33(2): 133-41.
[http://dx.doi.org/10.1016/j.ajem.2014.09.009] [PMID: 25530194]
[130]
Oktay AA, Shah SJ. Diagnosis and management of heart failure with preserved ejection fraction: 10 key lessons. Curr Cardiol Rev 2015; 11(1): 42-52.
[http://dx.doi.org/10.2174/1573403X09666131117131217] [PMID: 24251461]
[131]
Konstam MA. RELAX-AHF: rising from the doldrums in acute heart failure. Lancet 2013; 381(9860): 5-6.
[http://dx.doi.org/10.1016/S0140-6736(12)61896-0] [PMID: 23141815]
[132]
Ahmed A, Rich MW, Fleg JL, et al. Effects of digoxin on morbidity and mortality in diastolic heart failure: the ancillary digitalis investigation group trial. Circulation 2006; 114(5): 397-403.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.628347] [PMID: 16864724]
[133]
Cleland JG, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J. PEP-CHF Investigators. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006; 27(19): 2338-45.
[http://dx.doi.org/10.1093/eurheartj/ehl250] [PMID: 16963472]
[134]
van Veldhuisen DJ, Cohen-Solal A, Böhm M, et al. SENIORS Investigators. Beta-blockade with nebivolol in elderly heart failure patients with impaired and preserved left ventricular ejection fraction: Data From SENIORS (Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure). J Am Coll Cardiol 2009; 53(23): 2150-8.
[http://dx.doi.org/10.1016/j.jacc.2009.02.046] [PMID: 19497441]
[135]
Kiowski W, Sütsch G, Hunziker P, et al. Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Lancet 1995; 346(8977): 732-6.
[http://dx.doi.org/10.1016/S0140-6736(95)91504-4] [PMID: 7658874]
[136]
Serneri GG, Boddi M, Cecioni I, et al. Cardiac angiotensin II formation in the clinical course of heart failure and its relationship with left ventricular function. Circ Res 2001; 88(9): 961-8.
[http://dx.doi.org/10.1161/hh0901.089882] [PMID: 11349007]
[137]
Yu L, Cao L, Sun J, Li Z, Yao F, Zhou Y. Serelaxin, recombinant human relaxin-2, for heart failure patients: A systematic review and meta-analysis. Medicine (Baltimore) 2018; 97(25)e11010
[http://dx.doi.org/10.1097/MD.0000000000011010] [PMID: 29923986]
[138]
Wang TS, Hellkamp AS, Patel CB, Ezekowitz JA, Fonarow GC, Hernandez AF. Representativeness of RELAX-AHF clinical trial population in acute heart failure. Circ Cardiovasc Qual Outcomes 2014; 7(2): 259-68.
[http://dx.doi.org/10.1161/CIRCOUTCOMES.113.000418] [PMID: 24594552]
[139]
Casten GG, Gilmore HR, Houghton FE, Samuels SS. A new approach to the management of obliterative peripheral arterial disease. Angiology 1960; 11: 408-14.
[http://dx.doi.org/10.1177/000331976001100506] [PMID: 13691417]
[140]
Sonaglia F, Milia P, Caserio M, et al. Efficacy and safety of oral porcine relaxin (pRLX) in adjunct to physical exercise in the treatment of peripheral arterial disease (PAD). Italian J Anatomy Embryol 2013; 118(1 Suppl): 84-91.
[141]
Papoutsis K, Kapelouzou A, Tsilimigras DI, et al. Associations between serum relaxin 2, aneurysm formation/size and severity of atherosclerosis: a preliminary prospective analysis. Acta Pharmacol Sin 2018; 39(7): 1243-8.
[http://dx.doi.org/10.1038/aps.2018.8] [PMID: 29565035]
[142]
Kobalava Z, Villevalde S, Kotovskaya Y, et al. Pharmacokinetics of serelaxin in patients with hepatic impairment: a single-dose, open-label, parallel group study. Br J Clin Pharmacol 2015; 79(6): 937-45.
[http://dx.doi.org/10.1111/bcp.12572] [PMID: 25511105]
[143]
Dahlke M, Halabi A, Canadi J, Tsubouchi C, Machineni S, Pang Y. Pharmacokinetics of serelaxin in patients with severe renal impairment or end-stage renal disease requiring hemodialysis: A single-dose, open-label, parallel-group study. J Clin Pharmacol 2016; 56(4): 474-83.
[http://dx.doi.org/10.1002/jcph.607] [PMID: 26239266]
[144]
Brauser D. RELAX-REPEAT: Multiple Doses of Serelaxin Safe, Tolerable for Chronic Heart Failure 2016. Available from:. https://www.medscape.com/viewarticle/863962#vp_2

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