Current treatments for acute heart failure: focus on serelaxin

References

• Go AS, Mozaffarian D, Roger VL, et al. Executive summary: heart disease and stroke statistics – 2014 update: a report from the American Heart Association. Circulation. 2014;129(3):399–410.
   PubMed Web of Science ®Google Scholar
• Bui AL, Horwich TB, Fonarow GC. Epidemiology and risk profile of heart failure. Nat Rev Cardiol. 2011;8(1):30–41.
   PubMed Web of Science ®Google Scholar
• Felker GM, Adams KF Jr, Konstam MA, O’Connor CM, Gheorghiade M. The problem of decompensated heart failure: Nomenclature, classification, and risk stratification. Am Heart J. 2003;145(Suppl 2):S18–S25.
   Web of Science ®Google Scholar
• Gheorghiade M, Zannad F, Sopko G, et al. Acute heart failure syndromes: current state and framework for future research. Circulation. 2005;112(25):3958–3968.
   PubMed Web of Science ®Google Scholar
• Fonarow GC, Abraham WT, Albert NM, et al. Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF): rationale and design. Am Heart J. 2004;148(1):43–51.
   PubMed Web of Science ®Google Scholar
• Schappert SM, Rechtsteiner EA. Ambulatory medical care utilization estimates for 2006. Natl Health Stat Reports. 2008;(8):1–29.
   Google Scholar
• Adams KF Jr, Fonarow GC, Emerman CL, et al. Characteristics and outcomes of patients hospitalized for heart failure in the United States: Rationale, design, and preliminary observations from the first 100,000 cases in the acute decompensated heart failure national registry (ADHERE). Am Heart J. 2005;149(2):209–216.
   PubMed Web of Science ®Google Scholar
• Nieminen MS, Brutsaert D, Dickstein K, et al. EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population. Eur Heart J. 2006;27(22):2725–2736.
   PubMed Web of Science ®Google Scholar
• Follath F, Yilmaz MB, Delgado JF, et al. Clinical presentation, management and outcomes in the Acute Heart Failure Global Survey of Standard Treatment (ALARM-HF). Intensive Care Med. 2011;37(4):619–626.
   PubMed Web of Science ®Google Scholar
• Fonarow GC, Abraham WT, Albert NM, et al. Influence of a performance-improvement initiative on quality of care for patients hospitalized with heart failure: Results of the organized program to initiate lifesaving treatment in hospitalized patients with heart failure (OPTIMIZE-HF). Arch Intern Med. 2007;167(14):1493–1502.
   PubMed Web of Science ®Google Scholar
• Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol. 2009;53(7):557–573.
   PubMed Web of Science ®Google Scholar
• Solomon SD, Dobson J, Pocock S, et al. Influence of nonfatal hospitalization for heart failure on subsequent mortality in patients with chronic heart failure. Circulation. 2007;116(13):1482–1487.
   PubMed Web of Science ®Google Scholar
• Kociol RD, Hammill BG, Fonarow GC, et al. Generalizability and longitudinal outcomes of a national heart failure clinical registry: Comparison of Acute Decompensated Heart Failure National Registry (ADHERE) and non-ADHERE medicare beneficiaries. Am Heart J. 2010;160(5):885–892.
   PubMed Web of Science ®Google Scholar
• Giamouzis G, Kalogeropoulos A, Georgiopoulou V, et al. Hospitalization epidemic in patients with heart failure: Risk factors, risk prediction, knowledge gaps, and future directions. J Card Fail. 2011;17(1):54–75.
   PubMed Web of Science ®Google Scholar
• Gheorghiade M, Abraham WT, Albert NM, et al. Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure. JAMA. 2006;296(18):2217–2226.
   PubMed Web of Science ®Google Scholar
• Poss J, Link A, Bohm M. Pharmacological treatment of acute heart failure: Current treatment and new targets. Clin Pharmacol Ther. 2013;94(4):499–508.
   Web of Science ®Google Scholar
• Gheorghiade M, Pang PS, Ambrosy AP, et al. A comprehensive, longitudinal description of the in-hospital and post-discharge clinical, laboratory, and neurohormonal course of patients with heart failure who die or are re-hospitalized within 90 days: Analysis from the EVEREST trial. Heart Fail Rev. 2012;17(3):485–509.
   Web of Science ®Google Scholar
• Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the management of heart failure: A report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. J Am Coll Cardiol. 2013;62(16):e147–e239.
   PubMed Web of Science ®Google Scholar
• McMurray JJ, Adamopoulos S, Anker SD, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the european society of cardiology developed in collaboration with the heart failure association (HFA) of the ESC. Eur Heart J. 2012;33(14):1787–1847.
   PubMed Web of Science ®Google Scholar
• De Luca L, Klein L, Udelson JE, et al. Hyponatremia in patients with heart failure. Am J Cardiol. 2005;96(12A):19L–23L.
   Web of Science ®Google Scholar
• Klein L, O’Connor CM, Leimberger JD, et al. Lower serum sodium is associated with increased short-term mortality in hospitalized patients with worsening heart failure: Results from the outcomes of a prospective trial of intravenous milrinone for exacerbations of chronic heart failure (OPTIME-CHF) study. Circulation. 2005;111(19):2454–2460.
   PubMed Web of Science ®Google Scholar
• Schrier RW, Sharma S, Shchekochikhin D. Hyponatraemia: More than just a marker of disease severity? Nat Rev Nephrol. 2013;9(1):37–50.
   PubMed Web of Science ®Google Scholar
• Gheorghiade M, Gattis WA, O’Connor CM, et al. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: A randomized controlled trial. JAMA. 2004;291(16):1963–1971.
   PubMed Web of Science ®Google Scholar
• Rossi J, Bayram M, Udelson JE, et al. Improvement in hyponatremia during hospitalization for worsening heart failure is associated with improved outcomes: Insights from the acute and chronic therapeutic impact of a vasopressin antagonist in chronic heart failure (ACTIV in CHF) trial. Acute Card Care. 2007;9(2):82–86.
   PubMedGoogle Scholar
• Gheorghiade M, Konstam MA, Burnett JC Jr, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: The EVEREST clinical status trials. JAMA. 2007;297(12):1332–1343.
   PubMed Web of Science ®Google Scholar
• Konstam MA, Gheorghiade M, Burnett JC Jr, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The EVEREST outcome trial. JAMA. 2007;297(12):1319–1331.
   PubMed Web of Science ®Google Scholar
• Pitt B, Gheorghiade M. Vasopressin V1 receptor-mediated aldosterone production as a result of selective V2 receptor antagonism: A potential explanation for the failure of tolvaptan to reduce cardiovascular outcomes in the EVEREST trial. Eur J Heart Fail. 2011;13(12):1261–1263.
   Web of Science ®Google Scholar
• Hauptman PJ, Burnett J, Gheorghiade M, et al. Clinical course of patients with hyponatremia and decompensated systolic heart failure and the effect of vasopressin receptor antagonism with tolvaptan. J Card Fail. 2013;19(6):390–397.
   PubMed Web of Science ®Google Scholar
• Burnett JC Jr, Kao PC, Hu DC, et al. Atrial natriuretic peptide elevation in congestive heart failure in the human. Science. 1986;231(4742):1145–1147.
   PubMed Web of Science ®Google Scholar
• Mukoyama M, Nakao K, Saito Y, et al. Increased human brain natriuretic peptide in congestive heart failure. N Engl J Med. 1990;323(11):757–758.
   Web of Science ®Google Scholar
• Mukoyama M, Nakao K, Hosoda K, et al. Brain natriuretic peptide as a novel cardiac hormone in humans evidence for an exquisite dual natriuretic peptide system, atrial natriuretic peptide and brain natriuretic peptide. J Clin Invest. 1991;87(4):1402–1412.
   PubMed Web of Science ®Google Scholar
• Yasue H, Yoshimura M, Sumida H, et al. Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure. Circulation. 1994;90(1):195–203.
   PubMed Web of Science ®Google Scholar
• Yoshimura M, Yasue H, Morita E, et al. Hemodynamic, renal, and hormonal responses to brain natriuretic peptide infusion in patients with congestive heart failure. Circulation. 1991;84(4):1581–1588.
   PubMed Web of Science ®Google Scholar
• Mills RM, LeJemtel TH, Horton DP, et al. Sustained hemodynamic effects of an infusion of nesiritide (human b-type natriuretic peptide) in heart failure: A randomized, double-blind, placebo-controlled clinical trial. J Am Coll Cardiol. 1999;34(1):155–162.
   PubMed Web of Science ®Google Scholar
• Colucci WS, Elkayam U, Horton DP, et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med. 2000;343(4):246–253.
   PubMed Web of Science ®Google Scholar
• Publication Committee for the VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: A randomized controlled trial. JAMA. 2002;287(12):1531–1540.
   PubMed Web of Science ®Google Scholar
• Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation. 2005;111(12):1487–1491.
   PubMed Web of Science ®Google Scholar
• Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA. 2005;293(15):1900–1905.
   PubMed Web of Science ®Google Scholar
• O’Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med. 2011;365(1):32–43.
   PubMed Web of Science ®Google Scholar
• Chen HH, Anstrom KJ, Givertz MM, et al. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: The ROSE acute heart failure randomized trial. JAMA. 2013;310(23):2533–2543.
   PubMed Web of Science ®Google Scholar
• Vaduganathan M, Greene SJ, Ambrosy AP, Gheorghiade M, Butler J. The disconnect between phase II and phase III trials of drugs for heart failure. Nat Rev Cardiol. 2013;10(2):85–97.
   PubMed Web of Science ®Google Scholar
• Kuhn M. Structure, regulation, and function of mammalian membrane guanylyl cyclase receptors, with a focus on guanylyl cyclase-A. Circ Res. 2003;93(8):700–709.
   Web of Science ®Google Scholar
• Vallon V, Miracle C, Thomson S. Adenosine and kidney function: Potential implications in patients with heart failure. Eur J Heart Fail. 2008;10(2):176–187.
   Web of Science ®Google Scholar
• Hocher B. Adenosine A1 receptor antagonists in clinical research and development. Kidney Int. 2010;78(5):438–445.
   Web of Science ®Google Scholar
• Funaya H, Kitakaze M, Node K, Minamino T, Komamura K, Hori M. Plasma adenosine levels increase in patients with chronic heart failure. Circulation. 1997;95(6):1363–1365.
   Web of Science ®Google Scholar
• Gottlieb S. Adenosine A1 antagonists and the cardiorenal syndrome. Curr Heart Fail Rep. 2008;5(2):105–109.
   Google Scholar
• Cotter G, Dittrich HC, Weatherley BD, et al. The PROTECT pilot study: A randomized, placebo-controlled, dose-finding study of the adenosine A1 receptor antagonist rolofylline in patients with acute heart failure and renal impairment. J Card Fail. 2008;14(8):631–640.
   Web of Science ®Google Scholar
• Massie BM, O’Connor CM, Metra M, et al. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med. 2010;363(15):1419–1428.
   PubMed Web of Science ®Google Scholar
• Voors AA, Dittrich HC, Massie BM, et al. Effects of the adenosine A1 receptor antagonist rolofylline on renal function in patients with acute heart failure and renal dysfunction: Results from PROTECT (placebo-controlled randomized study of the selective A1 adenosine receptor antagonist rolofylline for patients hospitalized with acute decompensated heart failure and volume overload to assess treatment effect on congestion and renal function). J Am Coll Cardiol. 2011;57(19):1899–1907.
   Web of Science ®Google Scholar
• Cleland JGF, Coletta AP, Clark AL. Clinical trials update from the European Society of Cardiology Heart Failure Meeting 2010: TRIDENT 1, BENEFICIAL, CUPID, RFA-HF, MUSIC, DUEL, handheld BNP, phrenic nerve stimulation, CHAMPION and CABG with CRT study. European Journal of Heart Failure. 2010;12(8):883–888.
   Google Scholar
• Pang PS, Mehra M, Maggioni AP, et al. Rationale, design, and results from RENO-DEFEND 1: A randomized, dose-finding study of the selective A1 adenosine antagonist SLV320 in patients hospitalized with acute heart failure. Am Heart J. 2011;161(6):1012–1023. e3.
   Web of Science ®Google Scholar
• Albrecht-Kupper BE, Leineweber K, Nell PG. Partial adenosine A1 receptor agonists for cardiovascular therapies. Purinergic Signal. 2012;8(Suppl 1):91–99.
   PubMed Web of Science ®Google Scholar
• Weber KT. Aldosterone in congestive heart failure. N Engl J Med. 2001;345(23):1689–1697.
   PubMed Web of Science ®Google Scholar
• Shearer F, Lang CC, Struthers AD. Renin-angiotensin-aldosterone system inhibitors in heart failure. Clin Pharmacol Ther. 2013;94(4):459–467.
   PubMed Web of Science ®Google Scholar
• Bomback AS, Klemmer PJ. The incidence and implications of aldosterone breakthrough. Nat Clin Pract Nephrol. 2007;3(9):486–492.
   PubMedGoogle Scholar
• Wood JM, Maibaum J, Rahuel J, et al. Structure-based design of aliskiren, a novel orally effective renin inhibitor. Biochem Biophys Res Commun. 2003;308(4):698–705.
   PubMed Web of Science ®Google Scholar
• Hollenberg NK, Fisher ND, Price DA. Pathways for angiotensin II generation in intact human tissue: Evidence from comparative pharmacological interruption of the renin system. Hypertension. 1998;32(3):387–392.
   PubMed Web of Science ®Google Scholar
• Gradman AH, Schmieder RE, Lins RL, Nussberger J, Chiang Y, Bedigian MP. Aliskiren, a novel orally effective renin inhibitor, provides dose-dependent antihypertensive efficacy and placebo-like tolerability in hypertensive patients. Circulation. 2005;111(8):1012–1018.
   PubMed Web of Science ®Google Scholar
• Pool JL, Schmieder RE, Azizi M, et al. Aliskiren, an orally effective renin inhibitor, provides antihypertensive efficacy alone and in combination with valsartan. Am J Hypertens. 2007;20(1):11–20.
   PubMed Web of Science ®Google Scholar
• Andersen K, Weinberger MH, Egan B, et al. Comparative efficacy and safety of aliskiren, an oral direct renin inhibitor, and ramipril in hypertension: A 6-month, randomized, double-blind trial. J Hypertens. 2008;26(3):589–599.
   PubMed Web of Science ®Google Scholar
• McMurray JJ, Pitt B, Latini R, et al. Effects of the oral direct renin inhibitor aliskiren in patients with symptomatic heart failure. Circ Heart Fail. 2008;1(1):17–24.
   PubMed Web of Science ®Google Scholar
• Solomon SD, Shin SH, Shah A, et al. Effect of the direct renin inhibitor aliskiren on left ventricular remodelling following myocardial infarction with systolic dysfunction. Eur Heart J. 2011;32(10):1227–1234.
   PubMed Web of Science ®Google Scholar
• Gheorghiade M, Bohm M, Greene SJ, et al. Effect of aliskiren on postdischarge mortality and heart failure readmissions among patients hospitalized for heart failure: The ASTRONAUT randomized trial. JAMA. 2013;309(11):1125–1135.
   PubMed Web of Science ®Google Scholar
• Mentz RJ, Felker GM, Ahmad T, et al. Learning from recent trials and shaping the future of acute heart failure trials. Am Heart J. 2013;166(4):629–635.
   PubMed Web of Science ®Google Scholar
• Bomback AS, Rekhtman Y, Klemmer PJ, Canetta PA, Radhakrishnan J, Appel GB. Aldosterone breakthrough during aliskiren, valsartan, and combination (aliskiren + valsartan) therapy. J Am Soc Hypertens. 2012;6(5):338–345.
   Web of Science ®Google Scholar
• Sidik NP, Solomon SD, Latini R, et al. Effect of aliskiren in patients with heart failure according to background dose of ACE inhibitor: A retrospective analysis of the aliskiren observation of heart failure treatment (ALOFT) trial. Cardiovasc Drugs Ther. 2011;25(4):315–321.
   Web of Science ®Google Scholar
• Parving HH, Brenner BM, McMurray JJ, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367(23):2204–2213.
   PubMed Web of Science ®Google Scholar
• Maggioni AP, Greene SJ, Fonarow GC, et al. Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: Insights from the ASTRONAUT trial. Eur Heart J. 2013;34(40):3117–3127.
   PubMed Web of Science ®Google Scholar
• Sherwood OD. Relaxin’s physiological roles and other diverse actions. Endocr Rev. 2004;25(2):205–234.
   Web of Science ®Google Scholar
• 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):405–480.
   PubMed Web of Science ®Google Scholar
• Eddie LW, Bell RJ, Lester A, et al. Radioimmunoassay of relaxin in pregnancy with an analogue of human relaxin. Lancet. 1986;1(8494):1344–1346.
   Web of Science ®Google Scholar
• Du X, Bathgate RAD, Samuel CS, Dart AM, Summers RJ. Cardiovascular effects of relaxin: From basic science to clinical therapy. Nat Rev Cardiol. 2010;7(1):48–58.
   PubMed Web of Science ®Google Scholar
• Conrad KP. Maternal vasodilation in pregnancy: The emerging role of relaxin. Am J Physiol Regul Integr Comp Physiol. 2011; 301(2):R267–R275.
   PubMed Web of Science ®Google Scholar
• Conrad KP, Debrah DO, Novak J, Danielson LA, Shroff SG. Relaxin modifies systemic arterial resistance and compliance in conscious, nonpregnant rats. Endocrinology. 2004;145(7):3289–3296.
   PubMed Web of Science ®Google Scholar
• 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 (1985). 2005;98(3):1013–1020.
   Web of Science ®Google Scholar
• 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):4713–4720.
   Web of Science ®Google Scholar
• 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):1367–1376.
   Web of Science ®Google Scholar
• 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):1525–1527.
   PubMedGoogle Scholar
• Zhang J, Qi Y, Geng B, et al. Effect of relaxin on myocardial ischemia injury induced by isoproterenol. Peptides. 2005;26(9):1632–1639.
   Web of Science ®Google Scholar
• Lewis M, Deshpande U, Guzman L, et al. Systemic relaxin administration stimulates angiogenic cytokine expression and vessel formation in a rat myocardial infarct model. In: Tregear G, Ivell R, Bathgate R, Wade J, editors. Relaxin 2000. Springer Netherlands; 2001:159–167.
   Google Scholar
• Nistri S, Chiappini L, Sassoli C, Bani D. Relaxin inhibits lipopolysaccharide-induced adhesion of neutrophils to coronary endothelial cells by a nitric oxide-mediated mechanism. FASEB J. 2003;17(14):2109–2111.
   Google Scholar
• Masini E, Nistri S, Vannacci A, Bani Sacchi T, Novelli A, Bani D. Relaxin inhibits the activation of human neutrophils: Involvement of the nitric oxide pathway. Endocrinology. 2004;145(3):1106–1112.
   PubMed Web of Science ®Google Scholar
• 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):158–166.
   PubMed Web of Science ®Google Scholar
• Dschietzig T, Richter C, Bartsch C, et al. The pregnancy hormone relaxin is a player in human heart failure. FASEB J. 2001;15(12):2187–2195.
   PubMed Web of Science ®Google Scholar
• 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):292–295.
   PubMed Web of Science ®Google Scholar
• 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):879–881.
   Web of Science ®Google Scholar
• 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):789–790.
   Web of Science ®Google Scholar
• 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):2266–2268.
   Web of Science ®Google Scholar
• 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(2):195–198.
   Web of Science ®Google Scholar
• Xu Q, Lekgabe ED, Gao X, et al. Endogenous relaxin does not affect chronic pressure overload-induced cardiac hypertrophy and fibrosis. Endocrinology. 2008;149(2):476–482.
   Web of Science ®Google Scholar
• Masini E, Cuzzocrea S, Mazzon E, et al. Protective effects of relaxin in ischemia/reperfusion-induced intestinal injury due to splanchnic artery occlusion. Br J Pharmacol. 2006;148(8):1124–1132.
   PubMed Web of Science ®Google Scholar
• Boehnert MU, Armbruster FP, Hilbig H. Relaxin as a protective substance in preservation solutions for organ transplantation, as shown in an isolated perfused rat liver model. Transplant Proc. 2008;40(4):978–980.
   Web of Science ®Google Scholar
• 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;1160:265–268.
   Web of Science ®Google Scholar
• Alexiou K, Matschke K, Westphal A, Stangl K, Dschietzig T. Relaxin is a candidate drug for lung preservation: Relaxin-induced protection of rat lungs from ischemia-reperfusion injury. J Heart Lung Transplant. 2010;29(4):454–460.
   Web of Science ®Google Scholar
• Alexiou K, Wilbring M, Matschke K, Dschietzig T. Relaxin protects rat lungs from ischemia-reperfusion injury via inducible NO synthase: Role of ERK-1/2, PI3K, and forkhead transcription factor FKHRL1. PLoS One. 2013;8(9):e75592.
   Web of Science ®Google Scholar
• Yoshida T, Kumagai H, Kohsaka T, Ikegaya N. Relaxin protects against renal ischemia-reperfusion injury. Am J Physiol Renal Physiol. 2013;305(8):F1169–F1176.
   Web of Science ®Google Scholar
• Burchfield JS, Xie M, Hill JA. Pathological ventricular remodeling: Mechanisms: Part 1 of 2. Circulation. 2013;128(4):388–400.
   PubMed Web of Science ®Google Scholar
• Samuel CS. Relaxin: Antifibrotic properties and effects in models of disease. Clin Med Res. 2005;3(4):241–249.
   Google Scholar
• Samuel CS, Lekgabe ED, Mookerjee I. The effects of relaxin on extracellular matrix remodeling in health and fibrotic disease. Adv Exp Med Biol. 2007;612:88–103.
   PubMed Web of Science ®Google Scholar
• Bennett RG. Relaxin and its role in the development and treatment of fibrosis. Transl Res. 2009;154(1):1–6.
   Web of Science ®Google Scholar
• Samuel CS, Zhao C, Bathgate RA, et al. The relaxin gene-knockout mouse: A model of progressive fibrosis. Ann N Y Acad Sci. 2005;1041:173–181.
   Web of Science ®Google Scholar
• 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):4125–4133.
   PubMed Web of Science ®Google Scholar
• Samuel CS, Hewitson TD, Zhang Y, Kelly DJ. Relaxin ameliorates fibrosis in experimental diabetic cardiomyopathy. Endocrinology. 2008;149(7):3286–3293.
   Web of Science ®Google Scholar
• Lekgabe ED, Kiriazis H, Zhao C, et al. Relaxin reverses cardiac and renal fibrosis in spontaneously hypertensive rats. Hypertension. 2005;46(2):412–418.
   Web of Science ®Google Scholar
• Samuel CS, Cendrawan S, Gao X, et al. Relaxin remodels fibrotic healing following myocardial infarction. Lab Invest. 2011;91(5):675–690.
   Web of Science ®Google Scholar
• 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):313–321.
   PubMed Web of Science ®Google Scholar
• Williams EJ, Benyon RC, Trim N, et al. Relaxin inhibits effective collagen deposition by cultured hepatic stellate cells and decreases rat liver fibrosis in vivo. Gut. 2001;49(4):577–583.
   Web of Science ®Google Scholar
• Hewitson TD, Ho WY, Samuel CS. Antifibrotic properties of relaxin: In vivo mechanism of action in experimental renal tubulointerstitial fibrosis. Endocrinology. 2010;151(10):4938–4948.
   Web of Science ®Google Scholar
• Mookerjee I, Solly NR, Royce SG, Tregear GW, Samuel CS, Tang ML. Endogenous relaxin regulates collagen deposition in an animal model of allergic airway disease. Endocrinology. 2006;147(2):754–761.
   Web of Science ®Google Scholar
• Mookerjee I, Tang ML, Solly N, Tregear GW, Samuel CS. Investigating the role of relaxin in the regulation of airway fibrosis in animal models of acute and chronic allergic airway disease. Ann N Y Acad Sci. 2005;1041:194–196.
   Web of Science ®Google Scholar
• Samuel CS, Mookerjee I, Masterson R, Tregear GW, Hewitson TD. Relaxin regulates collagen overproduction associated with experimental progressive renal fibrosis. Ann N Y Acad Sci. 2005;1041:182–184.
   Web of Science ®Google Scholar
• Royce SG, Cheng V, Samuel CS, Tang MLK. The regulation of fibrosis in airway remodeling in asthma. Mol Cell Endocrinol. 2012;351(2):167–175.
   PubMed Web of Science ®Google Scholar
• 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):182–190.
   PubMed Web of Science ®Google Scholar
• 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;1160:387–392.
   Web of Science ®Google Scholar
• Voors AA, Davison BA, Felker GM, et al. Early drop in systolic blood pressure and worsening renal function in acute heart failure: Renal results of pre-RELAX-AHF. Eur J Heart Fail. 2011;13(9):961–967.
   Web of Science ®Google Scholar
• 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):1429–1439.
   PubMed Web of Science ®Google Scholar
• 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(4):745–750.
   PubMed Web of Science ®Google Scholar
• 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):2786–2796.
   PubMed Web of Science ®Google Scholar
• Li Y, Brookes ZLS, Kaufman S. Acute and chronic effects of relaxin on vasoactivity, myogenic reactivity and compliance of the rat mesenteric arterial and venous vasculature. Regul Pept. 2005;132(1–3):41–46.
   Google Scholar
• 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(9860):29–39.
   PubMed Web of Science ®Google Scholar
• Ponikowski P, Metra M, Teerlink JR, et al. Design of the RELAXin in acute heart failure study. Am Heart J. 2012;163(2):149–155. e1.
   Web of Science ®Google Scholar
• 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):431–441.
   PubMed Web of Science ®Google Scholar
• Metra M, Teerlink JR, Felker GM, et al. Dyspnoea and worsening heart failure in patients with acute heart failure: Results from the pre-RELAX-AHF study. Eur J Heart Fail. 2010;12(10):1130–1139.
   Web of Science ®Google Scholar
• 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(2):196–206.
   PubMed Web of Science ®Google Scholar
• Du XJ, Hewitson TD, Nguyen MN, Samuel CS. Therapeutic effects of serelaxin in acute heart failure. Circ J. 2014;78:542–552.
   PubMed Web of Science ®Google Scholar
• Wang TS, Hellkamp AS, Patel CB, Ezekowitz JA, Fonarow GC, Hernandez AF. Representativeness of RELAX-AHF clinical trial population in acute heart failure. Circulation: Cardiovascular Quality and Outcomes. 2014;7(2):259–268.
   Web of Science ®Google Scholar
• Givertz MM, Teerlink JR, Albert NM, et al. Acute decompensated heart failure: Update on new and emerging evidence and directions for future research. J Card Fail. 2013;19(6):371–389.
   PubMed Web of Science ®Google Scholar
• Konstam MA, Pang PS, Gheorghiade M. Seeking new heights in acute heart failure syndromes: Lessons from ASCEND and EVEREST. Eur Heart J. 2013;34(18):1345–1349.
   Web of Science ®Google Scholar
• O’Connor CM, Fiuzat M. Lessons learned from clinical trials in acute heart failure: Phase 3 drug trials. Heart Fail Clin. 2011;7(4):451–456.
   Web of Science ®Google Scholar