Serelaxin and acute heart failure

Tietjens, Jeremy; Teerlink, John R.

doi:10.1136/heartjnl-2014-306786

Cited by 22 publications

(13 citation statements)

References 36 publications

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“…Serelaxin, a recombinant form of human relaxin-2, can inhibit the activation of fibroblasts and decrease collagen production to suppress the fibrotic process (Table 2; Tietjens and Teerlink, 2016). An in vivo animal experiment discovered that serelaxin could effectively suppress myocardial fibrosis better than the ACE inhibitor, enalapril.…”

Section: Treatmentsmentioning

confidence: 99%

Current Understanding of the Pathophysiology of Myocardial Fibrosis and Its Quantitative Assessment in Heart Failure

et al. 2017

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Myocardial fibrosis is an important part of cardiac remodeling that leads to heart failure and death. Myocardial fibrosis results from increased myofibroblast activity and excessive extracellular matrix deposition. Various cells and molecules are involved in this process, providing targets for potential drug therapies. Currently, the main detection methods of myocardial fibrosis rely on serum markers, cardiac magnetic resonance imaging, and endomyocardial biopsy. This review summarizes our current knowledge regarding the pathophysiology, quantitative assessment, and novel therapeutic strategies of myocardial fibrosis.

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Section: Treatmentsmentioning

confidence: 99%

Current Understanding of the Pathophysiology of Myocardial Fibrosis and Its Quantitative Assessment in Heart Failure

et al. 2017

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“…Nitric oxide, endothelial endothelin type B receptor, vascular endothelial growth factor, and cAMP act as mediators for the vasodilatory as well as anti‐fibrotic and anti‐inflammatory effects of serelaxin 16. With these pleiotropic effects ( Figure 2), serelaxin may benefit AHF patients18 not only through its favourable haemodynamic effects, but also via its protective effects on the heart, kidney, and other organs, leading to potential mortality benefits19 as suggested by the data from RELAX‐AHF 20…”

Section: Introductionmentioning

confidence: 99%

Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study

Teerlink

Voors

Ponikowski

et al. 2017

European J of Heart Fail

109

103

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Patients admitted for acute heart failure (AHF) experience high rates of in‐hospital and post‐discharge morbidity and mortality despite current therapies. Serelaxin is recombinant human relaxin‐2, a hormone with vasodilatory and end‐organ protective effects believed to play a central role in the cardiovascular and renal adaptations of human pregnancy. In the phase 3 RELAX‐AHF trial, serelaxin met its primary endpoint of improving dyspnoea through day 5 in patients admitted for AHF. Compared to placebo, serelaxin also reduced worsening heart failure (WHF) by 47% through day 5 and both all‐cause and cardiovascular mortality by 37% through day 180. RELAX‐AHF‐2 ( ClinicalTrials.gov NCT01870778) is designed to confirm serelaxin's effect on these clinical outcomes. RELAX‐AHF‐2 is a multicentre, randomized, double‐blind, placebo‐controlled, event‐driven, phase 3 trial enrolling ∼6800 patients hospitalized for AHF with dyspnoea, congestion on chest radiograph, increased natriuretic peptide levels, mild‐to‐moderate renal insufficiency, and systolic blood pressure ≥125 mmHg. Patients are randomized within 16 h of presentation to 48 h intravenous infusions of serelaxin (30 µg/kg/day) or placebo, both in addition to standard of care treatments. The primary objectives are to demonstrate that serelaxin is superior to placebo in reducing: (i) 180 day cardiovascular death, and (ii) occurrence of WHF through day 5. Key secondary endpoints include 180 day all‐cause mortality, composite of 180 day combined cardiovascular mortality or heart failure/renal failure rehospitalization, and in‐hospital length of stay during index AHF. The results from RELAX‐AHF‐2 will provide data on the potential beneficial effect of serelaxin on cardiovascular mortality and WHF in selected patients with AHF.

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“…Relaxin is a pregnancy hormone with roles that differ between species, but common mechanistic actions include tissue remodelling as well as having cardiovascular effects such as vasodilation and organ protection 1–3 . The human relaxin peptide, human gene-2 (H2) relaxin, has attracted recent attention due to its successful passage through three phases of clinical trials for acute heart failure where the drug significantly reduced mortality in groups receiving recombinant H2 relaxin (serelaxin) compared to placebo 4 . The precise mechanism by which relaxin functions in heart failure is not known but is thought to involve numerous positive actions on vessels and organs 5 .…”

Section: Introductionmentioning

confidence: 99%

Distinct activation modes of the Relaxin Family Peptide Receptor 2 in response to insulin-like peptide 3 and relaxin

Bruell

Sethi

Smith

et al. 2017

Sci Rep

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Relaxin family peptide receptor 2 (RXFP2) is a GPCR known for its role in reproductive function. It is structurally related to the human relaxin receptor RXFP1 and can be activated by human gene-2 (H2) relaxin as well as its cognate ligand insulin-like peptide 3 (INSL3). Both receptors possess an N-terminal low-density lipoprotein type a (LDLa) module that is necessary for activation and is joined to a leucine-rich repeat domain by a linker. This linker has been shown to be important for H2 relaxin binding and activation of RXFP1 and herein we investigate the role of the equivalent region of RXFP2. We demonstrate that the linker’s highly-conserved N-terminal region is essential for activation of RXFP2 in response to both ligands. In contrast, the linker is necessary for H2 relaxin, but not INSL3, binding. Our results highlight the distinct mechanism by which INSL3 activates RXFP2 whereby ligand binding mediates reorientation of the LDLa module by the linker region to activate the RXFP2 transmembrane domains in conjunction with the INSL3 A-chain. In contrast, relaxin activation of RXFP2 involves a more RXFP1-like mechanism involving binding to the LDLa-linker, reorientation of the LDLa module and activation of the transmembrane domains by the LDLa alone.

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Serelaxin and acute heart failure

Cited by 22 publications

References 36 publications

Current Understanding of the Pathophysiology of Myocardial Fibrosis and Its Quantitative Assessment in Heart Failure

Current Understanding of the Pathophysiology of Myocardial Fibrosis and Its Quantitative Assessment in Heart Failure

Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study

Distinct activation modes of the Relaxin Family Peptide Receptor 2 in response to insulin-like peptide 3 and relaxin

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