Serelaxin for the treatment of acute heart failure: a review with a focus on end-organ protection

Abstract

Acute heart failure (AHF) is a complex clinical syndrome characterized by fluid overload and haemodynamic abnormalities (short-term clinical consequences) and the development of end-organ damage (long-term consequences). Current therapies for the treatment of AHF, such as loop diuretics and vasodilators, help to relieve haemodynamic imbalance and congestion, but have not been shown to prevent (and may even contribute to) end-organ damage, or to provide long-term clinical benefit. Serelaxin is the recombinant form of human relaxin-2, a naturally occurring hormone involved in mediating haemodynamic changes during pregnancy. Preclinical and clinical studies have investigated the effects mediated by serelaxin and the suitability of this agent for the treatment of patients with AHF. Data suggest that serelaxin acts via multiple pathways to improve haemodynamics at the vascular, cardiac, and renal level and provide effective congestion relief. In addition, this novel agent may protect the heart, kidneys, and liver from damage by inhibiting inflammation, oxidative stress, cell death, and tissue fibrosis, and stimulating angiogenesis. Serelaxin may therefore improve both short- and long-term outcomes in patients with AHF. In this review, we examine the unique mechanisms underlying the potential benefits of serelaxin for the treatment of AHF, in particular, those involved in mediating end-organ protection.

Keywords: Acute heart failure; Congestion relief; Long-term outcomes; Organ protection; Serelaxin.

Figure 1

The ‘continuum’ of pathophysiological changes associated with acute heart failure that may lead to both short- and long-term effects on the heart and other end organs.^–

Figure 2

Risk for all-cause mortality through Day 180 in Pre-RELAX-AHF and RELAX-AHF. AHF, acute heart failure; RELAX-AHF, RELAXin in Acute Heart Failure; Pre-RELAX-AHF, preliminary RELAXin in Acute Heart Failure. Reproduced under the terms of the Elsevier user license (http://www.elsevier.com/about/open-access/open-access-policies/oa-license-policy/elsevier-user-license) for Metra et al.

Figure 3

All-cause mortality through Day 180 in RELAX-AHF by markers of organ damage/dysfunction: troponin T (A); cystatin C (B); AST (C); ALT (D), and NT-proBNP (E). ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; HR, hazard ratio; NT-proBNP, N-terminal pro-B-type natriuretic peptide. Reproduced under the terms of the Elsevier user license (http://www.elsevier.com/about/open-access/open-access-policies/oa-license-policy/elsevier-user-license) for Metra et al.

Figure 4

Time-dependent effects of intravenously administered serelaxin on vasoactive systems that result in vasorelaxation.^,, A, time after serelaxin administration, when the hormone is detectable in the blood ranges from minutes to hours; B, time after serelaxin administration, when the hormone is not detected in the blood ranges from 1 to several days; Ang II, angiotensin II; AVP, arginine vasopressin; BK, bradykinin; COX2, cyclo-oxygenase 2; EDHF, endothelium-derived hyperpolarizing factor; eNOS, endothelial nitric oxide synthase; ET, endothelin; ET-B_R, endothelin receptor type B; MMP, metalloproteinase; NE, norepinephrine; nNOS, neuronal nitric oxide synthase; RXFP1, relaxin/insulin-like family peptide receptor 1; TGF-β, transforming growth factor β; VEGF, vascular endothelial growth factor.

Figure 5

Serelaxin activates multiple pathways to improve haemodynamics and may protect cells and organs via anti-apoptotic/necrotic, anti-inflammatory, anti-fibrotic, antioxidant, and pro-angiogenic effects.^,,,–,,,, ET, endothelin; ET-B_R, endothelin receptor type B; MDA, malondialdehyde; MMP, metalloproteinase; NADPH, nicotinamide adenine dinucleotide phosphate-oxidase; NO, nitric oxide; NOS, nitric oxide synthase; TBARs, thiobarbituric acid-reactive substance; TGF-β, transforming growth factor β; TNF-α, tumour necrosis factor α; VEGF, vascular endothelial growth factor. Adapted from Teichman et al. Reproduced under the terms of the Creative Commons Attribution Non-commercial License for open access.