Relaxin: A Novel Agent for the Treatment of Acute Heart Failure

Abstract

Acute heart failure (AHF) is defined by a constellation of signs and symptoms that manifest when new or decompensated ventricular dysfunction is triggered by an acute precipitant such as excessive preload, afterload, or myocardial ischemia. Despite being one of the most frequent causes of hospitalization and cardiovascular mortality, little to no progress has been made over the last few decades to advance the treatment of AHF. Current mainstays of pharmacotherapy for AHF including diuretics, vasodilators, and inotropes can improve symptoms; however, no currently approved agent has been shown to provide lasting outcome benefit for patients with AHF. First discovered in pregnant women where it is known to help with growth of the cervix and assist with the maternal cardiovascular and renovascular responses to pregnancy, relaxin is an endogenous neurohormone that has novel vasoactive properties. In particular, relaxin is a potent vasodilator with a number of pleiotropic effects that may affect cardiac remodeling, making relaxin an attractive compound for use in the management of AHF. Indeed, in two randomized controlled trials, a single 48-hour infusion of relaxin relieved symptoms of AHF with no evidence of major adverse effects. A signal of mortality benefit at 180 days was noted in both trials, prompting a third trial of relaxin powered for 180-day mortality that is currently under way. The pharmacology that underscores the potential benefit of relaxin is discussed and insight is provided into future clinical application of this novel drug should it prove to be the first therapy capable of reducing mortality in AHF.

Relaxin-2 and Soluble Flt1 Levels in Peripartum Cardiomyopathy

“…Recently it has been proposed that biological mediators with hemodynamic or vascular effects that are produced in the pregnant or peripartum state may play a role in the pathogenesis of PPCM (13,14,15). One of these factors is relaxin-2, a hormone produced in the corpus luteum of the ovary and in the heart (16,17). Relaxin-2 increases during pregnancy with hemodynamic and vasoactive effects including increased cardiac output, plasma volume, heart rate, and renal blood flow and lower vascular resistance (18).…”

“…Relaxin-2 increases during pregnancy with hemodynamic and vasoactive effects including increased cardiac output, plasma volume, heart rate, and renal blood flow and lower vascular resistance (18). In addition, relaxin-2 has anti-inflammatory, angiogenic, and antifibrotic properties (16). Both the vasodilatory and angiogenic effects of relaxin-2 are mediated in part by vascular endothelial growth factor (VEGF) (19,20), which may exert a protective effect in heart failure of multiple etiologies (21).…”

Towards comprehensive cardiac repair and regeneration after myocardial infarction: Aspects to consider and proteins to deliver

“…Relaxin is another molecule with potent vasodilation properties and can affect cardiac remodeling [59]. It has also been shown to have anti-inflammatory, anti-fibrotic, and angiogenic effects, all considered beneficial to teat MI patients.…”

Production of human pro-relaxin H2 in the yeast Pichia pastoris

“…Moreover, the latest studies have also established the potential of relaxin as vasodilator, and its contribution in angiogenesis and extracellular-matrix remodeling [3–7]. Most of these functions are important in the underlying pathology of acute heart failure (AHF), in fact, cardio-renal protective effects along with a significant benefit of dyspnea relief in patients with this pathology seem to be attributable to the capacity of relaxin to improve systemic, cardiac and renal hemodynamics, and protect cells and organs from damage via its neuro-hormonal, anti-inflammatory, anti-remodeling, anti-fibrotic, anti-ischemic, and pro-angiogenic effects [3, 8]. In 2012 serelaxin, recombinant human relaxin, passed Phase III clinical trials for the treatment of AHF [9] and was appointed as “Breakthrough Therapy” by the US Food and Drug Administration [8].…”

“…Most of these functions are important in the underlying pathology of acute heart failure (AHF), in fact, cardio-renal protective effects along with a significant benefit of dyspnea relief in patients with this pathology seem to be attributable to the capacity of relaxin to improve systemic, cardiac and renal hemodynamics, and protect cells and organs from damage via its neuro-hormonal, anti-inflammatory, anti-remodeling, anti-fibrotic, anti-ischemic, and pro-angiogenic effects [3, 8]. In 2012 serelaxin, recombinant human relaxin, passed Phase III clinical trials for the treatment of AHF [9] and was appointed as “Breakthrough Therapy” by the US Food and Drug Administration [8]. Furthermore, by using an in vivo mouse model Hampel and colleagues found a novel role for Relaxin 2 for the maintenance and regeneration of the ocular epithelial cell layer, underlying a new potential therapeutic application in ophthalmology for the treatment of corneal ulcerations [6].…”