Serelaxin in acute heart failure: Most recent update on clinical and preclinical evidence

Abstract

SummaryHeart failure continues to be a widely prevalent disease across the world, affecting millions of Americans annually. Acute heart failure (AHF) has a substantial effect on rising healthcare costs and is one of the major causes of morbidity and mortality. The search for new drugs for symptom relief and to improve long-term outcomes in heart failure has led to development of serelaxin, a recombinant human relaxin-2 hormone.Relaxin was discovered in pregnancy, but eventually found to have a number of other physiological actions, not only in pregnancy, but also in nonpregnant women and men.The actions of serelaxin are primarily via nitric oxide, leading to the observed vasodilatory effects, and increase in renal plasma flow. It has also been found to increase expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP)-2 and MMP-9. The antifibrotic and antiinflammatory effects of the drug also play a role in heart failure. In Phase II studies, serelaxin has shown reduction in pulmonary arterial pressure, pulmonary capillary wedge pressure, and NT-proBNP. The recently published results of the RELAX-AHF, a phase III clinical trial on serelaxin, has opened new avenues into our understanding of its effects in heart failure. The trial showed improvement in short-term dyspnea scores and 180-day mortality, but, interestingly, failed to show any improvement of the secondary endpoints of death or readmission at 60 days. Ongoing Phase III trials like RELAX-AHF-2 and RELAX-AHF-ASIA would explain these data better and improve understanding of the use of serelaxin in clinical practice. This article summarizes the most updated published preclinical and clinical study data on serelaxin, including pharmacokinetic, pharmacodynamic, safety studies in hepatic, renal impaired patients, Phase II and Phase III trials.

Transcriptional up-regulation of relaxin-3 by Nur77 attenuates β-adrenergic agonist–induced apoptosis in cardiomyocytes

“…Of the three known relaxin genes, Relaxin-2 is the only relaxin known to circulate in the blood. Indeed, the circulating and/or cardiac levels of relaxin-2 have been reported to be increased in patients with congestive heart failure, suggesting the pathological significance of relaxin peptide in development and progression of heart disease (13) (14) (15).…”

Potential therapeutic use of relaxin in accelerating closure of cranial bone defects in mice

“…Moreover, relaxin has a good safely record based on human clinical trials for other indications (Said and Mukherjee ; Ghosh et al. ).…”

“…; Ghosh et al. ). Several investigators reported that relaxin promotes angiogenesis in cycling and pregnant endometrium, skin wounds, muscle injury, and ischemic myocardium (reviewed in (Jeyabalan et al.…”

“…Relaxin is a natural hormone in women secreted by the corpus luteum, which circulates in the luteal phase and during pregnancy (Sherwood 1994). Although it is unlikely to circulate in men, relaxin administration is nevertheless bioactive, leading to vasodilation, because males also have relaxin receptors in arteries (Danielson et al 2000;Debrah et al 2005;Novak et al 2006;Jelinic et al 2014;Ghosh et al 2017). Several investigators reported that relaxin promotes angiogenesis in cycling and pregnant endometrium, skin wounds, muscle injury, and ischemic myocardium (reviewed in (Jeyabalan et al 2007)).…”

Imbalanced Angiogenesis in Peripartum Cardiomyopathy ― Diagnostic Value of Placenta Growth Factor ―

“…13 Intravenous serelaxin (a relaxin-2 analog) has recently been shown to improve clinical symptoms and organ function when given at the time of hospital admission to patients with AHF. 14 In the present study, plasma concentrations of relaxin-2 (measured in 2 independent laboratories) were very low in patients admitted with AHF, regardless of whether they were non-pregnant AHF or PPCM patients.…”