Intravenous Recombinant Human Relaxin in Compensated Heart Failure: A Safety, Tolerability, and Pharmacodynamic Trial

Dschietzig, Thomas; Teichman, Sam L.; Unemori, Elaine; Wood, Susy; Boehmer, Julia; Richter, Christoph; Baumann, Gert; Stangl, Karl

doi:10.1016/j.cardfail.2009.01.008

Cited by 137 publications

(126 citation statements)

References 16 publications

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“…In contrast, long-term administration for weeks in patients with mild scleroderma produced a 15-20% increase in predicted creatinine clearance (65). In a phase 1 trial of RLN in stable congestive heart failure, the hormone reduced SVR, pulmonary capillary wedge pressure, serum creatinine, and BUN and increased CO (62). In a recently conducted evaluation of RLN administration in acute heart failure (158), the hormone reduced SVR, arterial pressure, pulmonary vascular resistance, pulmonary capillary wedge pressure, pulmonary artery pressure, and right atrial pressure and increased 24-h endogenous creatinine clearance.…”

Section: Hormonal Mechanisms Of Renal and Systemic Vasodilation In Prmentioning

confidence: 99%

The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?

Conrad

Davison

2014

American Journal of Physiology-Renal Physiology

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Conrad KP, Davison JM. The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?. Am J Physiol Renal Physiol 306: F1121-F1135, 2014. First published March 19, 2014 doi:10.1152/ajprenal.00042.2014.-During the first trimester of human pregnancy, the maternal systemic circulation undergoes remarkable vasodilation. The kidneys participate in this vasodilatory response resulting in marked increases in renal plasma flow (RPF) and glomerular filtration rate (GFR). Comparable circulatory adaptations are observed in conscious gravid rats. Administration of the corpus luteal hormone relaxin (RLN) to nonpregnant rats and humans elicits vasodilatory changes like those of pregnancy. Systemic and renal vasodilation are compromised in midterm pregnant rats by neutralization or elimination of circulating RLN and in women conceiving with donor eggs who lack a corpus luteum and circulating RLN. Although RLN exerts both rapid (minutes) and sustained (hours to days) vasodilatory actions through different molecular mechanisms, a final common pathway is endothelial nitric oxide. In preeclampsia (PE), maternal systemic and renal vasoconstriction leads to hypertension and modest reduction in GFR exceeding that of RPF. Elevated level of circulating soluble vascular endothelial growth factor receptor-1 arising from the placenta is implicated in the hypertension and disruption of glomerular fenestrae and barrier function, the former causing reduced K f and the latter proteinuria. Additional pathogenic factors are discussed. Last, potential clinical ramifications include RLN replacement in women conceiving with donor eggs and its therapeutic use in PE. Another goal has been to apply knowledge gained from investigating circulatory adaptations in pregnancy toward identifying and developing novel therapeutic strategies for renal and cardiovascular disease in the nonpregnant population. So far, one candidate to emerge is RLN and its potential therapeutic use in heart failure. renal hemodynamics; glomerular filtration; osmoregulation; relaxin; nitric oxide; assisted reproductive technology; glomerular endotheliosis; soluble vascular endothelial growth factor receptor-1; heart failure Renal Plasma Flow and Glomerular Filtration in Normal PregnancyMARKED VASODILATION OF THE MATERNAL CIRCULATION occurs in the first trimester of human pregnancy. Consequently, there is a precipitous and profound decline in systemic vascular resistance (SVR) that in turn abets a reciprocal increase in cardiac output (CO) of ϳ40% or 2 l/min lasting throughout pregnancy (23,163). Vasodilation of nonreproductive organs like the kidneys accounts mostly for the early gestational fall in SVR and rise in CO. The fall in SVR is nearly offset by the rise in CO; hence, mean arterial pressure (MAP) declines, but only modestly, by 5-10 mmHg (23,38,163). Although counterintuitive, this metamorphosis of the maternal circulation is virtually complete by the end of the first or beginning of the second trimester, when fetal crown rump length and place...

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Section: Hormonal Mechanisms Of Renal and Systemic Vasodilation In Prmentioning

confidence: 99%

The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?

Conrad

Davison

2014

American Journal of Physiology-Renal Physiology

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“…There were two subjects that experienced serious adverse events related to decreased blood pressure, both in the highest-dose relaxin group. Unlike the phase I trial of stable compensated heart failure, 113,114 there was no significant improvement in renal function in the relaxin group, but there was a trend toward an increase in the percentage of subjects experiencing an increase greater than 26 µmol/L (0.29 mg/dL) at day 14, which was significant at the highest relaxin dose.…”

Section: Phase II Study: Pre-relax-ahfmentioning

confidence: 63%

“…113,114 The aim of this open-label study was to determine safety, tolerability, and pharmacokinetics, as well as hemodynamic properties of intravenously administered recombinant human relaxin. The subjects were males with New York Heart Association Class II-III, left ventricular ejection fraction ,35%, and were on standard chronic heart failure medication (ARBs or ACE inhibitors, beta-blockers, diuretics, and antiplatelet treatment).…”

mentioning

confidence: 99%

“…No changes in the second primary endpoint, cardiac index, were detected at any time point, which is in contrast to the preclinical data and the phase I relaxin study. 74,75,113 However, because of the low number of patients in both clinical trials (16 in the phase I, 63 in the phase II), the large difference in the doses studied, and the difference in the patient population (stable chronic HF in the phase I study vs ADHF in phase II), it is difficult to compare the effect on cardiac index between these trials, and clearly more studies are needed to resolve this question. Serelaxin significantly reduced peak systolic, diastolic and mean pulmonary artery pressure at all time points during infusion.…”

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confidence: 99%

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Current treatments for acute heart failure: focus on serelaxin

Bennett¹

2014

RRCC

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Acute heart failure remains an enormous health concern worldwide, and is a major cause of death and hospitalization. In spite of this, the treatment strategies for acute heart failure have remained largely unchanged for the past 2 decades. Several large randomized, placebocontrolled clinical trials have recently been conducted to attempt to improve the treatment and outcomes of acute decompensated heart failure. Some studies, including the EVEREST (tolvaptan) and ASCEND (nesiritide) showed efficacy at relieving early symptoms, but failed to improve long-term outcomes. Others, including PROTECT (rolofylline) and ASTRONAUT (aliskiren) showed little benefit in the relief of early symptoms or long-term outcomes. The recent RELAX-AHF studies using serelaxin, a recombinant form of relaxin, have shown considerable promise. Importantly, serelaxin improved congestion (dyspnea) and other early targets of acute decompensated heart failure treatment, but also improved mortality at 180 days. The purpose of this review is to provide an overview of current treatment strategies for acute decompensated heart failure, and a discussion of the recent clinical trials, with an emphasis on the serelaxin studies.

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“…Although human studies are limited through 2011, a phase 1 clinical trial of short-term, 24-h intravenous infusion of rhRLX in patients with stable congestive heart failure has been conducted (32). The hormone significantly increased cardiac index, and reduced systemic vascular resistance, pulmonary capillary wedge pressure, serum creatinine, and blood urea nitrogen, with only modest decreases in systolic blood pressure analogous to the conscious rat studies, as described above.…”

Section: Relaxin Administration Mimics Maternal Vasodilation Of Pregnmentioning

confidence: 99%

Maternal vasodilation in pregnancy: the emerging role of relaxin

Conrad

2011

American Journal of Physiology-Regulatory, Integrative and Comp

179

141

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Conrad KP. Maternal vasodilation in pregnancy: the emerging role of relaxin. Am J Physiol Regul Integr Comp Physiol 301: R267-R275, 2011. First published May 25, 2011 doi:10.1152/ajpregu.00156.2011.-Pregnancy is a unique physiological condition of profound maternal renal and systemic vasodilation. Our goal has been to unveil the reproductive hormones mediating this remarkable vasodilatory state and the underlying molecular mechanisms. In addition to advancing our knowledge of pregnancy physiology, reaching this goal may translate into therapeutics for pregnancy pathologies such as preeclampsia and for diseases associated with vasoconstriction and arterial stiffness in nonpregnant women and men. An emerging player is the 6 kDa corpus luteal hormone relaxin, which circulates during pregnancy. Relaxin administration to rats and humans induces systemic and renal vasodilation regardless of sex, thus mimicking the pregnant condition. Immunoneutralization or elimination of the source of circulating relaxin prevents renal and systemic vasodilation in midterm pregnant rats. Infertile women who become pregnant by donor eggs (IVF with embryo transfer) lack a corpus luteum and circulating relaxin, and they show a markedly subdued gestational increase in glomerular filtration rate. These data implicate relaxin as one of the vasodilatory reproductive hormones of pregnancy. There are different molecular mechanisms underlying the so-called rapid and sustained vasodilatory actions of relaxin. The former is mediated by G␣ i/o protein coupling to phosphatidylinositol-3 kinase/Akt (protein kinase B)-dependent phosphorylation and activation of endothelial nitric oxide synthase, the latter by vascular endothelial and placental growth factors, and increases in arterial gelatinase(s) activity. The gelatinases, in turn, hydrolyze big endothelin (ET) at a gly-leu bond to form ET 1-32, which activates the endothelial ET B receptor/nitric oxide vasodilatory pathway.

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Intravenous Recombinant Human Relaxin in Compensated Heart Failure: A Safety, Tolerability, and Pharmacodynamic Trial

Cited by 137 publications

References 16 publications

The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?

The renal circulation in normal pregnancy and preeclampsia: is there a place for relaxin?

Current treatments for acute heart failure: focus on serelaxin

Maternal vasodilation in pregnancy: the emerging role of relaxin

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