Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Relaxin is upregulated and plays a compensatory role in human heart failure. We therefore determined the safety of and dose response to human relaxin in stable patients with heart failure. Sixteen patients were treated with open-label intravenous relaxin in three sequential dose cohorts and monitored hemodynamically during the 24-h infusion and postinfusion periods. The safety demonstrated in group A (treatment for 8 h each with dosages equivalent to 10, 30, and 100 microg/kg/day) allowed escalation to group B (240, 480, and 960 microg/kg/day), and the highest safe dose, 960 microg/kg/day, was selected for a 24-h dosing in group C. Relaxin showed no relevant adverse effects and produced hemodynamic effects consistent with systemic vasodilation, i.e., trends toward increases in the cardiac index and decreases in pulmonary wedge pressure, without inducing hypotension. The first therapeutic use of relaxin in human heart failure demonstrated favorable hemodynamic effects and indicated that it may be of value in the treatment of this widespread disease.
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PMID:First clinical experience with intravenous recombinant human relaxin in compensated heart failure. 1941 26

This article provides information and a commentary on trials relevant to the pathophysiology, prevention and treatment of heart failure presented at the American College of Cardiology meeting in 2009. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. (123)I-mIBG myocardial scintigraphy was a good predictor of mortality in patients with heart failure in ADMIRE-HF. In PRIMA, use of individualized target NT-proBNP levels failed to improve outcomes compared with usual care in patients hospitalized with symptomatic heart failure. In the STICH trial, additional ventricular reconstruction surgery failed to improve outcomes in patients with ischaemic heart failure undergoing CABG. Cardiac resynchronization therapy may modify disease progression in patients with mild heart failure, according to data from REVERSE. Implantation of a defibrillator early after MI in high-risk patients in the IRIS study failed to improve outcomes compared with usual care. Cardiac contractility modulation showed some beneficial effects on symptoms and exercise capacity in the unblinded FIX-HF-5 study. Data from pre-RELAX-AHF show that relaxin may have potential as a treatment for acute heart failure. HF-ACTION showed that patients who complied with an exercise training regime achieved a better outcome, although this may be confounded by the ability of patients with a good prognosis to exercise for longer.
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PMID:Clinical trials update from the American College of Cardiology 2009: ADMIRE-HF, PRIMA, STICH, REVERSE, IRIS, partial ventricular support, FIX-HF-5, vagal stimulation, REVIVAL-3, pre-RELAX-AHF, ACTIVE-A, HF-ACTION, JUPITER, AURORA, and OMEGA. 1946 23

There has been significant progress in heart failure treatment; its stages are defined as a management platform for cardiovascular specialists. Surgical ventricular restoration adds no outcome advantage in ischemic heart failure over coronary artery bypass surgery alone. Novel medical therapies may include cytokine blockade and the vasodilator, relaxin. Although diastolic failure is prevalent, its clinical significance is unclear. Cardiac resynchronization reduces mortality and hospitalization. Perioperative enoximone facilitates beta-blockade for prophylaxis against myocardial ischemia. Heart failure still determines outcome in pulmonary embolism and cardiac surgery. The practice of ventricular assist devices continues to progress. A profile system based on urgency of mechanical support will guide future outcome assessment. Clinical scoring systems will guide the management of right heart failure. Device flow determines the risk of cerebral hyperperfusion and neurologic dysfunction. Regardless of device type, renal dysfunction remains an important outcome determinant. Postoperative heparinization is increasingly challenged because of the risks of bleeding and heparin-induced thrombocytopenia. The practice of heart transplantation continues to mature. The bicaval rather than the biatrial technique improves short-term outcome. Oral sildenafil is effective for pulmonary hypertension and right ventricular support. Although immunosuppression with tacrolimus is beneficial, sirolimus is less nephrotoxic and preserves coronary vasomotor function. The induction of immunosuppression may be modified as it has a weak evidence base. Psychosocial factors also continue to influence clinical outcome significantly. The future of heart failure treatment is bright with signs of active growth and progress in this vibrant subspecialty.
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PMID:Recent progress in heart failure treatment and heart transplantation. 1968 62

Although substantial advances have been achieved in recent decades in the clinical management of heart diseases, new therapies that provide better or additional efficacy with minimal adverse effects are urgently required. Evidence that has accumulated since the 1990s indicates that the peptide hormone relaxin has multiple beneficial actions in the cardiovascular system under pathological conditions and, therefore, holds promise as a novel therapeutic intervention. Clinical trials for heart failure therapy using relaxin revealed several beneficial actions. Here we review findings from mechanistic and applied research in this field, comment on the outcomes of recent phase I/II clinical trails on patients with heart failure, and highlight settings of cardiovascular diseases where relaxin might be effective.
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PMID:Cardiovascular effects of relaxin: from basic science to clinical therapy. 1993 41

Human gene 2 relaxin (RLX) is a member of the insulin superfamily and is a multi-functional factor playing a vital role in pregnancy, aging, fibrosis, cardioprotection, vasodilation, inflammation, and angiogenesis. RLX is currently applied in clinical trials to cure among others acute heart failure, fibrosis, and preeclampsia. The synthesis of RLX by chemical methods is difficult because of the insolubility of its B-chain and the required laborious and low yielding site-directed combination of its A (RLXA) and B (RLXB) chains. We report here that oxidation of the Met(25) residue of RLXB improves its solubility, allowing its effective solid-phase synthesis and application in random interchain combination reactions with RLXA. Linear Met(O)(25)-RLX B-chain (RLXBO) reacts with a mixture of isomers of bicyclic A-chain (bcRLXA) giving exclusively the native interchain combination. Applying this method Met(O)(25)-RLX (RLXO) was obtained in 62% yield and was easily converted to RLX in 78% yield, by reduction with ammonium iodide.
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PMID:An optimized chemical synthesis of human relaxin-2. 2019 7

Relaxin is a naturally occurring human peptide initially identified as a reproductive hormone. More recently, relaxin has been shown to play a key role in the maternal hemodynamic and renal adjustments that accommodate pregnancy. An understanding of these physiologic effects has led to the evaluation of relaxin as a pharmacologic agent for the treatment of patients with acute heart failure. Preliminary results have been encouraging. In addition, the other known biologic properties of relaxin, including anti-inflammatory effects, extracellular matrix remodeling effects, and angiogenic and anti-ischemic effects, all may play a role in potential benefits of relaxin therapy. Ongoing, large-scale clinical testing will provide additional insights into the potential role of relaxin in the treatment of heart failure.
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PMID:Relaxin: review of biology and potential role in treating heart failure. 2042 93

Acute heart failure (AHF) is a frequent medical condition associated with a poor prognosis. Based on systolic blood pressure at presentation, patients with AHF can be classified into 5 clinical profiles enabling a more targeted use of standard medications including diuretics, vasodilators and inotropes. The most recent guidelines underline the importance of a rapid management and the favorable impact of heart failure programs, which reduce morbidity and mortality after an admission for AHF. New therapeutic perspectives include ultrafiltration, vasopressin and adenosine antagonists, relaxin and new inotropes such as istaroxime.
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PMID:[What is new in the medical management of acute heart failure?]. 2061 57

Biochemical studies suggest that G-protein-coupled receptors (GPCRs) achieve exquisite signalling specificity by forming selective complexes, termed signalosomes. Here, using cAMP biosensors in single cells, we uncover a pre-assembled, constitutively active GPCR signalosome, that couples the relaxin receptor, relaxin family peptide receptor 1 (RXFP1), to cAMP following receptor stimulation with sub-picomolar concentrations of peptide. The physiological effects of relaxin, a pleiotropic hormone with therapeutic potential in cancer metastasis and heart failure, are generally attributed to local production of the peptide, that occur in response to sub-micromolar concentrations. The highly sensitive signalosome identified here provides a regulatory mechanism for the extremely low levels of relaxin that circulate. The signalosome includes requisite Galpha(s), Gbetagamma and adenylyl cyclase 2 (AC2); AC2 is functionally coupled to RXFP1 through AKAP79 binding to helix 8 of the receptor; activation of AC2 is tonically opposed by protein kinase A (PKA)-activated PDE4D3, scaffolded through a beta-arrestin 2 interaction with Ser(704) of the receptor C-terminus. This elaborate, pre-assembled, ligand-independent GPCR signalosome represents a new paradigm in GPCR signalling and provides a mechanism for the distal actions of low circulating levels of relaxin.
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PMID:Sub-picomolar relaxin signalling by a pre-assembled RXFP1, AKAP79, AC2, beta-arrestin 2, PDE4D3 complex. 2066 20

Relaxin, a naturally-occurring hormone in the insulin family, was discovered to have a physiologic role in pregnancy. Named initially for its relaxing effect on the pubic ligament, relaxin receptors have since been found to be widely distributed in many organs in both males and females. Acting through multiple pathways, including the stimulation of gelatinases leading to activation of endothelin type B receptors and subsequently nitric oxide, relaxin has been shown to cause vasodilation. In animal models and studies in humans, relaxin has been shown to increase cardiac output and renal perfusion. Due to these effects, relaxin has been examined as a treatment for acute heart failure. The results of phase I and II trials have shown favorable clinical trends without any major adverse events, suggesting that relaxin has the potential to be an effective medication for acute heart failure in conjunction with or in place of current treatments.
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PMID:Relaxin: a new approach for the treatment of acute congestive heart failure. 2092 40

Two members of the human insulin/relaxin superfamily, relaxins-2 and 3 (H2 and H3 respectively), are separated by nearly 75 years in terms of chronological identification but are both the subject of intense recent biological study. The physiological effects of H2 relaxin include vasodilatory, anti-inflammatory, extracellular matrix remodeling, and angiogenic and anti-ischemic. Because of its potent systemic and renal vasodilatory effects, it is currently undergoing phase III clinical trial for the treatment of acute heart failure. In contrast, H3 relaxin is a highly conserved neuropeptide that has rapidly emerged as an important regulator of homeostatic physiology and complex behaviors. Because of their immense clinical potential, an understanding of the structural features that control their functions is critical for rational drug design and development. The native receptor for H2 relaxin is RXFP1. It also strongly binds to the related receptor, RXFP2. The native receptor for H3 relaxin is the unrelated receptor, RXFP3; however, it also has high affinity for another related receptor, RXFP4. Interestingly, H3 relaxin also has a high affinity for RXFP1 and can interact with RXFP2 with a significantly lower affinity. H3 relaxin thus interacts with all four of the relaxin family receptors. Previous studies have shown that H2 and H3 relaxins interact with their receptors primarily using their B-chain specific residues. However, more recent studies suggest that the role of the respective A and B chains for their activity is both peptide- and receptor-dependent. This mini-review summarizes these recent findings on the structure-activity relationships of H2 and H3 relaxins.
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PMID:The roles of the A- and B-chains of human relaxin-2 and -3 on their biological activity. 2123 7


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