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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

One of the most important comorbidities in heart failure is renal dysfunction. Diminished estimated glomerular filtration rate is a potent predictor of cardiovascular mortality and complications. On the other hand, worsening heart failure or acute decompensated heart failure can accelerate worsening of renal function--the so-called cardiorenal syndrome. Risk factors include hypertension, diabetes, elderly age, and prior history of heart or renal failure. The pathophysiology of the cardiorenal syndrome involves intrarenal hemodynamics, transrenal perfusion pressure and systemic neurohormonal factors. Clinical management of the patient with cardiorenal syndrome includes the challenge of diuretic resistance, which may involve correcting the underlying cause, combination diuretics or diuretic infusions. The key to improved outcome is the optimization of proven heart failure therapies. The use of vasodilator therapy is the current mainstay of treatment. Nesiritide, or recombinant B-type natriuretic peptide, has courted controversy regarding its role in cardiorenal syndrome. However, data are emerging that low doses appear to be renal-protective. Other more recent strategies include ultrafiltration, vasopressin antagonists and adenosine antagonists. All of these newer modalities promise more rapid volume removal, but their ultimate impact on survival or preservation of renal function is unknown at the present time. Because of the complex nature of these patients, and the compromised outcome, it is important that cardiologists, nephrologists and internists all work together toward the common goal of protecting the patient with cardiorenal syndrome, and use the best available evidence for management.
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PMID:Cardiorenal syndrome in heart failure: a cardiologist's perspective. 1862 86

Congestive heart failure comprises a major public health problem destined to grow enormously over the next decade. Paradoxically, and in contrast to acute coronary disease, acute heart failure has been relatively understudied. Current standards of care involve the use of intravenous diuretics and vasodilators; inotropic agents have been restricted to in-hospital use because of concern about their potential harmful effects. The emergence of recombinant human B-type natriuretic peptide (BNP) provides an interesting therapeutic alternative because of its capacity to promote vasodilation as well as increase salt and water excretion, and improve pulmonary congestion by reducing left ventricular filling pressure. This agent will be explored in the Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure (ASCEND-HF), the largest ever trial conducted in acute decompensated heart failure. Patients will be studied through day 30 with end points of all-cause mortality in rehospitalization as the primary composite outcome. A variety of mechanistic substudies are planned as well as an assessment of the health care economic implications of acute heart failure and the pathophysiological elements hypothesized to modulate the expected treatment effect examined. The trial is embedded in an academic research organization motif and promises to provide a significant contribution to the body of knowledge in acute heart failure and the care of patients so afflicted.
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PMID:A Canadian context for the Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure (ASCEND-HF) trial. 1862 87

Acute decompensated heart failure (ADHF) is a growing public health problem with high mortality and costs. ADHF often, if not usually, occurs in the setting of cardiovascular and noncardiovascular comorbidities as well as advanced age. New insights provide support for the concept of heart failure as a state of deficiency of and/or resistance to endogenous B-type natriuretic peptide. The primary goals of ADHF therapy are to relieve symptoms and optimize volume status with minimal side effects. Few therapies are proven to effectively do so. Nesiritide is a balanced vasodilator with favorable neurohumoral effects and is superior to placebo in providing rapid symptom relief and to nitroglycerin in reducing filling pressures. Recent trials confirm a lack of renal toxicity at recommended doses. An adequately powered multinational mortality trial is underway. Nesiritide represents a proven therapy for normotensive/hypertensive ADHF patients with severe symptoms at rest.
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PMID:Nesiritide in acute decompensated heart failure: current status and future perspectives. 1895 74

In this review we investigate the role of particulate and soluble guanylate cyclase (pGC and sGC, respectively) pathways in heart failure, and several novel drugs that modify guanylate cyclase. Nesiritide and ularitide/urodilatin are natriuretic peptides with vasodilating, natriuretic and diuretic effects, acting on pGC, whilst cinaciguat (BAY 58-2667) is a novel sGC activator. Cinaciguat has a promising and novel mode of action because it can stimulate cyclic guanosine-3',5'-monophosphate synthesis by targeting sGC in its nitric oxide-insensitive, oxidised ferric (Fe(3+)) or haem-free state. Thus, cinaciguat may also be effective under oxidative stress conditions resulting in oxidised or haem-free sGC refractory to traditional organic nitrate therapies. Preliminary studies of cinaciguat in patients with acute decompensated heart failure show substantial improvements in haemodynamics and symptoms, whilst maintaining renal function.
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PMID:Role of guanylate cyclase modulators in decompensated heart failure. 1956 31

Heart failure is a complex clinical syndrome that manifests itself with signs and symptoms which are neither sensitive nor specific for the diagnosis of heart failure. Natriuretic peptides and in particular b-type natriuretic peptide (and nt-proBNP) are widely used in clinical practice around the world as a maker of heart failure. BNP is primarily released from the left ventricle in response to pressure and volume overload. The strongest evidence for the use of BNP is to rule in or rule out heart failure as cause of breathlessness in people who present to the emergency room. There is enthusiasm for use of BNP as a marker of heart failure severity as well as a predictor of outcomes in people with heart failure and trials are ongoing. Nesiritide, a recombinant form of BNP is currently being tested as a possible treatment in people with acutely decompensated heart failure.
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PMID:The role of b-type natriuretic peptide in heart failure management. 1958 95

Nesiritide, recombinant human B-type natriuretic peptide, is an intravenous vasodilator that is used to treat acutely decompensated heart failure. In addition to its modest diuretic and natriuretic properties, nesiritide reduces intracardiac filling pressures, increases cardiac index and improves symptoms. Long-term safety data are accruing, and a number of ongoing clinical trials will explore the potential benefit of nesiritide in a variety of clinical situations: peri-operative cardiac surgery, serial out-patient infusions, continuous out-patient or pretransplant infusions, and infusions in patients with pulmonary hypertension, bronchospasm, renal insufficiency, and acute coronary syndromes. Alternative delivery methods also are under development.
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PMID:Current and future uses of nesiritide. 1980 59

Decompensated heart failure accounts for approximately 1 million hospitalizations in the USA each year with an estimated cost of US$11,000 per hospitalization. Despite this prevalence and cost burden, relatively few therapies for decompensated heart failure have been developed over the past 30 years. Although once the mainstay of treatment of decompensated heart failure, the use of positive inotropic agents has fallen into disfavor. Although these agents improve hemodynamics and ejection fraction, there is evidence that the positive inotropes increase the risk of adverse clinical outcomes and mortality. Nesiritide is a naturetic peptide that produces balance vasodilation, inhibits sympathetic nervous system activity, and promotes diuresis and naturesis. At the time the drug received Food and Drug Administration approval for marketing in the USA, it had been shown to produce hemodynamic improvements to an extent greater than placebo or nitroglycerin. However, evidence of benefit in terms of clinical improvement and other outcomes was lacking. Recent trials have found that nesiritide reduces hospital length of stay (although not statistically significant in all trials) and healthcare resource utilization in patients admitted to hospital with decompensated heart failure. In a randomized, controlled trial, nesiritide given in the emergency room reduced hospital admissions for heart failure compared with placebo/usual care. Preliminary data from an outpatient intermittent infusion trial of nesiritide found that patients receiving nesiritide had fewer hospital admissions than patients randomized to standard care. There is currently little objective evidence that therapies used routinely in the management of patients with decompensated heart failure are associated with improved outcomes. Data with positive inotropic agents suggest that they do more harm than good. There is a growing body of evidence that nesiritide is associated with improvements in clinical outcomes in decompensated heart failure including fewer complications, less healthcare resource utilization, and lower costs when compared with standard therapy. Despite this evidence, larger, prospective trials demonstrating the impact of nesiritide on the costs and complications in decompensated heart failure are needed.
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PMID:Nesiritide for heart failure: impact on costs and complications. 1980 56

Discoveries of the cardiac natriuretic peptides ANP, BNP, and CNP along with studies of their function and regulation in health and disease, have led to breakthroughs in the understanding and clinical management of heart failure. Analysis of the ANP and BNP promoters and patterns of expression uncovered a set of key regulators and pathways that converge onto these sensitive markers of early myocyte differentiation and cardiac stress. Among the most studied are the transcription factors GATA4, TBX5, and NKX2-5, which are central to cardiac development and mutations of which are associated with congenital heart disease. In clinical practice, plasma natriuretic peptides levels have been used as quantitative biomarkers of heart failure and proved to be highly effective for the diagnosis of heart failure, for risk-stratification of patients and guided therapy, as well as for screening for subclinical cardiac stress. Emerging studies are revealing the cardioprotective attributes of these peptides and may offer new therapeutic venues for myocardial infarction and heart failure. Clinical trials have documented the benefits and risks of the use of synthetic ANP (Anaritide) and BNP (Nesiritide) for treating heart failure, renal failure, and hypertension. This review summarizes the function and regulation of cardiac natriuretic peptides and the translation of the basic biochemical discoveries into clinical practice both at the diagnostic and therapeutic level.
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PMID:Cardiac natriuretic peptides: from basic discovery to clinical practice. 2043 83

The mammalian Natriuretic Peptide (NP) system consists of neuro-hormones, such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), c-type natriuretic peptide (CNP), and the N-Terminal fragment of BNP (NT-pro-BNP). In response to some cardiovascular derangement the heart (acting as an endocrine organ), brain and other structures secretes natriuretic peptides in an attempt to restore normal circulatory conditions. Their actions are modulated through membrane-bound guanylyl cyclased (GC) receptors. They induce diuresis, natriuresis and vasodilation in the presence of congestive heart failure. These neuro-hormones also play a role in the suppression of neointimal formation after vascular injury. In addition, they act as antifibrotic and antihypertrophic agents preventing cardiac remodeling after myocardial infarction. Further, NP have diagnostic and prognostic role in heart failure, vasoconstriction, left ventricular late remodeling after MI and others. At present, some drugs such as Nesiritide, NEP inhibitors and vasopeptidase inhibitors were synthetized from NP, to antagonize these cardiovascular derengements. In future, it will be possibile to elaborate some drugs similar to petidase inhibitors and some CNP-like drugs able to reduce many symptoms of cardiovascular derangements without significant side effects.
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PMID:Natriuretic Peptide system and cardiovascular disease. 2104 58

Cyclic GMP is a ubiquitous second messenger that regulates a wide array of physiologic processes such as blood pressure, long bone growth, intestinal fluid secretion, phototransduction and lipolysis. Soluble and single-membrane-spanning enzymes called guanylyl cyclases (GC) synthesize cGMP. In humans, the latter group consists of GC-A, GC-B, GC-C, GC-E and GC-F, which are also known as NPR-A, NPR-B, StaR, Ret1-GC and Ret2-GC, respectively. Membrane GCs are activated by peptide ligands such as atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), C-type natriuretic peptide (CNP), guanylin, uroguanylin, heat stable enterotoxin and GC-activating proteins. Nesiritide and carperitide are clinically approved peptide-based drugs that activate GC-A. CD-NP is an experimental heart failure drug that primarily activates GC-B but also activates GC-A at high concentrations and is resistant to degradation. Inactivating mutations in GC-B cause acromesomelic dysplasia type Maroteaux dwarfism and chromosomal mutations that increase CNP concentrations are associated with Marfanoid-like skeletal overgrowth. Pump-based CNP infusions increase skeletal growth in a mouse model of the most common type of human dwarfism, which supports CNP/GC-B-based therapies for short stature diseases. Linaclotide is a peptide activator of GC-C that stimulates intestinal motility and is in late-stage clinical trials for the treatment of chronic constipation. This review discusses the discovery of cGMP, guanylyl cyclases, the general characteristics and therapeutic applications of GC-A, GC-B and GC-C, and emphasizes the regulation of transmembrane guanylyl cyclases by phosphorylation and ATP.
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PMID:Regulation and therapeutic targeting of peptide-activated receptor guanylyl cyclases. 2118 63


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