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

The addition of new agents to the armamentarium of treatment options for heart failure in pediatric patients is exciting and challenging. Administration of these therapies to pediatric patients will require careful scrutiny of the data and skilled application. Developmental changes in drug metabolism, excretion, and distribution are concerning in pediatric patients, and inappropriate evaluation of these parameters can have disastrous results. Manipulation of the neurohormonal pathways in heart failure has been the target of most recently developed pharmacologic agents. Angiotensin receptor blockers (ARBs), aldosterone antagonists, beta-blockers, and natriuretic peptides are seeing increased use in pediatrics. In particular, calcium sensitizing agents represent a new frontier in the treatment of acute decompensated heart failure and may replace traditional inotropic therapies. Endothelin receptor antagonists have shown benefit in the treatment of pulmonary hypertension, but their use in heart failure is still debatable. Vasopressin antagonists, tumor necrosis factor inhibitors, and neutral endopeptidase inhibitors are also targeting aspects of the neurohormonal cascade that are currently not completely understood. The future of pharmacologic therapies will include pharmacogenomic studies on new and preexisting therapies for pediatric heart failure. The education and skill of the practitioner when applying these agents in pediatric heart failure is of utmost importance.
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PMID:Future pharmacologic agents for treatment of heart failure in children. 1693 64

The use of aggressive treatments and the modification of current treatment in patients with heart failure (HF) relies heavily on the assessment of disease severity using prognostic markers. However, many such markers are unavailable in routine clinical practice, and others have little prognostic value. This study tested the hypothesis that low body temperature could predict short-term survival after discharge in patients hospitalized for HF. Data from the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) trial, which randomized 319 patients hospitalized for HF to receive placebo or tolvaptan, were retrospectively analyzed. Hypothermia was defined a priori as an oral body temperature <35.8 degrees C at randomization. Cox regression was used to analyze survival within a 60-day follow-up period. Hypothermia was observed in 32 patients (10%). Mortality rates at 60 days after discharge were 6.3% (20 of 319) overall, 9.4% (3 of 32) in hypothermic patients, and 5.9% (17 of 287) in nonhypothermic patients. Hypothermia was a strong multivariate predictor of mortality; hypothermic patients were 3.9 times more likely to die within 60 days than nonhypothermic patients (95% confidence interval 1.002 to 15.16, p = 0.0497) after adjustment for treatment group, age, and other confounders. Hypothermia was associated with such indicators of low cardiac output as an elevated blood urea nitrogen/creatinine ratio, narrow pulse pressure, and a reduced ejection fraction. In conclusion, hypothermia appears to be a strong predictor of mortality in patients with HF.
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PMID:Comparison of 60-day mortality in hospitalized heart failure patients with versus without hypothermia. 1712 55

Vasopressin antagonists have been studied in a variety of clinical settings, including patients with acute and chronic heart failure. The clinical trials published to date have sought to describe the clinical and physiologic effects of these agents in an effort to prove clinical efficacy and safety. A variety of agents with varying effects on V2 and V1a vasopressin receptor subtype have been studied. They have been shown to reduce bodyweight and improve serum sodium without worsening renal function. They may also decrease the need for loop diuretic use and may be particularly useful in patients with hyponatremia in the setting of volume overload. Further studies are underway that are powered to assess for morbidity and mortality benefits. The beneficial effects have been well documented but, until outcomes are understood more fully, the use of these agents should be limited to currently approved indications. In the USA, this includes only the treatment of euvolemic hyponatremia.
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PMID:Vasopressin antagonists in the management of heart failure. 1733 75

In a national heart failure registry, hyponatremia (serum sodium < 130 mEq/L) was initially reported in 5% of patients and considered a risk factor for increased morbidity and mortality. In a chronic heart failure study, serum sodium level on admission predicted an increased length of stay for cardiovascular causes and increased mortality within 60 days of discharge. Hyponatremia in patients with congestive heart failure (CHF) is associated with a higher mortality rate. Also, by monitoring and increasing serum sodium levels during hospitalization for CHF, patient outcomes may improve. This review describes the pathophysiology of hyponatremia in relation to CHF, including the mechanism of action of vasopressin receptors in the kidney, and assesses the preclinical and clinical trials of vasopressin receptor antagonists--agents recently developed to treat hyponatremia. In hospitalized patients with CHF, hyponatremia plays a major role in poor outcomes. Vasopressin receptor antagonists have been shown to be safe and effective in clinical trials in patients with hyponatremia.
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PMID:Hyponatremia and vasopressin antagonism in congestive heart failure. 1784 41

Vasopressin is a critical regulator of water homeostasis. There are two major receptors for vasopressin: V1 and V2 receptors. Disturbances in water balance are commonly encountered in clinical practice and can be divided into disorders of urinary dilution and concentration. The major representatives of such disorders are diabetes insipidus and the syndrome of inappropriate secretion of antidiuretic hormone (SI ADH). Recent studies show that genetic forms of nephrogenic diabetes insipidus are due to mutations in the genes coding for the vasopressin V2 receptor (V2R) or aquaporin-2 (AQP2). Identification of the genes involved and analysis of the cellular fate of the V2R and AQP2 mutants are relevant for understanding the functioning of the V2R and AQP2 protein. These developments also have implications for future therapeutic options. The development of nonpeptide vasopressin receptor antagonists (VRAs) offers prospects for the treatment of euvolaemic (SI ADH) or hypervolaemic hyponatraemia (congestive heart failure or cirrhosis). Several nonpeptide VRAs are now in various stages of clinical trials. At present, only conivaptan is registered by the FD A for intravenous treatment of euvolaemic and hypervolaemic hyponatremia. A recent long-term study comparing tolvaptan with placebo in patients with chronic heart failure showed no reduction in risk of death and hospitalisation.
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PMID:Water in health and disease: new aspects of disturbances in water metabolism. 1795 51

Vasopressin receptor antagonists are a new class of drugs that address the problems of fluid retention, hyponatremia, and renal dysfunction in heart failure. Elevated vasopressin levels in heart failure cause myocardial fibrosis, hypertrophy and vasoconstriction by activating the V1a receptors, as well as water retention and hyponatremia by activating V2 receptors. Antagonism of V1a receptors alone is of little benefit. In contrast, antagonism of V2 receptors results in increased free water excretion and increased sodium concentration. Vasopressin receptor antagonists may be viewed as the first new class of agents with predominantly aquaretic effects, in contrast to the natriuretic effects of loop diuretics. The predominant action of vasopressin receptor antagonists is water excretion, without depletion of other electrolytes, and less neurohormonal stimulation compared with loop diuretics. Classified as neurohormonal antagonists, vasopressin receptor antagonists acutely may improve congestion and hyponatremia, while chronically preventing progression of left ventricular dysfunction. Several compounds have been evaluated in late-stage clinical trial programs, and at least one may be used as an adjunct to standard medical therapy, combining aquaresis for congestion with neurohormonal antagonism for morbidity and mortality. We reviewed recent patents dealing with heart failure, hyponatremia, anti-diuretic hormone, and vasopressin antagonists.
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PMID:Vasopressin receptor antagonists in heart failure. 1823 27

The study conducted by Seligman and coworkers included in the previous issue of Critical Care demonstrates that copeptin is a promising marker to predict outcome in patients with ventilator-associated pneumonia. In recent years, copeptin has emerged as a new prognostic marker in a variety of diseases, such as sepsis, community-acquired pneumonia, chronic obstructive pulmonary failure, heart failure and myocardial infarction. What is the pathophysiological basis for these findings? Copeptin together with vasopressin is co-secreted from the posterior pituitary and therefore mirrors the amount of vasopressin in the circulation. Vasopressin is a main secretagogue of the hypothalamo-pituitary-adrenal axis, thereby mirroring the individual stress level. Furthermore, vasopressin is an important hormone in salt and volume regulation. In this context, copeptin is also a diagnostic marker in patients with diabetes insipidus and in patients with disordered water states.
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PMID:Copeptin: a new and promising diagnostic and prognostic marker. 1825 6

Impaired urinary dilution leading to water retention and hyponatremia may occur in patients with cardiac failure, cirrhosis, pregnancy, oxytocin administration, hypothyroidism, glucocorticoid, and mineralocorticoid deficiency. The mechanisms for these defects predominantly involve the nonosmotic stimulation of arginine vasopressin release with up-regulation of aquaporin 2 water channel expression and trafficking to the apical membrane of the principal cells of the collecting duct. These perturbations are reversed by V2 vasopressin receptor antagonists. In contrast, urinary concentration defects leading to polyuria are vasopressin resistant. They may involve several factors, such as impaired countercurrent concentration secondary to down-regulation of Na-K-2Cl cotransporter. Vasopressin-resistant down-regulation of aquaporin 2 expression has also been described as a factor in impaired urinary concentration.
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PMID:Vasopressin and aquaporin 2 in clinical disorders of water homeostasis. 1851 89

Impaired urinary dilution leading to water retention and hyponatremia may occur in patients with cardiac failure, cirrhosis, pregnancy, hypothyroidism, glucocorticoid and mineralocorticoid deficiency. The mechanisms for these defects predominantly involve the non-osmotic stimulation of arginine vasopressin release with upregulation of aquaporin 2 water channel expression and trafficking to the apical membrane of the principal cells of the collecting duct. These perturbations are reversed by V2 vasopressin receptor antagonists. In contrast, urinary concentration defects leading to polyuria are vasopressin-resistant. They may involve several factors, such as impaired counter-current concentration secondary to downregulation of Na-K-2Cl co-transporter. Vasopressin-resistant downregulation of aquaporin 2 expression has also been described as a factor in impaired urinary concentration.
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PMID:Molecular mechanisms of clinical concentrating and diluting disorders. 1865 7

Acute heart failure syndromes are a common cause of emergency department visits and hospitalization in North America and Europe. Although in-hospital mortality is relatively low, the postdischarge mortality and rehospitalization rates can be as high as 10-15 and 30%, respectively, within 60-90 days following discharge. It appears that the main reason for admission and readmission for heart failure is related to congestion manifested by dyspnea, jugular venous distension and edema. Often, congestion is associated with dilutional hyponatremia that is difficult to treat. Hyponatremia is an important predictor of increased mortality and the available therapies to treat congestion and/or hyponatremia are often ineffective and/or unsafe. Accordingly, there is an unmet need to develop a new agent that effectively relieves congestion due to high filling pressure without worsening renal function and improving or normalizing serum sodium in hyponatremic patients. This paper provides an overview of a new compound, tolvaptan, an oral selective V(2)-vasopressin antagonist in light of the recently published Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial. The biochemical and pharmacological properties are discussed in conjunction with its clinical efficacy and safety, exploring the potential role of tolvaptan in the management of acute heart failure syndromes presenting with or without hyponatremia.
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PMID:EVEREST study: Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan. 1901 85


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