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

Until recently, spironolactone was considered only as an antagonist at the aldosterone receptors of the epithelial cells of the kidney and was used clinically in the treatment of hyperaldosteronism and, occasionally, as a K(+)-sparing diuretic. The spironolactone renaissance started with the experimental finding that spironolactone reversed aldosterone-induced cardiac fibrosis by a cardiac action. Experimentally, spironolactone also has direct effects on blood vessels. Spironolactone reduces vascular fibrosis and injury, inhibits angiogenesis, reduces vascular tone and reduces portal hypertension. The rationale for the Randomized Aldactone Evaluation Study (RALES) of spironolactone in heart failure was that 'aldosterone escape' occurred through non-angiotensin II mechanisms. The RALES clinical trial was stopped early when it was shown that there was a 30% reduction in risk of death among the spironolactone patients. In RALES, spironolactone also reduced hospitalisation for worsening heart failure and improved the symptoms of heart failure. Other recent clinical trials have shown that spironolactone reduces cardiac and vascular collagen turnover, improves heart variability, reduces ventricular arrhythmias, improves endothelial dysfunction and dilates blood vessels in human heart failure and these effects probably all contribute to the increased survival in heart failure. Spironolactone may also be useful in the treatment of left ventricular hypertrophy, portal hypertension and cirrhosis. There have also been some recent small clinical trials of spironolactone as an anti-androgen showing potential in acne, hirsutism and precocious puberty.
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PMID:The spironolactone renaissance. 1132 68

Measurement of vascular compliance has assumed increasing importance as a marker of early disease of the vascular wall, a predictor of future vascular disease, and a way to monitor the effects of vasoactive agents on arterial wall stiffness. Vascular compliance can be estimated by several methods: measurement of the pulse pressure, or pulse pressure-stroke volume ratio; analysis of the systolic pulse wave augmentation index and the diastolic pulse wave contour; ultrasonic echo-tracking; and MRI. Because few comparative studies have been done, the physiologic significance of the measures of compliance obtained by each method is uncertain. Antihypertensive drugs may improve vascular compliance by reducing blood pressure, relaxing vascular smooth muscle, or promoting long-term effects on vascular smooth muscle and cardiomyocyte growth and remodeling. Angiotensin converting enzyme (ACE) inhibitors have been reported to improve vascular compliance in nearly all studies, suggesting a beneficial class effect independent of blood pressure reduction. Favorable changes in the vascular wall-lumen ratio of small vessels from subcutaneous gluteal biopsy specimens after treatment with ACE inhibitors and the persistence of improved vascular compliance after withdrawal of therapy indicate that these agents may produce long-term vascular remodeling. Although few studies have been done, angiotensin II receptor antagonists improve vascular compliance, possibly by blocking angiotensin II-mediated cell proliferation and increasing apoptosis via unopposed AT1 receptor stimulation. In contrast, calcium antagonists and beta-blockers have variable effects on vascular compliance, although beta-blockers with intrinsic sympathomimetic activity improve vascular compliance. Diuretics have little effect on vascular compliance beyond their blood pressure-lowering actions, except for spironolactone, which by improving vascular compliance may have contributed to the reduction in heart failure mortality seen in the Randomized Aldactone Evaluation Study.
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PMID:The effect of antihypertensive drugs on vascular compliance. 1147 12

Aldosterone, the final product of the renin-angiotensin-aldosterone system (RAAS), is a mineralocorticoid hormone that classically acts, via the mineralocorticoid (aldosterone) receptor, on epithelia of the kidneys, colon, and sweat glands to maintain electrolyte homeostasis. Aldosterone has also been shown to act at nonepithelial sites where it can contribute to cardiovascular disease such as hypertension, stroke, malignant nephrosclerosis, cardiac fibrosis, ventricular hypertrophy, and myocardial necrosis. Although angiotensin-converting enzyme (ACE) inhibitors and angiotensin type 1 (AT(1)) receptor antagonists act to suppress the RAAS, these agents do not adequately control plasma aldosterone levels--a phenomenon termed "aldosterone synthesis escape." Spironolactone, a nonselective aldosterone receptor antagonist, is an effective agent to suppress the actions of aldosterone; its use is, however, associated with progestational and antiandrogenic side effects due to its promiscuous binding to other steroid receptors. For these reasons, eplerenone--the first agent of a new class of drugs known as the selective aldosterone receptor antagonists (SARAs)--is under development. In rodent models, eplerenone provides marked protection against vascular injury in the kidney and heart. In phase II clinical trials, eplerenone demonstrates 24-h control of blood pressure with once or twice daily dosing, and is safe and well tolerated in patients with heart failure when given with standard of care agents. Pharmacokinetic studies reveal that eplerenone has good bioavailability with low protein binding, good plasma exposure, and is highly metabolized to inactive metabolites and excreted principally in the bile. Eplerenone is well tolerated in acute and chronic safety pharmacology studies. Ongoing phase III trials of eplerenone in the treatment of hypertension and heart failure are underway. These studies will extend our understanding of selective aldosterone receptor antagonism in the treatment of chronic cardiovascular disease.
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PMID:Eplerenone: a selective aldosterone receptor antagonist (SARA). 1160 37

The management of patients with dilated cardiomyopathy (DCM) heart failure starts with the determination of the underlying diagnosis, definition of the hemodynamic character (eg, systolic, diastolic, valvular, right- and left-sided heart dysfunction), recognition of complicating factors (eg, atrial fibrillation, renal dysfunction), and consideration for any surgically remedial lesions (eg, severe valvular regurgitation, high-grade coronary artery occlusive disease). Angiotensin-converting enzyme inhibitors, beta-blocking agents, digoxin, and judicious diuretic administration make up the therapeutic plan for patients with symptomatic DCM heart failure. Angiotensin-converting enzymes are indicated for patients with DCM who have mild or no detectable symptoms; whether this subgroup would benefit from long-term beta-blockade remains to be established. Spirolactone also has been shown to be effective in patients with more advanced stages of heart failure. Biventricular pacing (cardiac resynchronization therapy) recently has been approved for use in patients with DCM and a left ventricular or intraventricular conduction defect and a QRS duration of longer than 140 msec. More intense pharmacotherapy, mechanical devices, and transplantation are directed at patients with severely symptomatic end-stage DCM. The effectiveness of any heart failure treatment plan is very much dependent on nonpharmacologic approaches, including dietary measures, exercise conditioning, and similar considerations, all of which are best delivered by dedicated heart failure programs.
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PMID:Dilated Cardiomyopathy. 1169 65

Cardiac extracellular matrix undergoes extensive and continuous turnover involved in the lesion-reparation process, such as in cardiac remodeling, in hypertensive cardiac hypertrophy, in dilated cardiomyopathy, after myocardial infarction in the transition to heart failure, and during the progression of left ventricular dysfunction. Cardiac fibrosis is a major determinant of diastolic dysfunction and pumping capacity, and it may provide the structural substrate for arrhythmogenicity, thus potentially contributing the to progression of heart failure and sudden death. Aldosterone was shown to promote cardiac fibrosis in various experimental models. It was demonstrated that spironolactone may oppose the effect of aldosterone in promoting cardiac fibrosis. Measurement of cardiac collagen turnover by use of serological markers is a useful tool for monitoring cardiac tissue repair and fibrosis in experimental models or clinical conditions. We found that high serum levels of a marker of collagen turnover (procollagen type III N-terminal peptide ) in patients with chronic heart failure receiving conventional therapy, including ACE inhibitors, was associated with high mortality and hospitalization rates. In RALES (Randomized Aldactone Evaluation Study), in patients randomized to placebo, markers continued to increase or remained unchanged after 6-month follow-up. On the contrary, adding spironolactone 25 mg daily significantly decreased the levels of these serum markers during the same period. Most importantly, the spironolactone-related morbidity and mortality benefit was most predominant in subgroups with highest baseline levels of serum markers. These results suggest that limitation of the aldosterone-related excessive extracellular matrix turnover may be one of the various extrarenal mechanisms contributing to the beneficial effect of spironolactone in patients with chronic heart failure.
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PMID:Treatment of congestive heart failure: interfering the aldosterone-cardiac extracellular matrix relationship. 1171 28

In its simplest and most succinct definition, heart failure can be defined as an inability of the heart to meet the metabolic demands of the body. Despite the diverse etiologies of heart failure in the pediatric population, the presentation of heart failure represents a common constellation of symptoms, signs, and physical findings. In infants, an inability to maintain growth either secondary to decreased nutritional intake or an increased catabolic state is a hallmark of heart failure. Infants exhibit increased sympathetic tone with excessive diaphoresis and increased heart rate. Physical findings in the infants with congestive heart failure (CHF) include increased work of breathing, tachypnea and hepatomegaly. In older children, in contrast, new onset heart failure may be less overtly symptomatic. Malaise, decrease in the level of daily activity, and weight loss may be present. Symptoms of abdominal pain and nausea and anorexia can be present and sometimes divert attention from the real etiology. Physical findings include rales and peripheral edema. If there is hepatomegaly, there will likely be hepatic tenderness as well. A gallop rhythm and tachycardia are commonly present. The long-term treatment of CHF in children includes digoxin, diuretics and afterload reduction with angiotensin-converting enzyme (ACE) inhibitors. Digoxin decreases sympathetic tone and improves growth in infants. Diuretics should be used to relieve symptoms but may not be necessary in all children. ACE inhibitors are increasingly valuable in maintaining cardiac function long term. New uses of medications include the addition of spironalactone (Aldactone, G. D. Searle & Co., Chicago, IL) which, in adults, has been shown to significantly decrease both the death rate from CHF and the need for hospitalization. Beta-Blockers have been used in children in limited studies and may have a role in the treatment of patients with idiopathic dilated cardiomyopathy. Surgical treatment, such as partial vectriculectomy, has shown short-term benefit and has been used sparingly in infants.
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PMID:Treatment of heart failure in infants and children. 1172 82

Traditionally, the role of aldosterone in heart failure was thought to be a result of its effects on epithelial cells where it induces sodium reabsorption and potassium excretion with subsequent haemodynamic effects from intravascular volume expansion. On this basis, spironolactone, a non-selective aldosterone antagonist, has been used for the treatment of congestive heart failure to block aldosterone-mediated effects in epithelial cells. The Randomized Aldactone Evaluation Study (RALES), in which spironolactone was added to existing therapy in patients with heart failure, showed a significant reduction in morbidity and mortality. These results suggest that the role of aldosterone in the pathophysiology of cardiovascular disease may be more complex than previously recognised. There now is extensive experimental and growing clinical evidence for an important physiological role for aldosterone in the pathology of cardiac and renal disease. Classical effects of aldosterone are mediated via its nuclear receptor. Novel non-epithelial effects of aldosterone are mediated via a second messenger system, which involves activation of the sodium/hydrogen antiporter. These effects of aldosterone have been demonstrated in the kidney, vascular smooth muscle cell and leukocytes, and in the regulation of rapid corticotropin suppression. It has been hypothesised that cardiac damage induced by aldosterone is independent of the presence of hypertension. In support of this, experimental evidence demonstrates that cardiovascular damage induced by aldosterone can be prevented by administration of a selective mineralocorticoid receptor antagonist. These findings suggest the dissociation between cardiovascular lesions and high blood pressure, and highlight the importance of aldosterone in the pathological changes.
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PMID:Rationale for the use of aldosterone antagonists in congestive heart failure. 1192 27

Nongenomic action of aldosterone has been observed in many cell types which often are different from the classic target tissues for mineralocorticoid action, such as vascular cells. As judged from their time scale and insensitivity toward inhibitors of protein synthesis, effects are not mediated by the classic mineralocorticoid receptor pathway. Here we summarize studies on rapid in vitro aldosterone effects, e.g. ion fluxes, and second messengers involved therein. Furthermore, several clinical studies on in vivo aldosterone action have shown rapid effects on cardiovascular parameters, among them baroreflex and vascular resistance. Taken together with the beneficial effect of aldosterone antagonism in heart failure patients that was demonstrated in the Randomized Aldactone Evaluation Study (RALES), aldosterone may be an equally important factor of the renin-angiotensin-aldosterone system in cardiovascular pathogenesis.
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PMID:Nongenomic effects of aldosterone: cellular aspects and clinical implications. 1196 Jun 26

The main operational objective of diuretic therapy in patients who present congestive heart failure and hypertension is to reduce or to suppress excess bodily fluid. Effective diuretic therapy decreases cardiac size when the heart is dilated, and it reduces lung congestion and excess water. Consequently, external respiratory work diminishes and cardiac output would be redistributed in favour of systemic vascular beds other than that of the respiratory muscles; dyspnoea decreases markedly and there is a slight reduction in fatigue. This clinical improvement and the fall in body weight caused by diuretics entail an increase in effort capacity. Subsequent exercise training ameliorates the abnormal ventilatory response to physical effort and the skeletal muscle myopathy that occur in heart failure, and thereby it attenuates dyspnoea and decreases fatigue further. Loop and/or thiazide-type diuretics may be used to augment natriuresis in patients with congestive heart failure and hypertension. The state of renal function, the existence of certain co-morbid conditions, potential untoward drug actions, and possible interactions of diuretics with nutrients and with other drugs are some of the factors that must be considered at the time of deciding on the diuretic drug(s) and dose(s) to be prescribed. Spironolactone has been found to increase life expectancy and to reduce hospitalisation frequency when added to the conventional therapeutic regimen of patients with advanced congestive heart failure and systolic dysfunction. Therefore, spironolactone should be the drug of choice to oppose the kaliuretic effect of a loop or of a thiazide-type diuretic.
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PMID:Diuretics in the treatment of patients who present congestive heart failure and hypertension. 1198 6

The role of aldosterone in the pathophysiology of congestive heart failure (CHF) has long been recognized. The recent RALES (Randomized Aldactone Evaluation Study) trial demonstrated early reduction in morbidity and mortality using spironolactone, an aldosterone receptor antagonist, in combination with angiotensin converting enzyme (ACE) inhibitor and loop diuretic, in patients with heart failure. This effect of spironolactone highlighted the importance of understanding the contributions of the renin-angiotensin-aldosterone system (RAAS) in the progression of CHF, and increased interest in the use of aldosterone antagonists. While ACE inhibitors have had the largest impact on adverse events in CHF, numerous studies have shown that these drugs fail to completely suppress aldosterone. Blocking the effects of residual aldosterone has now been demonstrated to affect prognosis in these patients. This review will discuss the role of aldosterone in the pathophysiology of CHF, with an emphasis on both known and potential therapeutic benefits of aldosterone antagonism.
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PMID:Aldosterone antagonists in congestive heart failure. 1218 62


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