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Query: UMLS:C0018801 (heart failure)
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Spironolactone, a competitive aldosterone receptor antagonist (ARA), has traditionally been the treatment of first choice in idiopathic hyperaldosteronism (IHA) and for preoperative management of aldosterone producing adenoma (APA). Spironolactone is partially absorbed, is extensively metabolized mainly by the liver and its therapeutic properties are attributable to active metabolite canrenone. At therapeutic doses of 25 to 400 mg per day, spironolactone effectively controls blood pressure and hypokalemia in the majority of cases. Endocrine side effect are often associated and mainly consist of gynecomastia, decreased libido and impotence in man and menstrual irregularities in women. Canrenone and the K+ salt of canrenoate are also in clinical use: they avoid the formation of intermediate products with anti-androgenic and progestational actions, resulting in a decreased incidence of side effects. Furthermore, a relatively new selective ARA compound (eplerenone) with reduced affinity for androgen and progesterone receptors, is currently undergoing clinical trials. In essential hypertension aldosterone can contribute to hypertension and increases the incidence of myocardial hypertrophy and cardiovascular events. On the other hand, inhibition of Renin-Angiotensin-Aldosterone System (RAAS) is associated with a decrease in blood pressure, with a regression of left ventricular hypertrophy and a reduction of target organ damage. Thus, ARA have been proposed as complementary treatment associated to ACE inhibitors and angiotensin receptor antagonists. Aldosterone is also known to play an important role in pathophysiolgy of congestive heart failure (CHF). In vitro and in vivo evidences suggest that aldosterone promotes myocardial fibrosis. This effect reflects direct, extra-epithelial actions of aldosterone via cardiac MR which are counteracted by ARAs in animal models. The RAAS is chronically activated in CHF. Non potassium-sparing diuretics further stimulate the RAAS and cause hypokalemia. Thus, use of ARAs in CHF was first proposed to correct potassium and magnesium depletion. At present ARAs are indicated in the management of primary hyperaldosteronism, in oedematous conditions in patients with CHF, in cirrhosis of the liver accompanied by oedema and ascites, in essential hypertension and in hypokalemic states. Its indication as adjunctive therapy of heart failure is currently under investigation. In fact, it is well known that even high doses of ACE inhibitors may not completely suppress the RAAS; aldosterone 'escape' may occur through non angiotensin II dependent mechanisms. Addition of spironolactone to an ACE inhibitor causes marked diuresis and symptomatic improvement. During the last few years, the RALES study (Randomized Aldactone Evaluation Study) was organized to explore the efficacy of combination therapy with spironolactone and ACE inhibitor in patients with CHF, class III or IV NYHA. The study was stopped 18 months early because the results were so statistically and clinically significant that it would be unethical to continue the trial. It is reported a 30 percent decrease in mortality and hospitalisation for cardiac causes in spironolactone-treated group vs placebo group.
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PMID:Aldosterone antagonists in hypertension and heart failure. 1079 May 93

Diuretics were the first family of drugs to be used in cardiac failure. They improve symptoms but no randomised control trials show their efficacy in prolonging survival. The results of the recent RALES trial, however, provides evidence in favour of antialdosterone diuretics on survival in association with a loop diuretic and an angiotensin converting enzyme inhibitor. At present, the legal requirements in France state that "the association of spironolactone and converting enzyme inhibitors is possible with low doses of angiotensin converting enzyme inhibitors and diuretic hypokalaemiant; kalaemia and creatinine have to be monitored". "The association of hypokalaemia-inducing diuretics (loop diuretics, thiazides and similar: the association with this type of diuretic, rational and useful in certain patients, does not exclude the risk of hypo- or even hyperkalaemia, especially in renal failure and diabetes; it also imposes the monitoring of serum potassium and eventually of the electrocardiogram and, if necessary, to reconsider the treatment". Many points remain unclear concerning the value and harmlessness of the prescription of diuretics in asymptomatic left ventricular failure. In cases of diuretic resistance, the use of intravenous administration, the fragmentation of doses or the association of diuretics, may induce a diuretic response. Angiotensin converting enzyme inhibitors are the first line treatment of moderate and severe cardiac failure and in post-infarction left ventricular dysfunction. On the other hand, the value of this family of drugs in left ventricular failure and normal systolic function has not been demonstrated. Analysis of clinical practice shows an underprescription of angiotensin converting enzyme inhibitors, both in number of patients and in dosage. The results of the recent ATLAS trial suggest that high doses of lisinopril improve morbidity related to cardiac failure and the combined morbi-mortality criterion. The results of this study incite the prescription of high rather than low doses of angiotensin converting enzyme inhibitor.
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PMID:[Cardiac insufficiency: what treatment? what dose? For which patients? Converting enzyme inhibitors and diuretics]. 1083 83

The clinical diagnosis of heart failure is based upon history and physical examination. Careful questioning and examination requires understanding of the pathophysiology of this systemic disorder. Symptoms and signs of congestive heart failure need to be differentiated from the manifestations of the underlying cardiovascular disorder. Only then will the specific signs and symptoms be unraveled. Symptoms arise from pulmonary congestion and peripheral or organ-underperfusion. Findings related to congestion can be found over the lungs (rales, pleural effusion), or at the jugular veins displaying either frank central venous pressure elevation or paradoxic inspiratory venous pressure rise (Kussmaul sign), or the more discrete sign of right, left of biventricular failure, the hepatojugular reflux. Dilatation and hypertrophy of the cardiac chambers can clinically easily and reliably be assessed by careful palpation. Galopprhythm, right and/or left ventricular in origin, is a particularly reliable sign of a failing ventricle. While a presystolic, atrial sound indicates merely elevated resistance to ventricular filling, i.e. the presence diastolic dysfunction or increased chamber filling, is the ventricular diastolic galopp a reliable sign of ventricular failure. Especially the appearance of a quadruple rhythm or a summation galopp can be considered both highly specific as well as prognostically dubious. Relative mitral and/or tricuspid insufficiency as a sign of ventricular dilatation needs to be differentiated from organic valve disease. This requires often echocardiography. Oedema of cardiac origin is symmetric and more pronounced in the evening. It arises both from left and from right ventricular failure. History and physical examination are both reliable tools in the initial diagnosis, as well as during follow-up and for control of therapeutic measures. Technical methods, such as chest x-ray, echocardiography or else are used for quantification and documentation. Properly applied and utilized they allow the physician to sharpen his clinical acumen, thus allowing for both a reliable diagnosis and a semi-quantitative estimation of ventricular size, enddiastolic and atrial, as well as pulmonary pressures and valve function.
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PMID:[Clinical diagnosis of heart failure]. 1085 88

Cardiac fibroblasts are known to have high affinity corticoid receptors for aldosterone and account for the accumulation of collagen within the interstitium of the rat myocardium in acquired and genetic hypertension. This interstitial fibrosis is an important determinant of pathologic hypertrophy in chronic heart failure. To examine the relationship between aldosterone and myocardial fibrosis, collagen volume fraction of the left and right ventricles were analyzed by videodensitometry of sirius red stained tissue in the following rat models: 2 kidney/1 clip model of renovascular hypertension; continuous aldosterone administration via osmotic minipumps (0.75 microgram/hour s.c.), or in each model of primary and secondary hyperaldosteronism with concomitant treatment with either low (20 mg/kg/day) or high doses (200 mg/kg/day) of s.c. spironolactone for 8 weeks as well as in age matched controls. Systolic arterial pressure and left ventricular weight normalized to body weight were each increased with either model of experimental hypertension and were normalized with high-dose spironolactone treatment. Myocardial fibrosis induced by chronic aldosterone administration was comparable to renovascular hypertension and occurred in the pressure overloaded, hypertrophied left and in the normotensive, nonhypertrophied right ventricle. The competitive aldosterone receptor antagonist, spironolactone, was able to prevent fibrosis in both ventricles in either model of arterial hypertension irrespective of the development of left ventricular hypertrophy and hypertension. To examine whether aldosterone stimulates collagen synthesis in adult rat cardiac fibroblasts collagen synthesis, normalized per total protein synthesis, was measured by 3H-proline incorporation in cultured fibroblasts after 24 hours incubation with aldosterone at 10(-11) to 10(-6) M concentrations, or with 10(-9) M aldosterone + 10(-9) M spironolactone. Under serum-free conditions, aldosterone was able to stimulate collagen synthesis in a dose-dependent manner and at concentrations (10(-9) M) which were comparable to stimulated states in vivo (e.g., renovascular hypertension, or chronic heart failure). At equimolar concentrations, spironolactone abolished the aldosterone-mediated increase in collagen synthesis. Thus, in-vivo and in-vitro evidence could be provided that the mineralocorticoid, aldosterone, plays a pivotal role in promoting myocardial fibrosis and that could be antagonized by its competitive receptor blocker, spironolactone. These cardioprotective effects of spironolactone may explain the prognostic value of anti-aldosterone therapy in patients with severe chronic heart failure evaluated in the RALES mortality trial.
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PMID:Aldosterone and myocardial fibrosis in heart failure. 1090 56

Although results of randomized trials have demonstrated the beneficial effects of ACE-inhibitors, mortality and morbidity remain high in patients with heart failure and myocardial infarction. In fact, there are data suggesting that aldosterone production may occur despite ACE-inhibitor treatment. There is recent evidence that aldosterone exerts a pro-fibrotic effect, via the mineralocorticoid receptors in cardiovascular tissues resulting in partial aldosterone production during ACE-inhibitor treatment. Mineralocorticoids have also been identified within the cardiovascular system and they may determine increased collagen synthesis which within fibroblasts is largely controlled by locally generated aldosterone. Cardiovascular tissue also expresses genes which are responsible for the late stages of aldosterone and corticosterone formation. Cardiac and vascular tissues elaborate the aforementioned steroids, with the result that aldosterone is more concentrated in the cardiovascular tissue rather than in the circulation. It is probable that locally, while not contributing to the coronary circulation, aldosterone plays an autocrine and/or paracrine role within the tissue of origin. Such roles may relate to local modulation of vessel tonicity and structure, with consequent effects on blood pressure, and repair of damaged tissue through a possible up-regulation of collagen deposition. The ability of the cardiovascular system to elaborate aldosterone opens a vast new area of study since it is becoming increasingly apparent that this local production of mineralocorticoids results in high levels of steroids within the cells of origin and those in the immediate vicinity. The recent RALES trial has shown a significant reduction in mortality, non-fatal hospitalization and sudden death. The fact that patients were on ACE-inhibitors, and accordingly circulating aldosterone levels were presumably reduced, presents the intriguing possibility that spironolactone may block the autocrine and paracrine effects of locally generated aldosterone. This trial has contributed to better understand the pathophysiology of heart failure and its therapeutic strategies. Further studies are required to address this treatment in patients with other heart diseases (hypertension, post-myocardial infarction) and in lower heart failure classes.
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PMID:Mineralocorticoids and cardiovascular diseases. Status of knowledge from experimental and clinical studies. 1113 Aug 38

Congestive heart failure describes a syndrome with complex and variable symptoms and signs, including dyspnea, increased fatigability, tachypnea, tachycardia, pulmonary rales, and peripheral edema. Although this syndrome usually is associated with low cardiac output, it may occur in a number of so-called high output states, when the cardiac output is normal or greater than normal. A high output state may occur in chronic severe anemia, large arteriovenous fistula or multiple small arteriovenous shunts as in Paget's bone disease, some forms of severe hepatic or renal disorders, and acutely in septic shock. The syndrome of systemic congestion in a high output state is traditionally referred to as high output heart failure. However, the term is a misnomer because the heart in these conditions is normal, capable of generating very high cardiac output. The underlying problem in high output failure is a decrease in the systemic vascular resistance that threatens the arterial blood pressure and causes activation of neurohormones, resulting in an increase in salt and water retention by the kidney. Many of the high output states are curable conditions, and because they are associated with decreased peripheral vascular resistance, the use of vasodilator therapy for treatment of congestion may aggravate the problem. There are other clinically important issues in high output failure that have received little attention in the current medical literature. This article reviews the available data on high output cardiac failure with particular emphasis on the underlying mechanisms and treatment.
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PMID:High Output Cardiac Failure. 1124 61

n 1987 the results of the Consensus study were published, and showed that enalapril, an angiotensin convertor enzyme inhibitor (ACEI), was able to modify the clinical course of the heart failure syndrome thereby reducing mortality. Other ACEI later demonstrated the same effect on the different degrees of symptomatic heart failure, left ventricular dysfunction, myocardial infarction and more recently in diabetic patients. In 1996 studies on the betablockers carvedilol, bisoprolol and metoprolol showed their efficacy in reducing deaths due to progressive heart impairment and sudden death in chronic heart failure. The RALES study showed that small doses of spironolactone also improved the prognosis on this disease. Digital improves the quality of life but not the survival rate. Only amiodarone (among the antiarrhythmics) reduces sudden death. Other drugs and groups of drugs can not be considered for chronic outpatient treatment of heart failure. Multicenter trials make it possible to obtain scientific evidence for establishing rational treatments. Many groups of patients such as women, elderly people and the more severe cases of the disease are often not included in these trials. Occasionally, multicenter trials are badly designed (CIBIS and MCD), which in the case of betablockers, led to a substantial delay in their administration. Other times, as in the ELITE study, the results were badly interpreted. The knowledge obtained from these studies is slow in reaching patients, with few patients taking betablockers. It is known that most patients do not take the doses found to be effective in multicenter trials.
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PMID:[Clinical trials on heart failure]. 1153 85

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

Young mice tolerate myocardial loss after coronary artery ligation (CAL) without congestive heart failure (CHF) signs or mortality. We predicted a CHF phenotype after CAL in aged mice. Left coronary artery ligation produced permanent myocardial infarcts (MI). Mortality was higher in male 14-mo-old C57BL/6N mice (Older mice) than in 2-mo-old mice (Young mice) (16 of 25 Older mice died vs. 0 of 10 Young mice, P < 0.02). After 8 wk, rales, weight loss, and lethargy preceded deaths. Captopril (50 mg x kg(-1) x day(-1)) increased Older mouse survival (6 of 22 died, P < 0.02). Captopril improved systolic function (peak aortic blood velocity) from 76 +/- 6% of baseline in untreated Older mice to 93 +/- 8% (P < 0.036). At 24 h, MI comprised 28 +/- 4% of the left ventricle in Young mice, surprisingly larger than that in Older mice (18 +/- 2%, P < 0.011). Endocardial area underlying the infarct scar was significantly larger in Older mice than in Young mice. Captopril did not reduce expansion but markedly reduced septal hypertrophy. Aging reduces compensatory ability in mice despite smaller acute infarcts. Less effective myocardial repair, greater infarct expansion, and septal hypertrophy are seen with aging. Aging is a more relevant murine model of post-MI heart failure in patients.
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PMID:Heart failure and greater infarct expansion in middle-aged mice: a relevant model for postinfarction failure. 1178 10


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