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

Although angiotensin converting enzyme inhibitor therapy is an established approach in the treatment of chronic heart failure, the required dosage remains unclear. This open 6 month study investigated the influence of different captopril dosages on the clinical course and neurohumoral activity of patients with severe heart failure (left ventricular ejection fraction < or = 20%). Eighty-five patients in New York Heart Association class II-IV despite treatment with digitalis, diuretics, and captopril (mean dose +/- SEM 28 +/- 2 mg.day-1 at baseline) for > or = 3 months received either 'low dose' captopril (< 75 mg.day-1, mean 32 +/- 2 mg.day-1; n = 46) or 'high dose' captopril (> or = 75 mg.day-1, mean 99 +/- 4 mg.day-1; n = 39) during the follow-up period. Both groups were comparable in clinical, haemodynamic and neurohumoral parameters at baseline. Functional state improved significantly only in the high dose group (P < 0.0001). Of 31 low dose and 20 high dose patients considered as heart transplantation candidates at baseline, 21 low dose and only six high dose patients remained on the waiting list (P < 0.0001). In patients in the low dose group, eight deaths were observed (P < 0.001). Seven patients remained on low dose captopril due to adverse effects. The initially elevated plasma levels of aldosterone and atrial natriuretic peptide decreased significantly only in high dose patients (P < 0.01). Renin increased significantly in both groups. These observations underline the necessity of suppressing neurohumoral overactivation with adequate doses of captopril reflected by sequential humoral plasma determination.
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PMID:Clinical and neurohumoral response of patients with severe congestive heart failure treated with two different captopril dosages. 844 5

Renin inhibitors may offer an exciting new therapeutic means of blocking the action of the renin-angiotensin-aldosterone system. These compounds interfere with the first, rate-limiting step in the synthesis of angiotensin II by binding directly to the highly specific enzyme, renin. This approach may represent a more focused alternative to angiotensin-converting enzyme inhibitor therapy with an improved side-effect profile. Renin inhibitors given parenterally safely lower blood pressure in patients with essential heart failure. Under conditions of salt limitation, normal subjects show increases in renal plasma flow during infusion of renin inhibitors. The systemic and renal hemodynamic responses to renin inhibition are accompanied by suppression of plasma renin activity, plasma angiotensin II and plasma aldosterone levels. Recent scientific advances in discovering how to address the limitations of the low oral bioavailability of peptide-based compounds have made it possible to invent orally active renin inhibitors. Orally active renin inhibitors are presently being evaluated in clinical trials. The availability of intravenous and oral delivery of renin inhibitors broadens the potential of these agents to treat a wide variety of acute and chronic cardiorenal disorders.
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PMID:Hemodynamic effects of renin inhibitors. 873 85

Neurohumoral activation characterizes heart failure. Patients with the greatest amount of neurohumoral activation, as estimated by plasma norepinephrine levels, have the worst prognosis. The fundamental mechanisms underlying this neurohumoral activation remain unknown, however. Recent data support the hypothesis that early sympathetic dysregulation in heart failure is attributable to early attenuation of cardiac and arterial baroreceptor control of sympathetic nerve activity. Neurohumoral excitation is organ specific, affecting the heart first. Neurohumoral activation follows a stepwise pattern, with resistance to atrial natriuretic peptide and marked sympathetic activation characterizing a transition period from left ventricular dysfunction to overt heart failure. Renin-angiotensin-aldosterone system activation then occurs. Additional abnormalities of afferent systems, such as augmented muscle metaboreceptor sensitivity and increased peripheral chemoreceptor sensitivity, may modulate the sympathetic activation in established heart failure. Brain ouabainlike activity has been shown to cause sympathetic excitation in two animal models of heart failure and may play a key (although presently undefined) role in neurohumoral excitation in humans with heart failure. Therapies that interrupt, or even reverse, the neurohumoral activation in heart failure hold the greatest promise for the growing patient population afflicted with this syndrome.
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PMID:Mechanisms and implications of autonomic nervous system dysfunction in heart failure. 924 84

Renin, angiotensin II and aldosterone levels are elevated in congestive heart failure, especially when diuretics are introduced. This activation is clearly deleterious by elevating myocardial workload and is related to prognosis of heart failure. The link between hormonal activation and prognosis is causal, as hormonal inhibition by converting enzyme inhibitors improves heart failure prognosis. Angiotensin II and aldosterone appears to be toxic for the myocardium. The results of the trial conducted with angiotensin II antagonist losartan confirm data derived from converting-enzyme-inhibitors trials. The exact role of aldosterone is currently being evaluated in the RALES programme.
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PMID:[Renin-angiotensin-aldosterone system and heart failure: therapeutic aspects]. 977 28

Treatment of patients with severe heart failure by ACE inhibition is often limited by worsening of renal function. To evaluate whether trandolapril, a potent lipophilic ACE inhibitor, affects renal function in severe heart failure, we studied 12 patients with severe heart failure treated with only diuretics and digoxin. Patients received increasing oral dosages of trandolapril (0, 1, and 2 mg) on 3 consecutive days (A). Patients were then discharged on 2 mg trandolapril bid and re-evaluated 8 weeks later (B). Mean arterial and pulmonary wedge pressures decreased by maximal 14% and 43%, and stroke volume and work indexes increased by 24% and 20% at A and similarly at B (11, 45, and 25 ns and 33%, respectively). In contrast, heart rate, systemic resistance, pulmonary artery pressure, and cardiac index decreased by 6%, 23%, 29%, and 17%, respectively, at only A. Renal blood flow improved by approximately 40% both at A and B. In contrast, the glomerular filtration rate decreased by 25% at only B, whereas serum creatinine, creatinine clearance, and urine osmolality were unaffected during the study. Norepinephrine, angiotensin II, and aldosterone levels decreased by approximately 30%, 60%, and 65%, respectively, at both A and B. Renin levels increased by 136% at A and remained elevated at B. Thus, whereas the initial systemic vasodilating and inotropic effects did not persist, long-term trandolapril results in sustained neurohormonal modulation, reduced preload, and improved organ perfusion, indicated by a persistent increase in renal blood flow and preservation of renal function in severe heart failure.
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PMID:Renal hemodynamic effects in patients with moderate to severe heart failure during chronic treatment with trandolapril. 982 86

Renin-angiotensin-aldosterone and sympathetic nervous systems overactivity play a major role in worsening the extent of heart failure. Attenuation of neurohumoral activation with angiotensin-converting enzyme (ACE) inhibitors and beta-blockers has proven beneficial in congestive heart failure. Because ACE inhibition is a recommended treatment for heart failure, this study was designed to test the effects on neurohumoral activation, hemodynamics, and left ventricular (LV) volume of the combination of an ACE inhibitor (delapril) with a DA2-dopaminergic receptor/alpha2-adrenoceptor agonist (CHF-1024) or a beta1-adrenoceptor antagonist (metoprolol) after a moderate to large myocardial infarction (MI) in rats. MI was induced by left coronary artery ligation in 134 rats, and six were not operated on. After 2 months, the animals with ECG evidence of MI were treated for 1 more month with CHF- 1024, 0.33 mg/kg/day or with metoprolol (10 mg/kg/day), delivered through implanted osmotic minipumps, in addition to delapril (6 mg/kg/day) in the drinking water. Daily urinary excretion of norepinephrine (NE) and circulating concentration were measured. Hemodynamic variables were measured, and three-dimensional morphometric analysis was done on the diastole-arrested hearts to quantify infarct size and LV geometry. In conscious animals, delapril alone or with CHF-1024 or metropolol did not modify heart rate or systolic blood pressure. Both combination treatments, however, significantly reduced heart rate in anesthetized animals compared with the group receiving vehicle. Infarct size was not different between treatments, averaging 20-22% of LV volume. The threefold increase of LV chamber volume in infarcted rats was significantly attenuated by delapril alone or with CHF-1024 or metoprolol (-37 to -44%, p<0.05). Treatment with a combination of the ACEi and CHF-1024 tended to normalize the shape of the LV cavity. Urinary NE excretion was unaffected by delapril alone but was reduced by the addition of CHF-1024 or metoprolol. In conclusion, 1 month of treatment with doses of delapril having no hemodynamic effect, reduced LV volume in a model of chronic heart failure. When CHF-1024 or metoprolol was given with delapril, sympathetic activation decreased with no unwanted effects, such as excessive hypotension.
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PMID:Effects of a DA2/alpha2 agonist and a beta1-blocker in combination with an ACE inhibitor on adrenergic activity and left ventricular remodeling in an experimental model of left ventricular dysfunction after coronary artery occlusion. 1047 Sep 87

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

Renin-angiotensin-aldosterone systems play a critical role in the development and progression of cardiovascular diseases, and inhibitors of angiotensin-converting enzyme have proven effective for the treatment of these diseases. Since angiotensin II receptor antagonists can inhibit the effects of angiotensin II via ACE-independent pathways, e.g., chymase, they were considered to be more effective than ACEIs. On the other hand, ACE inhibitors can increase bradykinin, and thus, nitric oxide, which may cause potent cardioprotection, inhibition of smooth muscle proliferation and attenuation of inflammation mechanisms. It appears that angiotensin II receptor antagonists and ACEIs may mediate cardioprotection in different ways. This is the rationale to explore the possibility of a combined administration of both drugs for the treatment of chronic heart failure and other cardiovascular pathology. In this review we try to analyze the role of ACE, kinins and chymase inhibition in the pathophysiology and treatment of cardiovascular diseases.
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PMID:Interactions of angiotensin-converting enzyme, kinins and nitric oxide in circulation and the beneficial effects of ACE inhibitors in cardiovascular diseases. 1134 78

Sympathetic overdrive in acute low cardiac output syndrome, diverts blood from cutaneous and visceral circulation centripetally. Microcirculation in general, and renal circulation in particular, deteriorates during these circulatory adjustments leading to multi-organ failure (MOF). Decreased afferent glomerular arteriolar blood flow, increased renal sympathetic nerve discharge and a resultant decreased sodium chloride delivery around macula densa stimulates the Juxta-glomerular apparatus (JGA) and triggers renin-angiotensin-aldosterone mechanism. This, along with increased ADH production results in a state of vasoconstriction, increased after-load, and continued fluid retention, further compromising the visceral microcirculation. Initially the fluid retention under the effect of aldosterone and ADH is iso-osmotic, but later under inappropriate ADH action more water than salt is retained, as evidenced by the presence of hyponatraemia and 'water-logging' in the endstage of this condition.The author hypothesizes that: although physiological, the persistent stimulation of the JGA during the low cardiac output state plays an important role in perpetuating a negative cardiovascular vicious cycle and further aggravating it into MOF. Furthermore, by infusing hypertonic saline and hence increasing the sodium chloride delivery to the distal tubules and the macula densa, the JGA could be inhibited. This strategy should work like angiotensin-converting-enzyme-inhibitor drugs in chronic cardiac failure, except by acting at the root cause and inhibiting Renin production at its source. It should further help by stimulating atrial natriuretic peptide secretion.
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PMID:Possible role of juxtaglomerular apparatus in low cardiac output syndrome and multiple organ failure: modulation by high sodium load. 1142 43

The important neuroendocrine systems involved in heart failure are reviewed with special emphasis on their possible role in pathophysiology and their relation to prognostic and diagnostic information. Plasma levels of noradrenaline (NA), renin, vasopressin, endothelin-1, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and tumour necrosis factor-alpha (TNF-alpha) are all elevated in heart failure. Activity of the sympathetic nervous system as reflected by NA is correlated to mortality and seems to possess independent prognostic information. Several studies have now documented the beneficial effect of beta-blockade in chronic heart failure (CHF). Renin seems to be a poor prognostic marker in CHF possibly because of the interference with diuretic treatment, angiotensin converting enzyme (ACE)-inhibitors and angiotensin II antagonist, and probably also because of the significance of tissue renin-angiotensin system (RAS), poorly reflected by plasma renin. On the other hand, several large-scale trials with ACE-inhibitors and angiotensin II antagonists have demonstrated reduced mortality and morbidity in CHF. Plasma vasopressin does not seem to possess prognostic information but testing of non-peptide antagonists is ongoing. Endothelin-1 seems to have independent prognostic information and endothelin receptor antagonists may represent a therapeutic possibility. The natriuretic peptides ANP and BNP are correlated to prognosis and possess independent information. Brain natriuretic peptide and N-terminal ANP seem to increase early, i.e. in asymptomatic heart failure. Plasma BNP being more stable than ANP is therefore a promising measure of left ventricular dysfunction. Increase in ANP and BNP, potentially beneficial, may be achieved by administration of neutral endopeptidase inhibitors, at present an unsettled therapeutic possibility. Several cytokines are increased in heart failure and especially TNF-alpha has drawn attention. Experimental studies suggest that TNF-alpha is important in the pathophysiology of heart failure and preliminary studies indicate that inhibition of TNF-alpha seems to be a possible therapeutic approach. Thus, neuroendocrine markers seem to (i) have a role in diagnosis and classification of heart failure, (ii) be useful in providing a 'neuroendocrine profile' which enlightens different aspects of heart failure, and therefore (iii) in the future probably will be valuable in the choice of medical treatment of the individual patient. In addition to beta-blockers, ACE-inhibitors and angiotensin II antagonists several new drugs based on neuroendocrine modification are on their way and might become important in the future.
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PMID:Heart failure and neuroendocrine activation: diagnostic, prognostic and therapeutic perspectives. 1172 73


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