UMLS:C0018801 - FACTA Search

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

The aims of the treatment of heart failure are to improve the quality of life and slow the progression of cardiac disease. Improvement of quality of life is best assessed by questionnaire; progression of the disease is assessed by measuring mortality and morbidity. The agenda for the future is to establish intermediate markers for progression of cardiac disease that can be substituted for morbidity and mortality, and thus improve the efficiency and shorten the follow-up of clinical trials. At present, polypharmacy is required to achieve optimal improvements in quality and duration of life. Furthermore, some drugs may favorably affect one end point and adversely affect the other; for example, beta-blockers may exert adverse short-term effects on quality of life but may slow progression of the disease. Certain inotropic drugs may reduce symptoms but shorten life expectancy. Angiotensin-converting enzyme (ACE) inhibitors have exerted favorable effects on both quality of life and mortality, but the magnitude of these benefits has been disappointingly small. Persistent angiotensin-induced vasoconstriction and endocrine effects, despite ACE inhibition, is one possible explanation. The Valsartan in Heart Failure Trial (Val-HeFT) has been designed to test the efficacy and safety of the AT(1) receptor blocker (ARB) valsartan in combination with ACE inhibitors and all other prescribed therapies in patients with heart failure. The study is powered to detect a mortality benefit and should therefore establish the role of ARBs in this patient group. When this trial and other ongoing studies are completed, we will be more able to define the role of ARBs in the treatment of heart failure.
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PMID:Improving outcomes in congestive heart failure: Val-HeFT. Valsartan in Heart Failure Trial. 1044 91

Angiotensin II plays a significant role in cell growth and proliferation in model systems and in humans. In addition, angiotensin II appears to facilitate sympathetic activation and the release of endothelin-1, and also to promote apoptosis. The use of angiotensin-converting enzyme (ACE) inhibitors has provided beneficial effects on left ventricular hypertrophy (LVH) regression and on cardiac remodelling in the presence of heart failure. Data from experimental models as well as studies in humans suggest that the increase of bradykinin mediated by ACE inhibitors provides most of the beneficial effects of ACE inhibitors. The new class of angiotensin receptor blocker appears to provide cardioprotective effects that are similar to those of the ACE inhibitors. Most of the beneficial effects provided by these agents appear to be related to a more complete blockade of angiotensin II type 1 (AT1) receptor. However, costimulation of the angiotensin II type 2 (AT2) receptor appears to increase nitric oxide and thus to cause some bradykinin-like effects. Evidence for the role of angiotensin II in promoting LVH and cardiac failure as well as for abnormal regulations of the angiotensin signal transduction pathways in model systems and in humans are reviewed. Second, the mechanisms for the beneficial effects of angiotensin II modulation by ACE inhibitors versus angiotensin II antagonists studied in model systems are presented. Finally, results from pivotal phase II studies such as Evaluation of Losartan In The Elderly (ELITE), as well as an overview of the ongoing phase III trials involving the use of ARB in high risk patients are presented.
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PMID:Cardioprotective effect of angiotensin II receptor antagonists. 1057 47

Over the past 4 years, six angiotensin II receptor antagonists (ARBs) were approved for treating essential hypertension. They differ with respect to dosing, metabolism, elimination, clinical efficacy, and investigational applications. Candesartan cilexetil is the only prodrug among the agents. Losartan is distinguished from other ARBs by cytochrome P450 (CYP) 3A4- and CYP2C9-mediated biotransformation to its active metabolite EXP-3174. No ARB requires dosage adjustment for renal impairment, but the initial dose of losartan should be reduced 50% in hepatically impaired patients. None of the drugs is significantly cleared by hemodialysis. Completion of continuing trials will elucidate the drugs' role in treating heart failure, cerebral stroke, and myocardial infarction.
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PMID:Pharmacologic, pharmacokinetic, and therapeutic differences among angiotensin II receptor antagonists. 1067 91

Angiotensin receptor antagonists (ARB) are equally effective but better tolerated than all the other blood pressure lowering agents. The reason, why they are not subscribed as first line drugs for uncomplicated hypertension, is the higher price for these products. What the real difference in costs is, remains unclear because calculations are missing to what extent lesser controls of therapy would shift the balance in favour of the ARBs. For other indications than hypertension, but often associated with that condition, be it per se or as a consequence of it, the effects of the ARBs are studied in large trials these days. For some of them the benefit, which has been proven for ACE inhibitors, is not yet established for the ARBs, but evidence emerges that they are also useful in the treatment of cardiac failure, left ventricular hypertrophy and diabetic and other kinds of nephropathy. A large percentage of hypertensive patients can be treated effectively with ARBs without considerable side effects, thus increasing adherence and minimizing the necessity of safety controls.
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PMID:[Angiotensin receptor blockers--significance for the therapy of hypertension]. 1145 Jan 62

Angiotensin (Ang) receptor blockers (ARBs) increase bradykinin (BK) by antagonizing Ang II at its type 1 (AT(1)) receptors and diverting Ang II to its counterregulatory type 2 (AT(2)) receptors. Because the effect of ARBs on BK is constrained by the short half-life of BK and because ACE inhibitors block the degradation of BK, this study was designed to test the hypothesis that an ACE inhibitor can potentiate ARB-induced increases in renal interstitial fluid (RIF) BK levels. We used a microdialysis technique to recover BK and cGMP in vivo from the RIF of sodium-depleted, conscious Sprague-Dawley rats infused for 60 minutes with the AT(1) receptor blocker valsartan (0.17 mg/kg per minute), with the active metabolite of the ACE inhibitor benazepril (benazeprilate, 0.05 mg/kg per minute), or with the specific AT(2) receptor blocker PD 123,319 (50 microg/kg per minute) alone or combined. Each animal served as its own control. RIF BK and cGMP levels increased significantly over 1 hour in response to valsartan, benazeprilate, or both but not to a vehicle control (P<0.01). The combined benazeprilate-valsartan effect was greater than the sum of their individual effects, suggesting potentiation rather than addition, and was abolished by PD 123,319. We demonstrate for the first time that an ACE inhibitor (benazepril) and an ARB (valsartan) potentiate each other, and we postulate that such combinations may be beneficial in clinical states marked by Ang II elevation, such as chronic heart failure, postinfarction left ventricular dysfunction, and hypertension.
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PMID:Angiotensin-converting enzyme inhibition potentiates angiotensin II type 1 receptor effects on renal bradykinin and cGMP. 1150 73

ACE inhibitors have been shown to reduce mortality, reduce hospitalization, reduce symptoms, and increase exercise capacity in patients with heart failure and a large heart (low ejection fraction). The evidence is overwhelming. There are some subgroups of patients, such as the very elderly and those with a normal ejection fraction, where uncertainty still exists. The combination of a diuretic and an ACE inhibitor is currently the proper treatment of congestive heart failure; a beta-blocker should be added in selected patients. The evidence for the efficacy of ARB is less persuasive and, for the present, this class of drug should be prescribed only when an ACE inhibitor cannot be tolerated. The results of the trials emphasize an emerging problem in medicine, namely how to evaluate a new treatment that may be as efficacious as current therapy but with fewer side-effects. Proving equivalence in efficacy will be difficult, requiring large studies comparing new drugs with the best current treatment. The most common etiology of heart failure is coronary heart disease. If further studies provide more support for the idea that ACE inhibitors prevent ischemic episodes and delay the onset of heart failure, then a new indication for ACE inhibitors will be the prevention of heart failure.
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PMID:ACE inhibitors and ARBs in chronic heart failure: the established, the expected, and the pragmatic. 1269 30

When observed in elderly hypertensive patients, increased pulse pressure (PP) and arterial stiffness are known to be independent risk factors for cardiovascular diseases. Increased systolic blood pressure (SBP) leads to left ventricular hypertrophy, while decreased diastolic blood pressure (DBP) results in decreased coronary circulation. It is known that increased arterial stiffness is the major cause of increased PP. Thus basic morbid states of cardiac failure or ischemic heart diseases are more likely to develop in elderly hypertensive patients with increased PP and arterial stiffness, and there is need of antihypertensive drugs that decrease these effects in elderly hypertensives. In this study, we compared the effects of an angiotensin-receptor blocker (ARB: valsartan), an angiotensin-converting enzyme inhibitor (ACE-I: temocapril), and long-acting Ca antagonists (L- and N-type Ca channel blocker: cilnidipine; and L-type Ca channel blocker: nifedipine CR) on PP and arterial stiffness measured by pulse wave velocity in elderly hypertensive patients for 3 months. The ARB yielded the largest reductions in PP and brachial-ankle pulse wave velocity (baPWV), followed by the ACE-I and L- and N-type Ca channel blocker, while the L-type Ca channel blocker yielded no improvement. The effects on arterial stiffness and PP thus varied among the drug characteristics. Although ARB achieved the largest reduction in baPWV, this decrease was not associated with any reductions in PP, SBP, DBP, or mean blood pressure, as were the baPWV-decreases achieved by the other drugs, suggesting that ARB may further reduce the risk of arteriosclerosis in elderly hypertensive patients by decreasing arterial stiffness in addition to its antihypertensive effect.
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PMID:Efficacy of various antihypertensive agents as evaluated by indices of vascular stiffness in elderly hypertensive patients. 1456 99

The aim of this study was to evaluate the effectiveness of an angiotensin-converting enzyne inhibitor (ACEI, quinapril) or angiotensin II receptor blocker (ARB, candesartan) on atrial natriuretic peptide (ANP) activity in rats with hypertension induced by nitric oxide (NO) inhibition. ACEI and ARB have a number of pharmacologic effects, including blood pressure reduction, myocardial preservation, and an unknown effect in the circulation. The changes in ANP in NO inhibitor-induced hypertensive rats were evaluated in order to elucidate the interaction between ANP and NO in the regulation of blood pressure. Thirty-six rats were divided into 4 groups and administered the experimental agents for 8 weeks: group CONTROL was given regular food (n=9), group N(G)-nitro-L-arginine (L-NNA) was administered L-NNA (25 mg. kg(-1). day(-1), n=9), group ACEI was administered L-NNA and quinapril (10 mg. kg(-1). day(-1), n=9), and group ARB was administered L-NNA and candesartan (10 mg. kg(-1). day(-1), n=9). Blood pressure, plasma ANP, atrial ANP, ANP mRNA, and ANP granules were measured. A significant elevation in blood pressure was observed in group L-NNA. However, there were no increases in plasma ANP (L-NNA: 138.8+/-64.4, CONTROL: 86.7+/-36.4), ANP mRNA (L-NNA: 2.2+/-1.0, CONTROL: 1.7+/-0.5) or ANP granules (L-NNA: 61.1+/-10.2, CONTROL: 64.5+/-8.5). No increase in blood pressure was seen in groups ACEI and ARB. However, plasma ANP (ACEI: 1,392.3+/-1,034.4, ARB: 1,142.8+/-667.3), ANP mRNA (ACEI: 52.8+/-29.1, ARB: 42.9+/-21.2), and ANP granules (ACEI: 122.5+/-23.4, ARB: 136.3+/-33.2) increased significantly. NO inhibitor-induced hypertension caused no changes in ANP concentrations. However, the ACEI and ARB had a direct effect on the induction of ANP secretion. The findings suggest that ANP secretion is directly effected by ACEI and ARB, which seems to play a key role in lowering blood pressure, relieving heart failure symptoms, and preserving the myocardium.
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PMID:Effectiveness of angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker on atrial natriuretic peptide. 1463 23

Reducing the effects of angiotensin II by blockade of AT1-receptors may be superior to inhibition of angiotensin II formation by angiotensin converting enzyme (ACE) inhibitors in chronic heart failure (CHF) patients. However, the results of several trials did not fulfil this expectation. In both ELITE II with symptomatic CHF patients and in OPTIMAAL involving high risk patients after acute myocardial infarction, angiotensin II type I (AT1) receptor blocker (ARB) losartan did not prove to be superior to captopril. There are several potential reasons, why ARBs did not fare better than ACE inhibitors. Although AT1-receptor blockade may block the effects of non-ACE pathways of tissue angiotensin II formation, no clinical evidence is available that a more powerful inhibition of the tissue renin-angiotensin system brings improved survival. The choice of patients for clinical trials of HF therapy is not based on the level of neurohumoral activation. Thus, the more effective attenuation of angiotensin II action with ARBs may not bring additional benefits. The potential antiremodeling effect of ARBs through the stimulation of AT2 receptors by angiotensin II could be counterbalanced by a failure of AT1-receptor blockers to enhance bradykinin, nitric oxide and prostacyclin formation with antigrowth properties. Although ACE-inhibitors seem to have slightly better results at present than AT1 blockers in the battle on heart failure patient, future trials will decide which is the definitive winner.
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PMID:ACE-inhibition and angiotensin II receptor blockers in chronic heart failure: pathophysiological consideration of the unresolved battle. 1466 46

Even well-conducted randomized controlled trials can only reduce uncertainty, not eliminate it. The trials presented in this article all have gaps, and like many studies, some raise more questions than answers. A summary of the current trials, however, can be presented as follows. For patients with essential hypertension who are at high risk for cardiovascular disease, the use of diuretic therapy (excluding simultaneous use of ACE or CCB) resulted in outcomes at least equivalent to the use of either ACE or CCB without diuretics. Naturally, the dilemma for clinicians is that these drugs are most often used in combination with thiazide diuretics, as indicated by the RENAAL trial where 80% of ARB were used with diuretics in patients with type II diabetes and known nephropathy. The increased risk of heart failure observed with ACE and CCB in that trial may be relevant only to patients in whom diuretics were not also used. The study does raise important awareness, however, that ACE or CCB use without diuretic therapy is no better than diuretic therapy, and may be associated with higher risk of certain outcomes. A substantial number of patients with essential hypertension might achieve adequate blood pressure control with diuretic monotherapy. If so, that certainly has important implications for the cost of medical care in this country. For African Americans with essential hypertension, ACE may have advantages as a component of therapy in comparison with CCBs or beta-blockers, although diuretics should probably be the cornerstone of therapy for them and supported by the Seventh Joint National Committee. For patients with proteinuric renal disease, whether associated with diabetes or hypertension, it should be considered inappropriate to use DHP CCB as monotherapy in any setting, whether as part of a clinical trial or in clinical practice. These drugs should not be considered as ethical placebo arms in trials, most especially in diabetic nephropathy, nor should they be used without an ACE or ARB in patients with proteinuric renal disease in the absence of documented contraindications or intolerance to ACE, ARB, or non-DHP CCB (which are now considered second-line agents for proteinuric renal disease, and are acceptable placebo or comparison arms in clinical trials). For patients with type I diabetes, ACE remain the cornerstone of therapy. Because of recent RENAAL and IDNT trial results, the greatest benefit for slowing progression of renal disease in type II diabetic nephropathy now belongs to ARBs. In contrast, however, the HOPE trial showed that ACE, specifically ramipril, had the greatest evidence for prevention of cardiovascular outcomes in patients with renal insufficiency, regardless of diabetic status. Cardiovascular outcomes were secondary end points in the RENAAL and IDNT trials, and with the exception of heart failure for losartan, no benefits on cardiovascular outcomes were statistically significant. Progression of renal disease has only been studied in a relatively small cohort of Israeli patients comparing enalapril with nifedipine. These gaps lead to a classic dilemma in medical decision-making. Because evidence has shown that patients with elevated serum creatinine (greater than or equal to 1.4 mg/dL) are just as likely to die from cardiovascular disease as they are to reach end-stage renal disease, which outcome should be the focus for clinicians, or for researchers? Using a strictly evidence-based approach, this question can only be answered by yet another large, long, randomized, controlled trial. Given the similarity of actions between the ARB and ACE, it is likely there is considerable overlap of both benefits and side-effects between the two, although ARB may have a lower incidence of cough and hyperkalemia. The decision of which antihypertensive agents to use will have to be tailored carefully to the needs of the patient and careful consideration of both medical and economic factors. Regardless of the choice between an ACE or ARB, however, post hoc analysis of clinical trials [21,47] and observational data clearly indicate that patients with chronic kidney disease, even if considered mild (ie, serum creatinine greater than or equal to 1.4 mg/dL) are at significantly greater risk of cardiovascular morbidity and mortality compared with those with better kidney function. As stated in a recent review by the authors of the HOPE trial [50], "the frequent practice of withholding ACE [or ARB] in patients with mild renal insufficiency is unwarranted," because not only are these patients precisely those who might benefit most from their use, but safety and tolerability are generally excellent. Based on the results of the AASK trial, the authors add the same for the use of ACE inhibitors in African Americans.
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PMID:What have we learned from the current trials? 1487 Oct 59

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