Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Collectively, a series of large, prospective randomised outcome trials has now shown that angiotensin receptor blockers (ARBs) are of clinical value in a broad spectrum of patients with symptomatic heart failure, regardless of background therapy and ventricular function. There is a clear benefit of ARBs in patients unable to tolerate an angiotensin- converting enzyme (ACE) inhibitor and this benefit is of a similar magnitude to that obtained with an ACE inhibitor (ACE-I). Both Val-HeFT and, particularly, CHARM-Added, also show that symptoms, morbidity and mortality are further reduced if an ARB is added to an ACE-I. This benefit is not only statistically significant but clinically important. CHARM-Preserved showed that candesartan can reduce hospital admission for heart failure in patients with preserved systolic function though more definitive outcome data are needed in this group.
J Renin Angiotensin Aldosterone Syst 2003 Sep
PMID:Angiotensin receptor blockers in heart failure. 1460 22

A markedly decreased aortic nitric oxide (NO) availability, probably due to impaired endothelial nitric oxide synthase activity with enhanced O2- and peroxynitrite production, seems to be attributable to endothelial dysfunction in spontaneously hypertensive rats (SHR) with severe congestive heart failure (CHF). In this study, we investigated the chronic effect of the angiotensin-converting enzyme inhibitor, ramipril (RA) and the loop diuretic, frusemide (FU), as well as the combination of both on endothelial NO, O2- and peroxynitrite production in aortae from SHR with failing hearts after myocardial infarction (MI). Heart failure was induced by permanent occlusion of the left coronary artery. SHR were randomised to receive either placebo, RA, (1 mg/kg/day), FU (4 mg/kg/day) or RA+FU (1 and 4 mg/kg/day, respectively). Treatments were started two weeks following MI and continued for six weeks. Reduced aortic and coronary flow indices in the working heart, which can be considered as markers for endothelial function, were significantly normalised and improved, respectively, by RA, FU or RA+FU-treatment. Similarly, all three treatment regimens significantly enhanced the reduced calcium ionophore (CaI)-induced NO-release (assessed by a NO-sensitive microsensor) from aortic endothelial cells of placebo-treated animals with CHF. Concomitantly, the increased CaI-stimulated O2- production (assessed by an electrochemical sensor) in aortic endothelial cells of placebo-treated animals with CHF was significantly reduced by RA and RA+FU-treatment. Treatment with RA and RA+FU also attenuated the dramatic increase in endothelial peroxynitrite concentration (chemiluminescence method), which was observed in placebo-treated rats with CHF. FU did not counteract improved haemo- and cardiodynamic parameters by RA. Thus, RA and FU act synergistically to enhance bioavailability of endothelium-derived NO, and this may contribute to the clinical usefulness of the combination of these drugs in treatment of heart failure.
J Renin Angiotensin Aldosterone Syst 2003 Sep
PMID:Ramipril improves nitric oxide availability in hypertensive rats with failing hearts after myocardial infarction. 1460 24

Congestive heart failure (CHF) is characterised by activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS). Both systems are known to interact and to potentiate each other s activities. We recently demonstrated that angiotensin II (Ang II) enhances sympathetic nerve traffic via prejunctionally-located AT1-receptors. At present, little is known about the effects of Ang II at the level of the sympathetic neurones in CHF. Accordingly, we investigated the effect of Ang II in the presence and absence of the AT1-receptor antagonist, eprosartan, on stimulation-induced nerve traffic in isolated thoracic aorta preparations obtained from rabbits suffering from experimentally-induced CHF. Control-preparations were obtained from age-matched animals. Sympathetic activity was assessed by a [3H]noradrenaline spill-over model. Additionally, Ang II constrictor responses were compared between CHF and control vessels in the presence and absence of eprosartan. Additionally, to study postjunctional facilitation, the effects of Ang II on postsynaptic a-adrenoceptor-mediated responses were studied using noradrenaline. Stimulation-evoked SNS-neurotransmission was similar in both groups (CHF versus control). Ang II (0.1 nM 0.1 M) caused a concentration-dependent increase of the stimulation-evoked sympathetic outflow in both groups, with a maximum at 10 nM (control [n=7], FR2/FR1 2.03+0.11 and CHF- preparations [n=7], FR2/FR1 1.71+0.07). The enhancement by Ang II was decreased in CHF- preparations compared with controls (p<0.05). Eprosartan concentration-dependently attenuated the Ang II-enhanced (10 nM) sympathetic outflow in both CHF- and control preparations. The sympatho-inhibitory potency of eprosartan was similar in both groups (control pIC50 8.81 0.31; CHF 8.65+0.42). Ang II (1 nM 0.3 M) concentration-dependently increased the contractile force in control preparations (Emax 21.64+3.86 mN, pD2 7.63+0.02, n=7). Eprosartan (1 nM 0.1 M) influenced the Ang II- contractions via a mixed form of antagonism. In CHF-preparations, Ang II caused impaired vascular contraction. The KCl-induced contraction was decreased in the CHF- compared with control preparations (13.02+0.64 mN versus 30.40+0.89 mN). The relative Ang II contraction (% of KCl) was also decreased (2.3% vs. 58.0%). Concentration-response curves to noradrenaline (%KCl) were similar (control pD2 6.93+0.05, Emax 131.0+2.7; CHF pD2 7.00+0.05, Emax 136.7+2.6) (p>0.05) and were not affected by Ang II. We conclude that Ang II-enhanced sympathetic neurotransmission is mediated by the prejunctional AT1-receptor in both control and CHF-preparations. The decreased facilitation of SNS effects by Ang II may be explained by down-regulation or desensitisation of the neuronal AT1-receptor. Additionally, the aortic contractile capacity in heart failure rabbits appears to be decreased, probably as a result of heart failure-associated neuroendocrine and functional changes.
J Renin Angiotensin Aldosterone Syst 2003 Dec
PMID:Impaired neuronal and vascular responses to angiotensin II in a rabbit congestive heart failure model. 1468 69

Left ventricular systolic dysfunction is associated with neurohormonal activation which contributes to progressive ventricular remodeling and worsening clinical heart failure. Renin-angiotensin-aldosterone and sympathetic nervous systems are activated, not only in patients with clinically overt heart failure, but also in patients with asymptomatic or minimally symptomatic left ventricular systolic dysfunction. Activation of the angiotensin and adrenergic systems produces deleterious effects on systemic and coronary hemodynamics, promotes myocyte hypertrophy and fibroblast growth, and myocyte necrosis and apoptosis. Thus, therapy of heart failure should consist of pharmacologic agents not only to relieve symptoms but also to prevent and attenuate ventricular remodeling and progressive heart failure, thereby improving prognosis. In patients who are symptomatic, ACE inhibitors along with digitalis and diuretics as initial therapy (triple therapy) have the greater potential to improve exercise tolerance and decrease the incidence of treatment failure compared with diuretics alone or a combination of diuretics and digitalis. Diuretics alone should not be considered for long-term therapy as plasma renin activity, angiotensin II, aldosterone, norepinephrine and vasopressin levels may increase. ACE inhibitors decrease mortality in patients with heart failure resulting from left ventricular systolic dysfunction. The results of presently available studies indicate that angiotensin II receptor blockers (ARBs) do not provide any advantage over ACE inhibitors regarding survival benefit but may be better tolerated. Long-term adrenergic inhibition with the use of ss-adrenoceptor antagonists added to ACE inhibitors is associated with attenuation of ventricular remodeling, improvement in ventricular function and clinical class and survival of patients with symptomatic systolic left ventricular failure. Thus, initial pharmacotherapy for systolic heart failure should consist of: maximal tolerated dosages of ACE inhibitors;ARBs if ACE inhibitors are not tolerated because of intractable cough or angioedema;adequate dosages of hydralazine and isosorbide dinitrate if ACE inhibitors or ARBs are not tolerated; relatively low dosages of digoxin (serum concentrations of < or = 1.0 ng/dl) if not contraindicated; and diuretics to relieve congestive symptoms. Addition of spironolactone to ACE inhibitors can result in a significant reduction in the risk of sudden death in patients with symptomatic severe heart failure. Myocardial infarction resulting from ischemic heart disease is the most common cause of systolic left ventricular failure and the therapeutic modalities with potential to reduce the risks of myocardial infraction, such as risk factor modification, adequate control of diabetes and hypertension, antiplatelet agents and lipid-lowering agents, should also be included in the initial therapy.
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PMID:Congestive heart failure: what should be the initial therapy and why? 1472 93

The renin-angiotensin system (RAS) is well recognized for its importance in regulation of BP, electrolyte balance and vascular growth. Pharmacological suppression of the RAS, through ACE inhibition and/or angiotensin receptor blockade, is a proven effective therapeutic approach to the treatment of a range of cardiovascular diseases. Renin is the enzyme that catalyzes the first and rate-limiting step of RAS, the cleavage of angiotensinogen to angiotensin I (A-I). A-I is then further converted by ACE to the biologically active vasoconstrictor, A-II. Interruption of the generation of A-II by renin inhibitors at this highly specific initial step of the cascade would be expected to have similar but not identical effects to those of the already well established RAS antagonists. Due to the lack of effective alternative enzyme pathways, blockade of A-II production may be more effective with renin inhibition than with ACE inhibition, and because of the high specificity of renin for only one substrate, namely angiotensinogen, adverse effects would be expected to be less frequent. It is currently unclear whether blockade of angiotensin II type 1 receptors (AT(1)), leaving other A-II receptors unblocked, is preferable to the reduction in plasma and tissue A-II levels achieved with either ACE or renin inhibition. The development of early peptidic and peptidomimetic renin inhibitors was hampered by problems with oral bioavailability and high costs of synthesis. However recent work has led to the synthesis of a potent non-peptidic inhibitor of renin, aliskiren, which has acceptable oral bioavailability. This renin inhibitor has been shown to effectively reduce A-II levels in normal volunteers and to lower BP in patients with mild to moderate hypertension. It appears likely that aliskiren is the first of a new class of agents that may prove useful in the management of patients with nephropathy, heart failure and atherosclerosis in addition to hypertension.
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PMID:Therapeutic potential of renin inhibitors in the management of cardiovascular disorders. 1472 59

Heart failure is a leading cause of hospital admissions in North America. Approximately half of patients with symptoms of heart failure have normal or minimally impaired systolic function and are therefore diagnosed, by exclusion, with diastolic dysfunction. The therapy of diastolic dysfunction to date is largely unsatisfactory. There have been few outcome-based clinical trials to guide clinicians, and most treatments have been empirically derived from the data from systolic heart failure studies. In general, acute management consists of central volume reduction with loop diuretics and long-acting nitrates. In some cases improvement in left ventricular filling can be achieved by reducing heart rate, usually with either beta blockers or calcium channel blockers. The role of digoxin is unclear and it should be used with caution. Theoretically, it has the capacity to further impair ventricular function, but one of the few trials in diastolic heart failure suggested that it improves symptoms and reduces hospitalization. Renin-angiotensin system blockade is a very attractive therapeutic avenue; angiotensin-converting enzyme inhibitors and angiotensin receptor blockers effectively reduce afterload, induce regression of left ventricular hypertrophy in excess of their blood pressure-lowering effect, and confer survival benefits to patients at high risk for cardiovascular death. Although the results of a recent trial using an angiotensin receptor blocker in patients with primarily diastolic heart failure were unimpressive, renin-angiotensin system blockade should still be considered because of its aforementioned benefits. The long-term management of these patients includes a careful assessment for and treatment of myocardial ischemia, treatment of hypertension, and reduction in left ventricular hypertrophy. For the treatment of ischemia, long-acting nitrates and calcium channel blockers may be particularly useful. The results of new trials in this area are expected soon, and hopefully therapy that directly targets the pathophysiologic pathways of this important disease is on the horizon.
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PMID:Diastolic Dysfunction. 1502 85

Heart failure is a clinical syndrome that may result from different disease states or conditions that injure the myocardium. The activation of circulating neurohormones, particularly aldosterone, may play a pivotal role in left ventricular (LV) remodelling. The Randomized Aldactone Evaluation Study and Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival trial have emphasised the clinical importance of aldosterone. This review addresses some of the proposed mechanisms of LV remodelling in heart failure.
J Renin Angiotensin Aldosterone Syst 2004 Mar
PMID:Aldosterone and cardiovascular remodelling: focus on myocardial failure. 1513 67

Angiotensin (Ang) II is a key player in left ventricular (LV) remodeling and cardiac fibrosis. Its effects are thought to be transferred at least in part by mitogen-activated protein kinases (MAPK), transforming growth factor (TGF) beta1, and the Smad pathway. In this study we sought to elucidate whether Ang II related effects on LV dysfunction and fibrosis in vivo are mediated via MAPK or rather via Smad stimulation. We treated homozygous REN2 rats (7-11 weeks) with placebo, Ang II type 1 (AT1) receptor blocker or tyrphostin A46 (TYR), an inhibitor of epidermal growth factor receptor tyrosine kinase that blocks extracellular signal-regulated kinase (ERK) activity. REN2 rats had LV hypertrophy (LVH) and LV dysfunction that progressed to heart failure between 10 and 13 weeks. Blood pressure normalized over time. Renin, N-terminal atrial natriuretic peptide (N-ANP), and ERK were activated while p38 MAPK was not. Treatment with AT1 receptor blockade prevented LVH and right ventricular hypertrophy, normalized systolic and diastolic d P/d t, N-ANP levels, and reduced collagen apposition. Similarly, TYR reduced LVH, N-ANP levels, and collagen apposition. Myocardial ERK activation did not depend on AT1 receptor signaling as it was not affected by AT1 receptor blockade. TYR abolished myocardial ERK activity. Smad2 activation was inhibited by AT1 receptor blockade but was unaltered by TYR. Ang II induced LV remodeling and fibrosis are dependent on both ERK and Smad2 activation. This process is prevented by both AT1 receptor blockade and TYR, and therefore inhibition of either pathway is equally efficacious in restoring LV function and architecture.
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PMID:Extracellular signal regulated kinase and SMAD signaling both mediate the angiotensin II driven progression towards overt heart failure in homozygous TGR(mRen2)27. 1537 67

Treatment of heart failure has undergone major changes in the last two decades. European and US guidelines have absorbed these major changes and set the new standards. It is therefore mandatory that treatment of heart failure is based on this knowledge. According to these guidelines, patients with chronic symptomatic heart failure should be treated with a diuretic and sometimes digoxin and vasodilators, to relieve symptoms, in addition to an angiotensin-converting enzyme inhibitor and/or an angiotensin receptor blocker (ARB) and a beta-blocker to improve prognosis. An aldosterone antagonist should be added in patients with more advanced heart failure. Prevention of heart failure has also become a major goal. We summarise here the major issues regarding the pharmacological treatment of chronic heart failure as indicated by the European and US guidelines.
J Renin Angiotensin Aldosterone Syst 2004 Sep
PMID:Current guidelines in the pharmacological management of chronic heart failure. 1552 36

Survival in patients with heart failure remains very poor, and is worse than that for most common cancers, including bowel cancer in men and breast cancer in women. The renin-angiotensin-aldosterone system (RAAS) is not completely blocked by angiotensin-converting enzyme (ACE) inhibition. Blockade of the RAAS at the AT1-receptor has the theoretical benefit of more effective blockade of the actions of angiotensin II. ACE inhibitors (ACE-Is) prevent the breakdown of bradykinin: this has been blamed for some of the unwanted effects of ACE-Is although bradykinin may have advantageous effects in heart failure. Consequently, ACE-Is and ARBs might be complementary or even additive treatments; recent trials have tested these hypotheses. The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (CHARM) programme compared the angiotensin receptor blocker (ARB) candesartan (target dose 32 mg once daily) to placebo in three distinct but complementary populations of patients with symptomatic heart failure. These were: patients with reduced left ventricular ejection fraction (LVEF) who were ACE-I-intolerant (CHARM-Alternative); patients with reduced LVEF who were being treated with ACE-Is (CHARM-Added); and patients with preserved left ventricular systolic function (CHARM-Preserved). There were substantial and statistically significant reductions in the primary composite end point (risk of cardiovascular death or hospital admission for heart failure) in CHARM-Alternative. This was also the case in CHARM-Added, supporting and extending the findings of Val-HeFT. In CHARM-Preserved, the effect of candesartan on the primary end point did not reach conventional statistical significance though hospital admission for heart failure was reduced significantly with candesartan. In the CHARM-Overall programme there was a statistically borderline reduction in all-cause mortality with a clear reduction in cardiovascular mortality. All-cause mortality was reduced by 12% in the two CHARM trials in patients with low LVEF. CHARM succeeded in answering a number of questions about the safety and efficacy of ARB use in heart failure. It showed evidence for a clinical benefit of candesartan both additive to and independent of ACE-I use. The benefits in terms of clinical outcomes were seen irrespective of beta-blocker usage. Benefits in patients with preserved LVEF were shown in the proportion of patients hospitalised with worsening heart failure and in overall number of admissions for heart failure. Candesartan had expected effects on blood pressure and renal function, emphasising the need for careful patient monitoring.
J Renin Angiotensin Aldosterone Syst 2004 Sep
PMID:Angiotensin inhibition in heart failure. 1552 37


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