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)

Activation of the RAAS has been linked with an increased risk of myocardial infarction and stroke,(1,2,37,38) and recently these beneficial effects have, in part, been attributed to the effects of the RAAS on the fibrinolytic system. Indeed, ACE seems to occupy a central position in modulating the fibrinolytic balance, where an angiotensin II-mediated increase of PAI-1 plays a major role. By contrast, the effect on bradykinin stimulated t-PA release may be of lesser importance, although the data are conflicting. Importantly, the impact of the RAAS on the fibrinolytic balance may also contribute to the favourable effects of ACE inhibition and AT1-receptor antagonists on cardiovascular events, particularly when considering the activation of the RAAS in hypertension and heart failure. More work is clearly required in this area to elucidate potential therapeutic targets.
J Renin Angiotensin Aldosterone Syst 2000 Sep
PMID:The renin-angiotensin-aldosterone system and fibrinolysis. 1188 Oct 31

Renin-angiotensin blockade is an important component of management of heart failure in the 21st century. It can be achieved by angiotensin-converting enzyme inhibition (ACEI) and angiotensin receptor blockade (ARB). Neuro-hormonal activation was considered a necessary mechanism for survival of patients with left ventricular dysfunction in 1960s and 1970s. This has been proven to be incorrect, and in fact, there is a large and growing body of evidence showing the cardio-protective effects of RAS and other neuro-hormonal blockade.
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PMID:Ace inhibitors in cardiovascular diseases. 1195 89

The increasing clinical burden of congestive heart failure (CHF) is exacerbated by our limited abilities in clinically identifying the various aetiologies of the condition, such as the differentiation between systolic and diastolic heart failure. This denies appropriate therapy to a substantial proportion of patients, particularly outside specialised centres, and can even lead to the use of potentially deleterious interventions. The development of practically applicable definitions of the various types of CHF, combined with the rationalisation of diagnostic techniques, has helped both primary and secondary care physicians to target therapies appropriately to specific patient groups. This should reduce the number of misdiagnoses, thus minimising the proportion of patients 'falling through the net' of effective CHF management, and thereby improving clinical outcomes and the quality-of-life of those affected.
J Renin Angiotensin Aldosterone Syst 2000 Sep
PMID:Diagnosis of CHF--often a trap in itself. 1196 85

The Heart Outcomes Prevention Evaluation (HOPE) study was designed to test the hypotheses that two preventive intervention strategies, namely angiotensin-converting enzyme (ACE) inhibition or vitamin E, would improve morbidity and mortality in patients at high risk of cardiovascular events compared with placebo. This review addresses the ACE inhibitor (ACE-I) (ramipril) arm of the study, both on the trial population as a whole, and on the large diabetic subgroup. Patients were included in the study who were considered to be at high risk of future fatal or non-fatal cardiovascular events, by virtue of their age (>55 years), existing or previous cardiovascular disease, or diabetes. Diabetics had at least one other risk factor, either known vascular disease or other factors such as cigarette smoking, high cholesterol or hypertension. Ramipril or placebo was added to concomitant medication, which included, in a substantial proportion of patients, antihypertensive drugs (excluding ACE-I), lipid-lowering agents or aspirin. As a result, despite a history of hypertension in nearly 50% of patients, blood pressure (BP) at baseline was normal and the reduction in BP attributable to ramipril modest (a fall of 3-4 mmHg systolic BP and 1-2 mmHg diastolic). The trial was stopped early on the advice of the Data Monitoring Committee because of convincing evidence of the benefit of ramipril treatment on the combined primary endpoint of cardiovascular death, non-fatal myocardial infarct (MI) and non-fatal stroke (14% vs. 17.8% on ramipril and placebo, respectively; relative risk reduction 22%, p<0.001). This comprised a risk reduction of 32% for stroke, 20% for MI, 26% for cardiovascular death and 16% for all-cause mortality, as well as a reduction in the risk of several other endpoints including heart failure and revascularisation procedures. The results among the 3577 diabetic subjects were even more striking, with a reduction of 25% in the combined primary endpoint. This reduction in the combined endpoint and in particular the reduction in MI far exceeded that which would be expected from the modest fall in BP. Furthermore, a multiple regression analysis of the diabetic subgroup showed similar relative risk reductions even after allowing for the effects of the fall in BP. Possible explanations for the non BP-mediated benefits of ramipril include reduction of angiotensin II-induced intimal and vascular smooth muscle proliferation and possible plaque stabilisation. The HOPE study results show that it is both safe and beneficial to lower BP that is already within the 'normal' range, particularly in patients with known vascular risk factors. This should greatly extend the use of ACE-I to a wider group of patients - not only those with left ventricular dysfunction, hypertension or diabetic microalbuminuria, but to the sort of high-risk patients who are currently given prophylactic treatment with aspirin.
J Renin Angiotensin Aldosterone Syst 2000 Mar
PMID:The HOPE Study (Heart Outcomes Prevention Evaluation). 1196 89

As with many large-scale long-term outcome trials, more questions have been posed than answered regarding the potential role of angiotensin II receptor blockers as first-line agents in chronic heart failure. Given the present data, in patients with left ventricular systolic dysfunction, ACE inhibitors must remain the treatment of choice, owing to the large body of data supporting their use in this clinical syndrome. However, ARBs seems a reasonable alternative for renin-angiotensin axis blockade in the significant number of heart failure patients who are genuinely intolerant of ACE inhibitors. The pendulum has now swung back in favour of ACE inhibition for chronic heart failure, although one can only await with great expectation the results of the ongoing trials comparing not only angiotensin II receptor blockers with ACE inhibitors but a combination of the two with regards tolerability and survival. Whether this potentially useful class of drugs will ultimately become the cornerstone of heart failure therapy in place of, or in addition to, ACE inhibitors is still in debate, but hopefully we should not have to wait too long for the definitive answers.
J Renin Angiotensin Aldosterone Syst 2000 Mar
PMID:Angiotensin II receptor blockers in chronic heart failure--not as ELITE as expected! 1196 90

Is heart failure an endocrine disease? Historically, congestive heart failure (CHF) has often been regarded as a mechanical and haemodynamic condition. However, there is now strong evidence that the activation of neuroendocrine systems, like the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system, as well as the activation of natriuretic peptides, endothelin and vasopressin, play key roles in the progression of CHF. In this context, agents targeting neurohormones offer a highly rational approach to CHF management, with ACE inhibitors, aldosterone antagonists and beta-adrenergic blockade improving the prognosis for many patients. Although relevant improvements in clinical status and survival can be achieved with these drug classes, mortality rates for patients with CHF are still very high. Moreover, most patients do not receive these proven life-prolonging drugs, partially due to fear of adverse events, such as hypotension (with ACE inhibitors), gynaecomastia (with spironolactone) and fatigue (with beta-blockers). New agents that combine efficacy with better tolerability are therefore needed. The angiotensin II type 1 (AT(1))-receptor blockers have the potential to fulfil both these requirements, by blocking the deleterious cardiovascular and haemodynamic effects of angiotensin II while offering placebo-like tolerability. As shown with candesartan, AT(1)-receptor blockers also modulate the levels of other neurohormones, including aldosterone and atrial natriuretic peptide (ANP). Combined with its tight, long-lasting binding to AT(1)-receptors, this characteristic gives candesartan the potential for complete blockade of the RAAS-neurohormonal axis, along with the great potential to improve clinical outcomes.
J Renin Angiotensin Aldosterone Syst 2000 Sep
PMID:Neurohumoral blockade in CHF management. 1196 92

Constitutive angiotensin-converting enzyme (ACE) is bound to endothelial cells where it serves to regulate circulating concentrations of angiotensin II (Ang II) that normally contribute to circulatory homeostasis. Recruitable ACE, bound to macrophage and myofibroblast cell membrane, regulates local concentrations of Ang II involved in tissue repair. De novo generation of Ang II modulates expression of TGF-beta1 whose autocrine/paracrine properties regulate collagen turnover at sites of fibrous tissue formation that appear in response to various forms of injury in diverse tissues. Persistent myofibroblasts and their ACE activity at the infarct site contribute to a sustained metabolic activity that can account for a progressive fibrosis at, and remote to, sites of myocardial infarction. Activation of the circulating renin-angiotensin-aldosterone system with sustained elevations in plasma Ang II and aldosterone induce a pro-inflammatory vascular phenotype of small arteries and arterioles. This further promotes the appearance of recruitable ACE bound to macrophages and myofibroblasts involved in vascular remodelling. Locally produced Ang II from these vascular sites leads to perivascular fibrosis of intramural coronary vasculature of non-infarcted myocardium. At these sites, remote to the infarct, such adverse structural remodelling by fibrous tissue eventuates in ICM, a major aetiologic factor involved in the appearance of chronic cardiac failure and contributes to its progressive nature.
J Renin Angiotensin Aldosterone Syst 2000 Dec
PMID:Recruitable ACE and tissue repair in the infarcted heart. 1196 15

Since the original discovery of atrial natriuretic peptide (ANP) nearly 20 years ago and the subsequent realisation of the existence of a family of natriuretic peptides, there has been considerable progress in the elucidation of the physiological and pathophysiological significance of these peptides. This review has examined two potentially important practical aspects arising from natriuretic peptide research - the significance of measurement of plasma levels of ANP and of brain natriuretic peptide BNP for cardiovascular disease and the therapeutic potential of targeting the natriuretic peptide system. Several situations where the measurement of plasma ANP and BNP may be of benefit in the overall assessment and prognosis of cardiac disease have been discussed. The measurement of plasma levels of these peptides appears to have limited value as a specific diagnostic tool and is unlikely to replace well-established procedures to assess cardiac function. Nevertheless, given the strong negative predictive value, the value of the measurement of plasma natriuretic peptides particularly BNPs, in people with suspected heart disease, rests on the evidence that a normal value indicates a low risk of cardiac impairment. Moreover, a consistently elevated plasma level of BNP after myocardial infarction is associated with a distinctly poor prognosis. In turn, this may help to select those with high plasma levels for subsequent detailed investigation of cardiac dysfunction. This may be an important option, especially where the facilities for the more invasive cardiological procedures are not available. Intriguingly, recent research also suggests the possibility that plasma levels of natriuretic peptides may have an important role in guiding more effective therapy for heart failure. The potent cardiovascular and renal effects of ANP and BNP provide an important therapeutic potential for hypertension and for conditions associated with volume overload. A number of approaches which have been used to enhance endogenous activity of these peptides have been highlighted. The use of the native peptides ANP and BNP may well be valuable in some circumstances, such as in critically ill individuals with congestive heart failure or renal failure. However, the limitations of the use of peptides, especially for long-term treatment, are obvious. In view of this, considerable effort has been devoted to the development of orally active agents to enhance endogenous natriuretic peptides by inhibition of breakdown by neutral endopeptidase. This research has led to the development of vasopeptidase inhibitors - dual inhibitors of both endopeptidase and angiotensin-converting enzyme - to enhance endogenous natriuretic peptide function on a background of reduced angiotensin II activity. The broad spectrum of action and the potentially important target-organ protection of these inhibitors offer potential benefits which may well go beyond existing treatment of hypertension and of conditions associated with overt volume overload.
J Renin Angiotensin Aldosterone Syst 2000 Dec
PMID:Practical implications of current natriuretic peptide research. 1196 16

Endothelins are a family of peptides, which comprises endothelin-1 (ET-1), endothelin-2 (ET-2) and endothelin-3 (ET-3), each containing 21 amino-acids. ET-1 is a peptide secreted mostly by vascular endothelial cells, the predominant isoform expressed in vasculature and the most potent vasoconstrictor currently known. ET-1 also has inotropic, chemotactic and mitogenic properties. In addition, it influences salt and water homeostasis through its effects on the renin-angiotensin-aldosterone system (RAAS), vasopressin and atrial natriuretic peptide and stimulates the sympathetic nervous system. The overall action of endothelin is to increase blood pressure and vascular tone. Therefore, endothelin antagonists may play an important role in the treatment of cardiac, vascular and renal diseases associated with regional or systemic vasoconstriction and cell proliferation, such as essential hypertension, pulmonary hypertension, chronic heart failure and chronic renal failure. Long-term anti-endothelin therapy may improve symptoms and favourably alter the progression of heart failure. Endothelin appears to participate in induction and progression of sclerotic renal changes, leading to progression to end-stage renal disease. Anti-endothelin therapy might offer additional benefits in the prevention of progression of chronic renal failure in addition to the known benefits of RAAS inhibition. Clinical trials have demonstrated potentially important benefits of endothelin antagonists for patients with essential hypertension, pulmonary hypertension and heart failure. Further studies are necessary to determine the role of anti-endothelin therapy in the treatment of cardiovascular diseases and determine the different roles of selective receptor antagonism vs. mixed ET(A/B)-receptor antagonism in human diseases.
J Renin Angiotensin Aldosterone Syst 2002 Mar
PMID:Role of endothelin in cardiovascular disease. 1198 41

This study in spontaneous hypertensive rats (SHR) was designed to determine whether a greater fall in blood pressure (BP) could be achieved with the combination of an angiotensin-converting enzyme inhibitor (ACE-I) and an AT(1)-receptor blocking drug than with higher doses of either drug alone. The peak effect of captopril occurred 3 4 hours post-dose and a plateau response was achieved with 10 mg/kg. The peak effect of losartan occurred 7 8 hours post-dose and a plateau response was achieved with 10 mg/kg. Increasing the dose of either drug caused no greater fall in BP, but increased the duration of the effect. Captopril, 10 mg/kg, administered with losartan 10 mg/kg caused a greater fall in BP than captopril or losartan, 20 mg/kg. This was present after acute doses or after one week of daily therapy. The combination of ACE-I and AT(1)-blocking drugs is more effective than either therapy alone and may be a useful combination to manage hypertension and/or cardiac failure.
J Renin Angiotensin Aldosterone Syst 2002 Mar
PMID:Interaction of ACE inhibitors and AT(1)-receptor blockers on maximum blood pressure response in spontaneous hypertensive rats. 1198 42


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