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)

Angiotensin II type I receptor antagonists (ARAs) have been tested in two large randomized trials, Evaluation of Losartan in the Elderly II (ELITE II) and the Valsartan Heart Failure Trial (Val-HeFT), and several other large trials are ongoing in the indication of chronic heart failure (CHF). Based on the available evidence, angiotensin converting enzyme inhibitors remain the cornerstone in the treatment of CHF. However, much more information should be available in the next few years, which will provide more evidence on how to use ARAs and in which patients.
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PMID:Are angiotensin II receptor antagonists indicated in chronic heart failure? 1263 89

This study prospectively investigated 3,118 standard 12-lead ECGs recorded in 1,804 patients, who participated in the Losartan Heart Failure Survival Study--ELITE II clinical trial. After exclusion of patients with rhythms other than sinus, or atrioventricular block, or poor quality ECGs, 986 (703 men, mean age 71 +/- 7 years) with baseline ECGs were retained, of whom 615 patients had follow-up ECGs 4 months after randomization. QT intervals were manually measured with a digitizing board. Heart rate, QRS duration, maximum QT and JT intervals, QT and JT dispersion (the interval ranges across all measurable ECG leads) were analyzed. In the overall population, there were 140 (14%) deaths from all causes, including 119 (12%) cardiac and 59 (6%) sudden deaths during a follow-up of 540 +/- 153 days. The mean heart rate was significantly faster in nonsurvivors than in survivors (77 +/- 16 vs 74 +/- 14 beats/min, P = 0.006), and in patients who died of cardiac death (76 +/- 16 beats/min, P = 0.04 vs survivors). Mean QRS duration was significantly longer in nonsurvivors (107 +/- 25 ms), and in the subgroups who died of cardiac (107 +/- 24 ms) or sudden death (112 +/- 23 ms) than in survivors (99 +/- 24 ms, P < 0.01 for all). The maximum and corrected (QTc) QT intervals were similar for nonsurvivors, regardless of cause of death, and in survivors (P = NS for all comparisons). Significantly shorter maximum and corrected (JTc) JT intervals were observed in victims of any mode of death compared to survivors (P < 0.05 for all). There was no significant difference in QT or JT dispersion between patients with any mode of death and survivors (P > 0.1 for all). Neither losartan nor captopril significantly modified QT or JT dispersion. In conclusion, increased QT dispersion is not associated with increased mortality in patients with heart failure, and is not suitable to examine drug efficacy in these patients.
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PMID:QT dispersion has no prognostic value in patients with symptomatic heart failure: an ELITE II substudy. 1268 53

In this article, 2 leading physicians debate the strength of outcome data on the efficacy of angiotensin-converting enzyme (ACE) inhibitors versus angiotensin II receptor blockers (ARBs) for reducing the incidence of cardiovascular, cerebrovascular, and renovascular events. Dr. Stephen G. Ball notes that the efficacy of ACE inhibitors for reducing the risk for myocardial infarction independent of their effects on blood pressure is controversial. In the Heart Outcomes Prevention Evaluation (HOPE) study, ramipril treatment in high-risk patients was associated with a 20% reduction in the risk for myocardial infarction; mean reduction in blood pressure was 3 mm Hg for systolic blood pressure and 1 mm Hg for diastolic blood pressure. The HOPE investigators propose that the 20% reduction was much greater than would be expected based on the observed blood pressure reduction. However, a meta-regression analysis of blood pressure reduction in >20 antihypertensive therapy outcome trials found that the reduction in myocardial infarction risk with ramipril observed in HOPE was consistent with the modest blood pressure reduction seen with that agent. Nevertheless, there are convincing data for prevention of myocardial infarction with ACE inhibitors in patients with heart failure, including those with heart failure after myocardial infarction, as well as supportive evidence from studies in patients with diabetes mellitus and concomitant hypertension. On the other hand, Dr. William B. White takes the position that ARBs are well-tolerated antihypertensive agents that specifically antagonize the angiotensin II type 1 (AT(1)) receptor and provide a more complete block of the pathologic effects of angiotensin II-which are mediated via the AT(1) receptor-than ACE inhibitors. The Evaluation of Losartan in the Elderly (ELITE) II study and the Valsartan Heart Failure Trial (ValHeFT) suggest that ARBs reduce the risk for mortality in patients with congestive heart failure. The Losartan Intervention for Endpoint (LIFE) Reduction in Hypertension trial also demonstrated beneficial effects of ARBs in the prevention of stroke events. The Irbesartan in Patients with Diabetes and Microalbuminuria (IRMA) study, the Irbesartan Diabetic Nephropathy Trial (IDNT), and the Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) study demonstrated significant reductions in the rate of progression of renal disease in patients receiving ARBs, independent of effects on blood pressure. These data support the use of ARBs, in addition to the standard of care, in hypertensive patients with heart failure who are intolerant of ACE inhibitors, and also provide compelling evidence for their use in patients with hypertension and type 2 diabetes.
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PMID:Debate: angiotensin-converting enzyme inhibitors versus angiotensin II receptor blockers--a gap in evidence-based medicine. 1451 6

Increased oxidative stress and reduction in antioxidant enzymes have been suggested to be involved in the pathophysiology of congestive heart failure subsequent to myocardial infarction (MI). The objective of the present study was to characterize changes in the mRNA abundance and protein levels for the enzymatic antioxidants, superoxide dismutase (SOD), glutathione peroxidase (GSHPx) and catalase during the sequelae of congestive heart failure in rats. MI was produced by the ligation of the left coronary artery and hearts from controls and 1, 4 and 16 week PMI groups were analyzed. Losartan treatment (2 mg/ml in drinking water, daily) was started at 4 weeks and continued for 12 weeks. The mRNA levels for SOD were reduced by about 40% at 1-week PMI, were near to the control levels at 4-week PMI and at 16 weeks PMI, the levels were reduced by about 73% below the controls. GSHPx mRNA levels remained unchanged at all time points. The mRNA levels for catalase remained unchanged at 1 and 4 weeks PMI and were significantly reduced by about 44% at 16 weeks PMI as compared to the controls. The protein levels for MnSOD, CuZnSOD, GSHPx at 1 and 16 weeks remained unchanged in treated and untreated PMI groups. However, the protein levels for catalase was significantly increased in the control and PMI groups treated with Losartan. It is concluded that changes in the SOD and catalase activities during severe heart failure correlated with changes in mRNA for these enzymes. The precise mechanism/s for the improvement in antioxidant reserve and protein levels after Losartan treatment is/are unclear at this time.
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PMID:Antioxidant enzyme gene expression in congestive heart failure following myocardial infarction. 1457 98

Hypertrophy and heart failure following a myocardial infarction in rodents are accompanied by a switch of myosin isoforms from V1 to V3. The angiotensin II receptor blocker, Losartan, has been demonstrated to improve cardiac function and long-term survival after myocardial infarction. In this study we have investigated whether chronic Losartan treatment affects myosin isoform composition in the hearts of rats following a myocardial infarction. Rats were subjected to coronary artery ligation and received either Losartan (1 g/L) in the drinking water or water only. Four months after myocardial infarction, rats were classified as having either congestive heart failure (cMI) or uncomplicated myocardial infarction (uMI) based on their lung weight to body weight ratio (LW/BW). Compared with sham operated rats, uMI rats showed a 68.5% increase in the relative contribution of V3 and a 33.7% decrease in the relative contribution of V1 (p < 0.05). Untreated cMI showed 39.7% more V3 and 38.2% less V1 when compared with untreated uMI (p < 0.05). Losartan treatment after myocardial infarction reduced the incidence of cMI from 30.4 to 4.5% and scar size from 1.52 +/- 0.07 to 0.94 +/- 0.11 cm2 respectively. The percentage of V1 in Losartan treated uMI (LuMI) was 25.2% higher than the percentage of V1 in untreated uMI (p < 0.05), whereas the percentage of V3 in LuMI was 24.2% lower than that in untreated uMI (p < 0.05). A positive correlation of V3 myosin and scar area was observed. Our study suggests that expression of V3 myosin in the left ventricle is associated with scar size and the progress of hemodynamic changes after myocardial infarction. Losartan treatment reduces scar size and wall stress of the heart after the infarct, and therefore inhibits the signals shifting myosin isoform expression from V1 to V3 after a myocardial infarction.
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PMID:Losartan inhibits myosin isoform shift after myocardial infarction in rats. 1457 12

The recent years have witnessed tremendous advances in the understanding of the pathophysiology of chronic heart failure (CHF), leading to significant improvement in therapy. Recognition of the deleterious effects of angiotensin II is an major therapeutic target. By blocking the transformation of angiotensin I to angiotensin II, angiotensin-converting enzyme inhibitors (ACEI) improve symptoms, exercise tolerance and survival at all stages of CHF. Angiotensin II-receptors blockers (ARB) have several theoretical advantages over ACEI, including a better tolerance profile, that may lead to a more favourable effect. In CHF with systolic dysfunction, randomised-controlled trials comparing losartan to captopril (ELITE 1 and ELITE 2) or valsartan versus placebo on top of conventional therapy (Val-HeFT) failed to demonstrate a superiority of ARB's compared to ACEI in terms of mortality. However, ARB's appeared better tolerated in this indication. The treatment of CHF with preserved systolic function remains unclear and may be defined in a near future by two studies addressing the role of on candesartan (CHARM study) or irbesartan (I-Preserve study) in this form of CHF. ACEI and beta-blockers remain on first line for treating CHF due to systolic dysfunction. Losartan or valsartan can be considered as an alternative if ACEI are not tolerated or contraindicated.
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PMID:[ACE inhibitors and/or sartans in heart failure: is there a difference?]. 1460 88

The renin-angiotensin system (RAS) plays an important role in the development of cardiovascular diseases. The favorable effects of inhibitors of this system are mainly due to a decrease of the production of angiotensin II. Usual association between angiotensin II receptor antagonists (AIIA) and angiotensin-converting enzyme (ACE) inhibitors results of a mutual action on the RAS, but important differences exist. ACE inhibitors demonstrated major benefits in heart failure and in post-infarction. In diabetic patients, ACE inhibitor treatment is associated with nephroprotective effects. In four main studies ACE inhibitors didn't demonstrated superior effect on primary outcome compare to standard antihypertensive treatment (diuretics or beta-blockers). However, in HOPE and PROGRESS studies, ACE inhibitors decrease myocardial infarction incidence, even after arterial pressure adjustment. Can we expect the same effects with the AIIA? Of course a direct comparison would be preferable, but some differences emerge. In a main study, AIIA treatment was compared to a standard antihypertensive treatment. The LIFE trial demonstrated superior benefits with losartan than with beta-blocker atenolol for the same degree of blood pressure reduction in hypertensive patients with left ventricular hypertrophy. Losartan had particularly strong effect on risk for stroke and prevented new-onset diabetes. So we have some data to emit the hypothesis that ACE inhibitors decrease the incidence of myocardial infarction and AIIA the incidence of stroke.
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PMID:[Angiotensin-converting enzyme inhibitors and/or angiotensin II receptors antagonists in the treatment of arterial hypertension]. 1474 83

The antihypertensive drug classes that have reduced cardiovascular events safely either in large placebo-controlled trials or in comparison with other effective antihypertensive drugs in large morbidity trials are diuretics, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers (CCBs). Although control of blood pressure (BP) is a primary goal of therapy, evidence from several clinical trials suggests that certain antihypertensive agents provide clinical benefits independent of their effect on BP. In the recently reported Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), an ACE inhibitor, a CCB, and an alpha-blocker reduced coronary events and mortality to a similar extent as a thiazide-type diuretic, but the diuretic reduced one or more major cardiovascular events, especially heart failure, more than the other agents. In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial, the ARB losartan reduced cardiovascular morbidity (primarily stroke) more than the beta-blocker atenolol. Although an ARB has not yet been compared with a diuretic in a morbidity trial, as most patients require more than one drug to control BP, and a diuretic plus an ARB is a very effective and well-tolerated combination, this uncertainty applies to a minority of patients. A primary goal in treating hypertension should be to reach a patient's goal BP, but initial selection of drugs based on hypertension morbidity study results and other compelling indications should be given priority.
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PMID:Are there benefits to specific antihypertensive drug therapy? 1462 58

Unlike most other experimental models of congestive heart failure, the volume overload model induced by aortocaval shunt (AVS) in rats was found to exhibit enhanced beta-adrenoceptor (beta-AR) signaling. To study whether the adenylyl cyclase (AC)-G protein system is involved in such a change, we examined cardiac AC activity and protein content as well as G(s)alpha and G(i)alpha activities, protein contents, and mRNA levels in both left (LV) and right (RV) ventricles at the failing stage (16 wk after surgery). Basal and forskolin-stimulated AC activities were significantly increased in both LV and RV from the failing hearts; this change was associated with an upregulation of type V/VI AC protein. In contrast to 5'-guanylyl imidodiphosphate and NaF, the stimulatory effect of isoproterenol on AC was increased in the failing heart. Although G(s)alpha and G(i)alpha protein contents in the failing hearts were not altered, the mRNA level for G(s)alpha was decreased by 20% and that for G(i)alpha was increased by 20%. In addition, the activity of G(s)alpha, but not G(i)alpha, as assessed by toxin-catalyzed ADP ribosylation, was significantly decreased in the failing heart. Losartan and imidapril treatments improved cardiac function and attenuated alterations in mRNA levels for G(s)alpha and G(i)alpha proteins, as well as G(s)alpha activity, without affecting changes in AC protein content or activities in heart failure due to volume overload. These data suggest that increased AC activity may contribute to the enhanced beta-AR signaling in the AVS model of heart failure, whereas alterations in gene expression for G proteins may be of an adaptive nature at this stage of heart failure.
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PMID:Alterations of adenylyl cyclase and G proteins in aortocaval shunt-induced heart failure. 1496 38

The pathophysiologic mechanisms of myocardial remodeling in heart failure (HF) remain poorly understood. Using differential mRNA display of myocardial tissue from rats with ischemic HF vs. controls we identified robust myocardial induction of the mRNA encoding connective tissue growth factor (CTGF). The aim of this study was to investigate the sites of synthesis and the mechanisms of induction of CTGF in failing myocardial tissue. The study demonstrates that myocardial expression of CTGF mRNA and protein is substantially elevated in non-ischemic tissue from both the left and the right ventricles of rats with experimentally induced myocardial infarction (MI). The induction of myocardial CTGF mRNA was shown to transcend from early post-infarction HF to chronic HF. In situ hybridization and immunohistochemical analysis of myocardial tissue sections demonstrated expression of CTGF confined to fibroblasts and endothelial cells of non-ischemic myocardial tissue. In subsequent experiments rats subjected to MI were randomized to treatment with the AT1 angiotensin receptor antagonist losartan (12.5 mg/kg b.i.d. per os) or vehicle. Losartan attenuated ventricular hypertrophy, improved hemodynamics, and prevented the induction of myocardial CTGF mRNA observed in rats post-MI. To provide the cellular basis of Ang II-stimulated CTGF mRNA expression, primary cultures of rat myocardial fibroblasts were stimulated with Ang II (10(-7) M). Real-time reverse transcription-polymerase chain reaction and western blot analysis demonstrate that Ang II induces rapid, AT1 receptor-mediated elevations of CTGF mRNA and protein in rat cardiac fibroblasts. Furthermore, CTGF was shown to stimulate fibroblast proliferation in vitro. In conclusion, this study demonstrates that CTGF is a myocardial effector of Ang II-induced myocardial remodeling in HF mediated via AT1 receptors situated on cardiac fibroblasts.
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PMID:Connective tissue growth factor--a novel mediator of angiotensin II-stimulated cardiac fibroblast activation in heart failure in rats. 1501 Feb 78


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