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)

Our understanding of the pathogenesis of congestive heart failure (CHF) has improved remarkably in recent years. However, despite better knowledge and novel pharmaceutical strategies, this disease is still one of the most brutal killers in the Western world. The pathophysiology of CHF is complex, and much of our comprehension revolves strictly around the neurohormonal and mechanical mechanisms involved. It has been suggested that CHF is associated with altered hemostasis, but whether a prothrombotic state contributes to the pathogenesis and progression of the disease is still not well known. The purpose of this review article is to discuss our current knowledge of platelet activation in patients with CHF and the potential role of antiplatelet agents in preventing these hemostatic abnormalities. Clopidogrel is an established medication that reduces the incidence of stroke, myocardial ischemia, or vascular death. It is currently the drug of choice in the prophylaxis of subacute stent thrombosis and postischemic stroke treatment. Promising results of the most resent trials (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events [CAPRIE] and Clopidogrel in Unstable angina to prevent Recurrent Events [CURE]) may expand future indications of this ADP receptor antagonist for prevention of thrombotic complications in the CHF population. Currently conducted clinical trials (Warfarin and Antiplatelet Therapy in Chronic Heart Failure [WATCH] and Plavix Use for Treatment of Congestive Heart Failure [PLUTO-CHF] should clarify the role of clopidogrel in these patients.
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PMID:Platelet activation in patients with congestive heart failure: do we have enough evidence to consider clopidogrel? 1266 Jun 60

Clopidogrel is a selective inhibitor of ADP-induced platelet aggregation. A large, multicenter, randomized study in 12 562 patients with acute coronary syndromes without ST-segment elevation demonstrated that treatment with clopidogrel (loading dose of 300 mg followed by once daily treatment with 75 mg) in addition to standard therapy including aspirin (75 to 325 mg/day) significantly reduced the risk of the combined endpoint of cardiovascular death, myocardial infarction or stroke compared with treatment with standard therapy. Furthermore, the composite risk of these outcomes or refractory ischemia was also significantly reduced in patients treated with clopidogrel plus aspirin. The effects of clopidogrel were independent of background treatment with cardiovascular medications and/or interventions. The risk of severe ischemia, recurrent angina or heart failure was also significantly reduced in patients receiving clopidogrel plus aspirin. There was also a significant reduction in the need for coronary revascularization during the initial period of hospitalization. In patients undergoing percutaneous coronary intervention (PCI), the relative risk of the combined endpoint of cardiovascular death, myocardial infarction or urgent target-vessel revascularization within 30 days of the intervention was significantly reduced. Moreover, the relative risk of the single endpoint of myocardial infarction within 30 days of PCI was significantly in favor of clopidogrel-treated patients. Hemorrhagic events (both major and minor) were significantly more frequent in patients with acute coronary syndromes receiving treatment with clopidogrel plus aspirin than in patients treated with aspirin alone. This was largely attributable to an increased incidence in the rate of gastrointestinal hemorrhage and bleeding at the site of arterial puncture. However, there was no difference between the two groups in the incidence of bleeding episodes that were considered to be life-threatening.
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PMID:Clopidogrel: potential in the prevention of cardiovascular events in patients with acute coronary syndromes. 1472 5

Hypomagnesemia is common in hospitalized patients, especially in elderly patients with coronary artery disease (CAD) and/or those with chronic heart failure. Hypomagnesemia is associated with increased all cause mortality and mortality from CAD. Magnesium supplementation improves myocardial metabolism, inhibits calcium accumulation and myocardial cell death; it improves vascular tone, peripheral vascular resistance, afterload and cardiac output, reduces cardiac arrhythmias and improves lipid metabolism. Magnesium also reduces vulnerability to oxygen-derived free radicals, improves endothelial function and inhibits platelet function, including platelet aggregation and adhesion, which potentially confers upon magnesium physiologic and natural effects similar to adenosine-diphosphate inhibitors such as clopidogrel. However, data regarding the use of magnesium in patients with acute myocardial infarction (AMI) are conflicting. Although some previous relatively small randomized clinical trials demonstrated a remarkable reduction in mortality when intravenous magnesium was administered to relatively high risk AMI patients, two recently published large-scale randomized clinical trials (the Fourth International Study of Infarct Survival [ISIS 4] and Magnesium in Coronaries [MAGIC]) were unable to demonstrate any advantage of intravenous magnesium over placebo. Nevertheless, the theoretical benefits of magnesium supplementation as a cardio-protective agent in CAD patients, promising results from animal and human studies, its relatively low-cost and ease of handling requiring no special expertise, together with its excellent tolerability, gives magnesium a place in treating CAD patients, especially in those at high risk, such as CAD patients with heart failure, the elderly and hospitalized patients with hypomagnesemia. Furthermore, magnesium therapy is indicated in life-threatening ventricular arrhythmias such as torsades de pointes and intractable ventricular tachycardia.
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PMID:Does magnesium have a role in the treatment of patients with coronary artery disease? 1472 75

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

Congestive heart failure and other cardiac diseases are characterized by increased activity of the sympathetic nervous system, whereas at the same time parasympathetic activity is often suppressed. Such imbalance may be a result of or at least enhanced by presynaptic inhibitory effects of sympathetic neurotransmitters on acetylcholine release. We investigated whether the sympathetic cotransmitters neuropeptide Y (NPY), norepinephrine (NE), and ATP are capable of modulating acetylcholine release in human heart atrium. Human atrial appendages were incubated with [(3)H]-choline to label cholinergic transmitter stores and placed in superfusion chambers. Electrical field stimulations (S1, S2) induced a tetrodotoxin-dependent [(3)H]-release, which was taken as an index of endogenous acetylcholine release. NE, NPY, ATP, and a P2-receptor analogue were added before S2. NPY (0.05-1.0 micromol/l) concentration dependently inhibited acetylcholine release. This effect was prevented by the NPY-Y(2)-receptor antagonist BIIE 0246 (0.1 micromol/l) but not by the NPY-Y(1)-receptor antagonist BIBP 3226 (10 micromol/l). ATP (10 micromol/l), a stable analogue ADP-beta S (3 micromol/l), and NE (1 micromol/l) had no effect on acetylcholine release. m-RNA for the NPY-receptor subtypes Y(1), Y(2), Y(4), Y(5), and y(6) was demonstrated by reverse transcription-polymerase chain reaction (RT-PCR). The results suggest that the sympathetic neurotransmitter NPY inhibits parasympathetic neurotransmission in the human heart through activation of presynaptic Y(2)-receptors. NE and ATP seem not to play a role. Since NPY plasma levels are high in chronic heart failure patients, NPY may be one component leading to impaired parasympathetic neurotransmission in those patients.
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PMID:Neuropeptide Y inhibits acetylcholine release in human heart atrium by activation of Y2-receptors. 1510 51

Energostim is a combined drug comprising a mixture of nicotinamide adenine dinucleotide (0.5 mg), cytochrome C (10 mg), and inosine (80 mg), representing antihypoxant and antioxidant of direct action in one ampule. After pretreatment and subsequent 3-day energostim therapy of animals with 3-day toxico-allergic myocarditis (3d-TAM), the ECG was free of any rhythm disorders and showed evidence of improved conduction, restoration of the normal form of T-wave and the position of ST segment, while the content of myofibrillar fraction of creatine phosphokinase and toxic products of disturbed metabolism (degree of endotoxemia) decreased to the upper normal level. Under the action of energostim, neither pressure nor the maximum rate of pressure buildup in the left ventricle are reduced (as they do upon 3d-TAM); neither systolic and diastolic functions are disturbed, nor their coordination (r = 0.79 between dP/dtmin and dP/dtmax, p < 0.01). The restoration of contractile activity and maximum rate of relaxation of myocardial microfibrils during 3d-TAM is accompanied by an increase in the content of adenyl nucleotides, in the ATP/ADP, ADP/AMP, NAD/NADH, and NADP/NADPH ratios, and in the cytosol phosphorylation potential. The energostim-induced improvement in the energy supply system are accompanied by restoration of the ability of sarcoplasmic reticulum to efflux Ca2+. Thus, it is demonstrated that the effect of energostim is related to its ability to actively participate in intracell metabolic processes in myocardium, abolish necrotic changes and endotoxicosis, and restore homeostasis in the systems responsible for the contraction--relaxation process (thus preventing from the development of dysfunction of the left ventricle and the heart failure).
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PMID:[Cardioprotective effect of energostim in toxic allergic myocarditis]. 1518 54

Oxidant stress-induced activation of poly(ADP-ribose) polymerase (PARP) plays a role in the pathogenesis of various cardiovascular diseases. We have now investigated the role of PARP in the process of cardiac remodeling and heart failure in a mouse model of heart failure induced by transverse aortic constriction (banding). The catalytic activity of PARP was inhibited by the potent isoindolinone-based PARP inhibitor INO-1001 or by PARP-1 genetic deficiency. PARP inhibition prevented the pressure overload-induced decrease in cardiac contractile function, despite the pressure gradient between both carotid arteries being comparable in the two experimental groups. The development of hypertrophy, the formation of collagen in the hearts, and the mitochondrial-to-nuclear translocation of the cell death factor apoptosis-inducing factor (AIF) were attenuated by PARP inhibition. The ability of the inhibitor to block the catalytic activity of PARP was confirmed by immunohistochemical detection of poly(ADP-ribose), the product of the enzyme in the heart. Plasma levels of INO-1001, as measured at the end of the experiments, were in the concentration range sufficient to block the oxidant-mediated activation of PARP in murine cardiac myocytes in vitro. Myocardial hypertrophy and AIF translocation was also reduced in PARP-1-deficient mice undergoing aortic banding, compared with their wild-type counterparts. Overall, the current results demonstrate the importance of poly(ADP-ribos)ylation in the pathogenesis of banding-induced heart failure.
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PMID:Poly(ADP-Ribose) polymerase promotes cardiac remodeling, contractile failure, and translocation of apoptosis-inducing factor in a murine experimental model of aortic banding and heart failure. 1552

In the present study, we examined whether the powerful antioxidant probucol (a clinically used lipid-lowering drug) would attenuate the oxidative stress and energy starvation in experimental model of heart failure (HF) using isoproterenol. Rats were injected subcutaneously with isoproterenol (2.4 mgkg-1) daily for 1 week, and then treated with probucol (61 mg/kg) daily for 2 weeks. Oxidative stress was assessed by measuring myocardial lipid peroxides level and antioxidant enzymes activities, glutathione peroxidase (GPx) and superoxide dismutase. In addition, cardiac metabolic damage was estimated by measuring myocardial ATP, ADP and AMP levels as well as ATP/ADP ratio. It was found that isoproterenol induced a significant increase in heart rate by approximately 30% as compared with the pre-value. These changes were significantly attenuated by post-treatment of rats with probucol. Also, isoproterenol induced several pathological changes including lymphocyte infiltration, myofibrillar hemorrhage and degeneration, and these changes were attenuated by probucol. In addition, animals treated with isoproterenol showed a significant increase in myocardial lipid peroxides level up to 163% and a significant decrease in myocardial GPx activity by 35% as compared with the control group. Probucol not only counteracted significantly the pronounced oxidative stress effect of isoproterenol but also it induced a significant increase in myocardial GPx as compared with the control group. The major new finding of the present study is that treatment with probucol induced a significant increase in myocardial ATP level (the source of energy) and ATP/ADP ratio. Moreover, there is a significant correlation between ATP/ADP ratio and myocardial probucol level. In conclusion, the cardioprotective effect of probucol in treatment of HF is a result of not only its antioxidant properties and an enhancement of endogenous antioxidant reserve (mainly GPx) but also an enhancement of myocardial energy state.
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PMID:Probucol attenuates oxidative stress and energy decline in isoproterenol-induced heart failure in rat. 1568 44

Free radical and oxidant production in cardiac myocytes during ischemia/reperfusion, cardiomyopathy, cardiotoxic drug exposure and ageing leads to DNA strand-breakage which activates the nuclear enzyme poly(ADP-ribose) polymerase (PARP) and initiates an energy consuming, inefficient cellular metabolic cycle with transfer of the ADP-ribosyl moiety of NAD+ to protein acceptors. These processes lead to the functional impairment of the myocytes and promote myocyte death. During the last decade a growing number of experimental studies demonstrated the beneficial effects of PARP inhibition in cell cultures through rodent models and more recently in pre-clinical large animal models of regional and global ischemia/reperfusion injury and various forms of heart failure. The current article provides an overview of the experimental evidence implicating PARP as a pathophysiological modulator of cardiac myocyte injury in vitro and in vivo.
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PMID:Cardioprotective effects of poly(ADP-ribose) polymerase inhibition. 1591 32

Oxidative stress is associated with endothelial dysfunction in heart failure. The goals of this study were to determine whether 1) gene transfer of extracellular superoxide dismutase (ecSOD) reduces levels of superoxide and improves endothelial function in the aorta and mesenteric artery in rats with heart failure, and 2) the heparin-binding domain (HBD) of ecSOD, by which ecSOD binds to cells, is required for protective effects of ecSOD. Seven weeks after coronary ligation, in rats with heart failure and sham-operated rats, we injected adenoviral vectors intravenously that express ecSOD, ecSOD with deletion of the HBD (ecSODDeltaHBD), or a control vector. Four days after injection of viruses, responses to acetylcholine, ADP, and sodium nitroprusside were examined in rings of the aorta and mesenteric artery. ecSOD bound to endothelium and increased SOD activity in the aorta after gene transfer of ecSOD, not ecSODDeltaHBD. Gene transfer of ecSOD, but not ecSODDeltaHBD, reduced levels of superoxide and improved relaxation to acetylcholine and ADP in the aorta and mesenteric artery from rats with heart failure. Improvement of relaxation to acetylcholine in the mesenteric artery from rats with heart failure after gene transfer of ecSOD was mediated in part by hydrogen peroxide. The major finding of this study is that the HBD of ecSOD is necessary for protection against endothelial dysfunction in rats with heart failure. We speculate that a common gene variant in the HBD of ecSOD, which is a risk factor for ischemic heart disease, may be a risk factor for vascular maladaptation and endothelial dysfunction in heart failure.
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PMID:Gene transfer of extracellular superoxide dismutase improves endothelial function in rats with heart failure. 1601 12


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