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)

Therapeutic strategies to protect the ischemic myocardium have been studied extensively. Reperfusion is the definitive treatment for acute coronary syndromes, especially acute myocardial infarction; however, reperfusion has the potential to exacerbate lethal tissue injury, a process termed "reperfusion injury." Ischemia/reperfusion injury may lead to myocardial infarction, cardiac arrhythmias, and contractile dysfunction. Ischemic preconditioning of myocardium is a well described adaptive response in which brief exposure to ischemia/reperfusion before sustained ischemia markedly enhances the ability of the heart to withstand a subsequent ischemic insult. Additionally, the application of brief repetitive episodes of ischemia/reperfusion at the immediate onset of reperfusion, which has been termed "postconditioning," reduces the extent of reperfusion injury. Ischemic pre- and postconditioning share some but not all parts of the proposed signal transduction cascade, including the activation of survival protein kinase pathways. Most experimental studies on cardioprotection have been undertaken in animal models, in which ischemia/reperfusion is imposed in the absence of other disease processes. However, ischemic heart disease in humans is a complex disorder caused by or associated with known cardiovascular risk factors including hypertension, hyperlipidemia, diabetes, insulin resistance, atherosclerosis, and heart failure; additionally, aging is an important modifying condition. In these diseases and aging, the pathological processes are associated with fundamental molecular alterations that can potentially affect the development of ischemia/reperfusion injury per se and responses to cardioprotective interventions. Among many other possible mechanisms, for example, in hyperlipidemia and diabetes, the pathological increase in reactive oxygen and nitrogen species and the use of the ATP-sensitive potassium channel inhibitor insulin secretagogue antidiabetic drugs and, in aging, the reduced expression of connexin-43 and signal transducer and activator of transcription 3 may disrupt major cytoprotective signaling pathways thereby significantly interfering with the cardioprotective effect of pre- and postconditioning. The aim of this review is to show the potential for developing cardioprotective drugs on the basis of endogenous cardioprotection by pre- and postconditioning (i.e., drug applied as trigger or to activate signaling pathways associated with endogenous cardioprotection) and to review the evidence that comorbidities and aging accompanying coronary disease modify responses to ischemia/reperfusion and the cardioprotection conferred by preconditioning and postconditioning. We emphasize the critical need for more detailed and mechanistic preclinical studies that examine car-dioprotection specifically in relation to complicating disease states. These are now essential to maximize the likelihood of successful development of rational approaches to therapeutic protection for the majority of patients with ischemic heart disease who are aged and/or have modifying comorbid conditions.
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PMID:Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning. 1804 61

B-type natriuretic peptide (BNP) and cardiac troponin (Tn) I or T have been demonstrated to provide prognostic information in patients with acute coronary syndromes. Whether admission BNP and Tn levels provide additive prognostic value in acutely decompensated heart failure (HF) has not been well studied. Hospitalizations for HF from April 2003 to December 2004 entered into ADHERE were analyzed. BNP assessment on admission was performed in 48,629 (63%) of 77,467 hospitalization episodes. Tn assessment was performed in 42,636 (88%) of these episodes. In-hospital mortality was assessed using logistic regression models adjusted for age, gender, blood urea nitrogen, systolic blood pressure, creatinine, sodium, pulse, and dyspnea at rest. Median BNP was 840 pg/ml (interquartile range 430 to 1,730). Tn was increased in 2,370 (5.6%) of 42,636 HF episodes. BNP above the median and increased Tn were associated with significantly increased risk of in-hospital mortality (odds ratios [OR] 2.09 and 2.41 respectively, each p value <0.0001). Mortality was 10.2% in patients with BNP >or=840/Tn increased compared with 2.2% with BNP <840/Tn not increased (OR 5.10, p <0.0001). After covariate adjustment, mortality risk remained significantly increased with BNP >or=840/Tn not increased (adjusted OR 1.56, 95% confidence interval 1.40 to 1.79, p <0.0001), BNP <840/Tn increased (adjusted OR 1.69, 95% confidence interval 1.17 to 2.45, p = 0.006), and BNP >or=840/Tn increased (adjusted OR 3.00, 95% confidence interval 2.47 to 3.66, p <0.0001). Admission BNP and cardiac Tn levels are significant, independent predictors of in-hospital mortality in acutely decompensated HF. Patients with BNP levels >or=840 pg/ml and increased Tn levels are at particularly high risk for mortality. In conclusion, a multimarker strategy for the assessment of patients hospitalized with HF adds incremental prognostic information.
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PMID:Usefulness of B-type natriuretic peptide and cardiac troponin levels to predict in-hospital mortality from ADHERE. 1817 12

Reactive oxygen and nitrogen species are thought to contribute to pathogenesis of many cardiovascular diseases including hypertension, atherosclerosis, restenosis, heart failure, and diabetic vascular complications. Some of these reactive oxygen species also play an important role in vascular signaling. In this chapter, we describe various techniques that we have successfully employed to reliably measure superoxide and hydrogen peroxide. Because reactive oxygen species are capable of rapidly inactivating nitric oxide and because endothelial function characterized by nitric oxide bioavailability is an important indicator of vascular health, we have also included novel techniques capable of directly measuring nitric oxide radical from vascular cells and tissues.
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PMID:Detection of reactive oxygen species and nitric oxide in vascular cells and tissues: comparison of sensitivity and specificity. 1828 81

Uric acid (urate), an organic compound comprised of carbon, nitrogen, oxygen and hydrogen, is the final oxidation product of purine catabolism in humans, higher primates and in a particular species of dog (Dalmatians). For decades it has been hypothesized that the antioxidant properties of uric acid might be protective against aging, oxidative stress, and oxidative cell injury. However, recent epidemiological and clinical evidences suggest that hyperuricaemia might be a risk factor for cardiovascular disease, where enhanced oxidative stress plays an important pathophysiological role. It has also been hypothesized that hyperuricaemia might be involved in chronic heart failure and metabolic syndrome. The apparent paradox between protective and toxic effects is supported by clinical evidences that antioxidant compounds may become pro-oxidant compounds in certain situations, particularly when they are present in blood at supranormal levels. The aim of this article is to review uric acid metabolism and physiology, highlighting its association with cardiovascular disease.
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PMID:The paradoxical relationship between serum uric acid and cardiovascular disease. 1834 69

A mainstay of therapy for congestive heart failure has been the use of potent diuretic agents, such as furosemide, that target the kidney to enhance sodium and water excretion. Although furosemide is widely used to treat the symptoms of acute decompensated heart failure (ADHF), the consequent activation of the renin-angiotensin-aldosterone system may limit the natriuretic response by reducing the glomerular filtration rate. In addition, excessive diuresis may reduce cardiac preload and result in systemic hypotension, which reduces renal perfusion pressure and prerenal azotemia and raises levels of blood urea nitrogen. In order to preserve and/or enhance renal function in ADHF, especially with agents such as conventional diuretics and vasodilators, an understanding of intrarenal factors that may protect the kidney may provide a direction for optimal use of current therapies and also lead to newer therapeutic strategies. Vasodilators, especially those that are linked to cGMP activation, may provide an alternative approach.
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PMID:Targeting the kidney in acute decompensated heart failure: conventional diuretics and renal-acting vasodilators. 1841 8

Nitric oxide (NO) is produced by different isoforms of nitric oxide synthases (NOSs) and operates as a mediator of important cell signaling pathways, such as the cGMP signaling cascade. Another mechanism by which NO exerts biological effects is mediated through S-nitrosation of target proteins. To explore thiol-based protein modifications in a situation of defined nitrosative stress, we used a transgenic mouse model with cardiac specific overexpression of inducible nitric oxide synthase (iNOS) and concomitant myoglobin deficiency (iNOS(+)/myo(-/-)). In comparison with the wild type hearts, protein glutathiolation detected by immunoblotting was significantly enhanced in iNOS(+)/myo(-/-) hearts, whereas protein S-nitrosation as measured by the biotin switch assay and two-dimensional PAGE revealed that nearly all of the detected proteins ( approximately 60) remained unchanged with the exception of three proteins. Tandem mass spectrometry revealed these proteins to be peroxiredoxins (Prxs), which are known to possess peroxidase activity, whereby hydrogen peroxide, peroxynitrite, and a wide range of organic hydroperoxides are reduced and detoxified. Immunoblotting with specific antibodies revealed up-regulation of Prx VI in the iNOS(+)/myo(-/-) hearts, whereas expression of Prx II and Prx III remained unchanged. Furthermore, the analysis of the cardiac S-nitrososubproteome identified several new proteins possibly being involved in NO-signaling pathways. Our data indicate that S-nitrosation and glutathiolation of cardiac proteins may contribute to the phenotype of NO-induced heart failure. The up-regulation of antioxidant proteins like Prx VI appears to be an additional mechanism to antagonize an excess of reactive oxygen/nitrogen species. Furthermore, S-nitrosation of Prxs may serve a new function in the signaling cascade of nitrosative stress.
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PMID:Nitrosative stress leads to protein glutathiolation, increased s-nitrosation, and up-regulation of peroxiredoxins in the heart. 1842 99

Patients with chronic kidney disease and heart failure (HF) have been shown to be at higher risk for major adverse cardiovascular events and death. Recent studies have demonstrated that blood urea nitrogen (BUN) might serve as a powerful predictor of mortality in acutely decompensated HF. The goal of this study was to determine the impact of BUN on long-term mortality in patients with stage B and C HF. Our retrospective analysis included patients undergoing percutaneous intervention with a calculated left ventricular ejection fraction < or =50%. Patients on dialysis or with technically inadequate left ventriculograms were excluded. Chart review was performed and mortality data were obtained. Our population included 444 patients with a mean ejection fraction of 38 +/- 10%, mean age of 59 +/- 11 years, median BUN of 14 mg/dl, and median glomerular filtration rate (GFR) of 81 ml/min/1.73 m(2); 31% had stage C HF, and 33% died during follow-up. Patients with increased BUN (> or =17 mg/dl) and decreased GFR (< or =69 ml/min/1.73 m(2)) had significantly increased long-term mortality on Kaplan-Meier analysis (8-year mortalities of 57% and 55%, respectively). In patients with stage C HF, mortalities at 8 years were 69% and 73% with abnormal BUN and GFR, respectively. Proportional hazard regression analysis demonstrated that BUN and stage C HF were independently associated with increased mortality, whereas GFR was not. In conclusion, we demonstrated that BUN is strongly associated with mortality in patients with stage B and C HF and may serve as a better biomarker than GFR for prognostication.
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PMID:Relation of blood urea nitrogen to long-term mortality in patients with heart failure. 1848 44

Throughout the last 2 decades, experimental evidence from in vitro studies and preclinical models of disease has demonstrated that reactive oxygen and nitrogen species, including the reactive oxidant peroxynitrite, are generated in parenchymal, endothelial, and infiltrating inflammatory cells during stroke, myocardial and other forms of reperfusion injury, myocardial hypertrophy and heart failure, cardiomyopathies, circulatory shock, cardiovascular aging, atherosclerosis and vascular remodeling after injury, diabetic complications, and neurodegenerative disorders. Peroxynitrite and other reactive species induce oxidative DNA damage and consequent activation of the nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1), the most abundant isoform of the PARP enzyme family. PARP overactivation depletes its substrate NAD(+), slowing the rate of glycolysis, electron transport, and ATP formation, eventually leading to functional impairment or death of cells, as well as up-regulation of various proinflammatory pathways. In related animal models of disease, peroxynitrite neutralization or pharmacological inhibition of PARP provides significant therapeutic benefits. Therefore, novel antioxidants and PARP inhibitors have entered clinical development for the experimental therapy of various cardiovascular and other diseases. This review focuses on the human data available on the pathophysiological relevance of the peroxynitrite-PARP pathway in a wide range of disparate diseases, ranging from myocardial ischemia/reperfusion injury, myocarditis, heart failure, circulatory shock, and diabetic complications to atherosclerosis, arthritis, colitis, and neurodegenerative disorders.
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PMID:Role of the peroxynitrite-poly(ADP-ribose) polymerase pathway in human disease. 1853 82

The substantial public health impact of hospitalization for acute decompensated heart failure, from an economic and clinical perspective, has generated substantial interest in understanding predictors of risk in this syndrome. Utilization of classification and regression tree (CART) analysis on the Acute Decompensated Heart Failure National Registry (ADHERE) dataset has provided important risk stratification from readily available clinical variables. Increasingly, high-risk patients were identified by combination of blood urea nitrogen level of 43 mg/dL, serum creatinine level of 2.75 mg/dL, and systolic blood pressure less than 115 mm Hg, which were all independent predictors of high risk for in-hospital mortality. On the basis of these 3 variables, acutely decompensated heart failure patients can be readily stratified into groups at low, intermediate, and high risk for in-hospital mortality, with mortality risks ranging from 2.1% to 21.9%. Although risk stratification alone cannot improve outcomes, identification of patients at high and low risk may improve resource utilization and better focus the intensity of care according to outcome.
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PMID:Clinical predictors of in-hospital mortality in acutely decompensated heart failure-piecing together the outcome puzzle. 1855 Sep 23

The cross talk between reactive oxygen species (ROS) and reactive nitrogen species (RNS) plays a pivotal role in the regulation of myocardial and vascular function. Both nitric oxide and redox-based signaling involve the posttranslational modification of proteins through S-nitrosylation and oxidation of specific cysteine residues. Disruption of this cross talk between ROS and RNS contributes to the pathogenesis of heart failure. Therefore, the elucidation of these complex chemical interactions may improve our understanding of cardiovascular pathophysiology. This chapter discusses the significant role of spatial confinement of nitric oxide synthases, NADPH oxidase, and xanthine oxidoreductase in the regulation of myocardial excitation-contraction coupling. This chapter describes techniques for assessing oxidative and nitrosative stress. A variety of assays have been developed that quantify S-nitrosylated proteins. Among them, the biotin-switch method directly evaluates endogenously nitrosylated proteins in a reproducible way. Identification of the biotinylated or S-nitrosylated proteins subjected to the biotin-switch assay are described and evaluated with a one-dimensional gel (Western blot) or with the newly developed two-dimensional fluorescence difference gel electrophoresis proteomic analysis. Quantifying the number of free thiols with the monobromobimane assay in a protein of interest allows estimation of cysteine oxidation and, in turn, the state of nitroso-redox balance of effector molecules. In summary, this chapter reviews the biochemical methods that assess the impact of nitroso/redox signaling in the cardiovascular system.
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PMID:Nitric oxide and cardiobiology-methods for intact hearts and isolated myocytes. 1855 46


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