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)

Among the multiple cardiac manifestations occurring in HIV-infected patients, cardiomyopathy is one of the most challenging. Its incidence has only slightly decreased since the introduction of highly active antiretroviral therapy (HAART). Also, its pathogenesis remains relatively unclear. Although several studies demonstrated the presence of HIV genome in the heart of patients, more recent developments found that viral infection plays an indirect role only, as well as they recognized the contribution of proinflammatory cytokines in the progression of the disease. Experimental studies on animals and cultured myocytes have established the signalling pathway triggered by proinflammatory cytokines in heart failure and cardiomyopathy. Tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) and IL-6 promote expression of inducible nitric oxide synthase (iNOS) in cardiomyocytes through activation of p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor kappaB (NFkappaB). TNF-alpha and high concentrations of NO also induce cardiomyocyte apoptosis by TNF type 1 receptor activation. This biological framework, which is also involved in progression of cardiomyopathy in humans, is more pronounced in HIV-infected patients, in whom proinflammatory cytokines TNF-alpha, IL-1 and IL-6 are increased, resulting in an enhanced expression of cardiac iNOS, especially in patients with a low CD4 T cell count. This may account for the worse outcome of heart failure in HIV-infected patients. However, there are only few data today to support future therapeutic implications of cytokines antagonism in treatment of HIV-infected patients with cardiomyopathy. Whether modulation of TNF production or selective inhibition of p38 MAPK pathway could be useful approaches remains uncertain.
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PMID:Cytokines in HIV-associated cardiomyopathy. 1733 7

The ischemic etiology of heart failure is an independent prognostic factor associated with worse long-term outcome. Recent evidence indicates a role for genetic susceptibility to ischemic heart failure. The authors systematically reviewed all known case-control studies that investigated the association between genetic variants and ischemic heart failure. Twenty-two articles, which examined 24 gene polymorphisms, were identified. In 22 polymorphisms, the variant form had a functional effect. Twenty-two polymorphisms were variants of genes involved in the maladaptive neurohormonal activation. Seven polymorphisms (ACE I/D, AGT M235T, ADRA2C Del322-325, ADRB2 Arg16Gly, ADRB2 Gln27Glu, EDN1 Lys198Asn, VEGF G-405C) showed a significant association in individual studies. Five polymorphisms (ACE I/D, ADRB1 Arg389Gly, ADRB2 Arg16Gly, ADRB2 Gln27Glu, TNF G308A) were examined by more than one study, and meta-analyses were performed. The meta-analyses showed no significant sign of heterogeneity. In all settings, there was no significant association, except for polymorphism ADRB2 Arg16Gly under a recessive model (fixed-effects odds ratio = 1.32, 95% confidence interval: 1.05, 1.65). Taking into account that ischemic heart failure is a complex disease with multifactorial etiology, a minor contributing pathogenetic role of the investigated gene polymorphisms cannot be totally excluded. Case-control studies that investigate gene-gene and gene-environment interactions might further elucidate the genetics of ischemic heart failure.
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PMID:Genetic variation associated with ischemic heart failure: a HuGE review and meta-analysis. 1764 25

Sequestration of tumor necrosis factor-alpha (TNFalpha) by TNF-receptor immunoglobulin G (IgG)-Fc fusion proteins can limit heart failure progression in rodent models. In this study we directly injected an adeno-associated viruses (AAV)-2 construct encoding a human TNF receptor II IgG-Fc fusion protein (AAV-TNFRII-Fc) into healthy baboon hearts and assessed virally encoded gene expression and clinical response. Adult baboons received direct cardiac injections of AAV-TNFRII-Fc ( approximately 5 x 10(12) viral/genomes/baboon) or an equivalent dose of AAV-2 empty capsids, and were analyzed after 5 or 12 weeks. Viral genomes were restricted to the myocardium, and routine analyses (blood cell counts, clinical chemistries) remained unremarkable. Echocardiograms were unchanged but electrocardiograms revealed marked ST- and T-wave changes consistent with myocarditis only in baboons receiving AAV-TNFRII-Fc. TNFRII serum levels peaked at approximately 3 times the baseline levels at 1-2 weeks postinjection and subsequently declined to baseline levels. TNFRII-Fc protein and transcripts were detected in the heart at harvest. After AAV injection, anti-AAV-2 antibody levels increased in all baboons, while anti-TNFRII-Fc could not be detected. Baboons that received AAV-TNFRII-Fc developed myocardial infiltrates including CD8+ cells. Thus, a cellular immune response to cardiac delivery of AAV encoding foreign proteins may be an important consideration for AAV-based cardiac gene therapy.
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PMID:Myocarditis following adeno-associated viral gene expression of human soluble TNF receptor (TNFRII-Fc) in baboon hearts. 1785 48

The results of some epidemiological studies point to the presence of an increased risk of cardiovascular disease (CVD), particularly atherosclerosis and congestive heart failure (CHF) in rheumatoid arthritis (RA). At least 50% of abnormalities remained asymptomatic. Pathological conditions contributing to myocardial dysfunction such as high serum levels of IL-6, C-reactive protein (CRP) and TNF alpha are present both in RA and CHF patients. The most common pathological mechanism leading to the development of heart failure is left ventricular (LV) diastolic dysfunction, which remains clinically asymptomatic for a long time. The aim of this study was to assess the systolic and diastolic functions of the LV in RA patients without clinically evident cardiovascular disease, using pulsed Doppler echocardiography. Our purpose was also to estimate whether there is a correlation between the duration and severity of RA and the degree of LV diastolic dysfunction. A comparison of the average values of echocardiographic measurements was made between the RA group and control group, which constituted healthy volunteers. Left ventricular mass index in RA group was significantly greater than in the control group (105.2 +/- 32.6 vs. 87.9 +/- 16.8; p < 0.05) so were the interventricular septum end-diastolic thickness (1.01 +/- 0.33 vs. 0.86 +/- 0.12; p < 0.05), the LV posterior wall end-diastolic thickness (0.94 +/- 0.08 vs. 0.83 +/- 0.11; p < 0.0001) and the aortic root diameter (3.18 +/- 0.31 vs. 3.10 +/- 0.63, p < 0.001). The ejection fraction in RA group was significantly lower than in the control group (64.4 +/- 1.3 vs. 66.3 +/- 1.3; p < 0.0001). The assessment of diastolic function parameters revealed significantly longer isovolumetrc relaxation time (IVRT) and shorter deceleration time (DT) in RA patients compared to the control group. Patients in stage II or III revealed significantly lower LV mass index (99 +/- 17 vs. 131 +/- 42; p < 0.05) and the interventricular septum end-diastolic thickness (0.94 +/- 0.10 vs. 1.28 +/- 0.5; p < 0.05) than those in stage IV. Mean aortic diameter was significantly greater in individuals in stages III and IV (3.73 +/- 0.28) than in the stage II of the disease (2.77 +/- 0.21), p < 0.05. No differences in echocardiographic parameters' values were observed between seropositive, seronegative, nodule-present and nodule-absent persons. Echocardiographic examination revealed valvular heart disease in 24 (80%) RA and 6 (20%) control patients (p < 0.0001).
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PMID:Diastolic heart function in RA patients. 1849 92

Pro-inflammatory cytokine over-expression may be implicated to the pathogenesis of anemia in chronic heart failure (CHF) through the suppression of bone marrow erythropoiesis. Erythropoietin administration has anti-inflammatory and anti-apoptotic properties in experimental CHF models and improves exercise capacity in anemic CHF patients. The present study investigates the effects of recombinant human erythropoietin analogue darbepoetin-alpha on circulating pro-inflammatory cytokines and soluble Fas/soluble Fas ligand system in patients with CHF and anemia. Forty-one CHF patients (NYHA class: II-III; left ventricular (LV) ejection fraction (EF) <40%; hemoglobin <12.5g/dl; serum creatinine <2.5mg/dl) were randomized to receive either 3-month darbepoietin-* at 1.5 microg/kg every 20 days plus iron orally (n=21) or placebo plus iron orally (n=20). LV systolic function, plasma B-type natriuretic peptide (BNP), inflammatory markers (TNF-*, IL-6, CRP), anti-inflammatory cytokine IL-10, endothelial adhesion molecules (soluble ICAM-1 and VCAM-1) and soluble apoptosis mediators (soluble Fas, soluble Fas ligand), and 6-min walking distance were assessed at baseline and 3 months post-treatment. In darbepoetin-* treated patients, plasma BNP (451 (62-2770) from 802 (476-4440) pg/ml, p=0.002), IL-6 (6.5+/-4.7 from 10.5+/-7.8 pg/ml, p=0.013) and soluble Fas ligand (53.2+/-16.6 from 59.2+/-17.9 pg/ml, p=0.023) decreased significantly, while LVEF (32+/-6 from 26+/-6%, p<0.001), hemoglobin (12.8+/-1.4 from 10.9+/-1.0 g/dl, p<0.001) and 6-min walked distance (274+/-97 from 201+/-113m, p<0.01) increased significantly. No significant changes were observed in the placebo arm, except for a worsening in 6-min walked distance (p=0.044). In conclusion, darbepoetin-alpha reduces circulating pro-inflammatory cytokine IL-6 and apoptotic mediator soluble Fas ligand in CHF patients with anemia, with a parallel improvement of cardiac performance and exercise capacity.
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PMID:Effects of darbepoetin-alpha on plasma pro-inflammatory cytokines, anti-inflammatory cytokine interleukin-10 and soluble Fas/Fas ligand system in anemic patients with chronic heart failure. 1799 71

Several lines of evidence suggest that inflammation plays a pathogenic role in the development and progression of congestive heart failure, influencing heart contractility and hypertrophy, promoting apoptosis, and contributing to the myocardial remodeling process. Proinflammatory cytokines are important mediators of immune response, associated with endothelial dysfunction in patients with coronary artery disease or heart failure. The presence, both at tissue level and in the circulation, of increased levels of pro-inflammatory cytokines suggests that immune activation might be a relevant mechanism contributing to cardiac as well as peripheral manifestations of the disease. Traditional cardiovascular drugs have little influence on the cytokine network. Results from randomized, placebo controlled anti-TNF studies suggest lack of effect of such therapy, but the concept of immune modulation is still intensively studied. In this review we evaluate the diagnostic and prognostic value of the activation of proinflammatory cytokines, theirs role in the pathogenesis of the cardiovascular diseases and the new ways of treatment.
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PMID:[Proinflammatory cytokines in cardiovascular diseases as potential therapeutic target]. 1835 Jul 17

The same drugs are used to treat hemorrhagic rectocolitis (HRC) and Crohn's disease (CD), although the aims are very different. Aminosalicylates are highly beneficial in HRC but virtually ineffective in CD, a disease in which immunosuppressants are more useful. Aminosalicylates exert their antiinflammatory effect directly on the lesions. Various oral and rectal preparations have been developed in order to deliver the active molecule to the intestinal target segment. These drugs are now known to act by stimulating the nuclear receptor PPAR-gamma, and this knowledge should help with the development of new agents. Chronic aminosalicylate treatment appears to diminish the risk of malignant transformation. Systemic steroids are still the mainstay of treatment for exacerbations of HRC and CD, yielding remissions in 60 to 90% of cases. In contrast, systemic steroids should not be used for maintenance therapy. Budesonide is a preparation that selectively releases steroids in the ileocolonic region, thereby reducing systemic adverse effects. Immunosuppressants such as azathioprine and 6-mercaptopurine, and also methotrexate in some cases, are used for maintenance therapy of steroid-dependent and highly recurrent forms. These drugs stabilize the disease in about half the patients who receive them. Treatment typically lasts several years and necessitates regular monitoring, especially of hematological status. Cyclosporine is used intravenously in severe HRC. Infliximab (RemicadeR), a chimeric monoclonal antibody targeting TNF is effective in acute forms and as maintenance therapy for CD. It was also recently shown to be effective in HRC. Infliximab is indicated in steroid-resistant forms and contraindicated in patients with latent systemic infections (tuberculosis, hepatitis B) and heart failure. Artificial nutrition is now only used in children with acute forms, in order to avoid the need for steroids. Probiotics might have a place in maintenance treatment of HRC. Surgical treatment of HRC consists of colectomy or, more radically, ileoprotectomy followed by ileoanal anastomosis with resection: however, the likely benefits and potential complications (especially nocturnal diarrhea) must be carefully weighed up. Surgical treatment of CD consists of resecting the worst-affected segments. As available medical and surgical treatments can only control these diseases, without curing them, patient management must be planned on a long-term basis. Control of exacerbations is judged on the basis of clinical parameters and biological markers of inflammation, rather than on lesion healing. The choice of maintenance therapy depends on the nature of the disease (HRC or CD) and its progressive nature. Surgery is reserved for patients with complicated and drug-resistant forms.
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PMID:[Treatment of chronic inflammatory bowel diseases]. 1840 68

The study objective is to prove an association among plasma concentration of big endothelin and endothelin-1, other clinical parameters and two frequent polymorphisms - G8002A and -3A/-4A - in the endothelin-1 (EDN-1) coding gene (6p21-23), and among plasma concentration of TNF alpha and gene polymorphisms TNF alpha -308 A/G, -238 A/G, TNF beta Ncol and 3'TACE (tumour necrosis factor alpha converting enzyme) in patients with chronic heart failure (CHF). The second objective is to find an association between polymorphisms G8002A and -3A/4A EDN-1 with diabetes mellitus (DM), peripheral artery disease (PAD) and myocardial infarction (MI) in patients with chronic heart failure (CHF). The study population included 266 patients with symptomatic CHF and proven dysfunction of the left ventricle (LV). Genotyping and plasma concentrations of humoral substances were examined in 224 patients with ejection fraction (EF) below 40%. No associations between plasma concentrations of endothelin-1 and big endothelin and polymorphisms G8002A (p=0.87, p=0.81) and -3A/-4A (p=0.871, p=0.749) in the gene coding endothelin-1 were found. No associations were observed between plasma concentration of TNF alpha and genotypes in four polymorphisms in TNF alpha, beta and TACE genes. A significant correlation was seen between plasma concentration of big endothelin and pulmonary congestion. Patients with ischemic heart disease (IHD) and previous MI showed a difference in the distribution of genotype G8002A for endothelin-1: allele G 0.718 and A 0.282 vs those without MI: allele G 0.882 and A 0.118, (p<0.05). Patients with IHD and DM had allele G in 0.67 and A 0.33, while those without DM had allele G in 0.790 and A in 0.209 (p<0.03). Patients with IHD and concomitant PAD had allele G in 0.718 and A in 0.282 vs those without PAD allele G in 0.882 and A in 0.118 (p<0.0004). Patients with dilative cardiomyopathy (DCMP) showed no differences in genotype G8002A and presence of DM or PAD. It might be speculated that in the case of endothelin-1 and TNF alpha in CHF the genetic determination is not important, and plasma concentrations are influenced more by the disease severity. Ischemics with previous MI, concomitant DM or PAD showed more frequently allele A and less often allele G than those without these diseases. A genotype with allele A is associated with higher risk of concomitant diseases.
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PMID:Genetics of humoral and cytokine activation in heart failure and its importance for risk stratification of patients. 1844 14

Crohn's disease and ulcerative colitis represent the most common forms of inflammatory bowel disease (IBD), clinical conditions affecting the small and/or large bowel. It is well known that IBD is an immune-mediated condition and that TNF-alpha plays a pivotal role in the pathogenesis of the disease. TNF-alpha has been scrupulously studied as a target for therapeutic intervention in this setting. A number of biologic compounds have been developed, including the European Medicine Agency (EMEA)-approved agents, infliximab and adalimumab. Although their efficacy in induction and maintenance of remission has been established by several clinical trials, many issues regarding safety remain to be elucidated. In fact, anti-TNF treatment may be associated with a number of rare, but serious, adverse events, including infusion reactions, infections, lymphomas and other malignancies. A black-box warning has to be taken into consideration when looking at potential serious infections such as tuberculosis. Active infections, demyelinating disorders and severe heart failure are contraindications for anti-TNF treatment. This review focuses on drug toxicity and adverse events related to infliximab treatment in IBD.
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PMID:Long-term treatment with infliximab in inflammatory bowel disease: safety and tolerability issues. 1875 14

Claudin-5, an integral tight junction protein component, plays a critical role in permeability of the endothelial cell barrier. Recently, we have shown that claudin-5 protein is down-regulated by the proinflammatory cytokine TNF alpha and its levels restored by dexamethasone treatment. In order to investigate the regulation of claudin-5 at the transcriptional level, we have cloned the murine claudin-5 promoter. The claudin-5 promoter sequence (1131 bp) showed no consensus TATA-box. We identified putative transcription factor binding sites, including six full and two half sites degenerated glucocorticoid-response elements (GREs), two NFkappaB, three Sp1, one Sp2, one Ap2, as well as three E-boxes. Serially deleted promoter constructs showed high basal activity. TNF alpha significantly reduced the promoter activity and mRNA levels of claudin-5 in brain cEND and myocardial MyEND endothelial cells. Dexamethasone treatment led to a significant increase of the murine claudin-5 promoter activity and mRNA levels in cEND cells. However, no claudin-5 induction could be observed in MyEND cells in response to dexamethasone. Our studies suggest tissue-specific regulation of the claudin-5 gene via glucocorticoids and a high vulnerability of claudin-5 to TNF alpha. This could be an important mechanism in diseases accompanied by the release of proinflammatory cytokines, for example in patients with chronic heart failure or multiple sclerosis.
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PMID:Cloning and characterization of the murine claudin-5 promoter. 1899 36


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