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)

Recent epidemiological studies associate health effects and particulate matter in ambient air. Exacerbation of the particle-induced inflammation can be a mechanism responsible for increased hospitalization and death due to cardiopulmonary events in high-risk groups of the population. Systems regulating blood pressure that depend on lung integrity can be involved in progression of cardiovascular diseases. This study focused on the expression levels of various genes involved in cardiovascular and pulmonary diseases to assess their role in the onset of cardiovascular problems due to ambient particulate matter and compared these with the corresponding products. Rats with ozone-induced (1600 microg/m(3); 8 h) pulmonary inflammation were exposed to 0.5 mg, 1.5 mg, or 5 mg of particulate matter (PM) from Ottawa Canada (EHC-93) by intratracheal instillation. mRNA levels of various genes and their products were measured 2, 4, and 7 d after instillation. At 2 d after exposures to PM, tumor necrosis factor (TNF)-alpha levels in bronchoalveolar lavage fluid (BALF) were elevated approximately 4 times for the highest EHC-93 dose. MIP-2 protein levels in BALF were elevated approximately three times during the entire time period studied, whereas IL-6 levels were not affected compared to control groups. The MIP-2 mRNA levels revealed a similar pattern of induction. A twofold increase in endothelin (ET)-1 levels at d 2 and a 20% decrease in angiotensin-converting enzyme (ACE) activity at d 7 were measured in plasma. A 60% decrease of ACE and ET-1 mRNA levels suggested a possible endothelial damage in the lung blood vessels. Inducible nitric oxide synthase (iNOS) mRNA was found to be increased 3.5 times 2 d after instillation of the particles. Therefore, the endothelial damage could have been caused by large amounts of the free radical NO. Also, plasma levels of fibrinogen were elevated (20%), which could presumably increase blood viscosity, leading to decreased tissue blood flow. These changes in hematological and hemodynamic parameters observed in our study are in line with heart failure in high-risk groups of the population after high air pollution episodes.
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PMID:Health effects and time course of particulate matter on the cardiopulmonary system in rats with lung inflammation. 1239 69

Several lines of evidence support a role of immune mechanisms in the pathogenesis of chronic heart failure (CHF). Proinflammatory cytokines (interleukin-1, -2, -6, and tumor necrosis factor) and chemokines are involved in cardiac depression and in the progression of heart failure. Other components believed to be relevant to the pathogenesis of CHF are adhesion molecules, autoantibodies, nitric oxide (NO), and endothelin-1. The origin of the immune activation in patients with CHF is still unknown, however two hypotheses have been proposed on the basis of experimental and clinical data. One suggests that the bowel wall edema leads to bacterial translocation with subsequent endotoxin release and immune activation. The second suggests that the heart in CHF is the main source of cytokines, as is shown by the fact that TNF alpha is produced by the failing myocardium but not by a normal one. No single source of cytokine production (gut or heart) seems sufficient to fully explain the multiple organ involvement and the systemic inflammation of CHF, which is probably related to systemic hypoxia, a potent stimulus for activation of the immune system and for cytokine production. The effort of define the immune system's role has opened new perspectives of therapeutic strategies, such as anti-cytokine drugs, to treat CHF.
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PMID:Chronic heart failure and the immune system. 1240 15

Excessive biohumoral activation participates in the pathophysiology and progression of congestive heart failure (CHF). Pharmacological inhibition of the renin-angiotensin-aldosterone and beta-adrenergic systems improves the mortality and morbidity of this disease. Among other detrimental molecules, two local factors, tumor necrosis factor (TNF)-alpha and endothelin (ET) both contribute to the worsening of CHF. TNF-alpha can induce many of the cellular modifications typically associated with CHF, such as myocyte death, interstitial tissue derangement and negative inotropism. On the other hand ET promotes vasoconstriction, and cell growth and proliferation. On the premise of some favorable experimental studies, selective antagonism of TNF-alpha or ET has been tested in clinical trials in order to control the progression of or even reverse CHF. However, contrasting results have been obtained so far with either approach, in accordance with other unfavorable data from animal models of heart failure. Etanercept (Enbrel, a recombinant dimer of two p75sTNFR molecules fused to the Fc fragment of human IgG1) has proved to be useful and effective in basic and animal experiments, while contrasting data have been reported on humans. The Randomized EtaNErcept Worldwide evALuation (RENEWAL) trial has recently been prematurely stopped due to impossibility of showing statistically significant results with the pre-specified sample size. Results of phase II to III clinical trials on different ET receptor antagonists in CHF have yielded conflicting results, so that none of the agents of this class have been labeled for CHF. The mechanisms by which TNF-alpha and ET might exert their negative biological actions are discussed together with an analysis of the possible reasons why they have failed so far in human CHF.
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PMID:[Refractory heart failure. Antagonism of tumor necrosis factor alpha and endothelin in humans: 2 promises still to be honored]. 1240 34

Heart failure and hypertension have each been linked to an induction of oxidative stress transduced by neurohormones, such as angiotensin II and catecholamines. Herein, we hypothesized that aldosterone (ALDO) likewise induces oxidative stress and accounts for a proinflammatory/fibrogenic phenotype that appears at vascular and nonvascular sites of injury found in both right and left ventricles in response to ALDO/salt treatment and that would be sustained with chronic treatment. Uninephrectomized rats received ALDO (0.75 micro g/hour) together with 1% dietary NaCl, for 3, 4, or 5 weeks. Other groups received this regimen in combination with an ALDO receptor antagonist, spironolactone (200 mg/kg p.o. daily), or an antioxidant, either pyrrolidine dithiocarbamate (PDTC) (200 mg/kg s.c. daily) or N-acetylcysteine (NAC) (200 mg/kg i.p. daily). Unoperated and untreated age- and gender-matched rats served as controls. We monitored spatial and temporal responses in molecular and cellular events using serial, coronal sections of right and left ventricles. Our studies included: assessment of systolic blood pressure; immunohistochemical detection of NADPH oxidase expression and activity; analysis of redox-sensitive nuclear factor-kappaB activation; in situ localization of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha mRNA expression; monitoring cell growth and infiltration of macrophages and T cells; and analysis of the appearance and quantity of fibrous tissue accumulation. At week 3 of ALDO/salt treatment and comparable to controls, there was no evidence of oxidative stress or pathological findings in the heart. However, at weeks 4 and 5 of treatment, increased gp91(phox) and 3-nitrotyrosine expression and persistent activation of RelA were found in endothelial cells and inflammatory cells that appeared in the perivascular space of intramural coronary arteries and at sites of lost cardiomyocytes in both ventricles. Coincident in time and space with these events was increased mRNA expression of intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha. Macrophages, lymphocytes, and proliferating endothelial and vascular smooth muscle cells and fibroblast-like cells were seen at each of these sites, together with an accumulation of fibrillar collagen, or fibrosis, as evidenced by a significant increase in ventricular collagen volume fraction. Co-treatment with spironolactone, PDTC, or NAC attenuated these molecular and cellular responses as well as the appearance of fibrosis at vascular and nonvascular sites of injury. Furthermore, elevated systolic blood pressure in ALDO-treated rats was partially suppressed by spironolactone or either antioxidant. Thus, chronic ALDO/salt treatment is accompanied by a time-dependent sustained activation of NADPH oxidase with 3-nitrotyrosine generation and nuclear factor-kappaB activation expressed by endothelial cells and inflammatory cells. This leads to a proinflammatory/fibrogenic phenotype involving vascular and nonvascular sites of injury found, respectively, in both normotensive and hypertensive right and left ventricles. Spionolactone, PDTC, and NAC each attenuated these responses suggesting ALDO/salt induction of oxidative/nitrosative stress is responsible for the appearance of this proinflammatory phenotype.
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PMID:Aldosterone-induced inflammation in the rat heart : role of oxidative stress. 1241 24

Bacterial endotoxin activity is elevated in patients with decompensated chronic heart failure (HF) and acts as a potent stimulus for immune activation. We sought to determine whether endotoxin, at an activity level seen in vivo (around 0.6 EU/ml), is sufficient to stimulate the secretion of tumor necrosis factor-alpha (TNF-alpha) and TNF-alpha soluble receptor (sTNFR2) in ex vivo whole blood from patients with HF. We studied 15 patients with HF (aged 65 +/- 1.9 years, New York Heart Association class 2.1 +/- 0.3, left ventricular ejection fraction 31 +/- 5%; mean +/- SEM), of whom 5 had cardiac cachexia, and 7 healthy control subjects (59 +/- 5 years, p = NS). Reference endotoxin was added to venous blood at concentrations of 0.6, 1.0, and 3.0 EU/ml, and was incubated for 6 hours. Endotoxin induced a dose-dependent increase in TNF-alpha release (p <0.05 in all groups). Patients with noncachectic HF produced significantly more TNF-alpha compared with controls after stimulation with 0.6, 1.0, and 3.0 EU/ml of endotoxin (113 +/- 46 vs 22 +/- 4 [p = 0.009], 149 +/- 48 vs 34 +/- 4 [p = 0.002], and 328 +/- 88 vs 89 +/- 16 pg/ml [p = 0.002], respectively; mean +/- SEM). Patients with cardiac cachexia produced significantly less TNF-alpha compared with patients without cardiac cachexia for all given concentrations (all p <0.05, analysis of variance p = 0.02). Production of sTNFR2 was greater at all concentrations of endotoxin versus controls (all p <0.05, analysis of variance p = 0.002). Plasma endotoxin levels were higher in patients with cardiac cachexia (4.3 times higher than in control subjects, p <0.005). Thus, low endotoxin activity, at levels seen in vivo in patients with HF, induces significant TNF-alpha and sTNFR2 production ex vivo. These results suggest that elevated plasma endotoxin activity observed in patients with HF is of pathophysiologic relevance.
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PMID:Pathophysiologic quantities of endotoxin-induced tumor necrosis factor-alpha release in whole blood from patients with chronic heart failure. 1245 Jun 3

Recent studies have identified the importance of proinflammatory mediators in the development and progression of heart failure. The growing appreciation of the pathophysiological consequences of sustained expression of proinflammatory mediators in preclinical and clinical heart failure models culminated in a series of multicenter clinical trials that used "targeted" approaches to neutralize tumor necrosis factor in patients with moderate to advanced heart failure. However, these targeted approaches have resulted in worsening heart failure, thereby raising a number of important questions about what role, if any, proinflammatory cytokines play in the pathogenesis of heart failure. This review will summarize the tremendous growth of knowledge that has taken place in this field, with a focus on what we have learned from the negative clinical trials, as well as the potential direction of future research in this area.
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PMID:Inflammatory mediators and the failing heart: past, present, and the foreseeable future. 1245 84

Large myocardial infarction (MI) causes substantial cardiac remodeling and often leads to heart failure. The genetically engineered mouse is believed to provide a powerful tool for investigating the underlying pathophysiological mechanisms and for developing new therapeutic strategies. The present study investigates the functional parameters and expression levels of transforming growth factor (TGF) beta isoforms, interleukin-6 (IL-6) and tumor necrosis factor (TNF) alpha, which may be involved in the remodeling mechanisms, in a mouse model of MI; comparisons with data from rats were also made. Female Sprague-Dawley rats ( n=10-12 at each time point) and female Balb/c mice ( n=6-8 at each time point) were used. In both mice and rats MI induced a time-dependent reduction in heart function with subsequent development of heart failure. The hemodynamic consequences after 4 weeks are characterized by reduced left ventricular (LV) developed pressure and increased right ventricular (RV) developed pressure. The pattern of increased expression of most, but not all, of the analyzed cytokines and growth factors is comparable. This emphasizes the important role of these factors in the remodeling processes. However, TNFalpha was more strongly expressed in both the infarct and the non-infarcted area of mice. Since functional and molecular biological parameters can readily be measured in mice with advanced technologies, this qualifies this species as a powerful experimental model, particularly in view of the various transgenic and knock-out mice that are available.
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PMID:Heart function and cytokine expression is similar in mice and rats after myocardial infarction but differences occur in TNFalpha expression. 1245 50

The Randomized Aldactone Evaluation Study (RALES) demonstrated a substantial clinical benefit to blocking the effects of aldosterone (Aldo) in patients with heart failure. We recently demonstrated that the enhanced renal conservation of sodium and water in rats with heart failure can be reduced by blocking the central nervous system effects of Aldo with the mineralocorticoid receptor (MR) antagonist spironolactone (SL). Preliminary data from our laboratory suggested that central MR might contribute to another peripheral mechanism in heart failure, the release of proinflammatory cytokines. In the present study, SL (100 ng/h for 21 days) or ethanol vehicle (Veh) was administered via the 3(rd) cerebral ventricle to one group of rats after coronary ligation (CL) or sham CL (Sham) to induce congestive heart failure (CHF). In Veh-treated CHF rats, tumor necrosis factor-alpha (TNF-alpha) levels increased during day 1 and continued to increase throughout the 3-wk observation period. In CHF rats treated with SL, started 24 h after CL, TNF-alpha levels rose initially but retuned to control levels by day 5 after CL and remained low throughout the study. These findings suggest that activation of MR in the central nervous system plays a critical role in regulating TNF-alpha release in heart failure rats. Thus some of the beneficial effect of blocking MR in heart failure could be due at least in part to a reduction in TNF-alpha production.
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PMID:Central mineralocorticoid receptor blockade decreases plasma TNF-alpha after coronary artery ligation in rats. 1252 82

Recent studies have identified the importance of biologically active molecules such as neurohormones in disease progression in heart failure. More recently, it has become apparent that in addition to neurohormones another portfolio of biologically active molecules termed cytokines are also expressed in the setting of heart failure. This article will review the role of tumor necrosis factor-induced signal transduction and the process of left ventricular remodeling.
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PMID:Tumor necrosis factor-induced signal transduction and left ventricular remodeling. 1255 49

Dilated cardiomyopathy, resulting from myocarditis, is the most common cause of heart failure in young patients. We here show that interleukin (IL)-1 receptor type 1-deficient (IL-1R1(-/-)) mice are protected from development of autoimmune myocarditis after immunization with alpha-myosin-peptide(614-629). CD4(+) T cells from immunized IL-1R1(-/-) mice proliferated poorly and failed to transfer disease after injection into naive severe combined immunodeficiency (SCID) mice. In vitro stimulation experiments suggested that the function of IL-1R1(-/-)CD4(+) T cells was not intrinsically defect, but their activation by dendritic cells was impaired in IL-1R1(-/-) mice. Accordingly, production of tumor necrosis factor (TNF)-alpha, IL-1, IL-6, and IL-12p70 was reduced in dendritic cells lacking the IL-1 receptor type 1. In fact, injection of immature, antigen-loaded IL-1R1(+/+) but not IL-1R1(-/-) dendritic cells into IL-1R1(-/-) mice fully restored disease susceptibility by rendering IL-1R1(-/-) CD4(+) T cells pathogenic. Thus, IL-1R1 triggering is required for efficient activation of dendritic cells, which is in turn a prerequisite for induction of autoreactive CD4(+) T cells and autoimmunity.
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PMID:Activation of dendritic cells through the interleukin 1 receptor 1 is critical for the induction of autoimmune myocarditis. 1256 16


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