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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytokine tumor necrosis factor (TNF)-alpha has been causally linked to left ventricular (LV) remodeling, but the molecular basis for this effect is unknown. Matrix metalloproteinases (MMPs) have been implicated in cardiac remodeling and can be regulated by TNF-alpha. This study tested the central hypothesis that administration of a TNF-alpha blocking protein would prevent the induction of MMPs and alter the course of myocardial remodeling in developing LV failure. Adult dogs were randomly assigned to the following groups: 1) chronic pacing (250 beats/min, 28 days, n = 12), 2) chronic pacing with concomitant administration of a TNF-alpha blocking protein (TNF block) using a soluble p75 TNF receptor fusion protein (TNFR:Fc; administered at 0.5 mg/kg twice a week subcutaneously, n = 7), and 3) normal controls (n = 10). LV end-diastolic volume increased from control with chronic pacing (83 +/- 12 vs. 118 +/- 10 ml, P < 0.05) and was reduced with TNF block (97 +/- 9 ml, P < 0.05). MMP zymographic levels (92 kDa, pixels) increased from control with chronic pacing (36,848 +/- 9,593 vs. 87,247 +/- 12,912, P < 0.05) and was normalized by TNF block. Myocardial MMP-9 and MMP-13 levels by immunoblot increased with chronic pacing relative to controls (130 +/- 10% and 118 +/- 6%, P < 0.05) and was normalized by TNF block. These results provide evidence to suggest that TNF-alpha contributes to the myocardial remodeling process in evolving heart failure through the local induction of specific MMPs.
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PMID:TNF-alpha and myocardial matrix metalloproteinases in heart failure: relationship to LV remodeling. 1189 63

Tumor necrosis factor (TNF) is a proinflammatory cytokine that can produce widespread deleterious effects when expressed in large amounts. It is produced in the heart by both cardiac myocytes and resident macrophages under conditions of cardiac stress, and is thought to be responsible for many of the untoward manifestations of cardiac disease. This article discusses the role of TNF in heart disease and some potential therapeutic modalities that can influence the cytokine activity. The results of controlled studies would suggest that TNF inhibition does not influence the clinical course of patients with heart failure.
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PMID:The role of tumor necrosis factor in cardiac disease. 1197 13

There is growing evidence that increased plasma concentrations of CRP strongly predict cardiovascular death in both non-renal and renal patient populations. The interleukin-6 (IL-6) system activity, which is the major mediator of the acute phase response, is often markedly up-regulated in uremic patients and has also been shown to predict outcome. This raises the issue of whether or not IL-6 per se may contribute to increased mortality from malnutrition and atherosclerotic cardiovascular disease in uremic patients. The causes of elevated IL-6 levels in the uremic circulation are not fully understood, although a number of factors prevalent in uremic patients, such as hypertension, adiposity, infections, and chronic heart failure may all contribute. However, factors associated with the dialysis procedure, such as bioincompatibility and non-sterile dialysate, may stimulate IL-6 production. Furthermore, available evidence suggests that genetic factors may also have an impact on circulating plasma IL-6 levels. We advance the hypothesis that IL-6 may play a central role in the genesis of inflammatory-driven malnutrition and that it may be regarded as a significant proatherogenic cytokine. This hypothesis may provide a rationale to test if targeted anti-cytokine therapy may be one way to combat the unacceptable high cardiovascular mortality rate among dialysis patients.
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PMID:Mortality, malnutrition, and atherosclerosis in ESRD: what is the role of interleukin-6? 1198 23

Both experimental and clinical studies have shown a role for inflammation in the pathogenesis of heart failure. This seems related to an imbalance between pro-inflammatory and anti-inflammatory cytokines. Certain categories in patients with dilated cardiomyopathy have shown the presence of humoral and cellular immunity activation suggesting a possible relation between myocarditis and dilated cardiomyopathy. Recent studies suggest a link between the circulating levels of cytokines (TNF alpha IL-1 et IL-6), the clinical status and prognostic. However, the mechanisms connecting heart failure and cytokine activation are unclear and the sites of cytokines production remain controversial. In the clinical setting, specific measurements of cytokines are not available. As tests of inflammation, erythrocyte sedimentation rate and C-reactive protein concentration appear to have interesting pronostic values. Current conventional therapy i.e. ACE inhibitors, type I angiotensin II antagonist and beta-blockers have shown some anti-cytokine properties. Recently, immunosuppressive therapies have shown their ability to improve symptoms and LV ejection in selected patients with dilated cardiomyopathy and clear sign of myocardium inflammation. Specific anti-cytokine therapy have been developed and showed interesting results in preliminary clinical studies. However large clinical trials testing this new therapy have been stoppel prematurely because of deterious effects.
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PMID:Inflammation, cytokines and anti-inflammatory therapies in heart failure. 1199 36

Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are of proven clinical benefit in coronary heart disease, at least in those patients who do not have overt chronic heart failure (CHF). However, as there have been no prospective clinical trials of statins in CHF patients, the question arises as to whether the benefits observed in the absence of CHF can be necessarily inferred in those patients in whom CHF is established. In this review, the evidence base stating support of the use of statins in CHF is presented, as well as theoretical considerations as to why these agents may not necessarily be of benefit in this setting. The beneficial potential of statins clearly relates to their plaque stabilization properties and associated improvements in endothelial function, which together should reduce the risk of further infarction and, perhaps, the ischemic burden on the failing ventricle. Furthermore, these agents may have beneficial effects independent of lipid lowering. These include actions on neoangiogenesis, downregulation of AT(1) receptors, inhibition of proinflammatory cytokine activity and favorable modulation of the autonomic nervous system. The potential adverse effects of statins in CHF include reduction in levels of coenzyme Q10 (which may further exacerbate oxidative stress in CHF) and loss of the protection that lipoproteins may provide through binding and detoxifying endotoxins entering the circulation via the gut. In support of these possibilities are epidemiologic data linking a lower serum cholesterol with a poorer prognosis in CHF. These uncertainties indicate the need for a definitive outcome trial to assess the efficacy and safety of statins in CHF, despite their current widespread, non-evidence based use in this population.
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PMID:Statins and chronic heart failure: do we need a large-scale outcome trial? 1202 Apr 81

Recent studies have suggested that cytokines such as macrophage colony-stimulating factor (M-CSF) might be involved in the pathogenesis of ischaemic heart disease. Macrophage colony-stimulating factor, granulocyte-colony stimulating factor (G-CSF), granulocyte-macrophage-colony stimulating factor (GM-CSF), stem cell factor (SCF), interleukin-3 (IL-3) and interleukin-7 (IL-7) are potent cytokines belonging to the same structual class that may affect function, growth and apoptosis both in the heart and other organs. The aims of the present study were to characterize a post-infarction model in the mouse and to examine mRNA expression of M-CSF, GM-CSF, SCF, IL-3 and IL-7 during the development of heart failure. Myocardial infarction (MI) was induced in mice by ligation of the left coronary artery. Average infarct size was 40% and the mice developed myocardial hypertrophy and pulmonary oedema. Ribonuclease (RNAase) protection assays showed abundant cardiac expression of M-CSF and SCF. After MI, we measured down-regulation of cytokine mRNA expression in the heart (M-CSF, SCF), lung (M-CSF), liver (M-CSF) and spleen (M-CSF) compared with sham. Cardiac G-CSF, GM-CSF and IL-7 mRNAs were not detected. In conclusion, abundant cardiac gene expression of M-CSF and SCF was found. In our mouse model of MI, M-CSF and SCF were down-regulated in the heart and several other organs suggesting specific roles for these cytokines during development of ischaemic heart failure.
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PMID:Gene expression of colony-stimulating factors and stem cell factor after myocardial infarction in the mouse. 1210 Mar 56

Mitogen-activated protein kinase kinase kinase (MEKK1) mediates activation of c-Jun NH(2)-terminal kinase (JNK). Although previous studies using cultured cardiac myocytes have suggested that the MEKK1-JNK pathway plays a key role in hypertrophy and apoptosis, its effects in cardiac hypertrophy and apoptosis are not fully understood in adult animals in vivo. We examined the role of the MEKK1-JNK pathway in pressure-overloaded hearts by using mice deficient in MEKK1. We found that transverse aortic banding significantly increased JNK activity in Mekk1(+/+) but not Mekk1(-/-) mice, indicating that MEKK1 mediates JNK activation by pressure overload. Nevertheless, pressure overload caused significant levels of cardiac hypertrophy and expression of atrial natriuretic factor in Mekk1(-/-) animals, which showed higher mortality and lung/body weight ratio than were seen in controls. Fourteen days after banding, Mekk1(-/-) hearts were dilated, and their left ventricular ejection fraction was low. Pressure overload caused elevated levels of apoptosis and inflammatory lesions in these mice and produced a smaller increase in TGF-beta and TNF-alpha expression than occurred in wild-type controls. Thus, MEKK1 appears to be required for pressure overload-induced JNK activation and cytokine upregulation but to be dispensable for pressure overload-induced cardiac hypertrophy. MEKK1 also prevents apoptosis and inflammation, thereby protecting against heart failure and sudden death following cardiac pressure overload.
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PMID:The MEKK1-JNK pathway plays a protective role in pressure overload but does not mediate cardiac hypertrophy. 1212 19

Chronic heart failure is no longer a mere cardiac entity, but involves several, initially adaptive and later detrimental, neurohumoral compensatory mechanisms. Peripheral manifestations of the disease, such as endothelial dysfunction, skeletal muscle changes, and disturbances in ventilatory control, are major determinants of symptoms. The independent prognostic value and the relevance of cachexia on morbidity of patients with chronic heart failure have only recently been recognised. Altered body composition in heart failure patients is reflected in the early loss of muscle tissue but affects all tissue compartments in case of cardiac cachexia. Recently, a new portfolio of biologically active molecules, termed cytokines, have been shown to play an important role in the development and progression of both cardiac and peripheral abnormalities. Similar to other chronic illnesses, covered in the remainder of this issue, a low-grade chronic inflammatory process may be of particular relevance in the development of tissue wasting in these patients. Whereas the presence of immune activation in chronic heart failure is now widely accepted, as well as the prognostic relevance of chronic inflammation, the site and the source of cytokine production remain the object of intense research. Although the inciting event is located in the heart, cross-talk between the myocardium on the one hand, and the immune system, peripheral tissues and organs on the other hand, will lead to the overproduction of proinflammatory cytokines and, inevitably, to their detrimental effects. The specific problems related to heart failure progression and inflammatory activation are described in this review.
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PMID:Chronic heart failure: an example of a systemic chronic inflammatory disease resulting in cachexia. 1216 8

The cachexia syndrome is characterised by progressive weight loss and depletion of lean body mass and has long been recognised as a poor prognostic sign. Whilst the clinical features of the wasting process are readily apparent, its pathogenesis is complex and poorly understood. There is increasing evidence that the immune system, in particular inflammatory cytokines, may play an important role in the development of cachexia. The cytokine considered to be the most relevant to this process is tumor necrosis factor alpha (TNF), although other mediators such as interleukin (IL) 1, IL-6 and interferon gamma have also been implicated. Apoptosis represents a potential pathway by which wasting can occur in chronic diseases. Cytokines and their corresponding receptors are known to be important regulators of cell death. Apoptosis has been demonstrated in the skeletal muscle of patients with chronic heart failure (CHF) and is thought to be partly responsible for the significant impairment of functional work capacity associated with this condition. An understanding of the mechanisms that regulate muscle protein breakdown is essential for the development of strategies for treating or even preventing muscle cachexia in patients. It is the aim of this article to review the role of inflammatory cytokines, particularly TNF, in the pathogenesis of wasting and also the potential for anti-cytokine therapy. Although this review will concentrate predominantly on the syndrome of CHF, other chronic illnesses such as liver disease, cancer, and sepsis will also be discussed.
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PMID:Cytokines, apoptosis and cachexia: the potential for TNF antagonism. 1216 21

The functional role of tumor necrosis factor (TNF)-alpha in the heart has been extensively studied over the last 15 years. Collectively, these studies have demonstrated that TNF-alpha has both diverse and potentially conflicting roles in cardiac function and pathology. These include beneficial effects, such as cardioprotection against ischemia, myocarditis, and pressure overload, as well as potentially adverse effects, such as the development of atherosclerosis, reperfusion injury, hypertrophy, and heart failure. TNF-alpha antagonist therapy recently has been demonstrated to be clinically applicable in inflammatory conditions, and clinical trials are currently in progress in the use of these agents in cardiovascular diseases. The scope for clinical applications of anti-TNF-alpha therapy in cardiovascular diseases is potentially extensive. Hence, this review has been undertaken to evaluate the cardiovascular effects of this pleiotropic cytokine and to evaluate the potential of targeting this cytokine in cardiovascular therapeutics. An overview of the TNF-alpha peptide and its associated signaling are described. This is followed by a discussion of the known roles of TNF-alpha in cardiac physiology and in a diverse array of cardiac pathologies. Reference to experimental and clinical studies using anti-TNF-alpha therapies are described where applicable. The postulated role of TNF-alpha signaling concerning innate cardiac cellular processes that may have direct adaptive effects in the heart will be reviewed with respect to future research directions. Finally, the author postulates that attenuation of TNF-alpha biosynthesis in selected individuals will need to be tested if true benefits of this therapeutic approach are to be realized in the management of cardiovascular diseases.
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PMID:Tumor necrosis factor-alpha in cardiovascular biology and the potential role for anti-tumor necrosis factor-alpha therapy in heart disease. 1219 98


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