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)

In many forms of cardiomyopathic left ventricular (LV) dysfunction, there is a rapid myocardial expression of pro-inflammatory cytokines such as interleukin 1, interleukin 6 and tumour necrosis factor-alpha (TNF-alpha) which mediate, via specific receptors, various processes such as gene expression, cell growth or apoptosis. In the initial stages of myocarditis, the myocardial expression of proinflammatory cytokines appears to be part of an inflammatory process. In many other conditions such as ischaemic cardiomyopathy and chronic LV pressure or volume overload, myocardial expression of proinflammatory cytokines is triggered by an elevation of LV wall stress. Myocardial expression of cytokines contributes to depression of contractile performance and adverse LV remodelling. Cytokine-induced depression of contractile performance appears to result from sphingosine production, which interferes with myocardial calcium handling. In transgenic mice, the rate of progression of LV dilatation appears to correlate with the intensity of myocardial TNF-alpha overexpression. In heart failure patients, cytokine concentrations are elevated not only in the myocardium but also in plasma. Cytokines are, therefore, responsible not only for autocrine and paracrine signalling within the myocardium but also for endocrine signalling throughout the body, especially affecting striated muscle mass with induction of muscle wasting and cachexia. The source of cytokine production in heart failure remains uncertain and several mechanisms have been proposed including endotoxin-induced immune activation due to bowel oedema, myocardial production due to haemodynamic overload and peripheral extramyocardial production due to tissue hypoperfusion and hypoxia. The latter seems to be the most likely mechanism, possibly modulated by the presence of bacterial endotoxins released from the gut. Numerous drugs have meanwhile been shown to influence this cardioinflammatory response to heart failure either by reducing basal levels of cytokines (e.g. amlodipine, pentoxifylline, beta-blockers) or by reducing endotoxin-induced cytokine gene expression (e.g. ouabain, amiodarone, adenosine, angiotensin converting enzyme inhibitors, angiotensin II-receptor blockers). Direct blockade of the deleterious actions of elevated plasma levels of cytokines recently became possible through intravenous infusion of a soluble TNF-alpha receptor fusion protein, which resulted in an increase in exercise tolerance and LV performance.
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PMID:Cytokines and heart failure. 1263 74

Cytokines are being increasingly recognized as important factors in the pathogenesis and pathophysiology of heart failure. Elevated levels of circulating cytokines have been reported in patients with heart failure, and various cytokines have been shown to depress myocardial contractility in vitro and in vivo. Our recent study showed that the various drugs for heart failure modulated the production of cytokines, and some of these drugs inhibited activation of NF-kappa B. Cytokine gene therapy which inhibits inflammatory response by viral IL-10 and IL-1 receptor antagonist has been shown to be effective in the animal models of heart failure. Mast cells have been shown to play important role in the pathogenesis of heart failure due to viral myocarditis, and transition from compensated hypertrophy to heart failure.
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PMID:[Roles of cytokines in the pathogenesis of heart failure]. 1275 97

It has been reported that proinflammatory cytokine activation is associated with both mesenteric venous congestion and peripheral tissue underperfusion in advanced chronic heart failure. The aim of our study was to investigate if plasma amylase (as an easily approached marker of a low-grade peripheral organ injury caused by elevated systemic venous pressure and reduced cardiac output) is elevated in severe heart failure and if this elevation is correlated with cytokine and neurohormonal activation in the plasma of heart failure patients. Plasma levels of amylase, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), norepinephrine, and renin activity were measured in 43 severe heart failure patients (ischemic, 28; dilated, 15; left ventricular ejection fraction [LVEF] 27 +/- 3%; New York Heart Association [NYHA] classes III-IV), in 37 mild heart failure patients (ischemic, 26; dilated, 11; LVEF, 33 +/- 5%; NYHA classes I-II), and in 20 age-matched and gender-matched healthy controls. NYHA III-IV heart failure patients exhibited significantly higher plasma levels of amylase (342 +/- 19 vs. 174 +/- 13 U/L, p < 0.01), TNF-alpha (6.2 +/- 0.5 vs. 4.2 +/- 0.3 pg/ml, p < 0.01), IL-6 (5.9 +/- 0.3 vs. 4.4 +/- 0.3 pg/ml, p < 0.05), GM-CSF (21.2 +/- 2.7 vs. 4.1 +/- 0.9 pg/ml, p < 0.001), and neurohormones (both p < 0.001) compared with NYHA I-II heart failure patients and healthy controls (amylase, 165 +/- 11 U/L, p < 0.01; TNF-alpha, 2.7 +/- 0.3 pg/ml, p < 0.001; IL-6, 3.2 +/- 0.2 pg/ml, p < 0.01; GM-CSF, 3.1 +/- 0.7 pg/ml, p < 0.001). Only in NYHA III-IV heart failure patients, plasma amylase levels were significantly correlated with plasma IL-6 activity (r = 0.86, p < 0.001), plasma norepinephrine levels (r = 0.82, p < 0.001) and right atrial pressure (r = 0.52, p < 0.05). Additionally, circulating IL-6 was also significantly correlated with plasma norepinephrine (r = 0.86, p < 0.001) and right atrial pressure (r = 0.57, p < 0.01). In conclusion, plasma amylase levels were elevated in severe heart failure patients and correlated well with circulating IL-6 activation, possibly as a result of both mesenteric venous congestion and impaired peripheral tissue perfusion observed in advanced chronic heart failure. However, the lack of association between plasma IL-6 and amylase levels in mild heart failure patients indicates an independent correlation of each variable with the functional status of the disease.
J Interferon Cytokine Res 2003 Jun
PMID:Elevated plasma amylase levels in advanced chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy: correlation with circulating interleukin-6 activity. 1285 59

Ventricular remodeling is an extremely complicated process that is not well understood. There seem to be multiple feedback loops that respond to mechanical events as well as to neurohormonal stimulation, cytokine release, and other, yet unidentified, agents. The progression of ventricular remodeling after the index event includes: Myocyte slippage and thinning of infarct area, chamber dilatation. Fibrosis and scar formation. Collagen strut dissolution and excessive accumulation of interstitial matrix. Increased wall stress. Myocyte hypertrophy. Neurohormonal activation. Cytokine release. Ongoing myocyte hypertrophy. Cell apoptosis and necrosis. Continued deterioration of cardiac function. It is impossible to place the sequence of events in order, because the multiple feedback systems create a complex interactive process. A basic awareness of the pathophysiology of ventricular remodeling can aid in understanding current and future treatments for heart failure. It is clear that therapeutic interventions solely aimed at improving cardiac pump function do not slow the progression of heart failure or reduce mortality. Drugs that block the neuroendocrine contribution to the remodeling process have been shown to have a greater impact. Current therapies with angiotensin-converting enzyme inhibition, beta blockade, and aldosterone antagonism are associated with significant reductions in morbidity and mortality in heart failure. Other therapeutic strategies suggested by knowledge of remodeling mechanisms, such as drugs to block cytokines, endothelins, and MMPs, may offer further benefit to patients with heart failure in the future.
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PMID:Ventricular remodeling. 1471 85

No in vivo data exist about the relationship of circulating granulocyte-macrophage colony stimulating factor (GM-CSF) and soluble adhesion molecules ICAM-1 and VCAM-1 (sICAM-1 and sVCAM-1) to the severity of acute myocardial infarction (AMI) and the pathophysiological events of post-infarction left ventricular dysfunction. We investigated the kinetics of these inflammatory mediators in the plasma of patients with AMI, and correlated the findings with the clinical severity of the disease during the first week of hospitalization as well as the degree of left ventricular dysfunction one month after the AMI. Plasma levels of inflammatory markers were determined in 41 AMI patients (all received thrombolytic treatment) by ELISA assays, serially during the first week of hospitalization and one month after hospital admission. Patients (n = 20) with uncomplicated AMI (Killip class I) were classified as group A, patients (n = 21) with AMI complicated by heart failure manifestations (Killip classes II and III) were classified as group B, while 20 age- and sex-matched volunteers were used as healthy controls. A sustained increase in GM-CSF, sICAM-1 and sVCAM-1 plasma concentrations was observed only in group B during the first week of the study. Patients from group B exhibited significantly higher levels of GM-CSF (P < 0.01), sICAM-1 (P < 0.05) and sVCAM-1 (P < 0.01) than patients from group A and the healthy controls (P < 0.001). In group B patients, significant correlations were observed between the peak of GM-CSF levels and the peak of serum creatine kinase-MB (r = 0.42; P < 0.05), white blood cell counts (r = 0.67; P < 0.001) and LVEF (r =- 0.51; P < 0.01). At one month follow-up, patients (n = 17) with severe post-infarction left ventricular dysfunction (LVEF <or=35%) exhibited significantly higher levels of GM-CSF (21.8 +/- 1.5 versus 11.7 +/- 0.9 pg/mL, P < 0.001), sICAM-1 (331.4 +/- 18.4 versus 201.3 +/- 12.1 ng/mL, P < 0.001) and sVCAM-1 (748.4 +/- 34.7 versus 512.9 +/- 18.8 ng/mL, P < 0.001) than did the other patients (n = 24) without this condition (LVEF > 35%). Significant correlations were observed between GM-CSF levels and left ventricular end-diastolic volume index (r = 0.55; P < 0.001) or left ventricular end-systolic volume index (r = 0.49; P = 0.001). We have found a significant elevation of plasma GM-CSF and soluble adhesion molecules during the course of AMI, with the highest values in patients with AMI complicated by heart failure manifestations and severe left ventricular dysfunction. These monocyte-related inflammatory mediators may actively contribute to the pathophysiology of the disease and post-infarction cardiac dysfunction.
Eur Cytokine Netw
PMID:Plasma profiles of circulating granulocyte-macrophage colony-stimulating factor and soluble cellular adhesion molecules in acute myocardial infarction. Contribution to post-infarction left ventricular dysfunction. 1531 74

The circulating form of a membrane-bound intercellular adhesion molecule-1 (ICAM-1), has been the source of recent debate as a candidate marker of vascular inflammation in atherosclerosis and myocardial infarction, although its increased levels were also observed in other diseases affecting the cardiovascular system, such as myocarditis, inflammatory cardiomyopathy and heart failure per se. Faulty dietary habits, a sedentary mode of life, smoking, and alcohol abuse, are factors which at least in part contribute to atherosclerosis. This paper describes the responses of sICAM-1 levels to nutrients, physical activity, smoke exposure and alcohol consumption.
Cytokine 2005 Jul 21
PMID:Soluble ICAM-1: a marker of vascular inflammation and lifestyle. 1591 14

Matrix metalloproteinases (MMP) degrade myocardial fibrillar collagen in acute myocardial infarction (MI) patients. Their activity is tightly controlled in normal myocardium by a family of closely related tissue inhibitors known as TIMP. An imbalance in their activity might contribute to post-MI remodeling. Plasma levels of MMP-1, TIMP-1 and MMP-1/TIMP-1 complex were measured, using relevant ELISA kits, in 24 (22 males-2 females), acute MI patients with a mean age 59 +/- 14 years. Blood samples were taken on admission (0 h), and 3 h, 6 h, 9 h, 18 h, 24 h, 36 h, 48 h, 3rd, 4th, 5th, 7th, 15th, 30th days after MI. All patients underwent coronary arteriography with ventriculography for estimation of left ventricular ejection fraction (LVEF) and extent of coronary artery diseases, and echocardiographic study for measuring end-diastolic diameter (EDD). Ten patients with an LVEF < 45%, an EDD > 47.5 mm, and heart failure symptoms were included in group A and compared against 12 patients with an LVEF > 45% an EDD < 47.5 mm in group B. Mean plasma concentrations of MMP-1 were higher by 21% in group A (1.3 +/- 0.2 ng/mL) compared to group B (1 +/- 0.1 ng/mL) over the total study period. TIMP-1 plasma concentrations showed very little difference between the 2 groups, (704 +/- 213 ng/mL versus 691 +/- 165 ng/mL, (6%)). Finally, plasma concentrations of MMP-1/TIMP-1 complex were lower by -36% in group A with a mean value of 2.7 +/- 0.6 ng/mL versus 3.7 +/- 0.5 ng/mL in group B. Mean values for the differences were significant at time points 0, 6, 18, 24 and 48 hours for MMP-1 (p < 0.036), and on 48 h and the 4th day for MMP-1/TIMP-1 complex (p < 0.031). Moreover, a good correlation was found between plasma concentrations of creatine kinase (CK) and MMP-1 at 18 h (r = 0.422, p = 0.041) and on the 4th day (r = 0.67, p = 0.046), and TIMP-1 on the 4th day (r = 0.67, p = 0.047). Additionally, mean values for LVEF were 35.8 +/- 8.8% in group A versus 51.2 +/- 1.8% (p = 0.00014) in group B. Also, the EDD in-group A was 52.1 +/- 6.9 mm versus 42.9 +/- 3.2 mm in group B (p = 0.00013). In acute MI patients, increased MMP-1, with no change in TIMP-1, is associated with left ventricular dysfunction and dilatation, suggesting that increased collagenolytic activity contributes to loss of LV function.
Eur Cytokine Netw 2005 Jun
PMID:Clinical significance of matrix metalloproteinases activity in acute myocardial infarction. 1594 87

The role of cytokines in the pathogenesis of cardiovascular disease is increasingly evident since the identification of immune/inflammatory mechanisms in atherosclerosis and heart failure. In this review, we describe how innate and adaptive immune cascades trigger the release of cytokines and chemokines, resulting in the initiation and progression of atherosclerosis. We discuss how cytokines have direct and indirect effects on myocardial function. These include myocardial depressant effects of nitric oxide (NO) synthase-generated NO, as well as the biochemical effects of cytokine-stimulated arachidonic acid metabolites on cardiomyocytes. Cytokine influences on myocardial function are time-, concentration-, and subtype-specific. We provide a comprehensive review of these cytokine-mediated immune and inflammatory cascades implicated in the most common forms of cardiovascular disease.
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PMID:Cytokines and cardiovascular disease. 1600 37

Cytokine and extracellular matrix (ECM) homeostasis are distinct systems that are each dysregulated in heart failure. Here we show that tissue inhibitor of metalloproteinase (TIMP)-3 is a critical regulator of both systems in a mouse model of left ventricular (LV) dilation and dysfunction. Timp-3(-/-) mice develop precipitous LV dilation and dysfunction reminiscent of dilated cardiomyopathy (DCM), culminating in early onset of heart failure by 6 weeks, compared with wild-type aortic-banding (AB). Timp-3 deficiency resulted in increased TNFalpha converting enzyme (TACE) activity within 6 hours after AB leading to enhanced tumor necrosis factor-alpha (TNFalpha) processing. In addition, TNFalpha production increased in timp-3(-/-)-AB myocardium. A significant elevation in gelatinase and collagenase activities was observed 1 week after AB, with localized ECM degradation in timp-3(-/-)-AB myocardium. Timp-3(-/-)/tnfalpha(-/-) mice were generated and subjected to AB for comparative analyses with timp-3(-/-)-AB mice. This revealed the critical role of TNFalpha in the early phase of LV remodeling, de novo expression of Matrix metalloproteinases (MMP)-8 in the absence of TNFalpha, and highlighted the importance of interstitial collagenases (MMP-2, MMP-13, and MT1-MMP) for cardiac ECM degradation. Ablation of TNFalpha, or limiting MMP activity with a synthetic MMP inhibitor (PD166793), each partially attenuated LV dilation and cardiac dysfunction in timp-3(-/-)-AB mice. Notably, combining TNFalpha ablation with MMP inhibition completely rescued heart disease in timp-3(-/-)-AB mice. This study provides a basis for anti-TNFalpha and MMP inhibitor combination therapy in heart disease.
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PMID:Combination of tumor necrosis factor-alpha ablation and matrix metalloproteinase inhibition prevents heart failure after pressure overload in tissue inhibitor of metalloproteinase-3 knock-out mice. 1603 68

Cytokine production in idiopathic dilated cardiomyopathy (IDC) may depend on neurohumoral stimulation, haemodynamic impairment or auto-antibody production. We aimed to ascertain the impact of haemodynamic improvements with standard medical therapy and neurohumoral blockade on white cell tumour necrosis factor- alpha (TNF-alpha ) production in patients with IDC. Twenty-seven patients with IDC and NYHA class I to IV heart failure but without evidence of oedema, reduced peripheral perfusion, or elevated plasma endotoxin concentrations were evaluated for indicators of cytokine activation. Plasma TNF-alpha concentrations were raised (p < 0.001) in patients prior to commencement of medical therapy as compared to controls (n = 27). In addition, endotoxin-free cultured whole blood TNF-alpha production was enhanced (p < 0.02) in the patients. Although plasma TNF-alpha tended to decrease, excessive whole blood TNF-alpha production remained unaltered following marked improvements in haemodynamics and functional class (increase in absolute left ventricular ejection fraction = 8.7 +/- 2.6%, p < 0.01, 37% in NYHA functional class I after therapy) with six to 12 months of medical therapy (diuretic, angiotensin converting enzyme inhibitor and beta-blocker). Against a role for neurohumoral substances in promoting excessive white cell TNF-alpha synthesis the angiotensin II receptor antagonist, losartan, failed to modulate white cell TNF- alpha production in patients with IDC. We concluded that white cell TNF-alpha overproduction is sustained in patients with IDC despite haemodynamic improvement with standard medical therapy and blockade of angiotensin II receptors. These data suggest that mechanisms other than haemodynamic impairment and neurohumoral activation contribute to excess white cell TNF-alpha production in IDC.
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PMID:Sustained white cell cytokine activation in idiopathic dilated cardiomyopathy despite haemodynamic improvement with medical therapy. 1621 Nov 23


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