Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0264733 (ventricular dilatation)
 2,163 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Survivors of both human and animal bacterial shock develop a characteristic pattern of progressive changes in cardiovascular function over a period of 7-10 d. In this present study, we examined whether endotoxin (a product of Gram-negative bacteria) or TNF (a cytokine released from macrophages) could reproduce the same complex cardiovascular changes observed in septic shock over a period of 7-10 d. To test this hypothesis, we implanted a thrombin-fibrin clot containing purified endotoxin from E. coli into the peritoneal cavity of eight dogs, and infused TNF into eight different dogs. Over the next 10 d, serial simultaneous heart scans and thermodilution cardiac outputs were performed in these awake nonsedated animals. By day 2 after challenge with either endotoxin or TNF, animals developed a decrease (p less than 0.05) in both mean arterial pressure and left ventricular ejection fraction. With fluid resuscitation, animals manifested left ventricular dilatation (increased [p less than 0.05] end diastolic volume index), increased or normal cardiac index, and decreased or normal systemic vascular resistance index. In surviving animals, these changes returned to normal with 7-10 d. The time course of these changes was concordant (p less than 0.05) with that previously described in a canine model of septic shock using viable bacteria. During the 10-d study, control animals receiving sterile clots or heat-inactivated TNF had not significant changes in hemodynamics. The results from this canine model demonstrate that either endotoxin or TNF alone can produce many of the same hemodynamic abnormalities seen in human septic shock and in a canine septic shock model induced by live bacteria. These findings support the hypothesis that the action of endogenous mediators (TNF) responding to bacterial products (endotoxin) is the common pathway that produces the serial cardiovascular changes found in septic shock.
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PMID:Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock. 264 95

Cardiotrophin-1 (CT-1) is a potent cytokine that stimulates the assembly of sarcomeric units in series in cardiomyocytes through gp130 signaling, resulting in myocardial cell hypertrophy. To clarify the role of CT-1 and the gp130-signaling pathway during ventricular remodeling after myocardial infarction, we examined the expression of CT-1 and gp130 in a rat model of myocardial infarction. At 1, 3, 7, 14, 28 and 56 days (n=12 for each group) after ligation of a coronary artery, tissue samples were obtained from infarct tissue, the ventricular septum and the right ventricle. All animals developed large myocardial infarctions, with infarct sizes ranging from 39.8% to 50.3%. Progressive left ventricular dilatation and inadequate hypertrophy of the surviving myocardium were confirmed by echocardiography. CT-1 and gp130 mRNA levels were determined by semiquantitative reverse transcription-polymerase chain reaction using 1 or 5 microg of total RNA followed by Southern blotting. The densitometric analysis of the Southern blots revealed a significant increase in CT-1 and gp130 mRNA levels (P<0.01) compared with those of the sham-operated rats at 1, 3, 7, 14, 28 and 56 days post-infarct in the infarct area, the ventricular septum (non-infarcted area) and right ventricle. The protein levels of CT-1 and gp130, determined by Western blot analysis, were significantly increased (P<0.05) compared with those of sham-operated rats, peaked during the acute stage and declined thereafter in the three regions described above. Immunohistochemical staining showed that CT-1 and gp130-immunoreactivities were detected in cardiomyocytes and fibroblast-like cells and that the intensity of staining was increased at 7 days post-infarct compared with that in sham-operated rats. An augmented CT-1 and gp130 system thus appears to play an important role during ventricular remodeling after myocardial infarction.
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PMID:Augmented expression of cardiotrophin-1 and its receptor component, gp130, in both left and right ventricles after myocardial infarction in the rat. 1101 26

The apoptosis of smooth muscle cells, the translocation, structural and functional impairments of remaining cardiomyocytes, ventricular dilatation, and the altered extracellular matrix underlie myocardial remodeling in chronic heart failure (CHF). Among the above factors, apoptosis, which is a membrane-dependent process of programmed cell death, and cytokine derangement are of primary importance. To recognize the cytokine concept of the pathogenesis of CHF permits the clinical application of cytokine synthesis inhibitors and their functional activity.
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PMID:[Molecular and cellular mechanisms of myocardial remodeling in heart failure]. 1268 26

Post haemorrhagic ventricular dilatation is associated with a high rate of disability, multiple impairments and adverse effects of shunt surgery for hydrocephalus. Post haemorrhagic ventricular dilatation results initially from multiple small blood clots throughout the cerebrospinal fluid channels impeding circulation and re-absorption. Transforming growth factor beta is released into the cerebrospinal fluid and there is evidence that this cytokine stimulates the laying down of extracellular matrix proteins which produce permanent obstruction to the cerebrospinal fluid pathways. Prolonged raised pressure, pro-inflammatory cytokines and free radical damage from iron may contribute to periventricular white matter damage and subsequent disability. Interventions such as early lumbar punctures, diuretic drugs to reduce cerebrospinal fluid production and intraventricular fibrinolytic therapy have been tested and, not only fail to prevent shunt dependence, death or disability, but have significant adverse effects. Surgical interventions such as subcutaneous reservoir, external drain, choroid plexus coagulation and third ventriculostomy have not been subject to controlled trial. Ventriculoperitoneal shunt is not feasible in the early phase after intraventricular haemorrhage but, despite the problems with blockages and infections, remains the only option for infants with excessive head expansion over periods of weeks. We have piloted drainage, irrigation and fibrinolytic therapy as a way of removing blood early enough to stop the progressive deposition of matrix proteins, permanent hydrocephalus and shunt dependence.
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PMID:Posthaemorrhagic ventricular dilatation: new mechanisms and new treatment. 1503 55

Mice that overexpress the inflammatory cytokine tumor necrosis factor-alpha in the heart (TNF mice) develop heart failure characterized by atrial and ventricular dilatation, decreased ejection fraction, atrial and ventricular arrhythmias, and increased mortality (males > females). Abnormalities in Ca2+ handling, prolonged action potential duration (APD), calcium alternans, and reentrant atrial and ventricular arrhythmias were previously observed with the use of optical mapping of perfused hearts from TNF mice. We therefore tested whether altered voltage-gated outward K+ and/or inward Ca2+ currents contribute to the altered action potential characteristics and the increased vulnerability to arrhythmias. Whole cell voltage-clamp recordings of K+ currents from left ventricular myocytes of TNF mice revealed an approximately 50% decrease in the rapidly activating, rapidly inactivating transient outward K+ current Ito and in the rapidly activating, slowly inactivating delayed rectifier current IK,slow1, an approximately 25% decrease in the rapidly activating, slowly inactivating delayed rectifier current IK,slow2, and no significant change in the steady-state current Iss compared with controls. Peak amplitudes and inactivation kinetics of the L-type Ca2+ current ICa,L were not altered. Western blot analyses revealed a reduction in the proteins underlying Kv4.2, Kv4.3, and Kv1.5. Thus decreased K+ channel expression is largely responsible for the prolonged APD in the TNF mice and may, along with abnormalities in Ca2+ handling, contribute to arrhythmias.
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PMID:Electrical remodeling of cardiac myocytes from mice with heart failure due to the overexpression of tumor necrosis factor-alpha. 1633 42

Grb2-associated binder (Gab) family of scaffolding adaptor proteins coordinate signaling cascades downstream of growth factor and cytokine receptors. In the heart, among EGF family members, neuregulin-1beta (NRG-1beta, a paracrine factor produced from endothelium) induced remarkable tyrosine phosphorylation of Gab1 and Gab2 via erythroblastic leukemia viral oncogene (ErbB) receptors. We examined the role of Gab family proteins in NRG-1beta/ErbB-mediated signal in the heart by creating cardiomyocyte-specific Gab1/Gab2 double knockout mice (DKO mice). Although DKO mice were viable, they exhibited marked ventricular dilatation and reduced contractility with aging. DKO mice showed high mortality after birth because of heart failure. In addition, we noticed remarkable endocardial fibroelastosis and increase of abnormally dilated vessels in the ventricles of DKO mice. NRG-1beta induced activation of both ERK and AKT in the hearts of control mice but not in those of DKO mice. Using DNA microarray analysis, we found that stimulation with NRG-1beta upregulated expression of an endothelium-stabilizing factor, angiopoietin 1, in the hearts of control mice but not in those of DKO mice, which accounted for the pathological abnormalities in the DKO hearts. Taken together, our observations indicated that in the NRG-1beta/ErbB signaling, Gab1 and Gab2 of the myocardium are essential for both maintenance of myocardial function and stabilization of cardiac capillary and endocardial endothelium in the postnatal heart.
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PMID:Gab family proteins are essential for postnatal maintenance of cardiac function via neuregulin-1/ErbB signaling. 1757 Nov 62

The activity of TIMP-3, a natural tissue inhibitor of matrix metalloproteinases (MMPs), is decreased in the failing heart. This study evaluated the response to coronary ligation of cardiac structure, function, and matrix remodeling in wild-type (WT) mice, and those deficient in TIMP-3 (timp-3(-/-)). The coronary artery was ligated in timp-3(-/-) and age-matched WT mice. At various time points over the following 28-day period, left ventricular structure and function (by echocardiography, pressure-volume measurements and morphometry), MMP levels and activity, blood vessel density, cell proliferation, apoptosis, matrix structure, and inflammatory cytokine levels were assessed in both groups. After ligation, mortality was significantly greater in timp-3(-/-) than in WT mice. Morphometry and echocardiography demonstrated no difference in heart size or function prior to ligation; however, the progression of left ventricular systolic dysfunction was accelerated in timp-3(-/-) mice at 7, 14 and 28 days after infarction compared to WT controls. Left ventricular dilatation, gelatinase MMP activity, and TNF-alpha levels were significantly greater in timp-3(-/-) than in WT mice at different times after ligation. By histological evaluation, timp-3(-/-) mice exhibited significantly increased blood vessel density, cell proliferation, and apoptosis in the infarct area, and reduced collagen content in the viable remote myocardium compared to WT mice at 7 and 14 days after ligation. TIMP-3 deficiency accelerated maladaptive cardiac remodeling after a myocardial infarction by promoting matrix degradation and inflammatory cytokine expression. This study supports further investigations to determine whether such remodeling could be reduced by augmenting TIMP-3 expression in the infarcted myocardium.
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PMID:TIMP-3 deficiency accelerates cardiac remodeling after myocardial infarction. 1794 52

Clinically, the differentiation between ischemic (ICM) and nonischemic (NICM) human cardiomyopathies is highly relevant, because ICM and NICM differ with respect to prognosis and certain aspects of pharmacological therapy, despite a common final phenotype characterized by ventricular dilatation and reduced contractility. So far, it is unclear whether microarray-based signatures can be used to infer the etiology of heart failure. Using three different classification algorithms, we independently analyzed one cDNA and two publicly available high-density oligonucleotide microarray studies comprising a total of 279 end-stage human heart failure samples. When classifiers identified in a single study were applied to the remaining studies, misclassification rates >25% for ICM and NICM specimens were noted, indicating poor separation of both etiologies. However, data mining of 458 classifier genes that were concordantly identified in at least two of the three data sets points to different biological processes in ICM vs. NICM. Consistent with the underlying ischemia, cytokine signaling pathways and immediate-early response genes were overrepresented in ICM samples, whereas NICM samples displayed a deregulation of cytoskeletal transcripts, genes encoding for the major histocompatibility complex, and antigen processing and presentation pathways, potentially pointing to immunologic processes in NICM. Overall, our results suggest that ICM and NICM exhibit substantial heterogeneity at the transcriptomic level. Prospective studies are required to test whether etiology-specific gene expression patterns are present at earlier disease stages or in subsets of both etiologies.
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PMID:Genomic analysis reveals poor separation of human cardiomyopathies of ischemic and nonischemic etiologies. 1843 Aug 5

Transforming growth factor (TGF)-beta1, a cytokine released into the cerebrospinal fluid (CSF) after intraventricular hemorrhage (IVH), stimulates the expression of the components of the extracellular matrix (ECM), which causes progressive ventricular dilatation by impaired CSF absorption. Matrix metalloproteinase-9 (MMP-9), a proteinase involved in the removal of ECM proteins, has been shown to contribute to the resolution of progressive ventricular dilation after IVH. The aim of this study is to clarify the mechanism by which MMP-9 is expressed following IVH. Cultured human meningeal cells were treated with human recombinant TGF-beta1. RT-PCR demonstrated that TGF-beta1 induced MMP-9 expression in the meningeal cells in a dose-dependent manner. The TGF-beta1-induced MMP-9 expression was attenuated in the presence of either MEK or Smad 3 inhibitor. Our data indicated that MMP-9 is released into the CSF from meningeal cells in response to TGF-beta1, most probably through the activation of ERK and Smad pathways.
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PMID:Transforming growth factor-beta1 induces matrix metalloproteinase-9 expression in human meningeal cells via ERK and Smad pathways. 1937 20

Tumor necrosis factor (TNF)-alpha is a proinflammatory cytokine that has been implicated in the pathogenesis of heart failure. In contrast, we have recently shown that myocardial levels of TNF-alpha are acutely elevated in the aortocaval (AV) fistula model of heart failure. Based on these observations, we hypothesized that progression of adverse myocardial remodeling secondary to volume overload would be prevented by inhibition of TNF-alpha with etanercept. Furthermore, a principal objective of this study was to elucidate the effect of TNF-alpha inhibition during different phases of the myocardial remodeling process. Eight-week-old male Sprague-Dawley rats were randomly divided into the following three groups: sham-operated controls, untreated AV fistulas, and etanercept-treated AV fistulas. Each group was further subdivided to study three different time points consisting of 3 days, 3 wk, and 8 wk postfistula. Etanercept was administered subcutaneously at 1 mg/kg body wt. Etanercept prevented collagen degradation at 3 days and significantly attenuated the decrease in collagen at 8 wk postfistula. Although TNF-alpha antagonism did not prevent the initial ventricular dilatation at 3 wk postfistula, etanercept was effective at significantly attenuating the subsequent ventricular hypertrophy, dilatation, and increased compliance at 8 wk postfistula. These positive adaptations achieved with etanercept administration translated into significant functional improvements. At a cellular level, etanercept also markedly attenuated increases in cardiomyocyte length, width, and area at 8 wk postfistula. These observations demonstrate that TNF-alpha has a pivotal role in adverse myocardial remodeling and that treatment with etanercept can attenuate the progression to heart failure.
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PMID:TNF-alpha inhibition attenuates adverse myocardial remodeling in a rat model of volume overload. 1966 42


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