UMLS:C0018801 - FACTA Search

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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

An echocardiogram demonstrated a large tumor in the left atrium of a 47-year-old woman with sudden heart failure. Emergent cardiotomy showed that the tumor arose from the left atrial wall, and almost entirely occupied the left atrium. Grossly, the tumor had partly undergone necrosis. Histologically, the tumor consisted predominantly of round to polygonal cells with ill-defined cell borders surrounding 'stag horn'-shaped blood vessels. Mitosis was frequently seen with abnormal mitotic figures. Immunohistochemically, the tumor cells diffusely expressed vimentin and focally expressed factor XIIIa and human leukocyte antigen-DR. A few tumor cells expressed S-100 protein or alpha-smooth muscle actin. Histopathological diagnosis was malignant hemangiopericytoma of the left atrium. Most tumor cells expressed matrix metalloproteinase (MMP)-2 and MMP-3, and several cells expressed MMP-9, all of which are capable of degrading a major component of basement membrane (i.e. type IV collagen). Furthermore, tumor cells expressed membrane type 1 MMP and tissue inhibitor of metalloproteinase-2, both of which are required for activation of proMMP-2. Fourteen months after the surgical removal, she died of systemic recurrent tumors.
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PMID:Case of primary malignant hemangiopericytoma of the heart expressing basement membrane-degradable enzymes. 1236 15

Matrix metalloproteinase-2 (MMP-2) is prominently overexpressed both after myocardial infarction (MI) and in heart failure. However, its pathophysiological significance in these conditions is still unclear. We thus examined the effects of targeted deletion of MMP-2 on post-MI left ventricular (LV) remodeling and failure. Anterior MI was produced in 10- to 12-wk-old male MMP-2 knockout (KO) and sibling wild-type (WT) mice by ligating the left coronary artery. By day 28, MI resulted in a significant increase in mortality in association with LV cavity dilatation and dysfunction. The MMP-2 KO mice had a significantly better survival rate than WT mice (56% vs. 85%, P < 0.05), despite a comparable infarct size (50 +/- 3% vs. 51 +/- 3%, P = not significant), heart rate, and arterial blood pressure. The KO mice had a significantly lower incidence of LV rupture (10% vs. 39%, P < 0.05), which occurred within 7 days of MI. The KO mice exerted less LV cavity dilatation and improved fractional shortening after MI by echocardiography. The LV zymographic MMP-2 level significantly increased in WT mice after coronary artery ligation; however, this was completely prevented in KO mice. In contrast, the increase in the LV zymographic MMP-9 level after MI was similar between KO and WT mice. MMP-2 activation is therefore considered to contribute to an early cardiac rupture as well as late LV remodeling after MI. The inhibition of MMP-2 activation may therefore be a potentially useful therapeutic strategy to manage post-MI hearts.
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PMID:Targeted deletion of MMP-2 attenuates early LV rupture and late remodeling after experimental myocardial infarction. 1277 62

Cardiac hypertrophy can lead to heart failure (HF), but it is unpredictable which hypertrophied myocardium will progress to HF. We surmised that apart from hypertrophy-related genes, failure-related genes are expressed before the onset of failure, permitting molecular prediction of HF. Hearts from hypertensive homozygous renin-overexpressing (Ren-2) rats that had progressed to early HF were compared by microarray analysis to Ren-2 rats that had remained compensated. To identify which HF-related genes preceded failure, cardiac biopsy specimens were taken during compensated hypertrophy and we then monitored whether the rat progressed to HF or remained compensated. Among 48 genes overexpressed in failing hearts, we focused on thrombospondin-2 (TSP2). TSP2 was selectively overexpressed only in biopsy specimens from rats that later progressed to HF. Moreover, expression of TSP2 was increased in human hypertrophied hearts with decreased (0.19+/-0.01) versus normal ejection fraction (0.11+/-0.03 [arbitrary units]; P<0.05). Angiotensin II induced fatal cardiac rupture in 70% of TSP2 knockout mice, with cardiac failure in the surviving mice; this was not seen in wild-type mice. In TSP2 knockout mice, angiotensin II increased matrix metalloproteinase (MMP)-2 and MMP-9 activity by 120% and 390% compared with wild-type mice (P<0.05). In conclusion, we identify TSP2 as a crucial regulator of the integrity of the cardiac matrix that is necessary for the myocardium to cope with increased loading and that may function by its regulation of MMP activity. This suggests that expression of TSP2 marks an early-stage molecular program that is activated uniquely in hypertrophied hearts that are prone to fail.
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PMID:Thrombospondin-2 is essential for myocardial matrix integrity: increased expression identifies failure-prone cardiac hypertrophy. 1534 66

Left ventricular (LV) hypertrophy is a natural response of the heart to increased pressure loading, but accompanying fibrosis and dilatation may result in irreversible life-threatening heart failure. Matrix metalloproteinases (MMPs) have been invoked in various cardiac diseases, however, direct genetic evidence for a role of the plasminogen activator (PA) and MMP systems in pressure overload-induced LV hypertrophy and in heart failure is lacking. Therefore, the consequences of transverse aortic banding (TAB) were analyzed in mice lacking tissue-type PA (t-PA(-/-)), urokinase-type PA (u-PA(-/-)), or gelatinase-B (MMP-9(-/-)), and in wild-type (WT) mice after adenoviral gene transfer of the PA-inhibitor PAI-1 or the MMP-inhibitor TIMP-1. TAB elevated LV pressure comparably in all genotypes. In WT and t-PA(-/-) mice, cardiomyocyte hypertrophy was associated with myocardial fibrosis, LV dilatation and dysfunction, and pump failure after 7 weeks. In contrast, in u-PA(-/-) mice or in WT mice after PAI-1- and TIMP-1-gene transfer, cardiomyocyte hypertrophy was moderate and only minimally associated with cardiac fibrosis and LV dilatation, resulting in better preservation of pump function. Deficiency of MMP-9 had an intermediate effect. These findings suggest that the use of u-PA- or MMP-inhibitors might preserve cardiac pump function in LV pressure overloading.
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PMID:Loss or inhibition of uPA or MMP-9 attenuates LV remodeling and dysfunction after acute pressure overload in mice. 1563 96

Tumor embolism occurs in 30 to 50% of all cases of cardiac myxoma, but the causes are still uncertain. Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade the extracellular matrix (ECM) and play a crucial role in plaque instability and aortic aneurysm development, in addition to cancer and heart failure. To determine whether MMP activity contributes to tumor embolism, we examined 27 left atrium-sided myxomas, 10 of which showed clinical signs of peripheral embolism. Immunohistochemistry (in all cases) and Western blotting, and in situ and in-gel zymography (in four embolic and six nonembolic consecutive tumors) demonstrated higher expression and activity of MT1-MMP, pro-MMP-2, and pro-MMP-9 in embolic myxomas, whereas pro-MMP-1, MMP-3, and TIMP-1 levels were similar to those of nonembolic tumors. Reverse transcriptase-polymerase chain reaction demonstrated that increased MMP activity was due, at least in part, to increased transcription and that TIMP-2 transcripts increased in embolic myxomas. In vitro, embolic tumor cells retained higher MT1-MMP and pro-MMP-2 levels in basal conditions and after stimulation with interleukin-1beta and interleukin-6. Increased MMP synthesis and release correlated with enhanced ECM degradation products containing glycosaminoglycan chains in embolic myxoma tissue. Our results strongly suggest that MMP overexpression may contribute to an excessive degradation of tumor ECM and increase the risk of embolism in cardiac myxomas.
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PMID:Increased expression and activity of matrix metalloproteinases characterize embolic cardiac myxomas. 1592 Jan 47

Extracellular matrix (ECM) turnover is regulated by matrix metalloproteinases (MMPs) and plays an important role in cardiac remodeling. Previous studies from our lab demonstrated an increase in gelatinolytic-MMP-2 and -9 activities in endocardial tissue from ischemic cardiomyopathic (ICM) and idiopathic dilated cardiomyopathic (DCM) hearts. The signaling mechanism responsible for the left ventricular (LV) remodeling, however, is unclear. Administration of cardiac specific inhibitor of metalloproteinase (CIMP) prevented the activation of MMP-2 and -9 in ailing to failing myocardium. Activation of MMP-2 and -9 leads to induction of proteinase activated receptor-1 (PAR-1). We hypothesize that the early induction of MMP-9 is a key regulator for modulating intracellular signaling through activation of PAR and various downstream events which are implicated in development of cardiac fibrosis in an extracellular receptor mediated kinase-1 (ERK-1) and focal adhesion kinase (FAK) dependent manner. To test this hypothesis, explanted human heart tissues from ICM and DCM patients were obtained at the time of orthotopic cardiac transplants. Quantitative analysis of MMP-2 and -9 gelatinolytic activities was made by real-time quantitative zymography. Gel phosphorylation staining for PAR-1 showed a significant increase in ICM hearts. Western blot and RT-PCR analysis and in-situ labeling, showed significant increased expression of PAR-1, ERK-1and FAK in ICM and DCM. These observations suggest that the enhanced expression and potentially increased activity of LV myocardial MMP-9 triggers the signal cascade instigating cardiac remodeling. This early mechanism for the initiation of LV remodeling appears to have a role in end-stage human heart failure.
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PMID:Early induction of matrix metalloproteinase-9 transduces signaling in human heart end stage failure. 1620 18

Biventricular dilation and severe cardiac dysfunction are observed during septic shock. However, when endotoxemia and vasoconstrictor-masked hypovolemia work in concert in the pathogenesis of shock, the clinical scenario is more adverse compared to one of the insults acting alone. Matrix metalloproteinases (MMPs) are involved in chronic and acute heart failure by degrading the mechanical scaffold of the heart and several intracellular proteins. Therefore, the roles of MMP-2, MMP-9, MT1-MMP, focal adhesion kinase (FAK), and Paxillin in hearts of early multiple organ failure induced by norfenefrine-masked hypovolemia and endotoxemia were investigated in an ovine model. Experimental groups included (1) norfenefrine-masked hypovolemia plus endotoxemia (NMH+ENDO) (n=6), (2) norfenefrine-masked hypovolemia without endotoxemia (NMH) (n=6), (3) recurrent endotoxemia during normovolemia (ENDO) (n=6), and (4) healthy untreated controls (CON) (n=3). Apoptosis was determined by TUNEL-staining. Gel zymography revealed significantly increased MMP-2 activity in NMH+ENDO compared to ENDO and controls. MMP-9 activity was significantly elevated in all experimental groups. MMP-2 was significantly increased at the protein level, while MMP-9 was unaltered. MT1-MMP was not significantly changed in any group. Increased MMP activities were associated with cardiac deterioration. MMP-2/-9 activity and phosphorylated Paxillin (p-Paxillin) expression correlated positively with cardiomyocyte apoptosis. This study underscores the pivotal roles of MMP in acute cardiac dysfunction during early multiple organ failure in combined vasoconstrictor-masked hypovolemic and endotoxemia shock.
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PMID:Roles of MMP-2/-9 in cardiac dysfunction during early multiple organ failure in an ovine animal model. 1630 6

Cardiac remodeling following myocardial infarction (MI) is a maladaptive process, fundamental to the progression of ischemic heart failure. The extent of remodeling is influenced by mechanical stress, inflammatory response and activation of matrix metalloproteinases (MMPs). This study examined regional association between these parameters in response to acute MI. Coronary ligation was performed in ten sheep. Sonomicrometer transducers measured segmental length in the infarcted, border and non-infarcted region. Regional tissue samples obtained 3 h post MI from six sheep were analysed using RT-PCR, gelatin zymography and Western blot. Six sham-operated sheep served as controls.Region-specific dilation and reduced contraction was associated with corresponding alterations in matrix molecules.IL-6 and MMP-9 mRNA were increased in the infarcted and border regions compared to controls.MMP-2 and TIMP-1 mRNA increased in non-infarcted myocardium and both correlated positively with segmental shortening. IL-6 mRNA levels, in contrast, were negatively associated with segmental shortening. In summary, inflammatory cytokines and MMPs are altered early after MI in a region-specific manner, and these changes correspond to acute regional myocardial dysfunction. Therapies for LV remodeling from the time of reperfusion may benefit from further understanding this portfolio of acute alterations.
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PMID:Regional cardiac dysfunction is associated with specific alterations in inflammatory cytokines and matrix metalloproteinases after acute myocardial infarction in sheep. 1681 25

Myocardial infarction (MI) is the result, in mostly cases, of the destabilization and rupture of atherosclerotic lesions. The destruction of cardiac tissue resulting from myocardial ischemia could further result in heart failure. It has been suggested that plaque instability may be mediated by matrix metalloproteinase (MMP) family. Studies have identified increased MMP-2 and MMP-9 in human platelets, and acute myocardial infarction patients with elevated MMP-2 and MMP-9 levels. However, the alteration of MMP-2 and MMP-9 from post MI left ventricle remodeling to heart failure remains to be clarified. The purpose of this study is to investigate the serum concentrations and activities of MMP-2 and MMP-9 in the developing heart failure from post MI patients. Twenty eight patients with MI without heart failure (Killip FC I) (group A; compensated) and twenty seven MI patients with heart failure (Killip II-III) (group B; decompensated) were collected to evaluate the serum levels and activities of MMP-2 and MMP-9 by ELISA and Zymography, respectively. It was observed that the both serum levels and activities of MMP-9 significantly increased (P < 0.01) in decompensated group compared to compensated group, but there was no significant difference of serum MMP-2 levels and activities between two groups. The highly elevated serum MMP-9 concentration of decompensated patients is not related with inflammatory or localized infarct area of myocardium and the real mechanisms remain to be revealed. We suggest that the increase of MMP-9 levels and activity may be used as a new marker to diagnose the development of heart failure in patients with post MI, and provide the therapeutic implications in the future.
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PMID:Serum MMP-9 activity as a diagnosing marker for the developing heart failure of post MI patients. 1683 Jul 92

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