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)

A Japanese kindred with dominantly inherited amyloid polyneuropathy, commonly called familial amyloid polyneuropathy (FAP), has been identified. Amyloid protein was transthyretin (TTR) related and the patients were heterozygous for the mutant gene encoding TTR with a single amino acid substitution of cysteine for tyrosine at position 114. This family originated in Nagasaki Prefecture, Japan, and 12 of the 36 known members of six generations have been affected. The initial symptoms occurred in their thirties with the cardinal features of polyneuropathy, vitreous opacities and cardiac disease. Sensory neuropathy was severe in the lower limbs. Autonomic disturbances, especially postural hypotension, were the most debilitating to the patients. Amyloid deposits were detected widely in most organs except for the central nervous system. The duration from the onset of the disease to death was within 10 yrs. Heart failure caused by heavy amyloid deposits was the most common cause of sudden death.
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PMID:Familial amyloid polyneuropathy associated with the transthyretin Cys114 gene in a Japanese kindred. 133 Feb 2

The effects of emestrin (EMS), a secondary metabolite of the Emericella species, on male ICR mice were examined. The intraperitoneal LD50 values of EMS were 17.7 and 13.0 mg/kg at 24 and 48 hr, respectively. The target organs of EMS were the heart, liver and thymus. In doses over 30 mg/kg the experimental animals died from cardiac failure shortly after the injections. Several survivors that were given EMS in doses under 20 mg/kg showed severe centrilobular necrosis in the liver at 24 hr. Marked degeneration of mitochondria was seen in electron micrographs of both cardiac muscle cells and hepatocytes. In the degenerated hepatocytes, prominent proliferation of RER, membrane-limited inclusions containing both ribosome-like granules and RER, and fenestrated lamella-like structures were observed. Massive necrosis of lymphocytes was always observed in the cortical layer of the thymus of the survivors within 24 hr, while bilateral adrenalectomized mice showed no discernible pathomorphological changes in the lymphoid tissues. Pretreatment of mice with diethyl maleate increased the incidence and severity of hepatic necrosis, whereas that with either cysteine or CoCl2 reduced the severity of centrilobular necrosis of the liver. Pretreatment with phenobarbital had no significant effect on EMS-induced hepatic lesions.
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PMID:Experimental acute poisoning in mice induced by emestrin, a new mycotoxin isolated from Emericella species. 229 35

Prolonged administration of nitroglycerin and its derivatives results in pharmacodynamic tolerance: although the dosage of these drugs is kept at the same level, their therapeutic effects decrease in amplitude. Experimental and clinical studies have shown that this escape phenomenon is due to depletion of cysteine in the vascular wall. This amino acid, which gives off SH radicals, is indispensable to the ultimate transformation of nitroglycerin enabling in to exert its vasodilator action. Molsidomine does not require any transformation to act on the vascular smooth muscle and should therefore remain insensitive to tolerance. The experimental and clinical data available at present seem to confirm that the effects of molsidomine administered for long periods in the treatment of coronary disease and heart failure are sustained. However, for the long-term effectiveness of molsidomine and nitrites to be compared objectively a prospective double-blind randomized trial would be needed, with both treatments being in optimal doses and intervals of administration.
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PMID:[Comparative course of maintenance of the effects of nitrite derivatives and molsidomine after prolonged administration]. 296 4

Nitrate tolerance is a clinical problem in patients with coronary artery disease and heart failure. Human internal mammary arteries and saphenous veins obtained intraoperatively were suspended in organ chambers, and isometric tension was measured. In the artery, nitroglycerin elicited a potent relaxation, which was significantly diminished after prolonged incubation with nitroglycerin (10(-6) M, 1 h). In contrast, no tolerance occurred in saphenous vein under the same conditions. However, incubation with 10(-5) M nitroglycerin also developed tolerance. Compared to nitroglycerin, the new cysteine-containing mononitrate SPM 5185 exhibited a lower sensitivity but comparable maximal relaxation in arteries and veins. In nitroglycerin-tolerant arteries and veins, SPM 5185 caused relaxations similar to those under control conditions. Our results show that in isolated blood vessels, vascular nitrate tolerance occurs more readily in the mammary artery than in the saphenous vein. SPM 5185 seems to be less prone to the development of tolerance, which may be advantageous during chronic nitrate therapy.
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PMID:Development of nitrate tolerance in human arteries and veins: comparison of nitroglycerin and SPM 5185. 858 81

Latent matrix metalloproteinases (MMPs) in normal myocardium are activated in end-stage heart failure. In vitro oxidized glutathione (GSSG) activates myocardial MMPs which contains a cysteine residue. In vivo GSSG induce the collagen lysis and cardiac dilatation. To assess whether thiol and non-thiol reducing agents have direct effect on the interstitial human heart fibroblast (HHF) proliferation and MMP expression, HHF and polyoma virus transformed fibroblast cells were cultured with or without the thiol-containing reduced (GSH) or oxidized (GSSG) glutathiones, pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC), and non-thiol ascorbic acid. After 100 micrograms/ml (approximately 0.3 mM) GSH or PDTC treatment the proliferative (synthetic) phenotype of transformed fibroblast cells was changed to quiescent (contractile) phenotype. Also, after GSH, PDTC, and ascorbic acid treatment the medium was then analyzed for MMP activity by zymography. The results indicate reduction in MMP expression in transformed fibroblast cells after GSH and PDTC treatments and no effect after ascorbic acid treatment. Based on reverse zymography, we observed the level of tissue inhibitor of metalloproteinase (TIMP) at a decreased level in transformed cells. The effect of the reducing agent at the gene transcription was measured by estimating mRNA (Northern blot analysis) of MMP and of TIMP in the cells that were cultured in medium in the presence and absence of GSH. These results indicate that GSH induces MMP-2 and MMP-1 expression in normal HHF and that GSH reduces MMP-2 and MMP-1 in transformed fibroblast cells. After the treatment, the TIMP-2 level was repressed in normal HHF and TIMP-2 level increased in transformed fibroblast cells. These events are dependent on the nuclear transcription factor activity on the collagenase promoter in normal HHF cells. On the other hand, in polyoma transform fibroblast cells these events are not dependent on this collagenase promoter. These results suggest that oxidative environment induces normal HHF cell proliferation, and the reducing agent decreases normal HHF cell proliferation by inducing MMP and repressing TIMP gene transcription. In transformed cells reducing agents inhibit MMP expression and increase TIMP levels, which suggests a role of antioxidants in preventing tumorigenesis.
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PMID:Reduction-oxidation (redox) state regulation of extracellular matrix metalloproteinases and tissue inhibitors in cardiac normal and transformed fibroblast cells. 872 63

Since mammalian cardiac myocytes essentially rely on aerobic energy metabolism, it has been assumed that cardiocytes die in a catastrophic breakdown of cellular homeostasis (i.e. necrosis), if oxygen supply remains below a critical limit. Recent observations, however, indicate that a process of gene-directed cellular suicide (i.e. apoptosis) is activated in terminally differentiated cardiocytes of the adult mammalian heart by ischemia and reperfusion, and by cardiac overload as well. Apoptosis or programmed cell death is an actively regulated process of cellular self destruction, which requires energy and de novo gene expression, and which is directed by an inborn genetic program. The final result of this program is the fragmentation of nuclear DNA into typical 'nucleosomal ladders', while the functional integrity of the cell membrane and of other cellular organelles is still maintained. The critical step in this regulated apoptotic DNA fragmentation is the proteolytic inactivation of poly-[ADP-ribose]-polymerase (PARP) by a group of cysteine proteases with some structural homologies to interleukin-1 beta-converting enzyme (ICE-related proteases [IRPs] such as apopain, yama and others). PARP catalyzes the ADP-ribosylation of nuclear proteins at the sites of spontaneous DNA strand breaks and thereby facilitates the repair of this DNA damage. IRP-mediated destruction of PARP, the 'supervisor of the genome', can be induced by activation of membrane receptors (e.g. FAS or APOI) and other signals, and is inhibited by activation of 'anti-death genes' (e.g. bcl-2). Overload-triggered myocyte apoptosis appears to contribute to the transition to cardiac failure, which can be prevented by therapeutic hemodynamic unloading. In myocardial ischemia, the activation of the apoptotic program in cardiocytes does not exclude their final destiny to catastrophic necrosis with release of cytosolic enzymes, but might be considered as an adaptive process in hypoperfused ventricular zones, sacrificing some jeopardized myocytes to regulated apoptosis, which may be less arrhythmogenic than necrosis with the primary disturbance of membrane function.
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PMID:Apoptosis in the heart: when and why? 897 66

A case of neonatal Marfan syndrome is presented. The patient was noted to have cardiomegaly and tricuspid regurgitation on antenatal ultrasound scan. She was born with long, slender fingers and toes, an aged appearance and non-paralytic hypotonia. Echocardiogram revealed a dilated right atrium, right ventricle, dysplastic tricuspid valve and severe tricuspid regurgitation. She subsequently died of severe heart failure. Post-mortem examination showed the pathological features of lobar emphysema and cystic medial necrosis of the aorta. These features supported the diagnosis of neonatal Marfan syndrome. Nucleotide sequencing showed substitution of G by A at codon 1032 in exon 25 located in the long arm of chromosome 15. This resulted in the substitution of a cysteine by a tyrosine. A de novo mutation is suggested by the absence of affected family members.
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PMID:Neonatal Marfan syndrome: a case report. 1040 62

The incidence of heart failure in the population increases steeply among older people. Overactivation of the sympathetic nervous system is associated to and responsible for worsening of heart failure. This study describes the influence of aging on short-term left ventricular (LV) adaptation to b-adrenergic stimulation in Wistar rats. In controls at 18 mo, interstitial fibrosis was increased with respect to 3-mo-old rats, whereas myocytes dimension and the messenger RNA (mRNA) abundance of atrial natriuretic peptide (ANP), a2(I) procollagen, transforming growth factor (TGF-b1, TGF-b3), and secreted protein, acidic and rich in cysteine (SPARC) were not different. To determine how aging affects LV adaptation to adrenergic stimulation, two groups of animals received isoproterenol (ISO, 1 mg/kg/d) for 3 days. There was no significant difference between young and older rats with respect to increase in LV weight, myocytes dimension, and mRNA abundance of all the genes considered, except a1(III) procollagen. These findings indicate that despite limited compensatory hypertrophy and higher fibrosis, LV from aged nonsenescent rats preserves the capacity to adapt to b-adrenergic stimulation through the upregulation of several genes encoding extracellular matrix-related proteins.
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PMID:Left ventricular response to beta-adrenergic stimulation in aging rats. 1071 61

Dilated cardiomyopathy is a frequent cause of heart failure and is associated with high mortality. Progressive remodeling of the myocardium leads to increased dimensions of heart chambers. The role of intracellular proteolysis in the progressive remodeling that underlies dilated cardiomyopathy has not received much attention yet. Here, we report that the lysosomal cysteine peptidase cathepsin L (CTSL) is critical for cardiac morphology and function. One-year-old CTSL-deficient mice show significant ventricular and atrial enlargement that is associated with a comparatively small increase in relative heart weight. Interstitial fibrosis and pleomorphic nuclei were found in the myocardium of the knockout mice. By electron microscopy, CTSL-deficient cardiomyocytes contained multiple large and apparently fused lysosomes characterized by storage of electron-dense heterogeneous material. Accordingly, the assessment of left ventricular function by echocardiography revealed severely impaired myocardial contraction in the CTSL-deficient mice. In addition, echocardiographic and electrocardiographic findings to some degree point to left ventricular hypertrophy that most likely represents an adaptive response to cardiac impairment. The histomorphological and functional alterations of CTSL-deficient hearts result in valve insufficiencies. Furthermore, abnormal heart rhythms, like supraventricular tachycardia, ventricular extrasystoles, and first-degree atrioventricular block, were detected in the CTSL-deficient mice.
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PMID:Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L. 1197 68

The balance of reactive oxygen species (ROS) and nitric oxide, the cell redox state, appears to be important in the mechanisms of heart failure. This balance has significant impact on calcium-handling proteins, affecting excitation-contraction coupling. Both ROS and nitric oxide appear to be elevated in heart failure and are accompanied by significant impairments in the number and function of calcium-handling proteins. These proteins contain sulfhydryl groups or disulfide linkages involving cysteine residues, making them susceptible to the action of oxidizing-reducing agents and nitrosylation, thereby altering their properties. Initial increases in nitric oxide may be an adaptive response to myocardial dysfunction, elevated cytokines, and increases in ROS, while a further increase in nitric oxide and overwhelming ROS can be damaging. Abundant nitric oxide and ROS can cause formation of peroxynitrite, a strong oxidant, or nitric oxide can activate alternate pathways aiding the ROS, causing impaired calcium handling contributing to contractile dysfunction.
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PMID:Heart failure, oxidative stress, and ion channel modulation. 1204 83


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