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)

Chagas' disease, caused by the intracellular protozoan parasite Trypanosoma cruzi, is a major cause of heart failure in endemic areas. Antigenic mimicry by T. cruzi antigens sharing epitopes with host macromolecules has been implicated in the pathogenesis which is thought to have a significant autoimmune component. We report herein on the cloning and characterization of a full-length cDNA from a T. cruzi expression library encoding a protein, TcP0, that is homologous to the human 38-kD ribosomal phosphoprotein HuP0. The T. cruzi P0 protein shows a clustering of residues that are evolutionarily conserved in higher eukaryotes. This includes an alanine- and glycine-rich region adjacent to a highly charged COOH terminus. This "hallmark" domain is the basis of the crossreactivity of the highly immunogenic eukaryotic P protein family. We found that T. cruzi-infected individuals have antibodies reacting with host (self) P proteins, as well as with recombinant TcP0. Deletion of the six carboxy-terminal amino acids abolished the reactivity of the T. cruzi infection sera with TcP0. This is similar to the specificity of anti-P autoantibodies described for a subset of patients with systemic lupus erythematosus (SLE) (Elkon, K., E. Bonfa, R. Llovet, W. Danho, H. Weissbach, and N. Brot. 1988. Proc. Natl. Acad. Sci. USA. 85:5186). These results suggest that T. cruzi P proteins may contribute to the development of autoreactive antibodies in Chagas' disease, and that the underlying mechanisms of anti-P autoantibody may be similar in Chagas' and SLE patients. This study represents the first definitive report of the cloning of a full-length T. cruzi antigen that mimics a characterized host homologue in structure, function, and shared antigenicity.
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PMID:Cloning and expression of Trypanosoma cruzi ribosomal protein P0 and epitope analysis of anti-P0 autoantibodies in Chagas' disease patients. 137 23

The ideal sympathomimetic derivative should possess the positive inotropic and relaxing effects of catecholamines whilst remaining free of their side-effects. Theoretically, such properties could be present in beta 1-adrenoceptor partial agonists. Xamoterol (ICI 118,587, Corwin; ISA 43 p. 100) seems to be the most promising beta 1 partial agonist. The aim of the study was to determine if the beneficial effects of Xamoterol were maintained during long term administration. Xamoterol (200 mg twice dialy) was administered to 14 patients with anterior myocardial infarction and moderate heart failure (class II-III NYHA). After 3 months' therapy, left ventricular function improved as indicated by reduction in left ventricular (LV) end-diastolic pressure (23 +/- 5 to 16 +/- 5 mm Hg; P less than 0.0005), LV end-diastolic volume (153 to 140 ml/m2; P less than 0.05) and in LV end-systolic volume especially in 11 patients with a control end-systolic volume less than 100 ml/m2 (- 15 p. 100; P less than 0.05). LV inotropic state was also enhanced as indicated by 21 p. 100 increases in EMax, the maximal LV pressure/volume ratio (P less than 0.02) and 20 p. 100 increases in the ratio end-systolic stress/ end-systolic volume (P less than 0.02). Myocardial oxygen consumption was unchanged, global lactate extraction fraction increased from 20 +/- 18 to 33 +/- 14 p. 100 (P less than 0.05) and LV alanine release was reduced (-1.7 to -0.2 muMol/min; P less than 0.05). The rate of LV pressure fall accelerated from 57 to 52 ms (P less than 0.05) and the mean diastolic wall stress was reduced by 35 p. 100 (P less than 0.05), reflecting the improvement in LV relaxation and diastolic function. Thus, the beneficial effects of Xamoterol were maintained after prolonged therapy particularly in patients with class II-III heart failure; patients in class IV benefited less from this therapy. No tachyphylaxis or side-effects were observed.
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PMID:[Role of adrenergic beta receptor partial agonists in left ventricular failure of ischemic origin. Value of xamoterol (ICI 118,587, Corwin)]. 286 23

Intravenous infusion of L-glutamic acid results in the augmentation of the cardiac output and an improvement of the circulation in patients with postoperative cardiac failure. This effect is not accompanied by increased myocardial oxygen demand. Arterial plasma glutamate level rises 10-fold and arterial-coronary sinus plasma glutamate difference increases fivefold during intravenous L-glutamic acid infusion. This leads to cessation of ammonia release from the myocardium, probably due to augmentation of glutamine synthesis and to an increase in alanine formation coupled with a change from lactate release to lactate uptake by the myocardium. The data obtained suggest that the beneficial effect of L-glutamic acid on depressed cardiac function in postoperative patients is related to changes in myocardial metabolism. Glutamic acid may be useful in treatment of circulatory and metabolic disturbances in cardiac failure.
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PMID:Cardiac metabolism and performance during L-glutamic acid infusion in postoperative cardiac failure. 286 48

The long-term follow-up of 80 heart transplant patients (70 men, 10 women) from January 1982 to July 1985 who had received cyclosporine (CsA) showed a high incidence of mild to severe liver dysfunction. Fifty patients (62.5%) had long-lasting postoperative biological disturbances (alanine amino transferase greater than 2N and/or alkaline phosphatase greater than 1.5N for 3 months or more). Most patients were asymptomatic; eight were icteric, and one had arthralgia. The most common biological feature consisted of isolated elevation of ALAT (27 cases). Assessment of causes led to a definite etiology in 42 patients: 7 cardiac failure, 13 HBsAg-positive liver disease (26%) (chronic persistent hepatitis 8, chronic active hepatitis 2, subacute necrosis 2). Fourteen patients (28%) sustained non-A, non-B (NANB) hepatitis (chronic persistent hepatitis 5, chronic active hepatitis 1, cirrhosis 1), and 7 (14%) sustained a drug-related hepatitis. Liver biopsy and complete virus screening was contributive to the diagnosis in nearly all patients. Additionally, prolonged impairment of liver function tests occurred in 62% of heart transplant recipients, mostly during the first 6 postoperative months. Hepatitis B virus (HBV) and NANB hepatitis accounted for 26% and 28% of the cases of liver dysfunction, respectively; drug-induced hepatitis may have been involved in 14% of the cases. Complete hepatitis virus screening should be performed before heart transplant and in any case of abnormal liver function posttransplantation. HBV vaccination prior to heart transplant is recommended in HBsAg- and HBcAb-negative candidates for heart replacement. Long-term follow-up of these patients is mandatory to assess the severity of these liver dysfunctions.
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PMID:Prevalence and causes of long-lasting hepatic dysfunction after heart transplantation: a series of 80 patients. 329 31

Trypanosoma cruzi, a protozoan parasite, is the etiologic agent of American trypanosomiasis or Chagas' disease. Chagas' disease afflicts more than 24 million individuals in South and Central America producing a debilitating life-long disease. It is the leading cause of heart failure in many Latin American countries. Currently, there is no satisfactory treatment for this parasitic infection. Cruzain (also known as cruzipain, gp 57/51), the major cysteine protease present in T. cruzi, is critical for the development and survival of the parasite within the host cells, making this enzyme a target for potential trypanocidal drugs. Here we report the X-ray crystal structure of cruzain complexed with the potent inhibitor Z-Phe-Ala-fluoromethyl ketone. The structure was determined at 2.35 A (Rcryst = 0.15) by molecular replacement using a modified papain as the search model. The refined structure is compared to papain. Features which distinguish cruzain from papain are discussed since they may aid in the design of specificity inhibitors. Fluorescence microscopy shows that a biotinylated form of the bound inhibitor does not effectively reach host proteases in their lysosomal compartment, but is selectively taken up by the parasite. The inhibitor greatly reduces parasitemia in a cell culture system, without adverse effects to mammalian cells. This biological selectivity can be exploited, in conjunction with unique active site features revealed by the crystal structure, to develop chemotherapy for Chagas' disease.
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PMID:The crystal structure of cruzain: a therapeutic target for Chagas' disease. 770 73

The vasoconstrictor angiotensin II and atrial natriuretic peptide (ANP) are oppositely involved in the development of heart failure, as modeled by myocardial infarction (MI) in rats. MI is a model also characterized by sodium retention despite the elevated plasma ANP levels, showing a desensitization of responses to ANP. S21402 (RB105) {N-[2S,3R-(2-mercaptom-ethyl-1-oxo-3-phenylbutyl) L-alanine]} is a dual inhibitor that inhibits both neutral endopeptidase (Ki = 1.7 +/- 0.3 nM) and angiotensin-converting enzyme (Ki = 4.2 +/- 0.5 nM). Inhibition of neutral endopeptidase protects endogenous ANP, and inhibition of angiotensin-converting enzyme blocks angiotensin II production, whereas inhibition of both peptidases is required to protect endogenous bradykinin (BK). Induction of MI in rats, by ligation of the left coronary artery, increased the base-line plasma ANP, cyclic GMP (cGMP) and renin concentrations, which were related to the degree of MI (moderate and severe MI rats). Urinary excretion of ANP, cGMP and BK was also increased in MI rats and was linked to the infarction size. S21402 (RB105) (25 mg/kg bolus plus 25 mg/kg/hr i.v.) decreased the mean blood pressure and increased natriuresis in MI rats whatever the degree of MI. S21402 (RB105) induced an increase in plasma renin in MI rats despite the elevated base-line levels. S21402 (RB105) did not alter the plasma in ANP in MI rats. However, plasma cGMP was increased by the dual inhibitor, as a function of the infarction severity. Urinary excretion of ANP, cGMP and BK was also increased by S21402 (RB105), proportionally to the infarction size. Whatever the degree of MI, S21402 (RB105) was able to induce natriuresis, characterized by a desensitization of ANP-induced renal responses. Inhibition of both angiotensin-converting enzyme and neutral endopeptidase by potentiating endogenous ANP and BK and blocking angiotensin II production could be an interesting therapeutic approach in heart failure.
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PMID:Inhibition of both angiotensin-converting enzyme and neutral endopeptidase by S21402 (RB105) in rats with experimental myocardial infarction. 876 6

To evaluate the changes in myocardial energy metabolism in the progressively failing myocardium, we measured myocardial level of adenosine triphosphate (ATP) using high-performance liquid chromatography (HPLC), and levels of lactate, alanine and free carnitine using 1H-nuclear magnetic resonance (NMR) spectroscopy in rats injected with adriamycin. The drug was injected intraperitoneally 2.5 mg/kg 6 times over a period of 2 weeks. Measurements were obtained 1 day (1 d), 3 weeks (3 w) and 6 weeks (6 w) after the last injection. No deaths were observed until the end of the 3rd week. The cumulative mortality rate 6 weeks after the last injection was 48%. ATP and free carnitine levels were not significantly changed at 1 d, while myocardial lactate was increased by 33% from the control values (P < 0.05). Lactate levels were reduced significantly, but not progressively, at 3 w (31% of control values) and at 6 w (69% of control values). Similar changes were observed in alanine levels. Free carnitine levels were progressively decreased at 3 w (74% of control values) and at 6 w (57% of control values). Changes in ATP levels paralleled those of free carnitine. Data suggest that a decrease in the myocardial level of free carnitine may be involved in progression of the heart failure induced by adriamycin in rats.
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PMID:Cardiac energy metabolism at several stages of adriamycin-induced heart failure in rats. 887 21

To better characterize the role of skeletal muscle in chronic heart failure we studied energetic charge, metabolites and enzyme activity in the energy production pathway. We selected 15 males with severe chronic heart failure (NYHA class III, stable clinical conditions and in normal nutritional status) and seven controls. Controls and patients were submitted to biopsy of the vastus lateralis muscle in resting and fasting conditions. Hormone profiles were also evaluated. Our results showed near normal ATP, ADP and AMP concentrations, but there were substantially more reductions in glycogen (46 +/- 5 vs 77 +/- 6 mumoles glycosidic units.g-1 fresh tissue) and creatine phosphate (5 +/- 1 vs 13 +/- 1 mumoles.g-1 fresh tissue) in patients than in controls. We also found a reduction in glycolytic activity (pyruvate kinase 1009 +/- 79 vs 1625 +/- 26 nmoles. min-1.mg protein-1), despite normal tricarboxylic acid cycle velocity, an increase in alanine amino-transferase (964 +/- 79 vs 425 +/- 34 nmoles. min-1.mg protein-1) and in aspartate aminotransferase (515 +/- 44 vs 291 +/- 56 nmoles.min-1.mg protein-1). An increase was also observed in total NADH cytochrome c reductase (128 +/- 14 vs 68 +/- 5 nmoles.min-1.mg protein-1), while cytochrome oxidase activity was normal. The cortisol/insulin ratio was slightly elevated (77 +/- 4 vs 32 +/- 12). In conclusion, normonutritive patients with severe heart failure show an imbalance in the energy production/utilization ratio. The impairment is probably due both to a decrease in production and an increase in consumption of energy owing to greater cellular workload and/or a hypercatabolic state.
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PMID:Biochemical analysis of muscle biopsy in overnight fasting patients with severe chronic heart failure. 892 17

Cardiac hypertrophy is an adaptive response that normalizes wall stress and compensates for increased workload. It is accompanied by distinct qualitative and quantitative changes in the expression of protein isoforms concerning contractility, intracellular Ca(2+)-homeostasis and metabolism. Changes in the myosin subunit isoform expression improves contractility by an increase in force generation at a given Ca(2+)-concentration (increased Ca(2+)-sensitivity) and by improving the economy of the chemo-mechanical transduction process per amount of utilised ATP (increased duty ratio). In the human atrium this is achieved by partial replacement of the endogenous fast myosin by the ventricular slow-type heavy and light chains. In the hypertrophic human ventricle the slow-type beta-myosin heavy chains remain unchanged, but the ectopic expression of the atrial myosin essential light chain (ALC1) partially replaces the endogenous ventricular isoform (VLC1). The ventricular contractile apparatus with myosin containing ALC1 is characterised by faster cross-bridge kinetics, a higher Ca(2+)-sensitivity of force generation and an increased duty ratio. The mechanism for cross-bridge modulation relies on the extended Ala-Pro-rich N-terminus of the essential light chains of which the first eleven residues interact with the C-terminus of actin. A change in charge in this region between ALC1 and VLC1 explains their functional difference. The intracellular Ca(2+)-handling may be impaired in heart failure, resulting in either higher or lower cytosolic Ca(2+)-levels. Thus the state of the cardiomyocyte determines whether this hypertrophic adaptation remains beneficial or becomes detrimental during failure. Also discussed are the effects on contractility of long-term changes in isoform expression of other sarcomeric proteins. Positive and negative modulation of contractility by short-term phosphorylation reactions at multiple sites in the myosin regulatory light chain, troponin-I, troponin-T, alpha-tropomyosin and myosin binding protein-C are considered in detail.
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PMID:Modulation of contractility in human cardiac hypertrophy by myosin essential light chain isoforms. 961 95

Numerous studies have implicated Coxsackievirus in acute and chronic heart failure. Although enteroviral nucleic acids have been detected in selected patients with dilated cardiomyopathy, the significance of such persistent nucleic acids is unknown. To investigate the mechanisms by which restricted viral replication with low level expression of Coxsackieviral proteins may be able to induce cardiomyopathy, we generated transgenic mice which express a replication-restricted full-length Coxsackievirus B3 (CVB3) cDNA mutant (CVB3DeltaVP0) in the heart driven by the cardiac myocyte-specific myosin light chain-2v (MLC-2v) promoter. CVB3DeltaVP0 was generated by mutating infectious CVB3 cDNA at the VP4/VP2 autocatalytic cleavage site from Asn-Ser to Lys-Ala. Cardiac-specific expression of this cDNA leads to synthesis of positive- and negative-strand viral RNA in the heart without formation of infectious viral progeny. Histopathologic analysis of transgenic hearts revealed typical morphologic features of myocardial interstitial fibrosis and in some cases degeneration of myocytes, thus resembling dilated cardiomyopathy in humans. There was also an increase in ventricular atrial natriuretic factor mRNA levels, demonstrating activation of the embryonic program of gene expression typical of ventricular hypertrophy and failure. Echocardiographic analysis demonstrated the presence of left ventricular dilation and decreased systolic function in the transgenic mice compared with wild-type littermates, evidenced by increased ventricular end-diastolic and end-systolic dimensions and decreased fractional shortening. Analysis of isolated myocytes from transgenic mice demonstrate that there is defective excitation-contraction coupling and a decrease in the magnitude of isolated cell shortening. These data demonstrate that restricted replication of enteroviral genomes in the heart can induce dilated cardiomyopathy with excitation-contraction coupling abnormalities similar to pressure overload models of dilated cardiomyopathy.
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PMID:Transgenic expression of replication-restricted enteroviral genomes in heart muscle induces defective excitation-contraction coupling and dilated cardiomyopathy. 976 37


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