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)

Apoptosis of cardiomyocytes has been proposed as a factor contributing to severe heart failure. Since the trigger for apoptotic cellular suicide in nonischemic myocardium is unknown, we analyzed in human myocardial tissue the expression of the apoptosis-inducing membrane receptor Fas/APO-1 and of its alternatively spliced soluble isoforms which antagonize Fas by binding of the Fas ligand. Using reverse transcription polymerase chain reaction (RT-PCR) we found mRNA for Fas and 5 isoforms in nonfailing left ventricles, whereas Fas and only one isoform (FasExo6Del) were detectable in failing left ventricles. Standard calibrated, competitive RT-PCR revealed no significant increase of Fas mRNA in failing compared to nonfailing ventricles. However, the mRNA for FasExo6Del, expressed nearly on the same level as Fas in nonfailing ventricles, was decreased about 3-fold in failing ventricles. We propose that this altered expression of the Fas system renders the myocardium more susceptible for Fas-mediated apoptosis in end-stage heart failure.
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PMID:Alternative splicing of the primary Fas transcript generating soluble Fas antagonists is suppressed in the failing human ventricular myocardium. 936 48

A young woman committed suicide by ingesting benzine. We report the findings obtained at autopsy and the chemical analyses of the gastric contents, blood, and tissues in this case. Fatal concentrations of n-hexane, benzene, toluene and m-, p-xylene were detected. Pulmonary edema and hemorrhage were caused by the primary effect of the chemicals or secondarily by respiratory depression, suffocation due to volatile fluid, or heart failure. Mild hemorrhage around arterioles and venules in the brain cortex suggest hyperpermeability of the vessels. The fragmentation and waviness of the cardiac myofibrils indicate the presence of hypercontraction and possibly arrhythmia.
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PMID:A fatal case of oral ingestion of benzine. 1020 45

Cell suicide is a normal process that participates in a wide variety of physiological processes, including tissue homeostasis, immune regulation, and fertility. Physiological cell death typically occurs by apoptosis, as opposed to necrosis. Defects in apoptotic cell-death regulation contribute to many diseases, including disorders associated with cell accumulation (e.g. cancer, autoimmunity, inflammation and restenosis) or where cell loss occurs (e.g. stroke, heart failure, neurodegeneration, AIDS and osteoporosis). At the center of the apoptosis machinery is a family of intracellular proteases, known as 'caspases', that are responsible directly or indirectly for the morphological and biochemical events that characterize apoptosis. Multiple positive and negative regulators of these cell-death proteases have been discovered in the genomes of mammals, amphibians, insects, nematodes, and other animal species, as well as a variety of animal viruses. Inputs from signal-transduction pathways into the core of the cell-death machinery have also been identified, demonstrating ways of linking environmental stimuli to cell-death responses or cell-survival maintenance. Knowledge of the molecular mechanisms of apoptosis has provided important insights into the causes of multiple diseases where aberrant cell-death regulation occurs and has revealed new approaches for identifying small-molecule drugs for more effectively treating these illnesses.
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PMID:Drug discovery opportunities from apoptosis research. 1110 94

Apoptosis is the process by which cells are induced to activate their own suicide. Programmed cell death occurs in a wide variety of cell types, including cardiovascular tissues. There is increasing evidence of a relationship between apoptosis and cardiovascular disease, particularly ischemic heart disease and congestive heart failure, the most frequent heart diseases in the older population. Research directed to the treatment and possible prevention of apoptosis may provide a means of decreasing the incidence of cardiac failure and increasing the survival of endothelial and smooth muscle cells in the elderly. (c) 2000 by CVRR, Inc.
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PMID:Apoptosis in Cardiovascular Aging Research: Future Directions. 1141 77

Cardiovascular disease is a leading cause of death worldwide. In recent years it has emerged that loss of myocardial cells may be a major pathogenic factor. Cell death can occur in a destructive, uncontrolled manner via necrosis or by a highly regulated programmed cell suicide mechanism termed apoptosis. As cell death in conditions such as heart failure and myocardial infarction does not always follow a typically apoptotic pathway, it remains to be established whether it occurs by apoptosis, necrosis, or a novel uncharacterized mechanism combining aspects of both types of cell death. Apoptotic pathways have been well studied in nonmyocytes and it is thought that similar pathways exist in cardiomyocytes. These pathways include death initiated by ligation of membrane-bound death receptors or death initiated by release of cytochrome c from mitochondria. Increasing evidence supports the existence of these pathways and their regulators in the heart. These regulators include inhibitors of caspases, which are the key enzymes of apoptosis, the Bcl-2 family of proteins, growth factors, stress proteins, calcium, and oxidants. It is hoped that a better understanding of the pathways of apoptosis and their regulation may yield novel therapeutic targets for cardiovascular disease.
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PMID:Losing heart: the role of apoptosis in heart disease--a novel therapeutic target? 1181 61

The nonviral gene transfer technologies include naked DNA administration, electrical or particle-mediated transfer of naked DNA, and administration of DNA-synthetic macromolecule complex vectors. Each method has its advantage, such as low immunogenicity, inexpensiveness, ease in handling, etc., but the common disadvantage is that the transfection efficiency has been relatively poor as far as conventional plasmid vectors are involved. To improve the nonviral gene transfer systems, Epstein-Barr virus (EBV)-based plasmid vectors (also referred to EBV-based episomal vectors) have been employed. These vectors contain the EBNA1 gene and oriP element that enable high transfer efficiency, strong transgene expression and long term maintenance of the expression. In the current article, I review recent preclinical gene therapy studies with the EBV plasmid vectors conducted against various diseases. For gene therapy against malignancies, drastic tumor suppression was achieved by gancyclovir administrations following an intratumoral injection with an EBV plasmid vector encoding the HSV1-TK suicide gene. Equiping the plasmid with carcinoembryonic antigen (CEA) promoter sequences enabled targeted killing of CEA-positive tumor cells, which was not accomplished by conventional plasmid vectors without the EBV genetic elements. Transfection with an apoptosis-inducing gene was also effective in inhibiting tumors. Interleukin (IL)-12 and IL-18 gene transfer, either local or systemic, induced therapeutic antitumoral immune responses including augmentation of the cytotoxic T lymphocyte (CTL) and natural killer (NK) activities, while an autologous tumor vaccine engineered to secrete Th1 cytokines via the EBV system also induced growth retardation of tumors. Non-EBV conventional plasmids were much less effective in eliciting these therapeutic outcomes. Intracardiomuscular transfer of the beta-adrenergic receptor gene induced a significant elevation in cardiac output in cardiomyopathic animals, suggesting the usefulness of the EBV system in treating heart failure. The EBV-based nonviral delivery also worked as genetic vaccine that triggered prophylactic cellular and humoral immunity against acute lethal viral infection. All the nonviral delivery vehicles so far tested showed an improved transfection rate when combined with the EBV-plasmids. Collectively, the EBV-based plasmid vectors may greatly contribute to nonviral gene therapy against a variety of disorders, including malignant, congenital, chronic and infectious diseases.
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PMID:Improvement of nonviral gene therapy by Epstein-Barr virus (EBV)-based plasmid vectors. 1218 22

The report presents the case of an alleged double homicide or a homicide followed by suicide of a couple, in which the court-ordered autopsy of both victims revealed that the homicide had been committed by the husband immediately before he died himself from cardiac failure. The article gives a short summary of the pathophysiological relations between emotional tension (stress) and physical strain and the effects on the cardiovascular system. The case report describes a homicide by strangulation immediately followed by the perpetuator's death from a natural cause.
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PMID:[An unusual case of double death]. 1272 57

Mortality in anorexic patients is mainly due to suicide or cardiac failure. The aim of this study was to investigate structural and functional cardiovascular alterations further by means of echocardiography in a sample of 15 medication-free patients with DSM-IV anorexia nervosa (AN) (BMI < 17.5 kg/m2) and without any known cardiovascular disease and/or a family history of deafness or sudden death, and correlate the findings with clinical variables. The controls consisted of a sample of 10 constitutionally thin women (BMI < 19 kg/m2), of comparable age, height and degree of physical activity. All of the subjects underwent Doppler echocardiography (ECHO), and the patients were also administered the Diagnostic Schedule for Eating Disorders (DSED) in order to assess the features and course of the eating disorder. ECHO revealed silent pericardial effusion in 71.4% of the patients vs. 10% of the controls (p < 0.05); among the patients, the separation of pericardial leaflets was more frequent in those with a shorter duration of illness (p < 0.05). Mitral valve motion abnormalities were more frequent among the patients than the controls (69.2% vs. 10%, p < 0.005), and the left ventricular mass/body surface area was lower (54.8% vs. 59%, p < 0.001). Isovolumetric relaxation time was longer in the patients (98.4 vs. 65 msec, p < 0.01), but there were no significant differences in left ventricular ejection fraction (53.8% vs. 59%) or early diastolic deceleration time (146 vs. 155 msec). The results of this study support the association between AN and demonstrable anatomic and functional cardiac abnormalities, such as a reduced ventricular mass and mitral valve abnormalities. The ECHO findings provide evidence for clinically silent pericardial effusion in AN, which may be an early sign of cardiovascular involvement.
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PMID:Silent pericardial effusion in a sample of anorexic patients. 1276 27

A 78-year-old woman committed double suicide with a bolus injection of 1 g of lidocaine hydrochloride. The tissue distribution of lidocaine in this fatal poisoning was investigated using an improved gas chromatographic method. The blood level was 42 microg/ml and the brain concentration was 70 miccro/g. Thus, the cause of death in this case was clearly diagnosed as lidocaine overdosing. The blood level of 42 microg/ml was higher than that calculated using the standard pharmacokinetic parameters. Lower blood/tissue ratios were also detected compared with the data described in the literature. These results indicated that the cardiac failure should have occurred immediately after the lidocaine injection. The present data show the distribution of lidocaine after acute death due to overdosing.
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PMID:The tissue distribution of lidocaine in acute death due to overdosing. 1293 51

Apoptosis, the major form of cellular suicide, is central to various physiological processes and the maintenance of homeostasis in multicellular organisms. Presumably, even more important is a causative or contributing role of apoptosis to various human diseases. These include situations with unwanted cell accumulation (cancer) and failure to eradicate aberrant cells (autoimmune diseases) or disorders with an inappropriate loss of cells (heart failure, stroke, AIDS, neurodegenerative diseases, and liver injury). The past decade has witnessed a tremendous progress in the knowledge of the molecular mechanisms that regulate apoptosis and the mediators that either prevent or trigger cell death. Consequently, apoptosis regulators have emerged as key targets for the design of therapeutic strategies aimed at modulating cellular life-and-death decisions. Numerous novel approaches are currently being followed employing gene therapy and antisense strategies, recombinant biologics, or classical organic and combinatorial chemistry to target specific apoptotic regulators. Convincing proof-of-principle evidence obtained in several animal models confirms the validity of strategies targeting apoptosis and revealed an enormous potential for therapeutic intervention in a variety of illnesses. Although numerous apoptotic drugs are currently being developed, several therapeutics have progressed to clinical testing or are already approved and marketed. Here we review the recent progress of apoptosis-based therapies and survey some highlights in a very promising field of drug development.
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PMID:New approaches and therapeutics targeting apoptosis in disease. 1591 67


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