Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The identification of genetic loci involved in most forms of congenital heart disease has been hampered by the complex inheritance patterns of these disorders. Atrioventricular canal defects (AVCDs) are most commonly associated with Down syndrome, although non-syndromic cases also occur. Non-syndromic AVCDs have been attributed to multifactorial inheritance. However, the occurrence of a few kindreds with multiple affected individuals has suggested that a major genetic locus can account for the disorder in some families. We have used a combination of DNA pooling and shared segment analysis to perform a high density screen of the entire autosomal human genome in an extended kindred. In so doing, we have identified a genetic locus on chromosome 1 shared by all affected individuals. Our data demonstrate the existence of a congenital heart defect susceptibility gene, inherited as an autosomal dominant with incomplete penetrance, involved in AVCD. Furthermore, our data demonstrate the power of using key isolated kindreds in combination with high density genomic screens to identify loci involved in complex disorders such as congenital heart defects.
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PMID:Identification of a complex congenital heart defect susceptibility locus by using DNA pooling and shared segment analysis. 900 79

To identify diabetes mellitus caused by the mitochondrial gene substitution at genomic nucleotide pair 3243 (M3243A-->G) we selected 87 diabetic patients with high risk factors such as maternal inheritance and hearing loss. Total DNA was extracted from peripheral leukocytes, and mitochondrial DNA fragments containing M3243A-->G were amplified by polymerase chain reaction (PCR). The amplified fragments were digested with a restriction endonuclease Apa1 and analyzed by agarose gel electrophoresis. The incidence of the M3243A-->G mutation was 4.6% (four of 87) in diabetic patients with maternal inheritance and/or hearing loss. In a subgroup with both maternal inheritance and hearing loss, the incidence of the mutation was as high as 21.4% (three of 14). Cardiac disorders were also present in all four diabetic patients with the mutation. This study suggests that maternal inheritance and hearing loss are useful clinical findings to identify diabetic patients with the mutation, and that cardiac involvement is a high risk factor for the M3243A-->G mutation.
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PMID:High prevalence of mitochondrial diabetes mellitus in Japanese patients with major risk factors. 922 33

Apoptosis is a potentially important myocardial response to pathology including ischemia and reperfusion. Na-H exchange (NHE) represents an important mechanism for mediating such injury. The present study was done to determine if NHE inhibition can affect early apoptosis in an acute model of ischemia and reperfusion. Isolated rat hearts were subjected to zero-flow ischemia for various durations with or without subsequent 30 min of reperfusion. Nick-end-labelling of biotin-dUTP (TUNEL staining), as well as DNA extraction followed by agarose gel electrophoresis, were used to semiquantify apoptotic cells and identify DNA laddering, respectively. Apoptosis first appeared after 10 min of ischemia and reached a maximum level after 30 min. The number of apoptotic cells after 30 min of ischemia was 31 +/- 3 per 100 high power microscopic fields, whereas in reperfused hearts the number of cells was 34 +/- 3. To determine the effect of NHE inhibition, hearts were pretreated 15 min prior to ischemia with HOE 642, a potent and specific inhibitor of the isoform (NHE-1) found in myocardium. HOE 642 significantly reduced the number of apoptotic cells in the ischemic and reperfused heart to 2 +/- 1 and 6 +/- 1, respectively (P<0.05 from untreated hearts). DNA laddering was not observed with electrophoretic DNA analysis, likely owing to the small number of apoptotic cells involved. Hearts recovered nearly 100% of function in both groups, although there was a significantly higher recovery after 1 and 2 min of reperfusion in those hearts treated with HOE 642. Our study shows that apoptosis, albeit very mild in nature, can be rapidly induced in isolated hearts by a relatively brief period of ischemia without reperfusion, which can be markedly attenuated by the NHE inhibitor HOE 642. The ability of HOE 642 to markedly attenuate apoptosis may be important in terms of understanding the drug's cardioprotective properties as well as the overall role of NHE in heart disease.
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PMID:A rapid ischemia-induced apoptosis in isolated rat hearts and its attenuation by the sodium-hydrogen exchange inhibitor HOE 642 (cariporide). 940 90

Gender-specific differences in heart disease have long been known but it has only been since the advent of molecular biology that it has become possible to investigate the molecular mechanisms. Most biochemical work in the last 50 years has focused on the characterization of the steroid hormones involved in gender specificity. More recently, the cloning of the steroid receptors and characterization of the signaling pathways through these proteins has given new insights into the mechanisms underlying the mode of action of steroid hormones. It has also become clear that the steroid receptors can be classified into families (receptors for thyroid hormone, glucocorticoids, estrogens, androgens, retinoic acid, and so called orphan receptors of mostly unknown function). The structures of these receptors show very close resemblance and all are DNA-binding proteins acting as transcription factors. Some (if not all) act as repressors of transcription of some genes in the native state and are converted to activators (or perhaps repressors of other genes) upon binding of the cognate hormone. Naturally, classical target tissues for estrogens and androgens have been studied first and only in very recent years has it been recognized that estrogens and androgens act on a much wider spectrum of tissues. In the cardiovascular field, the beneficial effect of estrogen replacement therapy in postmenopausal women which reduces the incidence of cardiovascular disease by some 40% and the lower incidence of cardiovascular disease in premenopausal women have mostly been explained by the beneficial action of estrogens on the lipid profile (increase in HDL and decrease in LDL cholesterol). Recently, functional estrogen receptors have also been shown in vascular smooth muscle cells and in the endothelium. Our own group has characterized the presence of estrogen receptors in the myocardium and in cardiac fibroblasts. We have also shown that these receptors are transcriptionally active because they are able to drive a minigene composed of a triple estrogen responsive DNA regulatory element (promoter) coupled to the firefly luciferase gene which serves as a reporter by way of its ability to drive a light-emitting reaction. We are in the process of characterizing the target genes for estrogen in the myocardium. A specific series of immediate-early genes is induced by estradiol (the major premenopausal estrogen) and we have also characterized a number of tissue-specific genes whose expression is driven by estrogens in the myocardium. The ultimate goal of these investigations is to explore the use of estrogens in the treatment of cardiac hypertrophy (and failure) by way of their properties to counteract (at least some of) the pathological switches in gene expression in these disease entities.
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PMID:Modulation of cardiac hypertrophy by estrogens. 943 14

Resveratrol, a natural phytoalexin found in grapes, is well known for its presumed role in the prevention of heart disease, associated with red wine consumption. We show here that it is a remarkable inhibitor of ribonucleotide reductase and DNA synthesis in mammalian cells, which might have further applications as an antiproliferative or a cancer chemopreventive agent in humans.
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PMID:Resveratrol, a remarkable inhibitor of ribonucleotide reductase. 946 22

Long QT syndrome (LQTS), is an inherited cardiac disorder in which ventricular tachyarrhythmias predispose affected individuals to syncope, seizures, and sudden death. Characteristic electrocardiographic findings include a prolonged QT interval, T wave alternans, and notched T waves. We have screened LQTS patients from 89 families for mutations in the pore region of HERG , the K+ channel gene previously associated with chromosome 7-linked LQT2. In six unrelated LQTS kindreds, single-strand conformation polymorphism analyses identified aberrant conformers in all affected family members. These conformers were not seen in over 100 unaffected, unrelated control individuals, suggesting that they represent pathogenic LQTS mutations. DNA sequence analyses of the aberrant conformers demonstrated that they reflect five different missense mutations: V612L, A614V, N629D, N629S, and N633S. The missense mutation A614V was found in two unrelated families. Further functional studies will be required to determine what effect each of these changes may have on HERG channel function.
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PMID:Multiple different missense mutations in the pore region of HERG in patients with long QT syndrome. 954 37

During the last decade there were extensive investigations in clinical and molecular andrology with emphasis on assisted reproduction, micromanipulation techniques of gametes, sperm/egg interaction, male contraception, diabetes mellitus, varicocele, andropause versus menopause, sexual dysfunction, associated hypertension/stress, prostatic carcinoma and molecular parameters of male reproduction. Sperm hyperactivation is a required step in capacitation sequence. Sperm motility is measured by videotape to evaluate the Straight Line Velocity (microm/s) (VSLI). Fertilization/embryonic development results from single sperm transfer (S-MIST) and multiple sperm transfer. Fertilization/embryo development is achieved by injection of immotile sperm into the perivitelline space. To assess sperm viability, a supravital stain suitable for use in combination with immunofluorescent assay, Hoeschst 33258, is used. The dye fluoresces with an intense blue when bound to DNA. To assess sperm plasma membrane integrity, a hypo-osmotic swelling test (HOST) is performed, using fluoresceinated D-mannose enriched albumin (FITC-DMA). The ability of sperm to swell under hypo-osmotic conditions indicates an intact membrane. A human protein, C-peptide, thought to be a useless byproduct of insulin may protect against devastating heart and nerve damage that diabetes causes. Human diabetics may benefit from the substance. Over 15 million Americans have diabetes, in which blood sugar levels rise out of control. There are two types of diabetics: Type I diabetics produce no insulin, the hormone that regulates blood sugar. Type II diabetics are unable to use their insulin properly. Diabetics are at great risk of heart disease and nerve damage, as arteries throughout the body leak and nerve-cell impulses fail. C-peptide is a byproduct of insulin production; it can be produced by the body or synthetically. Production of this protein is not induced by insulin, so diabetics who take insulin do not get C-peptide with it. Varicocele occurs unilaterally on the left side in 78% to 93% of men. Typically the presence of a varicocele is associated with an abnormal semen analysis (sperm density and morphology) and a decreased testicular volume on the affected side. Impaired sperm motility occurs in 89.5% of all varicocele patients. Varicocele ligation improves semen parameters in two thirds of patients. A few studies on andropause included sexual dysfunction, hormonal changes, medical/psychological correlates of impotence, ostenopenia/osteoporosis and bone loss; indices of bone remodeling, testosterone supplementation, androgen, negative feedback and hypothalamo-pituitary-testicular axis. Prostatic cancer is the second leading cause of cancer death for men between the ages of 60 and 80. Early detection involves a simple blood test for prostate specific antigen (PSA). Regular screening and early detection are essential. This is an important test because a high antigen count can be the only symptom. Since no screening is 100% accurate, physicians recommend both a PSA blood test and a physical examination. Although heredity plays a major role in whether a man will develop prostate cancer, men who lead healthy lives can dramatically reduce their chances of cancer: low-fat diet, eating plenty of fruits and vegetables and not smoking. Recent advances in molecular andrology include peptide hormone binding proteins; gonadotropin-releasing hormone (GnRH) agonists/antagonists analog; gonadotropins/their receptors; growth factors/reproduction; peptides as intratesticular regulators; molecular cloning of reproductive proteins/peptides. Gene cloning is applied for characterization/expression of genes coding. The interaction of gp120 with CD4 receptor plays a role in syncytium formation, apoptosis and CD4 cell deletion in human immunodeficiency virus (HIV) infection. The recombinant V3 peptide of fragment 307-330 of HIV-1 can induce sperm head agglutination. The generation process of react
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PMID:Recent advances in clinical/molecular andrology. 958 57

In the report of the 1995 WHO/ISFC task force on the definition and classification of cardiomyopathies a new entity within the dilated cardiomyopathies was introduced as "inflammatory cardiomyopathy". It is defined as myocarditis associated with cardiac dysfunction. Idiopathic, autoimmune and infectious forms of inflammatory cardiomyopathy are now recognized through this definition. Dilated cardiomyopathy with inflammation (DCMi, chronic myocarditis) was also defined by a recent ISFC task force as > 14 lymphocytes/macrophages/mm3. Enteroviruses, adenoviruses and cytomegaloviruses are considered as main etiopathogenetic factors in the pathogenesis of inflammatory heart disease and have been demonstrated as important trigger for inflammatory cardiac disease. They may also cause dilated cardiomyopathy by viral persistence or secondary immunopathogenesis due to antigenic or molecular mimicry. For the detection of viral persistence the investigation of endomyocardial biopsies in patients with cardiomyopathy by the use of polymerase chain reaction and southern blot analysis is an important step for the standardization of diagnostic criteria on virally induced inflammatory cardiomyopathy. Present studies indicate an incidence of cytomegalovirus-DNA in patients with inflammatory cardiomyopathy in 10%, adenoviral-DNA in 17% and borreliosis only in rare cases (< 1%). In dilated cardiomyopathy without inflammation the respective incidences were for cytomegalovirus 12%, 15% for adenovirus and only 0.5% of cases for borreliosis. In addition the results of immunohistochemical analysis and molecular biological investigations of endomyocardial biopsies may have implications for future therapeutic studies. Depending on the etiology of the disease, immunosuppression may have benefit for patients with virus-negative cardiomyopathy with inflammation in contrast to patients with cytomegalo-, adenovirus-DNA or enteroviral persistence, in whom immunomodulation with hyperimmunoglobulins or immunoglobulins may be a feasible therapeutic option. Patients with a positive PCR for Borrelia burgdorferi should be treated with 3rd generation cephalosporines and/or sublactam.
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PMID:[Cardiotropic DNA viruses and bacteria in the pathogenesis of dilated cardiomyopathy with or without inflammation]. 959 31

Idiopathic ventricular tachycardia is a generic term that describes the various forms of ventricular arrhythmias that occur in patients without structural heart disease and in the absence of the long QT syndrome. Many of these tachycardias are focal in origin, localize to the right ventricular outflow tract (RVOT), terminate in response to beta blockers, verapamil, vagal maneuvers, and adenosine, and are thought to result from cAMP-mediated triggered activity. DNA was prepared from biopsy samples obtained from myocardial tissue from a patient with adenosine-insensitive idiopathic ventricular tachycardia arising from the RVOT. Genomic sequences of the inhibitory G protein Galphai2 were determined after amplification by PCR and subcloning. A point mutation (F200L) in the GTP binding domain of the inhibitory G protein Galphai2 was identified in a biopsy sample from the arrhythmogenic focus. This mutation was shown to increase intracellular cAMP concentration and inhibit suppression of cAMP by adenosine. No mutations were detected in Galphai2 sequences from myocardial tissue sampled from regions remote from the origin of tachycardia, or from peripheral lymphocytes. These findings suggest that somatic cell mutations in the cAMP-dependent signal transduction pathway occurring during myocardial development may be responsible for some forms of idiopathic ventricular tachycardia.
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PMID:Right ventricular outflow tract tachycardia due to a somatic cell mutation in G protein subunitalphai2. 963 20

Mutations in the gene encoding the homeobox transcription factor NKX2-5 were found to cause nonsyndromic, human congenital heart disease. A dominant disease locus associated with cardiac malformations and atrioventricular conduction abnormalities was mapped to chromosome 5q35, where NKX2-5, a Drosophila tinman homolog, is located. Three different NKX2-5 mutations were identified. Two are predicted to impair binding of NKX2-5 to target DNA, resulting in haploinsufficiency, and a third potentially augments target-DNA binding. These data indicate that NKX2-5 is important for regulation of septation during cardiac morphogenesis and for maturation and maintenance of atrioventricular node function throughout life.
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PMID:Congenital heart disease caused by mutations in the transcription factor NKX2-5. 967 15


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