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)

The BIO14.6 hamster is a widely used model for autosomal recessive cardiomyopathy. These animals die prematurely from progressive myocardial necrosis and heart failure. The primary genetic defect leading to the cardiomyopathy is still unknown. Recently, a genetic linkage map localized the cardiomyopathy locus on hamster chromosome 9qa2.1-b1, excluding several candidate genes. We now demonstrate that the cardiomyopathy results from a mutation in the delta-sarcoglycan gene that maps to the disease locus. This mutation was completely coincident with the disease in backcross and F2 pedigrees. This constitutes the first animal model identified for human sarcoglycan disorders.
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PMID:Identification of the Syrian hamster cardiomyopathy gene. 909 66

Cardiomyopathic (CM) hamsters have a disruption in the delta-sarcoglycan gene which leads to progressive cardiac necrosis by 30 to 40 days of age, hypertrophy by 120 days, and heart failure by 250 days. We used differential display to detect other changes in mRNA levels in 30-, 60-, and 90-day-old wild-type and CM hamsters. We identified a 400-bp cDNA with sequence similarity to the human alpha-interferon-inducible protein (p27). This cDNA annealed with a 570-base mRNA whose steady-state levels were increased in 30-, 60-, and 90-day-old CM compared to wild-type heart. Increased expression of this hamster homolog of p27 (p27-h) was detected in CM hamster cardiac and skeletal muscle at 60 days of age but not in liver, kidney, or brain. Thus, an inherited defect in CM hamsters leads to increased expression of p27-h in advance of the development of hypertrophy and heart failure.
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PMID:Increased expression of the gene for alpha-interferon-inducible protein in cardiomyopathic hamster heart. 1062 82

Animal models of cardiomyopathy have been used in many studies for our understanding of the pathophysiology of this disease. Syrian hamster, BIO 14.6, one of the most widely used models of cardiomyopathy, was reported to be caused by large deletion in the exon 1 and the promoter region of the delta-sarcoglycan gene. Cardiac hypertrophy or heart failure has been induced in dogs, rabbits, rats and many other animals by various manipulations such as drugs, pressure and/or volume overload and chronic rapid pacing. Recently, transgenic or knockout mice were examined to investigate the pathogenesis and development of the disease. It is important to select appropriate models for the aim of the studies.
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PMID:[Animal models of cardiomyopathy]. 1088 20

Enteroviral infection can cause an acquired form of dilated cardiomyopathy. We recently reported that dystrophin is cleaved, functionally impaired, and morphologically disrupted in vitro as well as in vivo during infection with coxsackievirus B3. Genetic dystrophin truncations lead to a marked decrease in dystrophin-associated glycoproteins, whereas expression of only the naturally occurring dystrophin carboxyl terminus, Dp-71, restores the sarcolemmal association of the dystrophin-associated glycoproteins. We sought to determine whether acute cleavage of dystrophin leads to a dissociation of the carboxyl-terminal dystrophin fragment and of the sarcoglycans from the sarcolemma during coxsackievirus B3 infection. We found that in cultured cardiac myocytes and murine hearts infected with coxsackievirus B3, the sarcolemmal localization of the dystrophin carboxyl terminus is lost. The dystrophin-associated glycoproteins alpha-, beta-, gamma-, and delta-sarcoglycan and beta-dystroglycan were markedly decreased in the membrane fraction of infected cells in culture, and the typical sarcolemmal localization for each of these proteins was lost in coxsackievirus-B3-infected cardiomyocytes in vivo. Furthermore, sucrose gradient ultracentrifugation demonstrated that delta-sarcoglycan was physically dissociated from dystrophin within the membrane fraction. In vivo, the sarcolemmal integrity was functionally impaired with Evans blue dye uptake even though there was no generalized disruption of the sarcolemma of infected myocytes evidenced by intact wheat germ agglutinin staining. In analogy to hereditary sarcoglycanopathies, this disintegration of the sarcoglycan complex may, in addition to the dystrophin cleavage, play an important role in the pathogenesis of enterovirus-induced cardiomyopathy. These results imply a potential role for disruption of the sarcoglycans in an acquired form of heart failure.
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PMID:Dissociation of sarcoglycans and the dystrophin carboxyl terminus from the sarcolemma in enteroviral cardiomyopathy. 1098 41

Sarcolemma integrity is stabilized by the dystrophin-associated glycoprotein complex that connects actin and laminin-2 in contractile machinery and the extracellular matrix, respectively. Interruption of the connection by the primary gene defect or acquired pathological burden can cause cardiac failure. The purposes of the present study were to verify whether dystrophin is disrupted in acute myocardial injury after the isoproterenol overload (10 mg/kg) and to examine its relation to myocardial cell apoptosis in rats. This injury from 4-16 h at the subendocardium was accompanied by dystrophin disruption and dislocation from subsarcolemma to cytoplasm, which were confirmed by immunohistology and Western blotting. However, delta-sarcoglycan was thoroughly preserved in sarcolemma. The dystrophin degradation preceded the appearance of apoptotic cells and exactly coincided with the transferase-mediated dUTP-biotin nick end labeling-positive cardiomyocytes (TUNEL), as was verified by double-staining. These data suggest that beta-adrenergic stimulation induces dystrophin breakdown followed by apoptosis.
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PMID:Dystrophin disruption might be related to myocardial cell apoptosis caused by isoproterenol. 1120 16

Heart failure is a major health problem and is associated with a high mortality and morbidity. Recently, the role of the genetic background in the onset and development of the disease has been evidenced in both heart failure with and without systolic dysfunction, and in familial and non-familial forms of this condition. Familial forms of dilated cardiomyopathy are more frequent than previously thought. Various modes of inheritance and phenotypes have been reported and this condition appears genetically highly heterogenous. Five genes (dystrophin, cardiac actin, desmin, lamin A/C and delta-sarcoglycan), and additional loci, have been identified in families in which dilated cardiomyopathy is isolated or associated with other cardiac or non-cardiac symptoms. It has been postulated that the molecular defect involved could lead to abnormal interactions between cytoskeletal proteins, responsible either for defect in force transmission or for membrane disruption. More recently, the identification of mutations in genes encoding sarcomeric proteins has led to a second hypothesis in which the disease might also result from a force generation defect. In non-monogenic dilated cardiomyopathy, susceptibility genes (role in the development of the disease) and modifier genes (role in the evolution/prognosis of the disease) have so far been identified. Some data suggest that the efficacy of angiotensin converting enzyme inhibitors, and side-effects, might be related to some genetic polymorphisms, such as the I/D polymorphism of the angiotensin converting enzyme gene. Although preliminary, these data are promising and might be the first step towards application of phamacogenetics in heart failure. This is of paramount importance as the medical treatment of heart failure is characterized by the need for polypharmacy. One of the major challenges of the next millenium, therefore, will be to identify genetic factors which might help define responders to major treatment classes, including angiotensin converting enzyme inhibitors, beta-adrenoreceptor antagonists, angiotensin AT1 receptor antagonists, spironolactone, vasopeptidase inhibitors and endothelin receptor antagonists.
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PMID:Are we ready for pharmacogenomics in heart failure? 1130 Oct 53

TO-2 strain hamsters with dilated cardiomyopathy, gene deletion of delta-sarcoglycan (SG) and no expression of alpha-, beta-, gamma-, and delta-SG proteins are useful for developing the potential gene therapy of intractable heart failure. We prepared recombinant adeno-associated virus vector including normal delta-SG gene driven by CMV promoter and intramurally administered in vivo. The transfected myocardium induced robust expression of both transcript and transgene for 2/3 period of the animal's life expectancy. Immunostaining demonstrated reexpression of not only delta-SG but also other three SGs in 40% cells in the transfected region and normalization of the diameter of transduced cardiomyocytes. Hemodynamic study revealed preferential amelioration of the diastolic indices (LVEDP, the dP/dt(min) and CVP). These results provide the first evidence that supplementation of a specific gene with efficient and sustained transfection capability restores the genetic, morphological, and functional deteriorations.
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PMID:Morphological and physiological restorations of hereditary form of dilated cardiomyopathy by somatic gene therapy. 1139 97

Dilated cardiomyopathy is one of the leading causes of heart failure and a primary cause for heart transplantation in patients below the age of 40 years. Despite major advances in diagnostic procedures such as examination of myocardial biopsies, the etiology remains unknown in many patients. Chronic inflammation or myocarditis and chronic alcohol abuse are considered two main etiologic factors in dilated cardiomyopathy. A third causal factor, namely genetic transmission of the disease, is at least as common as myocardial inflammation or toxic damage. Several prospective studies of relatives of patients with dilated cardiomyopathy proved that about 25-30% of all cases are of familial etiology. The most common mode of inheritance is autosomal dominant. Less frequently is the disease inherited as an X-chromosomal trait. Autosomal recessive and mitochondrial transmission is rare. The penetrance is highly variable and age dependent. Many relatives of patients with DCM show only minor cardiac abnormalities and it is unknown whether they progress to full cardiomyopathy in later life. Examination of families has identified so far eight disease genes, namely the dystrophin, tafazzin, cardiac actin, desmin, lamin A/C, delta- sarcoglycan, cardiac beta-myosin heavy chain, and cardiac troponin T gene. Certain mutations in lamin A/C cause conduction system disease and dilated cardiomyopathy, whereas other mutations cause in addition skeletal muscle myopathy. Dystrophin mutations are the cause of the rare X-linked dilated cardiomyopathy without skeletal muscle involvement and a progressive course in young men. Other mutations in the dystrophin gene, mainly deletions, are the cause of the muscular dystrophy Becker and Duchenne which also present with dilated cardiomyopathy. Mutations of the desmin, delta-sarcoglycan, the cardiac actin and beta-myosin heavy chain as well as the troponin T gene are known to cause autosomal dominant-dilated cardiomyopathy without other abnormalities. The infantile X-linked DCM is caused by mutations of the tafazzin gene. The onset of the disease is typically within the first year of life and death occurs usually in childhood. Most patients may in addition be characterized by skeletal myopathy, short stature, neutropenia and abnormal mitochondria, also referred to as Barth syndrome. Knowledge of the DCM disease genes led to the new hypothesis that dilated cardiomyopathy is a disease of the myocardial force generation or force transmission. Many more disease loci are known but the responsible disease genes are not yet identified. Better understanding of the expression and function of disease genes may eventually result in new diagnostic and therapeutic tools in order to improve the prognosis of this severe disorder.
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PMID:[Genetics of dilated cardiomyopathy]. 1151 75

The hereditary form comprises approximately 1/5 of patients with dilated cardiomyopathy (DCM) and is a major cause of advanced heart failure. Medical and socioeconomic settings require novel treatments other than cardiac transplantation. TO-2 strain hamsters with congenital DCM show similar clinical and genetic backgrounds to human cases that have defects in the delta-sarcoglycan (delta-SG) gene. To examine the long-term in vivo supplement of normal delta-SG gene driven by cytomegalovirus promoter, we analyzed the pathophysiologic effects of the transgene expression in TO-2 hearts by using recombinant adeno-associated virus vector. The transgene preserved sarcolemmal permeability detected in situ by mutual exclusivity between cardiomyocytes taking up intravenously administered Evans blue dye and expressing the delta-SG transgene throughout life. The persistent amelioration of sarcolemmal integrity improved wall thickness and the calcification score postmortem. Furthermore, in vivo myocardial contractility and hemodynamics, measured by echocardiography and cardiac catheterization, respectively, were normalized, especially in the diastolic performance. Most importantly, the survival period of the TO-2 hamsters was prolonged after the delta-SG gene transduction, and the animals remained active, exceeding the life expectancy of animals without transduction of the responsible gene. These results provide the first evidence that somatic gene therapy is promising for human DCM treatment, if the rAAV vector can be justified for clinical use.
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PMID:Rescue of hereditary form of dilated cardiomyopathy by rAAV-mediated somatic gene therapy: amelioration of morphological findings, sarcolemmal permeability, cardiac performances, and the prognosis of TO-2 hamsters. 1180 34

The hereditary form of dilated cardiomyopathy (DCM) accounts for about 20% of human DCM and is a major cause of heart failure. TO-2 strain hamsters show DCM, a gene deletion of delta-sarcoglycan (SG), loss of all four SGs, alpha-, beta-, gamma- and delta-SG proteins, and are useful for developing gene therapy of the hereditary DCM. The delta-SG is a component of dystrophin-associated glycoprotein complex that stabilizes sarcolemma. Four familial and sporadic DCM cases have been reported in human patients with the same delta-SG gene mutation. To establish the potential gene therapy of DCM, efficient and long-lasting transduction of the responsible gene is mandatory, especially for improving the functional defect. Recombinant adeno-associated virus (rAAV) vector with delta-SG gene was intramurally transfected to the TO-2 hearts at 5-weeks-old. The transfected myocardium revealed robust expression of both transcript and transgene after 10 and 20 weeks. Immunohistological analyses demonstrated re-expression of not only delta-SG but also the other three SGs and normalization of the diameter of transduced cardiomyocytes without the pathogenicity. Hemodynamic studies revealed preferential amelioration of the diastolic indices. It suggests a novel strategy for the treatment of DCM and the rAAV vector is available for the treatment of several human diseases because of its safety and efficacy.
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PMID:[Somatic gene therapy of dilated cardiomyopathy]. 1186 55


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