Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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The myocardial beta-adrenergic receptor (betaAR) system plays a key role in dysfunctional signaling and physiology of the failing heart. Recently we described a murine model of dilated cardiomyopathy (DCM) produced by cardiac-specific expression of a dominant negative form of the CREB transcription factor (CREB(A133) mice). CREB(A133) mice display abnormalities within the betaAR signaling system including loss of inotropic reserve. Rapid desensitization of betaARs is mediated by the betaAR kinase (betaARK1), which is upregulated during heart failure. Inhibition of betaARK1 activity in the heart via expression of a peptide inhibitor (betaARKct) has been shown to enhance myocardial function and to "rescue" several animal models of heart failure. To determine the role of betaAR dysfunction in the progression of DCM in the CREB(A133) mice, we interbred them with mice expressing the betaARKct. Concurrent expression of the betaARKct peptide and CREB(A133) in mouse hearts resulted in the normalization of elevated betaARK1 levels. This biochemical change resulted in partial restoration of isoproterenol-stimulated adenylate cyclase activity as well as improvement in fractional shortening in response to betaAR stimulation. Interestingly, the progression of DCM and premature mortality was not altered. Therefore, the pathogenesis of DCM in CREB(A133) mice does not appear to involve abnormal betaAR signaling as a key element in its pathological progression and accordingly, the restoration of betaAR signaling is not sufficient to prevent the development and progression of all forms of heart failure.
J Mol Cell Cardiol 2002 Jun
PMID:Inhibition of betaARK1 restores impaired biochemical beta-adrenergic receptor responsiveness but does not rescue CREB(A133) induced cardiomyopathy. 1205 54

In 2002, three reports described for the first time mutations in the sarcomeric protein titin associated with dilated cardiomyopathy in humans. Despite different locations (Z-line region, Z-I transitional zone, N2B region, half A band region) all mutations resulted in heart failure. In addition, an N2B mutation was found in zebrafish embryos with ventricular dilatation and cardiac insufficiency. It is concluded that titin mutations have significant functional consequences and need to be studied intensively in the future.
Trends Mol Med 2002 Jul
PMID:Weakness of a giant: mutations of the sarcomeric protein titin. 1211 4

Idiopathic dilated cardiomyopathy (IDC) is a distinct disease of the myocardium, of unknown etiology. The disease can occur acutely, or evolve in a subacute fashion. IDC is often associated with a substantial impairment of ventricular function, which may recover over time. Although spontaneous recovery of LV function occurs in 20%-45% of newly diagnosed patients, the majority of patients do not do well. IDC has an average 5-year mortality of 20%. Abnormalities of energetics, perfusion, and adrenergic control of the myocardium are markers of the status of LV dysfunction. As the heart fails, changes occur in the production and catabolism of high-energy substrates, the efficiency of mitochondrial oxidative processes, the distribution of resting perfusion and coronary vasodilating capacity and the adrenergic receptor density and function. This article reviews the information provided by metabolic and receptor imaging in patients with IDC, and the role the data may play in patient management.
Eur J Nucl Med Mol Imaging 2002 Oct
PMID:Myocardial metabolic and receptor imaging in idiopathic dilated cardiomyopathy. 1227 27

Dilated cardiomyopathy (DCM) is the major indication for heart transplantation. Approximately 30% of all DCM is thought to be inherited, while 70% is sporadic. Mutations in the dystrophin gene have been associated with the uncommon X-linked form of DCM. We hypothesized that missense mutations and other less severe mutations of the dystrophin gene might predispose to the common form of sporadic DCM. To test this hypothesis, 22kb of genomic dystrophin DNA was scanned with DOVAM-S in each of the 22 patients with sporadic DCM, including all 79 coding sequences and splice junctions, as well as six alternative exon 1 dystrophin isoforms (484kb, total). Three putative new mutations (IVS5+1 G>T, K18N, and F3228L) and seven polymorphisms were identified. The splice site mutation IVS5+1 is predicted to cause skipping of exon 5, which is within a region containing an actin binding site. The missense mutations occur at amino acids that display substantial evolutionary conservation. Screening of 236 control individuals failed to identify these three mutations. The three patients with putative mutations had CK-MM (creatine kinase, skeletal muscle) levels greater than 250 units while the 14 patients without mutations for which CK-MM were available had values ranging from 20 to 200. The first comprehensive mutation scanning of the exons and splice junctions of the dystrophin gene in patients with sporadic DCM presents the evidence that point mutations are associated with sporadic DCM without clinical evidence of skeletal myopathy. It may be prudent to measure CK-MM in all patients with dilated cardiomyopathy to identify candidates at high risk for dystrophin mutations.
Mol Genet Metab
PMID:Mutations in the dystrophin gene are associated with sporadic dilated cardiomyopathy. 1235 39

It is widely recognized that immune effector mechanisms contribute to cardiac dysfunction in major cardiac pathologies, such as myocarditis and the consequent dilated cardiomyopathy, Chagas' disease and heart transplant rejection. Of the wealth of immune mechanisms known to affect cardiac function, this review will deal with the adverse effects caused by cytotoxic T lymphocytes (CTL, CD4(+) and CD8(+) T lymphocytes), which participate in a broad range of heart pathologies. The interaction between cytotoxic lymphocytes and their target cells can set off two different effector mechanisms: (1) The perforin/granzymes, and (2) The Fas/FasL. In this review, I will discuss these mechanisms, and present experimental evidence showing that both can adversely affect cardiac myocytes in vitro, in a way that can contribute to a decline in the overall cardiac function.
J Mol Cell Cardiol 2002 Sep
PMID:Cytotoxic lymphocytes and cardiac electrophysiology. 1239 89

Myocarditis and dilated cardiomyopathy (DCM) are common causes of morbidity and mortality in children and adults, most commonly due to infection with coxsackievirus B or adenovirus. Increased expression of the common human coxsackievirus B-adenovirus receptor (CAR) has been reported in patients with DCM. We investigated the CAR gene in patients with acquired or familial myocarditis/DCM for mutations/polymorphisms. Several polymorphisms or intronic substitutions, distant from the intron-exon boundaries, were identified but no mutations. Based upon these data it appears that CAR gene mutations are not a major host determinant in the development of myocarditis and DCM.
Mol Genet Metab 2002 Nov
PMID:Analysis of the coxsackievirus B-adenovirus receptor gene in patients with myocarditis or dilated cardiomyopathy. 1240 75

Myocarditis is the most common cause of heart failure in children. We investigated viral etiology of myocarditis/dilated cardiomyopathy (DCM) in children and correlated molecular findings with pathologic and clinical data. Polymerase chain reaction (PCR) or reverse transcription (RT)-PCR were used to analyze 59 endomyocardial biopsies from 48 consecutive young (<18 yrs) patients (pts) with clinical and histologic diagnosis of myocarditis and DCM, employing primers designed to amplify specific sequences of various DNA and RNA viruses. Nucleic acids were successfully extracted in 41 pts and viral genomes were found in 20 (49%): 12 out of 26 pts (46%) with myocarditis, 6 out of 13 (46%) pts with DCM, and both patients with endocardial fibroelastosis. Enteroviruses were more common in DCM (72%), whereas adenoviruses and enteroviruses shared the same rate (36%) in myocarditis. The mumps virus genome was detected in the two pts with endocardial fibroelastosis. More diffuse inflammatory infiltrates and myocyte damage as well as more impaired left ventricular end diastolic volume and shortening fraction were noted in viral positive cases. PCR positive pts had a worse outcome, resulting in transplantation or death. Three out of 8 pts with viral myocarditis who underwent cardiac transplantation had recurrent PCR-proven graft viral infection. Viral myocarditis/DCM appeared to be a more severe disease than nonviral forms. Enteroviruses were more common in DCM, whereas adenoviruses were as frequent as enteroviruses in myocarditis. Persistence of viral infection was associated with disease deterioration. Viral myocarditis relapsed after transplantation.
Diagn Mol Pathol 2002 Dec
PMID:Molecular diagnosis of myocarditis and dilated cardiomyopathy in children: clinicopathologic features and prognostic implications. 1245 37

Myocardial disorders are major causes of morbidity and mortality, including heart failure, sudden death and the need for heart transplantation. The two most common forms of myocardial disorders, dilated cardiomyopathy and hypertrophic cardiomyopathy are paradigms of left ventricular systolic dysfunction and diastolic dysfunction. The genetics of these disorders are increasingly understood with the sarcomere playing a central role in the development of HCM and the link between sarcomere and sarcolemma being key to the development of DCM. In this review, the genetics of the myocardial diseases will be described.
Expert Rev Mol Diagn 2002 Nov
PMID:Molecular diagnosis of myocardial disease. 1246 55

Idiopathic cardiomyopathy is reviewed from molecular standpoint. About a half of all patients with hypertrophic cardiomyopathy show intra-familial occurrence. In familial hypertrophic cardiomyopathy, nine gene abnormalities have been discovered in the sarcomere, i.e. the genes of beta cardiac myosin heavy chain, cardiac troponin T, alpha-tropomyosin, cardiac myosin binding protein-C, essential or regulatory myosin light chain, cardac troponin I, alpha-cardiac actin, and titin. Sudden death can occur in patients with familial-type hypertrophic cardiomyopathy with abnormalities of the cardiac troponin T or troponin I gene, even if hypertrophy is not marked. Some cases of familial dilated cardiomyopathy show gene abnormalities for cytoskeletal components such as desmin and laminin A/C. Mutations of the delta-sarcoglycan gene have also been discovered in familial or sporadic dilated cardiomyopathy. Mutations in mitochondrial genes have been observed in both hypertrophic and dilated cardiomyopathy. It is postulated that chronic viral myocarditis may sometimes lead to dilated cardiomyopathy, and hepatitis C virus is also thought to be an etiological factor. Immunological abnormalities have also been reported, such as autoantibodies against myosin, beta-receptors, ADP/ATP carrier proteins.
Int J Mol Med 2003 Jan
PMID:Cardiomyopathy: molecular and immunological aspects (review). 1246 10

Heart failure (HF) is a progressive degenerative and malignant syndrome with a large number of aetiologies including coronary artery disease, chronic hypertension, exposure to toxins, bacteria and viruses and in a significant percentage of HF patients, the causal mechanism is unclear. The HF trail of morbidity and mortality is well documented and is characterised by step-like periods of relative symptomatic stability, compensation, separated by decompensatory episodes. The homeostatic response to the decline in cardiac function is diverse and involves most organs. There is an increase in resting rate, intra-cardiac hormone production (catecholamines, aldosterone, etc.) and in particular structural changes occur with increased mass and dilatation (dilated cardiomyopathy, DCM). DCM is associated with decreased cardiac output, contractility and energy efficiency and an increase in pro-arrhythmia and conduction defects. Kass et al. (Circulation 91(9) (1995) 2314) first demonstrated in patients who had undergone a dynamic cardio-myoplasty procedure, that, preventing further dilatation in DCM was beneficial and that the improved cardiovascular status was largely independent of muscle stimulation. We hypothesised that this outcome could be achieved by implanting a fabric cardiac support device around both ventricles to the AV junction. Subsequently, it was shown by us and others (Kass et al., 1995) (Cardiovasc. Res. 44(3) (1999) 549); (Ann. Thorac. Surg. 70(4) (2000) 1275) (in different animal models of DCM) that passive ventricular constraint prevented further dilatation, initiated left ventricular volume reduction and reversed the decline in ejection fraction, mitral valve integrity and left ventricular contractility, when compared with untreated controls. Subsequent European and North American clinical trials in patients with DCM of varying aetiologies have shown equal promise and an absence of device related complications (Circulation 104(12 Suppl. 1) (2001) I270); (Ann. Thorac. Cardiovasc. Surg. 7(5) (2001) 278). The mechanisms behind this improvement have yet to be fully clarified however the support generated by the device upon the right and ventricular freewall would lower wall tension. Not only is passive ventricular constraint a very promising treatment modality for heart failure and DCM it should provide a useful research tool for the study of the role of ventricular dilatation in the progression of heart failure.
Prog Biophys Mol Biol
PMID:Passive ventricular constraint. 1273 79


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