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)

In humans, cytoskeletal dystrophin and muscle LIM protein (MLP) gene mutations can cause dilated cardiomyopathy, yet these mutations may have different effects in mice, owing to increased accumulation of other, compensatory cytoskeletal proteins. Consequently, we characterized left-ventricular (LV) morphology and function in vivo using high-resolution cine-magnetic resonance imaging (MRI) in 2- to 3-month old dystrophin-deficient (mdx) and MLP-null mice, and their respective controls. LV passive stiffness was assessed in isolated, perfused hearts, and cytoskeletal protein levels were determined using Western blot analyses. In mdx mouse hearts, LV-to-body weight ratio, cavity volume, ejection fraction, stroke volume, and cardiac output were normal. However, MLP-null mouse hearts had 1.2-fold higher LV-to-body weight ratios (P<0.01), 1.5-fold higher end-diastolic volumes (P<0.01), and decreased ejection fraction compared with controls (25% vs. 66%, respectively, P<0.01), indicating dilated cardiomyopathy and heart failure. In both models, isolated, perfused heart end-diastolic pressure-volume relationships and passive left-ventricular stiffness were normal. Hearts from both models accumulated desmin and beta-tubulin, mdx mouse hearts accumulated utrophin and MLP, and MLP-null mouse hearts accumulated dystrophin and syncoilin. Although the increase in MLP and utrophin in the mdx mouse heart was able to compensate for the loss of dystrophin, accumulation of desmin, syncoilin and dystrophin were unable to compensate for the loss of MLP, resulting in heart failure.
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PMID:Dystrophin- and MLP-deficient mouse hearts: marked differences in morphology and function, but similar accumulation of cytoskeletal proteins. 1549 47

We describe the case of a 17-year-old boy with Becker's muscular dystrophy (BMD) presenting with rapid progression from hypertrophic cardiomyopathy to heart failure within 2 years. Initial echocardiogram showed severe hypertrophy of left ventricle (LV) and right ventricle (RV) with normal chamber size, and preserved LV systolic function. Microscopic study of cardiac muscle obtained by endomyocardial biopsy of the interventricular septum showed severe hypertrophy of the muscle fibers and interstitial fibrosis. Follow-up echocardiogram 2 years after the first examination exhibited marked dilated LV and RV with severe LV global hypokinesia. Follow-up endomyocardial biopsy demonstrated increased interstitial cellular matrix. Immunohistochemical staining for dystrophin revealed significant loss of dystrophin along the sarcoplasmic membrane of the right biceps brachii muscle, compatible with BMD.
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PMID:Rapid progression from hypertrophic cardiomyopathy to heart failure in a patient with Becker's muscular dystrophy. 1592 12

The precise mechanism(s) of the progression of advanced heart failure (HF) should be determined to establish strategies for its treatment or prevention. Based on pathological, molecular, and physiological findings in 3 animal models and human cases, we propose a novel scheme that a vicious cycle formed by increased sarcolemma (SL) permeability, preferential activation of calpain over calpastatin, and translocation and cleavage of dystrophin (Dys) commonly lead to advanced HF. The aim of this article was to assess our recent paradigm that disruption of myocardial Dys is a final common pathway to advanced HF, irrespective of its hereditary or acquired origin, but not intended to provide a comprehensive overview of the various factors that may be involved in the course of HF in different clinical settings. In addition, each component of Dys-associated proteins (DAP) was heterogeneously degraded in vivo and in vitro, i.e. Dys and alpha-sarcoglycan (SG) were markedly destroyed using isolated calpain 2, while delta-SG was not degraded at all. The up-regulation of calpain 2 was confirmed through previously published data that remain insufficient for precise evaluation, supporting our new scheme that the activation of calpain(s) is involved in the steady process of Dys cleavage. In addition, somatic gene therapy is discussed as a potential option to ameliorate the physiological/metabolic indices and to improve the prognosis.
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PMID:A novel paradigm for therapeutic basis of advanced heart failure--assessment by gene therapy. 1596 50

Dystrophin deficiency causes Duchenne muscular dystrophy (DMD) in humans, an inherited and progressive disease of striated muscle deterioration that frequently involves pronounced cardiomyopathy. Heart failure is the second leading cause of fatalities in DMD. Progress towards defining the molecular basis of disease in DMD has mostly come from studies on skeletal muscle, with comparatively little attention directed to cardiac muscle. The pathophysiological mechanisms involved in cardiac myocytes may differ significantly from skeletal myofibres; this is underscored by the presence of significant cardiac disease in patients with truncated or reduced levels of dystrophin but without skeletal muscle disease. Here we show that intact, isolated dystrophin-deficient cardiac myocytes have reduced compliance and increased susceptibility to stretch-mediated calcium overload, leading to cell contracture and death, and that application of the membrane sealant poloxamer 188 corrects these defects in vitro. In vivo administration of poloxamer 188 to dystrophic mice instantly improved ventricular geometry and blocked the development of acute cardiac failure during a dobutamine-mediated stress protocol. Once issues relating to optimal dosing and long-term effects of poloxamer 188 in humans have been resolved, chemical-based membrane sealants could represent a new therapeutic approach for preventing or reversing the progression of cardiomyopathy and heart failure in muscular dystrophy.
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PMID:Dystrophic heart failure blocked by membrane sealant poloxamer. 1610 27

The precise mechanism of the progression of advanced heart failure is unknown. We assessed a new scheme in two heart failure models: (I) congenital dilated cardiomyopathy (DCM) in TO-2 strain hamsters lacking delta-sarcoglycan (SG) gene and (II) administration of a high-dose of isoproterenol, as an acute heart failure in normal rats. In TO-2 hamsters, we followed the time course of the histological, physiological and metabolic the progressions of heart failure to the end stage. Dystrophin localization detected by immunostaining age-dependently to the myoplasm and the in situ sarcolemma fragility evaluated by Evans blue entry was increased in the same cardiomyocytes. Western blotting revealed a limited cleavage of the dystrophin protein at the rod domain, strongly suggesting a contribution of endogenous protease(s). We found a remarkable up-regulation of the amount of calpain-1 and -2, and no change of their counterpart, calpastatin. After supplementing TO-2 hearts with the normal delta-SG gene in vivo, these pathological alterations and the animals' survival improved. Furthermore, dystrophin but not delta-SG was disrupted by a high dose of isoproterenol, translocated from the sarcolemma to the myoplasm and fragmented. These results of heart failure, irrespective of the hereditary or acquired origin, indicate a vicious cycle formed by the increased sarcolemma permeability, preferential activation of calpain over calpastatin, and translocation and cleavage of dystrophin would commonly lead to advanced heart failure.
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PMID:A novel scheme of dystrophin disruption for the progression of advanced heart failure. 1605 19

Dilated cardiomyopathy (DCM) is the most frequent form of primary myocardial diseases and the third most common cause of heart failure. Clinically, DCM is characterized by a progressive course of ventricular dilatation and systolic dysfunction. The life expectancy is limited and varies according to the underlying etiology with a median survival time of about 5 years after diagnosis. Myocarditis, immunologic abnormalities, toxic myocardial damage, and genetic factors are all assumed to be causes. Familial occurrence of DCM, mostly as an autosomal dominant trait, is more common than generally believed and is responsible for 20-30% of all cases of DCM. Candidate gene screening and linkage analyses in large families were successful in identifying 24 disease genes. There is a wide variability in the onset, course and severity of the disease even within the same family. In addition, genotype-phenotype correlations included only small numbers of affected. This implies that in most cases no conclusion can be drawn from the clinical manifestation of DCM to the responsible disease gene. Mutations in the beta-myosin heavy chain and in cardiac troponin T are common causes of pure familial DCM. DCM associated with conduction disease is mainly due to mutations in lamin A/C and X-linked DCM is often caused by mutations in dystrophin. All other disease genes are rare causes of familial DCM. Genetic screening in all known disease genes is not possible, but more efficient screening methods are awaited in the near future. Until then, clinical examination of family members and, in case of familial DCM, genetic counseling are recommended in the work-up of patients with idiopathic DCM.
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PMID:[Familial dilated cardiomyopathy]. 1617 Jun 84

We examined the effects of trandolapril and candesartan on changes in the levels of sarcoglycans and dystrophin in the right ventricle of rats with the left coronary artery ligation. Hemodynamic and morphological alterations suggested the development of hypertrophy of the right ventricle and chronic heart failure by the 8th week. By the end of the 8th week, alpha- and beta-sarcoglycans and dystrophin were decreased. Increases in mu- and m-calpains in the hypertrophied right ventricle were associated with an elevation of casein-proteolytic activity in the cytosolic fraction. Oral administration of 3 mg/kg/day trandolapril or 1 mg/kg/day candesartan from the 2nd to 8th week after the left coronary artery ligation attenuated decreases in alpha-sarcoglycan and dystrophin and reduced the increased proteolytic activity. The results suggest that attenuation of decreases in sarcoglycans and dystrophin is a possible mechanism underlying trandolapril- and candesartan-mediated improvement of structural and functional alterations of the right ventricle in the coronary artery-ligated rat.
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PMID:Effects of angiotensin I-converting enzyme inhibitor and angiotensin II type 1 receptor blocker on the right ventricular sarcoglycans and dystrophin after left coronary artery ligation. 1618 85

In addition to functional alterations, heart failure has a structural basis as well. This concerns all components of the cardiac myocytes as well as the extracellular space. Proteins of the cardiomyocyte can be subdivided in 5 different categories: 1) Contractile proteins including myosin, actin, tropomyosin and the troponins. 2) Sarcomeric skeleton: titin, myosin binding protein C, alpha-actinin, myomesin, and M-protein. 3) True 'cytoskeletal' proteins: tubulin, desmin and actin. 4) Membrane-associated proteins: dystrophin, spectrin, talin, vinculin, ankyrin and others. 5) Proteins of the intercalated disc: desmosomes consisting of desmoplakin, desmocollin, desmoglein and desmin; adherens junctions with N-cadherin, the catenins and vinculin, and gap junctions with connexin. Failing myocardium obtained from patients undergoing cardiac transplantation exhibits ultrastuctural degeneration and an altered nucleus/cytoplasm relationship. The contractile proteins and those of the sarcomeric skeleton, especially titin, are downregulated, the cytoskeletal proteins desmin and tubulin and membrane-associated proteins such as vinculin and dystrophin are upregulated and those of the intercalated disc are irregularly arranged. Elevation of cytoskeletal proteins correlates well with diastolic and contractile dysfunction in these patients. The enlarged interstitial space contains fibrosis, i.e. accumulations of fibroblasts and extracellular matrix components, in addition to macrophages and microvascular elements. Loss of the contractile machinery and related proteins such as titin and alpha-actinin may be the first and decisive event initiating an adaptive increase in cytoskeleton and membrane associated components. Fibrosis may be stimulated by subcellular degeneration. The hypothesis is put forward that all proteins of the different myocardial compartments contribute to the deterioration of cardiac function in heart failure.
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PMID:The cytoskeleton and related proteins in the human failing heart. 1622 10

Cardiomyopathies are responsible for a high proportion of cases of congestive heart failure and sudden death, as well as for the need for transplantation. Understanding of the causes of these disorders has been sought in earnest over the past decade. We hypothesized that DCM is a disease of the cytoskeleton/sarcolemma, which affects the sarcomere. Evaluation of the sarcolemma in DCM and other forms of systolic heart failure demonstrates membrane disruption; and, secondarily, the extracellular matrix architecture is also affected. Disruption of the links from the sarcolemma to ECM at the dystrophin C-terminus and those to the sarcomere and nucleus via N-terminal dystrophin interactions could lead to a "domino effect" disruption of systolic function and development of arrhythmias. We also have suggested that dystrophin mutations play a role in idiopathic DCM in males. The T-cap/MLP/alpha-actinin/titin complex appears to stabilize Z-disc function via mechanical stretch sensing. Loss of elasticity results in the primary defect in the endogenous cardiac muscle stretch sensor machinery. The over-stretching of individual myocytes leads to activation of cell death pathways, at a time when stretch-regulated survival cues are diminished due to defective stretch sensing, leading to progression of heart failure. Genetic DCM and the acquired disorder viral myocarditis have the same clinical features including heart failure, arrhythmias, and conduction block, and also similar mechanisms of disease based on the proteins targeted. In dilated cardiomyopathy, the process of progressive ventricular dilation and changes of the shape of the ventricle to a more spherical shape, associated with changes in ventricular function and/or hypertrophy, occurs without known initiating disturbance. In those cases in which resolution of cardiac dysfunction does not occur, chronic DCM results. It has been unclear what the underlying etiology of this long-term sequela could be, but viral persistence and autoimmunity have been widely speculated.
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PMID:Inflammatory cardiomyopathy: there is a specific matrix destruction in the course of the disease. 1632 65

Mutation of cytoskeletal protein genes results in abnormal protein function and causes cardiomyopathy. We hypothesised that cardiac levels of cytoskeletal proteins, such as dystrophin, desmin and muscle LIM protein (MLP), would be altered during remodelling caused by myocardial infarction (MI). We measured left-ventricular morphology, function and cytoskeletal protein levels 10 weeks after coronary artery ligation or sham operation in male Wistar rats. Two-dimensional echocardiography revealed significant impairment of systolic function and decreased ejection fraction in infarcted hearts compared with sham (47+/-5% versus 73+/-4%), commensurate with the development of heart failure. Western blotting was used to measure levels of beta-myosin heavy chain (beta-MyHC), a marker of hypertrophy, and levels of dystrophin, desmin, MLP, beta-tubulin, utrophin and syncoilin, using GAPDH for normalization. Relative to shams, beta-MyHC and MLP levels were increased 1.9-fold and 1.7-fold, respectively, in infarcted rat hearts, whereas the levels of other cytoskeletal proteins were unchanged. Both MLP and desmin protein levels correlated negatively with ejection fraction, with the strongest relation between MLP and ejection fraction (r=-0.95, n=13, p<0.0001). This work suggests that MLP may play an important compensatory role in cardiac remodelling following MI.
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PMID:MLP accumulation and remodelling in the infarcted rat heart. 1633 Feb 55


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