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)

Duchenne muscular dystrophy (DMD) is a lethal degenerative disease of skeletal muscle, characterized by the absence of the cytoskeletal protein dystrophin. Some DMD patients show a dilated cardiomyopathy leading to heart failure. This study explores the possibility that dystrophin is involved in the regulation of a stretch-activated channel (SAC), which in the absence of dystrophin has increased activity and allows greater Ca(2+) into cardiomyocytes. Because cardiac failure only appears late in the progression of DMD, we examined age-related effects in the mdx mouse, an animal model of DMD. Ca(2+) measurements using a fluorescent Ca(2+)-sensitive dye fluo-4 were performed on single ventricular myocytes from mdx and wild-type mice. Immunoblotting and immunohistochemistry were performed on whole hearts to determine expression levels of key proteins involved in excitation-contraction coupling. Old mdx mice had raised resting intracellular Ca(2+) concentration ([Ca(2+)](i)). Isolated ventricular myocytes from young and old mdx mice displayed abnormal Ca(2+) transients, increased protein expression of the ryanodine receptor, and decreased protein expression of serine-16-phosphorylated phospholamban. Caffeine-induced Ca(2+) transients showed that the Na(+)/Ca(2+) exchanger function was increased in old mdx mice. Two SAC inhibitors streptomycin and GsMTx-4 both reduced resting [Ca(2+)](i) in old mdx mice, suggesting that SACs may be involved in the Ca(2+)-handling abnormalities in these animals. This finding was supported by immunoblotting data, which demonstrated that old mdx mice had increased protein expression of canonical transient receptor potential channel 1, a likely candidate protein for SACs. SACs may play a role in the pathogenesis of the heart failure associated with DMD. Early in the disease process and before the onset of clinical symptoms increased, SAC activity may underlie the abnormal Ca(2+) handling in young mdx mice.
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PMID:Intracellular calcium handling in ventricular myocytes from mdx mice. 1701 53

Duchenne muscular dystrophy (DMD) is an X-linked recessive disease that affects approximately 1 in 3500 male births. Boys with Duchenne have a progressive and predictable muscle deterioration: muscles lack dystrophin, a protein essential for membrane stability, whose absence induces contraction-related membrane damage and activation of the inflammatory cascade leading to muscle failure, necrosis, fibrosis. Although DMD is present at birth, clinical symptoms are not evident until 2-6 years of age. Initial symptoms include leg weakness, increasing spine kyphosis, and a waddle-like gait. Continuous muscle wasting leads to progressively weaker muscles, usually leading DMD patients on wheelchair by the age of 8-12. Scoliosis develops in 90% of boys who use a wheelchair full-time. Progression of muscle degeneration and worsening clinical symptoms lead to death in the late twenties from respiratory/cardiac failure.
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PMID:[Duchenne muscular dystrophy: rational basis, state of the art]. 1701 93

A viral infection is the most frequent cause of myocarditis. A viral invasion and viral-mediated cardiomyocyte lesion stimulate an immune system response directed towards the elimination of viral particles, the destruction of infected myocytes, and the limitation of viral dissemination. Numerous studies have shown that the balance of two subpopulations of CD4+ lymphocytes (T-helpers types 1 and 2) determines the character of the immune response in myocarditis, and that this balance is important at the initial stages of immunization, while the cytotoxic CD8+ lymphocytes participate in the myocardial lesion directly. Disorder in the elimination of activated lymphocytes' clones, the degree of which correlates with the degree of cardiac insufficiency, may be one of the mechanisms of myocarditis progression. Disbalance or defects in the system of the regulatory cytokine network also may lead to the activation of potentially autoreactive T-lymphocytes. A connection between viral myocarditis and dilated cardiomyopathy (DCMP) has been discussed for many years. One of the reasons for DCMP development is a viral invasion into the myocardium. Proteinase A, which induces dystrophin proteolysis, which impedes its function, is an ingredient of enteroviruses. Hence, a viral infection may cause two myocardial diseases: viral (infective-and-immune) myocarditis and DCMP.
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PMID:[Viral infection and myocardial pathology]. 1711 32

Duchenne muscular dystrophy (DMD) is a fatal disease of striated muscle deterioration resulting from the loss of the cytoskeletal protein dystrophin. Most patients develop significant cardiomyopathy, with heart failure being the second leading cause of death in DMD. Compared with the extensive studies on skeletal muscle defects and potential therapy in DMD, very little attention has been directed at the increasing incidence of heart failure in DMD. Here we show that a single systemic injection of recombinant adeno-associated virus (rAAV2/6) harboring micro-dystrophin leads to extensive cardiac transduction, with micro-dystrophin correctly localized at the periphery of the cardiac myocytes and functionally associated with the sarcolemmal membrane. Significantly, micro-dystrophin gene transfer corrected the baseline end-diastolic volume defect in the mdx mouse heart and prevented cardiac pump failure induced by dobutamine stress testing in vivo, although several parameters of systolic function were not corrected. These results demonstrate that systemic gene delivery of micro-dystrophin can restore ventricular distensibility and protect the mdx myocardium from pump dysfunction during adrenergic stimulation in vivo.
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PMID:Systemic administration of micro-dystrophin restores cardiac geometry and prevents dobutamine-induced cardiac pump failure. 1744 Apr 45

Duchenne muscular dystrophy (DMD) is caused by deficiency of the cytoskeletal protein dystrophin. Oxidative stress is thought to contribute to the skeletal muscle damage in DMD; however, little is known about the role of oxidative damage in the pathogenesis of the heart failure that occurs in DMD patients. The dystrophin-deficient (mdx) mouse is an animal model of DMD that also lacks dystrophin. The current study investigates the role of the antioxidant N-acetylcysteine (NAC) on mdx cardiomyocyte function, Ca(2+) handling, and the cardiac inflammatory response. Treated mice received 1% NAC in their drinking water for 6 wk. NAC had no effect on wild-type (WT) mice. Immunohistochemistry experiments revealed that mdx mice had increased dihydroethidine (DHE) staining, an indicator of superoxide production; NAC-treatment reduced DHE staining in mdx hearts. NAC treatment attenuated abnormalities in mdx cardiomyocyte Ca(2+) handling. Mdx cardiomyocytes had decreased fractional shortening and decreased Ca(2+) sensitivity; NAC treatment returned mdx fractional shortening to WT values but did not affect the Ca(2+) sensitivity. Immunohistochemistry experiments revealed that mdx hearts had increased levels of collagen type III and the macrophage-specific protein, CD68; NAC-treatment returned collagen type III and CD68 expression close to WT values. Finally, mdx hearts had increased NADPH oxidase activity, suggesting it could be a possible source of increased reactive oxygen species in mdx mice. This study is the first to demonstrate that oxidative damage may be involved in the pathogenesis of the heart failure that occurs in mdx mice. Therapies designed to reduce oxidative damage might be beneficial to DMD patients with heart failure.
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PMID:The role of reactive oxygen species in the hearts of dystrophin-deficient mdx mice. 1757 57

A cure for dystrophin-deficient muscular dystrophy requires treating both skeletal muscle and the heart. Whereas mosaic dystrophin expression has been shown to protect skeletal muscle, controversy exists over whether mosaic expression is protective in the heart. We have shown recently that mosaic dystrophin expression prevents stress-induced heart damage in young carrier mice. Although an interesting finding, the clinical relevance remains to be established because young dystrophin-null mdx mice do not have heart disease. On the other hand, heart failure has been reported in human carriers. To resolve this mouse/human discrepancy, we evaluated the cardiac phenotype in 21-month-old mdx, carrier, and normal mice. We found dilated cardiomyopathy in old mdx mice but not in age-matched carrier mice. All anatomical parameters and physiological assay results (ECG and closed-chest Millar catheter) were within the normal range in old carrier mice. Focal myocardial inflammation was found in a small fraction of old carrier mice, but it had no major impact on heart function. Dobutamine stress revealed a near normal hemodynamic profile except for a marginal reduction in systolic pressure in old carrier mice. Immunostaining and Western blot showed dystrophin expression in 50% cardiomyocytes in old carrier mice. Interestingly, utrophin was upregulated in dystrophin-negative heart cells in carrier mice. In summary, we have provided the first clear-cut evidence that dilated cardiomyopathy in old mdx mice was prevented by mosaic dystrophin expression or complementary dystrophin/utrophin expression. Our results raise the hope for ameliorating dystrophic cardiomyopathy through partial gene and/or cell therapy.
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PMID:Prevention of dystrophin-deficient cardiomyopathy in twenty-one-month-old carrier mice by mosaic dystrophin expression or complementary dystrophin/utrophin expression. 1796 82

Duchenne muscular dystrophy (DMD) is an X-linked hereditary dystrophinopathy due to the absence of dystrophin, a cytoskeleton protein; it is the most frequent of the dystrophinopathies. DMD affects one newborn boy in 3500. The disease locus is found on the short arm of the X chromosome (Xp21). Dystrophin plays an important role in the maintenance of the cellular architecture and permits signal transduction between the cytoskeleton and the extracellular matrix. Its absence is expressed by peripheral muscular damage, most often at the pelvic girdle, and sometimes associated with pseudohypertrophy of the calf. The disease is very often complicated by cardiac damage that develops towards the end of adolescence, together with restrictive lung disease that will usually end up requiring respiratory support. The prognosis is severe. Doppler examination of the myocardial tissue helps to screen for subclinical myocardial damage. Therapeutic management is multidisciplinary. Medical treatment of cardiac involvement relies on the drugs already proved effective in chronic heart failure. Ongoing research is currently studying gene therapy.
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PMID:[Cardiac involvement in Duchenne muscular dystrophy]. 1798 May 47

We review the clinical status of skeletal involvement and cardiac function in three unrelated patients harboring an in-frame deletion of exons 45 to 55 in the DMD gene followed up for 2 to 7 years. Two younger patients diagnosed as having X-linked dilated cardiomyopathy (XLDCM) developed congestive heart failure without overt skeletal myopathy. Heart failure recurred after viral infection but responded well to diuretics and angiotensin-converting enzyme inhibitors. One older patient diagnosed with Becker muscular dystrophy showed limb-girdle muscular atrophy and weakness at the age of 50, but did not have any cardiac symptoms. Skeletal muscle involvement in each patient remained unchanged, and cardiac function did not worsen in any of the patients during the study. In a younger XLDCM patient, the amount and molecular weight of mutant dystrophin were equally slightly decreased in both skeletal and cardiac muscles. Immunostaining for dystrophin and dystrophin-associated proteins was slightly reduced in both skeletal and cardiac muscle, with no discernible difference between the two. The phenotype of this dystrophinopathy can manifest as XLDCM in younger patients; however, careful attention to cardiac management may result in a favorable prognosis.
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PMID:Follow-up of three patients with a large in-frame deletion of exons 45-55 in the Duchenne muscular dystrophy (DMD) gene. 1826 11

The dystrophin-glycoprotein complex is a large complex of membrane-associated proteins linking the cytoskeleton to the extracellular matrix in muscle. Transmembrane heterodimeric (alphabeta) integrins serve also as cellular adhesion molecules and mechanotransducers. In the animal model for Duchenne muscular dystrophy, the mdx mouse, loss of dystrophin causes more severe abnormalities in skeletal than in cardiac muscle. We hypothesized that ablation of cardiac myocyte integrins in the mdx background would lead to a severe cardiomyopathic phenotype. Mdx mice were crossed to ones with cardiac myocyte-specific deletion of beta1 integrin (beta1KO) to generate beta1KOmdx. Unstressed beta1KOmdx mice were viable and had normal cardiac function; however, high mortality was seen in peri- and postpartum females by 6 months of age, when severe myocardial necrosis and fibrosis and extensive dystrophic calcification was seen. Decreased ventricular function and blunted adrenergic responsiveness was found in the beta1KOmdx mice compared with control (Lox/Lox, no Cre), beta1KO, and mdx. Similarly, adult beta1KOmdx males were more prone to isoproterenol-induced heart failure and death compared with control groups. Given the extensive calcification, we analyzed transcript levels of genes linked to fibrosis and calcification and found matrix gamma-carboxyglutamic acid protein, decorin, periostin, and the osteoblast transcription factor Runx2/Cbfa1 significantly increased in beta1KOmdx cardiac muscle. Our data show that combined deficiency of dystrophin and integrins in murine cardiac myocytes results in more severe cardiomyopathic changes in the stressed myocardium than reduction of either dystrophin or integrins alone and predisposes to myocardial calcification.
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PMID:Combined deficiency of dystrophin and beta1 integrin in the cardiac myocyte causes myocardial dysfunction, fibrosis and calcification. 1834 10

Claudin-5 is a transmembrane cell junction protein that is a component of tight junctions in endothelial cell layers. We have previously shown that claudin-5 also localizes to lateral membranes of murine cardiomyocytes at their junction with the extracellular matrix. Claudin-5 levels are specifically reduced in myocytes from a mouse model of muscular dystrophy with cardiomyopathy. To establish whether claudin-5 is similarly specifically reduced in human cardiomyopathy, we compared the levels of claudin-5 with other cell junction proteins in 62 cardiomyopathic end-stage explant samples. We show that claudin-5 levels are reduced in at least 60% of patient samples compared with non-failing controls. Importantly, claudin-5 reductions can be independent of connexin-43, a gap junction protein previously reported to be reduced in failing heart samples. Other cell junction proteins including alpha-catenin, beta-catenin, gamma-catenin, desmoplakin, and N-cadherin are reduced in only a small number of failing samples and only in combination with reduced claudin-5 or connexin-43 levels. We also show that reduced claudin-5 levels can be present independently from dystrophin alterations, which are known to be capable of causing and resulting from cardiomyopathy. These data are the first to show alterations of a tight junction protein in human cardiomyopathy samples and suggest that claudin-5 may participate in novel mechanisms in the pathway to end-stage heart failure.
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PMID:Claudin-5 levels are reduced in human end-stage cardiomyopathy. 1851 42


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