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 acute and chronic toxic effects of alcohol on skeletal and cardiac muscle are clinically important. Muscle weakness and atrophy are the main manifestations of skeletal myopathy, and arrhythmias and progressive left-ventricular dysfunction are those of cardiomyopathy. Most patients remain asymptomatic from these effects for a long time. Myocyte atrophy and death are the main pathological findings. A clear dose-related effect has been established with ethanol consumption, with gender and some specific gene polymorphisms being factors of increased susceptibility to alcohol-induced muscle damage. Pathogenic mechanisms are pleiotropic, the most relevant being disturbances in carbohydrate, protein, and energy cell turnover, signal transduction, and induction of apoptosis and gene dysregulation. Ethanol abstinence is the only effective treatment, although controlled drinking is useful in patients who do not achieve abstinence. Persistent high-dose consumption results in deterioration of muscle and heart function, with a high mortality due to arrhythmias and progression of heart failure.
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PMID:Effects of alcohol on skeletal and cardiac muscle. 1549 Apr 85

Desmin, the major muscle-specific intermediate filament (IF) protein, is essential for mitochondrial behavior and function and maintenance of healthy muscle. Mice null for desmin develop dilated cardiomyopathy characterized by extensive cardiomyocyte death, fibrosis, calcification and eventual heart failure. We sought to investigate the heart mitochondrial proteome of wild type and desmin null mice in order to understand the cardiac and skeletal myopathy phenotype of desmin deficiency. The proteins were analyzed by 2-D electrophoresis, followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Three hundred and eighty different gene products were identified, about 50% of which were enzyme subunits. Cytoskeletal and muscle-specific proteins, calcium-binding proteins, proteins with various other functions and about 70 unknown, hypothetical or poorly described gene products, were also identified. We have observed differences in most metabolic pathways, in apoptosis, calcium homeostasis, calcification and fibrosis and in different signaling pathways linked or not to mitochondrial function. The most significant changes were observed in ketone body and acetate metabolism, NADH shuttle proteins, amino-acid metabolism proteins and respiratory enzymes. Several of these changes are consistent with the known phenotype of desmin deficiency.
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PMID:Alterations in the heart mitochondrial proteome in a desmin null heart failure model. 1573 6

Heart failure is characterized by limited exercise tolerance and by a skeletal muscle myopathy with atrophy and shift toward fast fibres. An inflammatory status with elevated pro-inflammatory cytokines and exaggerated free radicals production, can worsen muscle damage. In a well established model of heart failure, the monocrotaline treated rat, we show that CHF is accompanied by oxidation of the skeletal muscle actin, tropomyosin and myosin, which further depresses muscle function and exercise capacity. We have also tested the efficacy of Carvedilol, a non-selective beta(1)-beta(2)-blocker, which has been widely used in clinical trials to improve exercise tolerance and reduce mortality in moderate and severe CHF, in preventing contractile protein oxidation in CHF rats. As comparison we used Bisoprolol a beta(1) selective agent, without known anti-oxidative properties. Carvedilol at the dose of 2 mg/kg per day was able to prevent the myofibrillar protein oxidation, while Bisoprolol (0.1 mg/kg) did it only partially, as demonstrated by the oxyblot analysis. While Carvedilol improved force production on isolated muscles, Bisoprolol did not. After the COMET trial, the anti-oxidative capacity of Carvedilol has been invoked as one of the mechanism that makes this drug superior to other selective beta-blockers in the treatment of CHF. One of the reason of Carvedilol superiority could be the effect on skeletal muscle with reduction of contractile protein peroxidation, amelioration of muscle function and improvement of exercise tolerance. Inhibition of reactive oxygen species (ROS) production, and of pro-inflammatory cytokines may also lead to a decreased muscle wastage, another factor contributing to worsening of exercise tolerance.
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PMID:Skeletal muscle myofibrillar protein oxidation in heart failure and the protective effect of Carvedilol. 1585 May 74

The purpose of this study was to determine the efficacy of resistance exercise in reversing skeletal muscle myopathy in heart transplant recipients. Myopathy, engendered by both heart failure and immunosuppression with glucocorticoids, is a post-transplant complication. The sequelae of myopathic disease includes fiber-type shifts and deficits in aerobic metabolic capability. We randomly assigned patients to either 6 months of resistance exercise (training group; n = 8) or a control (control group; n = 7) group. Exercise was initiated at 2 months after transplant. Biopsy of the right vastus lateralis was performed before and after the 6-month intervention. Myosin heavy chain (MHC) composition was assessed using sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Biochemical assays were performed to determine citrate synthase, 3-hydroxyacyl-CoA-dehydrogenase, and lactate dehydrogenase activity. There were no group differences (p >or=0.05) in MHC composition and enzymatic reserve at baseline. Improvements in the training group for citrate cynthase (+40%), 3-hydroxyacyl-CoA-dehydrogenase (+10%), and lactate dehydrogenase activity (+48%) were significantly greater (p <or=0.05) than in the control group (+10%, -15%, and +20%, respectively). Oxidative type 1 MHC isoform concentration increased significantly in the training group (+73%, p <or=0.05) but decreased in the control group (-28%; p <or=0.05). Glycolytic type 2x MHC isoform increased significantly (17%; p <or=0.05) in the control group but decreased (-33%; p <or=0.05) in the training group. This is the first study to demonstrate that resistance training elicits myofibrillar shifts from less oxidative type II fibers to more oxidative fatigue-resistant type I fibers in heart transplant recipients. Resistance exercise initiated early in the post-transplant period is efficacious in changing skeletal muscle phenotype through increases in enzymatic reserve and shifts in fiber morphology.
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PMID:Effect of resistance exercise on skeletal muscle myopathy in heart transplant recipients. 1587 92

Over activation of the renin-angiotensin-aldosterone system is known to be cardiotoxic but the potential injurious effects on the skeletal musculature have not been investigated. Male Wistar rats were given subcutaneous injections of aldosterone (1 microg-10 mg kg-1) and killed 7 h later, or continuous infusion (1 mg kg-1 d-1) and killed 48 h later. The role of the mineralocorticoid receptor in mediating aldosterone-induced apoptosis in vivo was investigated using spironolactone (200 mg kg-1). The number of apoptotic (caspase 3 positive) myocytes was counted on cryosections of the heart, soleus and Tibialis Anterior muscles. Injections of aldosterone induced significant (P<0.05) cardiomyocyte apoptosis (peak=2.46+/-0.6 per 10(4) viable myocytes) over the range of 100 microg-10 mg kg-1, whereas only administration of 1 mg kg-1 induced significant (P<0.05) apoptosis (2.47+/-0.8 per 10(4) viable myocytes) in the soleus muscle. In contrast, no apoptosis was detected in the striated muscles after administration of only the vehicle. Infusion of aldosterone induced less apoptosis than the same dose (1 mg kg-1) given as a single injection. Prior administration of spironolactone significantly (P<0.05) protected the heart (90%) and soleus muscle (79%) against the apoptosis induced by a single injection of 1 mg kg-1 aldosterone. These data confirm a myotoxic effect of aldosterone on the heart and provide the first description of aldosterone-induced myocyte apoptosis in skeletal muscle. High circulating levels of aldosterone are clearly capable of damaging all types of striated muscle and this may lend support to the concept that heart failure is a generalised, rather than cardiac-specific, myopathy.
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PMID:Aldosterone induces myocyte apoptosis in the heart and skeletal muscles of rats in vivo. 1597 10

Polysaccharide myopathy is a rare form of storage muscular disorder. The clinical picture of this particular form of myopathy is unspecific. We report a 62-year-old woman with late-onset progressive weakness and wasting, affecting proximal muscles of the four limbs and the girdles. No myalgia, dysphagia nor symptoms of cardiac failure were observed. Muscle biopsy revealed a vacuolar myopathy with accumulation of amylopectin-like polysaccharide. This material was strongly PAS-positive and diastase-resistant. At electron microscopy, the deposits were composed of non-membrane-bound filamentous and granular material surrounded by numerous mitochondria. No enzyme deficiency was found. Clinical presentation of our patient was similar to the 16 cases reported in the literature. She did not have myocardiopathy and her survival is much longer. Hypothetic mechanisms of polysaccharide accumulation are reviewed.
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PMID:Polysaccharide storage myopathy--case report and literature review. 1594 64

Abnormalities in intracellular calcium release and reuptake are responsible for decreased contractility in heart failure (HF). We have previously shown that cardiac ryanodine receptors (RyRs) are protein kinase A-hyperphosphorylated and depleted of the regulatory subunit calstabin-2 in HF. Moreover, similar alterations in skeletal muscle RyR have been linked to increased fatigability in HF. To determine whether restoration of calstabin binding to RyR may ameliorate cardiac and skeletal muscle dysfunction in HF, we treated WT and calstabin-2-/- mice subjected to myocardial infarction (MI) with JTV519. JTV519, a 1,4-benzothiazepine, is a member of a class of drugs known as calcium channel stabilizers, previously shown to increase calstabin binding to RyR. Echocardiography at 21 days after MI demonstrated a significant increase in ejection fraction in WT mice treated with JTV519 (45.8 +/- 5.1%) compared with placebo (31.1 +/- 3.1%; P < 0.05). Coimmunoprecipitation experiments revealed increased amounts of calstabin-2 bound to the RyR2 channel in JTV519-treated WT mice. However, JTV519 did not show any of these beneficial effects in calstabin-2-/- mice with MI. Additionally, JTV519 improved skeletal muscle fatigue in WT and calstabin-2-/- mice with HF by increasing the binding of calstabin-1 to RyR1. The observation that treatment with JTV519 improved cardiac function in WT but not calstabin-2-/- mice indicates that calstabin-2 binding to RyR2 is required for the beneficial effects in failing hearts. We conclude that JTV519 may provide a specific way to treat the cardiac and skeletal muscle myopathy in HF by increasing calstabin binding to RyR.
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PMID:Enhancing calstabin binding to ryanodine receptors improves cardiac and skeletal muscle function in heart failure. 1597 11

Skeletal muscle abnormalities are highly prevalent in chronic heart failure and are associated with an increase in the ergoreflex, a muscle reflex stimulated by work done. Stimulation of the ergoreflex results in increased ventilation and contributes to the increased sympathetic activation of the heart failure syndrome. The origin of the skeletal myopathy is related to a chronic imbalance between catabolic and anabolic processes, presumably as a consequence of chronic haemodynamic stress. Symptoms arise from the skeletal myopathy, causing the sensation of fatigue and contributing to the sensation of breathlessness as the myopathy affects respiratory muscle. Ergoreflex activation causes a greater ventilatory response to exercise than normal, contributing to the sensation of breathlessness.
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PMID:Origin of symptoms in chronic heart failure. 1615 69

The mechanisms underlying reduced exercise capacity in patients with nonobstructive hypertrophic cardiomyopathy (NHCM) could include perturbations of ventricular relaxation, diastolic compliance, or compensatory atrial systolic function. We hypothesized that a loss of atrial contractility in NHCM patients leads to reduced functional capacity. To test this hypothesis, we compared resting noninvasive left atrial ejection phase indices in 49 consecutive patients with NHCM (ages 36+/-10 years; 41% female) and normal left ventricular ejection fraction (mean, 68%+/-8%) with objective metabolic exercise parameters. Left atrial active emptying fraction, ejection force, and kinetic energy failed to predict exercise capacity. Only left atrial total and active emptying volumes correlated weakly with minute volume/CO2 production slope (r=0.31 and r=0.33; p<0.05 for both). Furthermore, when subjects were stratified by New York Heart Association symptomatology, exercise parameters--but not atrial contractility--differed between groups. These data, obtained at rest, fail to suggest that NHCM-related heart failure symptoms are due to an atrial myopathy.
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PMID:Is functional capacity related to left atrial contractile function in nonobstructive hypertrophic cardiomyopathy? 1623 Aug 64

Cell therapy in diverse organs has bloomed for degenerative diseases over the past decade, following a previous period of development in which haematopoietic stem cells grafts in oncology were its most prominent clinical application. One main limitation that has, however, been encountered on the path for transforming pioneering successes into real therapeutics, that would be applicable to a clinically relevant number of patients, is the difficulty in accessing "therapeutic" cells, such as foetal neurons in neurodegenerative diseases, adult pancreatic beta cells in diabetes or else myoblasts in heart failure and myopathy. The future of cell therapy definitely belongs to cell banks, from which physicians would simply have to draw according to their needs. However, besides haematopoietic stem cells, for which such infrastructures begin to exist for clinical purposes (in particular from cord blood), cell banks are still up to now essentially a scientific concept. This review focuses on the possibility for human ES cells to meet both the requirements of cell banking and the needs for substitutive cell therapy.
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PMID:Embryonic stem cells: meeting the needs for cell therapy. 1625 83


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