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)

Very long chain fatty acid dehydrogenase (VLCAD) deficiency is a rare but treatable cause of cardiomyopathy, fatty liver, skeletal myopathy, pericardial effusions, ventricular arrhythmias, and sudden death. Unrecognized, VLCAD deficiency may be rapidly progressive and fatal, secondary to its cardiac involvement. Because early diagnosis improves outcome, we present a neonate with VLCAD deficiency in whom retrospective analysis of the newborn screening card revealed that a correct diagnosis could have been made by newborn screening using tandem mass spectrometry. Our patient demonstrated a classic neonatal course with transient hypoglycemia at birth, interpreted as culture-negative sepsis, followed by a quiescent period notable only for hypotonia and poor feeding. At 3 months, he presented with cardiorespiratory failure and pericardial effusions, requiring pericardiocentesis, tracheostomy, and prolonged mechanical ventilation. Plasma free-fatty acid and acylcarnitine profiles demonstrated small but significant elevations of C14:2, C14:1, C16, and C18:1 acylcarnitine species, findings consistent with a biochemical diagnosis of VLCAD deficiency. Enteral feeds were changed to Portagen formula with marked improvement in cardiac symptoms over several weeks. To confirm the biochemical diagnosis, molecular analysis was performed by analysis of genomic DNA on a blood sample of the patient. Sequencing analysis and delineation of VLCAD mutations were performed using polymerase chain reaction and genomic sequencing. The patient was heterozygous for 2 different disease-causing mutations at the VLCAD locus. The maternal mutation was a deletion of bp 842-3 in exon 8, causing a shift in the reading frame. The paternal mutation was G+1A in the consensus donor splice site after exon 1; this splice-site mutation would likely result in decreased mRNA. The likely consequence of these mutations is essentially a null phenotype. To determine whether this case could have been picked up by tandem mass spectrometry analysis at birth when the patient was asymptomatic, acylcarnitine analysis was performed on the patient's original newborn card (after obtaining parental consent, the original specimen was provided courtesy of Dr Kenneth Pass, Director, New York State Newborn Screening Program). The blood sample had been obtained at 1 week of age and stored at room temperature for 6 months and at 70 degrees C thereafter for 18 months. Electrospray tandem mass spectrometry used a LC-MS/MS API 2000 operated in ion evaporation mode with the TurboIonSpray ionization probe source. The acylcarnitine profile obtained from the patient's original newborn card was analyzed 2 years after it was obtained. In comparison with a normal control, there was a significant accumulation of long chain acylcarnitine species, with a prominent peak of tetradecenoylcarnitine (C14:1), the most characteristic metabolic marker of VLCAD deficiency. This profile would have likely been even more significant if it had been analyzed at the time of collection, yet 2 years later is sufficient to provide strong biochemical evidence of the underlying disorder. Discussion. VLCAD was first discovered in 1992, and clinical experience with VLCAD deficiency has been accumulating rapidly. Indeed, the patients originally diagnosed with long chain acyl-CoA deficiency suffer instead from VLCAD deficiency. The phenotype of VLCAD deficiency is heterogeneous, ranging from catastrophic metabolic and cardiac failure in infancy to mild hypoketotic, hypoglycemia, and exertional rhabdomyolysis in adults. This case demonstrates that VLCAD deficiency could have been detected from the patient's own neonatal heel-stick sample. Most likely, a presymptomatic diagnosis would have avoided at least part of a lengthy and intensive prediagnosis hospitalization that had an estimated cost of $400 000. Although VLCAD is relatively rare, timely and correct diagnosis leads to dramatic recovery, so that detection by newborn screening could prevent the onset of arrhythmias, heart failure, metabolic insufficiency, and death. Fatty acid oxidation defects, including VLCAD deficiency, may account for as many as 5% of sudden infant death patients. Recent instrumentation advances have made automated tandem mass spectrometry of routine neonatal heel-stick samples technically feasible. Pilot studies have demonstrated an incidence of fatty acid oxidation defects, including short chain, medium chain, and very long chain acyl-CoA dehydrogenase deficiencies, of approximately 1/12 000. As a result, cost-benefit ratios for this approach should be systematically examined.
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PMID:Diagnosis of very long chain acyl-dehydrogenase deficiency from an infant's newborn screening card. 1143 98

Statins are competitive inhibitors of hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase and are the most commonly used drugs to treat hyperlipidaemia. Muscle toxicity is an adverse effect reported with a low incidence and rarely associated with acute renal failure due to rhabdomyolysis. We describe two patients with chronic renal failure treated with pravastatin and simvastatin who suffered rhabdomyolysis and acute renal failure. One patient started pravastatin several days after cessation of bezafibrate and developed acute renal failure without needing dialysis. The other was treated with simvastatin three years ago and suffered rhabdomyolysis when renal function was impaired after indomethacin was prescribed for backache. He needed hemodialysis because of acute cardiac failure and died from a respiratory infection while on mechanical ventilation. Myopathy was reversible in both patients. We recommend starting statins with the lower doses in chronic renal failure and monitoring muscle enzymes when renal function changes or when new drugs with potential interactions are prescribed.
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PMID:[Rhabdomyolysis and acute renal failure secondary to statins]. 1198 93

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

Chronic heart failure is one of the most serious medical problems in the United States, affecting some 4 million persons. In spite of its common occurrence, and comprehensive literature regarding this condition, no unifying hypothesis has been accepted to explain the signs and symptoms of chronic heart failure. The cardiocirculatory and neurohormonal models place an emphasis on left ventricular ejection fraction and cardiac output and do not provide appropriate explanations for the symptoms of breathlessness and fatigue. The muscle hypothesis supplements these conventional models. It proposes that abnormal skeletal muscle in heart failure results in activation of muscle ergoreceptors, leading to an increase in ventilation and sensation of breathlessness, the perception of fatigue, and sympathetic activation. At least one fourth of patients with chronic heart failure are limited by skeletal muscle abnormalities rather than cardiac output. Cardiac rehabilitation exercise can lead to an increase in exercise capacity that is superior to that gained from digitalis or angiotensin-converting enzyme inhibitors. Exercise tends to reverse the skeletal muscle myopathy of chronic heart failure and reduces the abnormal ergoreflex. Other interventions that have been shown to have a favorable outcome include localized muscle group training, respiratory muscle training, and dietary approaches. The possibility that osteopathic manipulative treatment might be of benefit is an attractive, but untested, possibility.
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PMID:The muscle hypothesis: a model of chronic heart failure appropriate for osteopathic medicine. 1168 Nov 64

Chronic obstructive pulmonary disease, COPD is a highly prevalent disorder of increasing medical and socio-economical importance. It is characterized by irreversible airflow obstruction. Besides airflow obstruction also other features are present. One of these is respiratory muscle weakness. Inspiratory muscle weakness is caused by hyperinflation and by generalized muscle weakness causing both respiratory and peripheral muscle dysfunction. The expiratory muscles partake in this generalized muscle weakness. Hyperinflation shortens the inspiratory muscles although in chronic hyperinflation sarcomere adaptation occurs. Generalized muscle weakness is caused by deconditioning, malnutrition, electrolyte disturbances, cardiac failure, systemic inflammation and treatment with corticosteroids causing steroid-induced myopathy. The latter disease was studied intensively both in patients and in animal models of disease. The major findings were that microscopically a myopathic pattern was present associated with generalized fiber atrophy. This is in contrast to classical belief that the atrophy would be confined to type IIx fibers. We noted severe down-regulation of the IGF-I mRNA expression, without important changes in the expression of the binding proteins. This may be responsible for the observed muscle atrophy and the myopathy. The latter is likely to be caused by a simultaneous upregulation of the ubiquitin protease pathway attacking structural proteins. Presently, we study the relationship between local and systemic cytokine expression and respiratory and peripheral muscle dysfunction in COPD patients. Respiratory and peripheral muscle dysfunction have significant consequences for COPD patients. Both respiratory and peripheral muscle dysfunction are associated with reduced exercise tolerance and reduced quality of life. Both are independent determinants of survival, in addition to the degree of airflow obstruction as measured by FEV1. Finally, also the utilization of health care resources appeared to be related to respiratory and peripheral muscle weakness. Treatment of respiratory and peripheral muscle weakness in COPD patients is possible. Respiratory and peripheral muscle training have been shown to produce beneficial effects. Nutritional intervention and anabolic steroids are only useful in combination with muscle training. Systemic administration of growth hormone and IGF-I only produces small effects. In animal models, local administration of IGF-I and transfer of the IGF-I gene transfer appear more promising for the future. Lung volume reduction surgery, LVRS, improves the force-generating capacity of the inspiratory muscles, presumably because of the geometrical alterations it causes in these muscles. It does not appear to improve intrinsic inspiratory muscle function.
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PMID:Respiratory muscles in COPD: regulation of trophical status. 1181 11

Selenium deficiency is a rare cause of cardiomyopathy that may be encountered by the forensic pathologist. Selenium deficiency is associated with a cardiomyopathy, myopathy and osteoarthropathy. In Asia and Africa, dietary selenium deficiency is associated with a cardiomyopathy known as Keshan disease and an osteoarthropathy called Kashin-Beck disease. Chronic selenium deficiency may also occur in individuals with malabsorption and long term selenium-deficient parenteral nutrition. Selenium deficiency causes myopathy as a result of the depletion of selenium-associated enzymes which protect cell membranes from damage by free radicals. We present a case of fulminant heart failure in a middle aged woman with a complex medical and surgical history including documented malabsorption and selenium deficiency. Pathological examination of the heart showed features consistent with Keshan disease.
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PMID:Fulminant heart failure due to selenium deficiency cardiomyopathy (Keshan disease). 1184 34

Lysosomal storage diseases are an intriguing target for gene therapy approaches, as transduction of a "depot" organ with a transgene encoding a lysosomal enzyme can be followed by secretion, systemic distribution, downstream uptake, and lysosomal targeting of the enzyme into non-transduced tissues. These benefits are of utmost importance when considering gene therapy approaches for glycogen storage disease type-II (GSD-II). GSD-II is a prototypical lysosomal storage disorder caused by lack of intralysosomal acid alpha-glucosidase (GAA) activity. Lack of GAA can result in a proximal limb myopathy and respiratory and cardiac failure, each due to abnormal glycogen accumulation in the skeletal muscles or cardiac tissues, respectively. After converting the liver into a "depot" organ, we found that intravenous injection of the [E1-,polymerase-]AdGAA vector allowed for hepatic secretion of GAA over an at least 20-fold dosage range. We noted that very low plasma GAA levels (derived from hepatic secretion of GAA) can allow for GAA uptake by muscle tissues (skeletal or cardiac), but significantly higher plasma GAA levels are required before glycogen "cross-correction" can occur in these same tissues. We also demonstrated that liver-specific enhancer/promoters prolonged GAA transgene expression from persistent [E1-,polymerase-] adenovirus based vector genomes for at least 180 days, and significantly diminished the amounts of neutralizing anti-GAA antibodies elicited in this animal model. Finally, we demonstrated that skeletal muscles can also serve as a "depot" organ for GAA secretion, allowing for secretion of GAA and its uptake by noninfected distal tissues, although glycogen reductions in non-injected muscles were not achieved by the latter approach.
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PMID:Efficacy of gene therapy for a prototypical lysosomal storage disease (GSD-II) is critically dependent on vector dose, transgene promoter, and the tissues targeted for vector transduction. 1194 71

The main operational objective of diuretic therapy in patients who present congestive heart failure and hypertension is to reduce or to suppress excess bodily fluid. Effective diuretic therapy decreases cardiac size when the heart is dilated, and it reduces lung congestion and excess water. Consequently, external respiratory work diminishes and cardiac output would be redistributed in favour of systemic vascular beds other than that of the respiratory muscles; dyspnoea decreases markedly and there is a slight reduction in fatigue. This clinical improvement and the fall in body weight caused by diuretics entail an increase in effort capacity. Subsequent exercise training ameliorates the abnormal ventilatory response to physical effort and the skeletal muscle myopathy that occur in heart failure, and thereby it attenuates dyspnoea and decreases fatigue further. Loop and/or thiazide-type diuretics may be used to augment natriuresis in patients with congestive heart failure and hypertension. The state of renal function, the existence of certain co-morbid conditions, potential untoward drug actions, and possible interactions of diuretics with nutrients and with other drugs are some of the factors that must be considered at the time of deciding on the diuretic drug(s) and dose(s) to be prescribed. Spironolactone has been found to increase life expectancy and to reduce hospitalisation frequency when added to the conventional therapeutic regimen of patients with advanced congestive heart failure and systolic dysfunction. Therefore, spironolactone should be the drug of choice to oppose the kaliuretic effect of a loop or of a thiazide-type diuretic.
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PMID:Diuretics in the treatment of patients who present congestive heart failure and hypertension. 1198 6

Skeletal muscle in congestive heart failure is responsible for increased fatigability and decreased exercise capacity. A specific myopathy with increased expression of fast-type myosins, myocyte atrophy, secondary to myocyte apoptosis triggered by high levels of circulating tumor necrosis factor-alpha (TNF-alpha) has been described. In an animal model of heart failure, the monocrotaline-treated rat, we have observed an increase of apoptotic skeletal muscle nuclei. Proapoptotic agents, caspase-3 and -9, were increased, as well as serum levels of TNF-alpha and its second messenger sphingosine. Treatment of rats with L-carnitine, known for its protective effect on muscle metabolism injuries, was found to inhibit caspases and to decrease the levels of TNF-alpha and sphingosine, as well as the number of apoptotic myonuclei. Staurosporine was used in in vitro experiments to induce apoptosis in skeletal muscle cells in culture. When L-carnitine was applied to skeletal muscle cells, before staurosporine treatment, we observed a reduction in apoptosis. These findings show that L-carnitine can prevent apoptosis of skeletal muscles cells and has a role in the treatment of congestive heart failure-associated myopathy.
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PMID:L-Carnitine: a potential treatment for blocking apoptosis and preventing skeletal muscle myopathy in heart failure. 1217 37

Duchenne muscular dystrophy (DMD) is the most common disabling and lethal genetic muscle disorder, afflicting 1 of every 3500 males. Patients with DMD experience progressive muscle degeneration and weakness and succumb to respiratory or cardiac failure by their early twenties. No treatment is currently available for DMD. Mutations in the dystrophin gene result in lack of a functional dystrophin protein in striated muscle, which induces instability in the muscle cell membrane leading to persistent muscle injury after contraction. We have previously created novel minidystrophin genes and demonstrated that adeno-associated virus (AAV)-mediated intramuscular delivery of the minigenes effectively ameliorated mdx dystrophic histopathology and led to normal cell membrane integrity for more than 1 year. In this paper, we investigated whether AAV-minidystrophin could also improve mdx muscle contractile function. Two-month-old adult male mdx mice, with established muscular dystrophy, were given a single-dose injection of an AAV-minidystrophin vector in the tibialis anterior (TA) muscle of one leg, with the untreated contralateral leg used as a control. The treated TA muscle showed both (1) a significant increase in isometric force generation and (2) a significant increase in resistance to lengthening activation-induced muscle force decrements. We conclude that AAV-minidystrophin gene treatment is effective in improving mdx muscle contractile function.
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PMID:Adeno-associated virus vector-mediated minidystrophin gene therapy improves dystrophic muscle contractile function in mdx mice. 1221 66


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