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)

Cardiolipin (CL) is a structurally unique dimeric phospholipid localized in the inner mitochondrial membrane where it is required for optimal mitochondrial function. In addition to its role in maintaining membrane potential and architecture, CL is known to provide essential structural and functional support to several proteins involved in mitochondrial bioenergetics. A loss of CL content, alterations in its acyl chain composition, and/or CL peroxidation have been associated with mitochondrial dysfunction in multiple tissues in a variety of pathological conditions, including ischemia, hypothyroidism, aging, and heart failure. Recently, aberrations in CL metabolism have been implicated as a primary causative factor in the cardioskeletal myopathy known as Barth syndrome, underscoring an important role of CL in human health and disease. The purpose of this review is to provide an overview of evidence that has linked changes in the CL profile to mitochondrial dysfunction in various pathological conditions. In addition, a brief overview of CL function and biosynthesis, and a discussion of methods used to examine CL in biological tissues are provided.
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PMID:Role of cardiolipin alterations in mitochondrial dysfunction and disease. 1689 48

Barth syndrome is an X-linked recessive disease caused by mutations in the tafazzin gene. Patients have reduced concentration and altered composition of cardiolipin, the specific mitochondrial phospholipid, and they have variable clinical findings, often including heart failure, myopathy, neutropenia, and growth retardation. This article provides an overview of the molecular basis of Barth syndrome. It is argued that tafazzin, a phospholipid acyltransferase, is involved in acyl-specific remodeling of cardiolipin, which promotes structural uniformity and molecular symmetry among the cardiolipin molecular species. Inhibition of this pathway leads to changes in mitochondrial architecture and function.
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PMID:Barth syndrome, a human disorder of cardiolipin metabolism. 1697 64

Myopathies are frequently not confined to the skeletal muscles but also involve other organs or tissues. One of the most frequently affected organ in addition to the skeletal muscle is the heart (cardiac involvement, CI). CI manifests as impulse generation or conduction defects, focal or diffuse myocardial thickening, dilation of the cardiac cavities, relaxation abnormality, hypertrophic, dilated, restrictive cardiomyopathy, apical form of hypertrophic cardiomyopathy, noncompaction, Takotsubo phenomenon, secondary valve insufficiency, intra-cardiac thrombus formation, or heart failure with systolic or diastolic dysfunction. CI occurs in dystrophinopathies, Emery-Dreifuss muscular dystrophy, facioscapulohumeral muscular dystrophy, limb girdle muscular dystrophies, laminopathies, congenital muscular dystrophies, myotonic dystrophies, congenital myopathies, metabolic myopathies, desminopathies, myofibrillar myopathy, Barth syndrome, McLeod syndrome, Senger's syndrome, and Bethlem myopathy. Patients with myopathy should be cardiologically investigated as soon as their neurological diagnosis is established, since supportive cardiac therapy is available, which markedly influences prognosis and outcome of CI in these patients.
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PMID:Primary myopathies and the heart. 1827 31

Cardiolipin is a unique phospholipid, which is almost exclusively localized in the mitochondrial inner membrane where it is synthesized from phosphatidylglycerol and cytidinediphosphate-diacylglycerol. After primary synthesis, the mature acyl chain composition of cardiolipin is achieved by at least two remodeling mechanisms. In the mitochondrial membrane cardiolipin plays an important role in energy metabolism, mainly by providing stability for the individual enzymes and enzyme complexes involved in energy production. Moreover, cardiolipin is involved in different stages of the mitochondrial apoptotic process and in mitochondrial membrane dynamics. Cardiolipin alterations have been described in various pathological conditions. Patients suffering from Barth syndrome have an altered cardiolipin homeostasis caused by a primary deficiency in cardiolipin remodeling. Alterations in cardiolipin content or composition have also been reported in more frequent diseases such as diabetes and heart failure. In this review we provide an overview of cardiolipin metabolism, function and its role in different pathological states.
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PMID:Cardiolipin, the heart of mitochondrial metabolism. 1842 14

The mitochondrial dimeric phospholipid cardiolipin is characterized by a high degree of unsaturation of its acyl chains, which is important for its functional interaction with mitochondrial enzymes. The unusual fatty acid composition of cardiolipin molecular species emerges from a de novo synthesized "premature" species by extensive acyl chain remodeling that involves as yet only partially identified acyltransferases and phospholipases. Recently, the yeast protein Taz1p was shown to function as a transacylase, which catalyzes the reacylation of monolysocardiolipin to mature cardiolipin. A defect in the orthologous human TAZ gene is associated with Barth syndrome, a severe genetic disorder, which may lead to cardiac failure and death in childhood. We now identified the protein encoded by reading frame YGR110W as a mitochondrial phospholipase, which deacylates de novo synthesized cardiolipin. Ygr110wp has a strong substrate preference for palmitic acid residues and functions upstream of Taz1p, to generate monolysocardiolipin for Taz1p-dependent reacylation with unsaturated fatty acids. We therefore rename the Ygr110wp as Cld1p (cardiolipin-specific deacylase 1).
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PMID:Identification of a cardiolipin-specific phospholipase encoded by the gene CLD1 (YGR110W) in yeast. 1924 44

Cardiolipin (CL) is a mitochondrial phospholipid that fundamentally contributes to the function of many proteins in the inner mitochondrial membrane, where it is actively involved in the integrity and flux of the electron transport chain. In the heart, functional CL is linoleic acid rich, and the loss of linoleic acid content is associated with cardiac disorders including ischemia and reperfusion, heart failure, and diabetes, as well as the X-linked recessive disease, Barth syndrome. To attain its high levels of linoleic acid, newly synthesized CL must initially undergo remodeling. CL modification and depletion by pathological processes may represent a failure of this remodeling pathway or activation of an alternative "pathological remodeling" pathway that causes the substitution of higher molecular weight, polyunsaturated fatty acyl side chains such as arachidonic or docosahexaenoic acid onto CL. This remodeling may occur in response to the alteration of CL by oxidative mechanisms, but the substituted side chains can also provoke further oxidation of CL. It is increasingly thought that cardiac pathology may result, at least partially, due to changes in CL resulting from the pathological remodeling process. Dietary interventions may restore CL to its linoleic acid-rich form and improve cardiac function by redirecting the remodeling process.
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PMID:Cardiolipin remodeling in the heart. 1927 88

Barth syndrome (BTHS) is an X-linked disorder characterized by skeletal myopathy, neutropenia, growth delay, and cardiomyopathy. It is caused by mutations in the tafazzin gene (TAZ). Although early diagnosis is critical to prevent the progression of heart failure, this disease remains unrecognized when heart failure is not clinically significant. Here we report on a 13-year-old boy with no family history of BTHS who was diagnosed with the syndrome in the subclinical stage of heart failure. The clues to the diagnosis of BTHS in this patient were the findings of lipid storage myopathy in the skeletal muscle biopsy, elevated plasma brain natriuretic peptide, and the diagnosis of isolated noncompaction of the ventricular myocardium in echocardiography. Genetic studies of TAZ revealed a disease-causing mutation (p.Gly216Arg) in this patient. Physicians should be aware of the possibility of this disease and carry out genetic studies when it is considered.
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PMID:Barth syndrome diagnosed in the subclinical stage of heart failure based on the presence of lipid storage myopathy and isolated noncompaction of the ventricular myocardium. 2193 11

Barth syndrome (BTHS) is associated with myocardial disease, frequently left ventricular noncompaction cardiomyopathy, which may necessitate cardiac transplantation or lead to death in some patients. We report a child with BTHS who had an "undulating cardiac phenotype" and ultimately developed decompensated heart failure requiring mechanical circulatory support with a ventricular assist device as a bridge to transplantation. His course was complicated by acute lung injury requiring placement of an in-line oxygenator to maintain end-organ function. Not only was his course complicated by cardiac and respiratory failure but his BTHS associated comorbidities complicated the management of his therapy using mechanical assist device support. He was successfully supported and subsequently was transplanted. Here we discuss the management of a child with BTHS using mechanical circulatory support and describe the use of an in-line oxygenator, Quadrox, with the Berlin Excor device.
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PMID:Left ventricular noncompaction cardiomyopathy in Barth syndrome: an example of an undulating cardiac phenotype necessitating mechanical circulatory support as a bridge to transplantation. 2242 93

Barth syndrome is an X-linked recessive disorder that is characterized by cardiomyopathy, variable neutropenia, skeletal myopathy, growth delay, and organic aciduria. The cardiac involvement typically results in a high risk of severe heart failure in infancy or early childhood. While Berlin Heart EXCOR is widely accepted as ventricular assistance in pediatric patients with end-stage cardiac failure, infections remain a frequent and potentially severe complication. Therefore, the extended use of the device in the setting of intermittent or severe neutropenia is challenging. We present the case of a three-yr child with Barth syndrome who was bridged successfully to transplant with a Berlin Heart EXCOR assist device for eight months (251 days) without major infectious complication, despite several episodes of severe neutropenia. This case demonstrates that prolonged mechanical circulatory support for a patient with neutropenia is feasible without important morbidity, with careful monitoring and a multidisciplinary approach. G-CSF provides an excellent support in managing neutropenia.
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PMID:Successful mechanical circulatory support for 251 days in a child with intermittent severe neutropenia due to Barth syndrome. 2319 Mar 23

Barth syndrome (BTHS) is an X-linked recessive disorder that is typically characterized by cardiomyopathy (CMP), skeletal myopathy, growth retardation, neutropenia, and increased urinary levels of 3-methylglutaconic acid (3-MGCA). There may be a wide variability of phenotypes amongst BTHS patients with some exhibiting some or all of these findings. BTHS was first described as a disease of the mitochondria resulting in neutropenia as well as skeletal and cardiac myopathies. Over the past few years, a greater understanding of BTHS has developed related to the underlying genetic mechanisms responsible for the disease. Mutations in the TAZ gene on chromosome Xq28, also known as G4.5, are responsible for the BTHS phenotype resulting in a loss-of-function in the protein product tafazzin. Clinical management of BTHS has also seen improvement. Patients with neutropenia are susceptible to life-threatening bacterial infections with sepsis being a significant concern for possible morbidity and mortality. Increasingly, BTHS patients are suffering from heart failure secondary to their CMP. Left ventricular noncompaction (LVNC) and dilated CMP are the most common cardiac phenotypes reported and can lead to symptoms of heart failure as well as ventricular arrhythmias. Expanded treatment options for end-stage myocardial dysfunction now offer an opportunity to change the natural history for these patients. Herein, we will provide a current review of the genetic and molecular basis of BTHS, the clinical features and management of BTHS, and potential future directions for therapeutic strategies.
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PMID:Barth syndrome. 2384 53


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