Heart and Muscle Metabolism in Barth Syndrome

Study Overview
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Brief Summary
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Barth syndrome (BTHS) is an X-linked disorder caused by abnormal cardiolipin metabolism and is characterized by skeletal and cardiomyopathy and high mortality rates. Through clinical metabolism and imaging studies and pluripotent stem cell induction and molecular techniques on skin biopsy samples, this project will produce novel translational information regarding the pathogenesis of BTHS, reveal potential targets for interventions and provide unique data regarding nutrient metabolism and abnormal cardiolipin and mitochondrial function. This project has the potential to provide information that could significantly improve morbidity and mortality in children and young adults with BTHS and may have relevance to other non-BTHS related conditions such as aging and adult heart failure.

Detailed Description
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Barth syndrome (BTHS) is an X-linked disorder characterized by abnormal cardiolipin metabolism, mitochondrial dysfunction, muscle wasting and heart failure. BTHS is a particularly significant disease as it is often fatal in childhood and there are no approved therapies for BTHS other than the standard treatment of heart failure. Therefore novel areas of research and platforms in which to test new therapies are highly needed. Through state-of-the-art and innovative methodologies, this project will focus on the novel role of skeletal muscle and heart nutrient (glucose, fatty acid, and amino acid) metabolism in the pathogenesis of BTHS. Phenotypic information regarding skeletal muscle and heart nutrient metabolism in BTHS and how it may relate to energy production and function of these organs is lacking and is significant as this may advance our understanding of the underlying pathogenesis of BTHS. With this understanding, safe and efficacious therapies can be targeted for BTHS. The investigators' overall hypothesis is that impaired fatty acid metabolism in skeletal muscle and the heart produces a fuel deficit in these organs leading to impaired energy production, exercise intolerance and heart failure. Further, as a consequence of impaired fatty acid metabolism in skeletal muscle and the heart, protein breakdown (wasting) in skeletal muscle and the heart occurs to provide amino acids as compensation for this inadequate fatty acid energy supply, thereby worsening heart and skeletal muscle function in BTHS. The investigators' aims to address this hypothesis in 30 young adults and children with BTHS and 30 healthy, age, puberty stage and activity level matched controls ages 8-35 years are: 1) To characterize skeletal muscle and heart nutrient metabolism and 2) To examine the relationship between skeletal muscle and heart nutrient metabolism, energy production and function (exercise tolerance and heart function). As an exploratory aim, we will examine mechanistic molecular pathways of nutrient metabolism; specifically protein breakdown, mitochondrial function and fatty acid metabolism, in human myocytes derived from inducible pluripotent stem cells (from skin fibroblasts) obtained from adults and children with BTHS and from adult controls. Skeletal muscle nutrient metabolism will be quantified by stable-isotope tracer methodology and mass spectrometry, heart nutrient metabolism using radio-isotope tracer methodology and PET imaging, skeletal muscle and heart energy production using magnetic resonance spectroscopy, skeletal muscle function by graded exercise testing and indirect calorimetry, heart function by echocardiography, and myocyte nutrient pathway mechanism examination by pluripotent stem cell induction and protein and RNA expression analyses.

Official Title
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Heart and Skeletal Muscle Metabolism, Energetics and Function in Barth Syndrome

Conditions
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Barth Syndrome

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: confirmed diagnosis of BTHS or healthy control age 8-35 years sedentary (physically active less than 2x/wk) stable on medications for ≥ 3 months including ß-blockers, ACE inhibitors, digoxin lives in North America, the UK, Europe, South Africa or other locations feasible for travel to the US Exclusion Criteria: current unstable heart disease diabetes or other known concurrent disease that may affect nutrient metabolism

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Barth syndrome<br>Children (8-17 yrs) and adults (18-35 yrs) | |
| Controls<br>Children (8-15 yrs) and adults (18-35 yrs) | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Whole-body fatty acid oxidation rate | Whole-body fatty acid oxidation rate will be measured by 13C-labeled fatty acid stable isotope tracer infusion and mass spectrometry | baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| whole-body amino acid oxidation rate | whole-body amino acid oxidation rate will be measured by 13C leucine stable isotope tracer infusion and mass spectrometry | baseline | 
| cardiac energetics | cardiac energetics will be measured by 31P magnetic resonance spectroscopy of the heart | baseline | 
| skeletal muscle energetics | skeletal muscle energetics will be measured by 31P magnetic resonance spectroscopy | baseline | 
| Myocardial fatty acid oxidation rate | Myocardial fatty acid oxidation rate will be measured by radio-isotope tracer infusion and PET imaging | baseline | 
| left ventricular systolic strain | Left ventricular systolic strain will be measured by tissue Doppler echocardiography | baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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barth syndrome, heart failure, mitochondria, metabolism, amino acid