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Characterization of the ‘metabolic phenotype’ in Barth syndrome with cardiac transplantation

Characterization of the 'metabolic phenotype' in Barth syndrome with cardiac transplantation
W. Todd Cade, PT, PhD, Professor, Washington University, St. Louis, Missouri

Award: US $49,820 over 1-year period with $21,000 in travel expenses

*Funding for this award was provided by the Will McCurdy Fund for Advancement in Therapies for Barth Syndrome


Barth syndrome (BTHS) is an X-linked disorder caused by recessive loss-of-function mutations in the tafazzin (TAZ) gene resulting in abnormal mitochondria and cardioskeletal myopathy, exercise intolerance, neutropenia and growth delay. BTHS can result in cardiac transplantation or death in childhood, adolescence, or young adulthood; all leading to the urgency for novel studies examining the pathophysiology of BTHS and finding effective treatments for it. To this end, our group is currently performing a federally funded study to characterize cardioskeletal morphology, substrate metabolism, energetics and function (i.e. ‘metabolic phenotype’) in BTHS children, adolescents and adults without cardiac transplantation (R01 HL107406-01; NCT01625663). Treatment of heart failure in BTHS is not optimal, and 15% of BTHS ultimately require cardiac transplant. Cardiac transplant in patients without BTHS improves muscle mass, skeletal muscle oxidative capacity, vascular function, and exercise tolerance and can cause a variety of changes in skeletal muscle metabolism including a shift towards improvements in oxidative and glycolytic enzymes. Therefore, it is likely that adaptations after heart transplant have a significant effect on the ‘metabolic phenotype’ in those BTHS patients who undergo cardiac transplantation. Despite this, the effects of cardiac transplantation on cardioskeletal body composition, substrate metabolism, energetics and function are unknown in patients with BTHS. Characterizing this ‘phenotype’ could provide information regarding important differences between BTHS patients with and without cardiac transplantation that might lead to unique treatment paradigms and tailored interventions. Therefore, through this study, we propose to obtain ‘phenotypic’ information on cardioskeletal morphology (mass and strength), substrate metabolism, energetics and function in BTHS participants with cardiac transplantation (n=10) and compare them to age-matched BTHS participants without transplantation (n=10) and unaffected controls (n=10, from our ongoing study) through the following aims:  Specific Aim 1: To characterize peak exercise tolerance, Specific Aim 2: To characterize skeletal muscle morphology and strength, and Specific Aim 3: To characterize skeletal muscle substrate metabolism and energetics. We plan to investigate these Aims using air displacement plethysmography, stable-isotope tracer methodologies, mass spectrometry, magnetic resonance spectroscopy (MRS), graded exercise testing, isokinetic dynamometry and 2-D, Doppler, tissue Doppler, and strain/strain rate echocardiography. This is a unique opportunity to leverage our current R01 funding and clinical metabolism study framework to provide non-transplanted BTHS and unaffected controls for comparison and to provide the additional funding necessary for the completion of this IDEA study. Information gained from this study will advance our understanding of the metabolic and clinical presentation of BTHS patients who have undergone cardiac transplantation and could provide insights into the pathophysiology of BTHS in the absence of overt cardiomyopathy.

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