title: Impaired cardiac reserve and severely diminished skeletal muscle O₂ utilization mediate exercise intolerance in Barth syndrome.
abstract: Barth syndrome (BTHS) is a mitochondrial myopathy characterized by reports of exercise intolerance. We sought to determine if 1) BTHS leads to abnormalities of skeletal muscle O(2) extraction/utilization and 2) exercise intolerance in BTHS is related to impaired O(2) extraction/utilization, impaired cardiac function, or both. Participants with BTHS (age: 17 ± 5 yr, n = 15) and control participants (age: 13 ± 4 yr, n = 9) underwent graded exercise testing on a cycle ergometer with continuous ECG and metabolic measurements. Echocardiography was performed at rest and at peak exercise. Near-infrared spectroscopy of the vastus lateralis muscle was continuously recorded for measurements of skeletal muscle O(2) extraction. Adjusting for age, peak O(2) consumption (16.5 ± 4.0 vs. 39.5 ± 12.3 ml·kg(-1)·min(-1), P < 0.001) and peak work rate (58 ± 19 vs. 166 ± 60 W, P < 0.001) were significantly lower in BTHS than control participants. The percent increase from rest to peak exercise in ejection fraction (BTHS: 3 ± 10 vs. control: 19 ± 4%, P < 0.01) was blunted in BTHS compared with control participants. The muscle tissue O(2) saturation change from rest to peak exercise was paradoxically opposite (BTHS: 8 ± 16 vs. control: -5 ± 9, P < 0.01), and the deoxyhemoglobin change was blunted (BTHS: 0 ± 12 vs. control: 10 ± 8, P < 0.09) in BTHS compared with control participants, indicating impaired skeletal muscle extraction in BTHS. In conclusion, severe exercise intolerance in BTHS is due to both cardiac and skeletal muscle impairments that are consistent with cardiac and skeletal mitochondrial myopathy. These findings provide further insight to the pathophysiology of BTHS.
authors.affiliation: Division of Cardiology, Department of Pediatrics, East Carolina University, Greenville, North Carolina, USA.
authors.forename: Carolyn T
authors.initials: CT
authors.lastname: Spencer
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne
authors.forename: Randall M
authors.initials: RM
authors.lastname: Bryant
authors.forename: Renee
authors.initials: R
authors.lastname: Margossian
authors.forename: Melissa
authors.initials: M
authors.lastname: Maisenbacher
authors.forename: Petar
authors.initials: P
authors.lastname: Breitenger
authors.forename: Paul B
authors.initials: PB
authors.lastname: Benni
authors.forename: Sharon
authors.initials: S
authors.lastname: Redfearn
authors.forename: Edward
authors.initials: E
authors.lastname: Marcus
authors.forename: W Todd
authors.initials: WT
authors.lastname: Cade
mesh_terms: D000293:Adolescent; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use; D000704:Analysis of Variance; D056889:Barth Syndrome / Q000150:complications* / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D001794:Blood Pressure; D002311:Cardiomyopathy, Dilated / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D016022:Case-Control Studies; D002648:Child; D003430:Cross-Sectional Studies; D004452:Echocardiography; D004562:Electrocardiography; D005080:Exercise Test; D017079:Exercise Tolerance; D006339:Heart Rate; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D008297:Male; D009119:Muscle Contraction; D010100:Oxygen / Q000097:blood / Q000378:metabolism*; D010101:Oxygen Consumption; D052097:Quadriceps Muscle / Q000378:metabolism* / Q000503:physiopathology; D015656:Respiratory Mechanics; D019265:Spectroscopy, Near-Infrared; D016277:Ventricular Function, Left; D055815:Young Adult
chemical_list: D000319:Adrenergic beta-Antagonists; D015415:Biomarkers; D006454:Hemoglobins; C100003:deoxyhemoglobin; D010100:Oxygen