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Longitudinal Observational Study of Cardiac Outcome Risk Factor Prediction in Children, Adolescents, and Adults with Barth Syndrome

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Abstract

Barth Syndrome (BTHS) is an X-linked mitochondrial cardioskeletal myopathy caused by defects in TAFAZZIN, a gene responsible for cardiolipin remodeling. Altered mitochondrial levels of cardiolipin lead to cardiomyopathy (CM), muscle weakness, exercise intolerance, and mortality. Cardiac risk factors predicting outcome are unknown. Therefore, we conducted a longitudinal observational study to determine risk factors for outcome in BTHS. Subjects with minimum two evaluations (or one followed by death or transplant) were included. Cardiac size, function, and QTc data were measured by echocardiography and electrocardiography at 7 time points from 2002 to 2018. Analysis included baseline, continuous, and categorical variables. Categorical risk factors included prolonged QTc, abnormal right ventricle fractional area change (RV FAC), left ventricle (LV) or RV non-compaction, and restrictive CM phenotype. The association between variables and cardiac death or transplant (CD/TX) was assessed. Median enrollment age was 7 years (range 0.5–22; n = 44). Transplant-free survival (TFS) was 74.4% at 15 years from first evaluation. The cohort demonstrated longitudinal declines in LV size and stroke volume z-scores (end-diastolic volume, p = 0.0002; stroke volume p < 0.0001), worsening RV FAC (p = 0.0405), and global longitudinal strain (GLS) (p = 0.0001) with stable ejection (EF) and shortening (FS) fraction. CD/TX subjects (n = 9) displayed worsening LV dilation (p = 0.0066), EF (p ≤ 0.0001), FS (p = 0.0028), and RV FAC (p = .0032) versus stability in TFS. Having ≥ 2 categorical risk factors predicted CD/TX (p = 0.0073). Over 15 years, 25% of BTHS subjects progressed to CD/TX. Those with progressive LV enlargement, dysfunction, and multiple cardiac risk factors warrant increased surveillance and intense therapy.

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Acknowledgements

The authors thank the Barth Syndrome Foundation and the health care providers, research staff, patients, and caregivers who participated in this longitudinal observational study. Writing and editing assistance, including incorporating author feedback and manuscript submission, was provided by James A. Shiffer, RPh (Write On Time Medical Communications, LLC) and Gene Kelly (Stealth Biotherapeutics). This support was funded by Stealth Biotherapeutics.

Funding

This study received no grant funding. The Barth Syndrome Foundation funded the Barth Syndrome Registry from which retrospective data were obtained.

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Authors and Affiliations

  1. Medical University of South Carolina, Charleston, SC, USA

    Shahryar Chowdhury, Lanier Jackson, Tammy Lane Churchill & Julia Buchanan

  2. School of Medicine, University of Florida, Gainesville, FL, USA

    Barry J. Byrne

  3. Sanger Heart and Vascular Institute, Charlotte, NC, USA

    Randall M. Bryant

  4. Duke University School of Medicine, Durham, NC, USA

    W. Todd Cade

  5. MUSC Children’s Heart Program, Pediatric Echocardiography Lab, Pediatric Cardiology, Shawn Jenkins Children’s Hospital, MSC 915, 10 McClennan Banks Dr., Charleston, SC, 29425-8905, USA

    Carolyn Taylor

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  1. Shahryar Chowdhury
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Contributions

All authors of this study participated in study design. All authors had access to the data, participated in the development and critical review of the manuscript, approved submission of the manuscript for publication, and are accountable for the accuracy and integrity of the work.

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Correspondence to Carolyn Taylor.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

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Informed consent was obtained from all individual participants included in the study.

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Chowdhury, S., Jackson, L., Byrne, B.J. et al. Longitudinal Observational Study of Cardiac Outcome Risk Factor Prediction in Children, Adolescents, and Adults with Barth Syndrome. Pediatr Cardiol 43, 1251–1263 (2022). https://doi.org/10.1007/s00246-022-02846-8

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