Cited by 89Glycogen Storage Diseases and MyoclonusCardiac electrophysiology and arrhythmiasCardiomyopathy and Myosin Studies

Reversibility of PRKAG2 Glycogen-Storage Cardiomyopathy and Electrophysiological Manifestations

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Wolf, Cordula M., Arad, Michael, Ahmad, Ferhaan, Sanbe, Atsushi, Bernstein, Scott A., Toka, Okan, Konno, Tetsuo, Morley, Gregory +4 more·2008·Circulation

Abstract

BACKGROUND: PRKAG2 mutations cause glycogen-storage cardiomyopathy, ventricular preexcitation, and conduction system degeneration. A genetic approach that utilizes a binary inducible transgenic system was used to investigate the disease mechanism and to assess preventability and reversibility of disease features in a mouse model of glycogen-storage cardiomyopathy. METHODS AND RESULTS: Transgenic (Tg) mice expressing a human N488I PRKAG2 cDNA under control of the tetracycline-repressible alpha-myosin heavy chain promoter underwent echocardiography, ECG, and in vivo electrophysiology studies. Transgene suppression by tetracycline administration caused a reduction in cardiac glycogen content and was initiated either prenatally (Tg(OFF(E-8 weeks))) or at different time points during life (Tg(OFF(4-16 weeks)), Tg(OFF(8-20 weeks)), and Tg(OFF(>20 weeks))). One group never received tetracycline, expressing transgene throughout life (Tg(ON)). Tg(ON) mice developed cardiac hypertrophy followed by dilatation, ventricular preexcitation involving multiple accessory pathways, and conduction system disease, including sinus and atrioventricular node dysfunction. CONCLUSIONS: Using an externally modifiable transgenic system, cardiomyopathy, cardiac dysfunction, and electrophysiological disorders were demonstrated to be reversible processes in PRKAG2 disease. Transgene suppression during early postnatal development prevented the development of accessory electrical pathways but not cardiomyopathy or conduction system degeneration. Taken together, these data provide insight into mechanisms of cardiac PRKAG2 disease and suggest that glycogen-storage cardiomyopathy can be modulated by lowering glycogen content in the heart.

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Crossref · 10.1161/circulationaha.107.726752

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Authors
Wolf, C. M., Arad, M., Ahmad, F., Sanbe, A., Bernstein, S. A., Toka, O., Konno, T., Morley, G., Robbins, J., Seidman, J. G., Seidman, C. E., & Berul, C. I.
Affiliations
Cincinnati Children's Hospital Medical Center (US)
Venue
Circulation
Published
2008-01-15
Volume
117
Issue
2
Pages
144-154
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
OpenAlex
W2095690908
Cited by
89
References
43
Citations by year
2026: 3 · 2025: 5 · 2024: 3 · 2023: 4 · 2022: 7 · 2021: 5 · 2020: 2 · 2019: 7 · 2018: 4 · 2017: 5 · 2016: 6 · 2015: 4 · 2014: 4 · 2013: 4 · 2012: 4
FWCI
3.68
Type
journal article
Language
en
Open access
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Howard Hughes Medical Institute
  • National Institutes of Health
  • National Heart, Lung, and Blood Institute (R01HL076751)
Topics
  • Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
Keywords
PRKAG2, preexcitation, accessory pathway, cardiac hypertrophy, dilated cardiomyopathy, cardiac glycogen, atrioventricular node dysfunction, sick sinus syndrome
MeSH terms
Age Factors, Animals, Electrocardiography, Electrophysiology, Glycogen, Humans, Mice, Transgenic, Multienzyme Complexes, Promoter Regions, Genetic, Tetracycline, Genetic Therapy, Protein Serine-Threonine Kinases, Mice, Glycogen Storage Disease Type IIb, AMP-Activated Protein Kinases

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