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(Circulation. 2008;117:144-154.)
© 2008 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Reversibility of PRKAG2 Glycogen-Storage Cardiomyopathy and Electrophysiological Manifestations

Cordula M. Wolf, MD^*; Michael Arad, MD^*; Ferhaan Ahmad, MD, PhD; Atsushi Sanbe, PhD; Scott A. Bernstein, MD; Okan Toka, MD; Tetsuo Konno, MD; Gregory Morley, PhD; Jeffrey Robbins, PhD; J.G. Seidman, PhD; Christine E. Seidman, MD; Charles I. Berul, MD

From the Department of Cardiology, Children’s Hospital Boston (C.M.W., C.I.B.) and Department of Genetics (T.K., J.G.S., C.E.S.), Harvard Medical School, Boston, Mass; Sheba Medical Center (M.A.), Tel Aviv University, Israel; Cardiovascular Institute and Department of Medicine and Human Genetics (F.A.), University of Pittsburgh, Pittsburgh, Pa; Molecular Cardiovascular Biology (A.S., J.R.), Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; Department of Cardiology, New York University School of Medicine (S.A.B., G.M.), New York, NY; Department of Cardiology, Friedrich-Alexander University (O.T.), Erlangen, Germany; and Howard Hughes Medical Institute (J.G.S.), Boston, Mass.

Correspondence to Charles I. Berul, MD, Department of Cardiology, Children’s Hospital Boston, 300 Longwood Ave, Boston, MA 02115. E-mail charles.berul{at}cardio.chboston.org

Received July 9, 2007; accepted October 11, 2007.

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 -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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Clinical Summaries
Circulation 2008 117: 127. [Full Text]