Abstract | BACKGROUND: METHODS AND RESULTS: To elucidate the mechanism by which PRKAG2 mutations produce hypertrophy with electrophysiological abnormalities, we constructed transgenic mice overexpressing the PRKAG2 cDNA with or without a missense N488I human mutation. Transgenic mutant mice showed elevated AMP-activated protein kinase activity, accumulated large amounts of cardiac glycogen (30-fold above normal), developed dramatic left ventricular hypertrophy, and exhibited ventricular preexcitation and sinus node dysfunction. Electrophysiological testing demonstrated alternative atrioventricular conduction pathways consistent with WPW. Cardiac histopathology revealed that the annulus fibrosis, which normally insulates the ventricles from inappropriate excitation by the atria, was disrupted by glycogen-filled myocytes. These anomalous microscopic atrioventricular connections, rather than morphologically distinct bypass tracts, appeared to provide the anatomic substrate for ventricular preexcitation. CONCLUSIONS:
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Authors | Michael Arad, Ivan P Moskowitz, Vickas V Patel, Ferhaan Ahmad, Antonio R Perez-Atayde, Douglas B Sawyer, Mark Walter, Guo H Li, Patrick G Burgon, Colin T Maguire, David Stapleton, Joachim P Schmitt, X X Guo, Anne Pizard, Sabina Kupershmidt, Dan M Roden, Charles I Berul, Christine E Seidman, J G Seidman |
Journal | Circulation
(Circulation)
Vol. 107
Issue 22
Pg. 2850-6
(Jun 10 2003)
ISSN: 1524-4539 [Electronic] United States |
PMID | 12782567
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Multienzyme Complexes
- Protein Serine-Threonine Kinases
- AMP-Activated Protein Kinases
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Topics |
- AMP-Activated Protein Kinases
- Animals
- Cardiomyopathies
(complications, pathology, physiopathology)
- Disease Models, Animal
- Electrocardiography
- Electrophysiologic Techniques, Cardiac
- Glycogen Storage Disease
(complications, pathology, physiopathology)
- Heart Conduction System
(physiopathology)
- Humans
- Mice
- Mice, Transgenic
- Multienzyme Complexes
(biosynthesis, genetics, metabolism)
- Mutation
- Myocardium
(pathology)
- Protein Serine-Threonine Kinases
(biosynthesis, genetics, metabolism)
- Survival Rate
- Wolff-Parkinson-White Syndrome
(etiology, pathology, physiopathology)
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