Abstract
BACKGROUND: Mutations in the gamma2 subunit (PRKAG2) of AMP-activated
protein kinase produce an unusual human cardiomyopathy characterized
by ventricular hypertrophy and electrophysiological abnormalities:
Wolff-Parkinson-White syndrome (WPW) and progressive degenerative
conduction system disease. Pathological examinations of affected
human hearts reveal vacuoles containing amylopectin, a glycogen-related
substance. 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: Our data establish PRKAG2
mutations as a glycogen storage cardiomyopathy, provide an anatomic
explanation for electrophysiological findings, and implicate disruption
of the annulus fibrosis by glycogen-engorged myocytes as the cause
of preexcitation in Pompe, Danon, and other glycogen storage diseases.
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