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(Circulation. 2008;117:134-135.)
© 2008 American Heart Association, Inc.

Editorial

Modulating Phenotypic Expression of the PRKAG2 Cardiac Syndrome

Michael H. Gollob, MD

From the Arrhythmia Research Laboratory, Department of Cellular and Molecular Medicine, and Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.

Correspondence to Dr Michael H. Gollob, Arrhythmia Research Laboratory, Department of Cellular and Molecular Medicine, and Division of Cardiology, University of Ottawa Heart Institute, Room H350, 40 Ruskin St, Ottawa, Ontario, Canada K1Y 4W7. E-mail mgollob@ottawaheart.ca

Key Words: Editorials • genes • cardiomyopathy

An extract of the first 250 words of the full text is provided, because this article has no abstract.

The PRKAG2 cardiac syndrome is a rare, autosomal-dominant genetic disease of the heart. Genetic defects in the Prkag2 gene, encoding the regulatory subunit of AMP-activated protein kinase (AMPK), lead to a diverse cardiac phenotype of variable clinical expressivity.¹ Typically, affected patients present in late adolescence with frequent paroxysms of supraventricular arrhythmias, demonstrate ventricular preexcitation on 12-lead ECG, and commonly progress to high-grade conduction system disease requiring a permanent pacemaker by their fourth or fifth decade of life. A significant proportion of patients develop mild to severe cardiac hypertrophy with progression to dilated cardiomyopathy. Phenotypic variability within a family is common, suggesting an influence of genetic modifiers. In addition, specific mutations of the Prkag2 gene may predict clinical expression. Mutations giving rise to atrial fibrillation and conduction disease only, severe neonatal cardiomyopathy with death, or skeletal myopathy with a cardiac phenotype have all been described.^2–4

Article p 144

Most intriguing, the arrhythmogenic nature and cardiomyopathic process of this disease are not caused by primary genetic defects in cardiac ion channels or structural proteins. Rather, the PRKAG2 cardiac syndrome is a disease of cardiac metabolism. AMPK enzymatic activity serves a critical role in regulating cellular glucose and fatty acid metabolic pathways. In situations of increased cellular energy demand in muscle, AMPK activation promotes ATP repletion by facilitating cellular glucose uptake and oxidative metabolism.⁵ A perturbation in the exquisite regulation of these metabolic pathways, as caused by mutations in the regulatory subunit of AMPK, leads to a derangement in cardiac metabolism, giving rise . . . [Full Text of this Article]