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Articles by S Thorn
Total Records ( 2 ) for S Thorn
  K. D Folmes , A. Y.M Chan , D. P.Y Koonen , T. C Pulinilkunnil , I Baczko , B. E Hunter , S Thorn , M. F Allard , R Roberts , M. H Gollob , P. E Light and J. R.B. Dyck

Background— Humans with an R302Q mutation in AMPK2 (the PRKAG2 gene) develop a glycogen storage cardiomyopathy characterized by a familial form of Wolff-Parkinson-White syndrome and cardiac hypertrophy. This phenotype is recapitulated in transgenic mice with cardiomyocyte-restricted expression of AMPK2R302Q. Although considerable information is known regarding the consequences of harboring the 2R302Q mutation, little is known about the early signaling events that contribute to the development of this cardiomyopathy.

Methods and Results— To distinguish the direct effects of 2R302Q expression from later compensatory alterations in signaling, we used transgenic mice expressing either the wild-type AMPK2 subunit (TG2WT) or the mutated form (TG2R302Q), in combination with acute expression of these proteins in neonatal rat cardiomyocytes. Although acute expression of 2R302Q induces AMPK activation and upregulation of glycogen synthase and AS160, with an associated increase in glycogen content, AMPK activity, glycogen synthase activity, and AS160 expression are reduced in hearts from TG2R302Q mice, likely in response to the existing 37-fold increase in glycogen. Interestingly, 2WT expression has similar, yet less marked effects than 2R302Q expression in both cardiomyocytes and hearts.

Conclusions— Using acute and chronic models of 2R302Q expression, we have differentiated the direct effects of the 2R302Q mutation from eventual compensatory modifications. Our data suggest that expression of 2R302Q induces AMPK activation and the eventual increase in glycogen content, a finding that is masked in hearts from transgenic adult mice. These findings are the first to highlight temporal differences in the effects of the PRKAG2 R302Q mutation on cardiac metabolic signaling events.

  A. C.T Ha , J. M Renaud , R. A deKemp , S Thorn , J DaSilva , L Garrard , K Yoshinaga , A Abraham , M. S Green , R. S.B Beanlands and M. H. Gollob

Background— The PRKAG2 cardiac syndrome is an inherited metabolic disease of the heart characterized by excessive myocardial glycogen deposition. The biochemical alterations associated with this condition remain controversial and have not previously been studied in affected humans.

Methods and Results— Positron emission tomography (PET) imaging was used to quantitatively assess myocardial glucose uptake (MGU) in 6 adult subjects with the PRKAG2 cardiac syndrome and 6 healthy, matched control subjects using the glucose analogue 18F-Fluoro-2-deoxyglucose (FDG). Studies were performed under a euglycemic hyperinsulinemic clamp to ensure stable blood glucose levels. Rubidium-82 perfusion scans were performed to ensure that myocardial differences in myocardial glucose uptake were not the result of significant myocardial scar. In adult patients with phenotypic expression of disease, the median myocardial glucose uptake of the left ventricle was 0.18 µmol/min/g (interquartile range, 0.14, 0.24), compared with 0.40 µmol/min/g (interquartile range, 0.30 to 0.45) in the control group (P=0.01). The median blood glucose during FDG-PET imaging was 4.72 mmol/L (interquartile range, 4.32 to 4.97) in the PRKAG2 group and 4.38 mmol/L (interquartile range, 3.90, 4.79) in the control group (P=NS). The significant decrease observed in myocardial glucose uptake in affected patients occurred in the absence of significant myocardial scar.

Conclusions— The PRKAG2 cardiac syndrome is associated with a reduction of glucose uptake in adult patients affected with this genetic condition. In this pilot study, 18F-FDG-PET imaging is a useful tool to assess alterations in myocardial glucose transport in this inherited metabolic disease and provide insight into the biochemical pathophysiology of the diseased state.

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