Transgenic knockdown of cardiac sodium/glucose cotransporter 1 (SGLT1) attenuates PRKAG2 cardiomyopathy, whereas transgenic overexpression of cardiac SGLT1 causes pathologic hypertrophy and dysfunction in mice.

BACKGROUND: The expression of a novel cardiac glucose transporter, SGLT1, is increased in glycogen storage cardiomyopathy secondary to mutations in PRKAG2. We sought to determine the role of SGLT1 in the pathogenesis of PRKAG2 cardiomyopathy and its role in cardiac structure and function. METHODS AND RESULTS: Transgenic mice with cardiomyocyte-specific overexpression of human T400N mutant PRKAG2 cDNA (TG(T400N)) and transgenic mice with cardiomyocyte-specific RNA interference knockdown of SGLT1 (TG(SGLT1-DOWN)) were crossed to produce double-transgenic mice (TG(T400N)/TG(SGLT1-DOWN)). Tet-off transgenic mice conditionally overexpressing cardiac SGLT1 in the absence of doxycycline were also constructed (TG(SGLT-ON)). Relative to TG(T400N) mice, TG(T400N)/TG(SGLT1-DOWN) mice exhibited decreases in cardiac SGLT1 expression (63% decrease, P<0.05), heart/body weight ratio, markers of cardiac hypertrophy, and cardiac glycogen content. TG(T400N)/TG(SGLT1-DOWN) mice had less left ventricular dilation at age 12 weeks compared to TG(T400N) mice. Relative to wildtype (WT) mice, TG(SGLT1-ON) mice exhibited increases in heart/body weight ratio, glycogen content, and markers of cardiac hypertrophy at ages 10 and 20 weeks. TG(SGLT1-ON) mice had increased myocyte size and interstitial fibrosis, and progressive left ventricular dysfunction. When SGLT1 was suppressed after 10 weeks of overexpression (TG(SGLT1-ON/OFF)), there was a reduction in cardiac hypertrophy and improvement in left ventricular failure. CONCLUSIONS: Cardiac knockdown of SGLT1 in a murine model of PRKAG2 cardiomyopathy attenuates the disease phenotype, implicating SGLT1 in the pathogenesis. Overexpression of SGLT1 causes pathologic cardiac hypertrophy and left ventricular failure that is reversible. This is the first report of cardiomyocyte-specific transgenic knockdown of a target gene.

fMRI-driven DTT assessment of corticospinal tracts prior to cortex resection.

BACKGROUND: The role of diffusion tensor tractography (DTT) has become increasingly important in the preoperative mapping of brain white matter. Recently, functional magnetic resonance imaging (fMRI) driven DTT has provided the ability to evaluate the spatial relationship between the corticospinal tract (CST) and motor resection tumor boundaries. The main objective of this study was improvement of the preoperative assessment of the CST in patients with gliomas involving the motor cortical areas. METHODS: Seventeen patients with gliomas involving motor cortical areas underwent 3 dimensions (3D) T1-weighted imaging for anatomical referencing, using both fMRI and diffusion tensor imaging (DTI). We used the fast-marching tractography (FMT) algorithm to define the 3D connectivity maps within the whole brain using seed points selected in the white matter adjacent to the location of fMRI activation. The target region of interest (ROI) was placed in the cerebral peduncle. Karnofsky performance status (KPS) scores were evaluated for each patient before and after surgery. RESULTS: The CST of a total seventeen patients were successfully tracked by choosing seed and target ROI on the path of the fibers. What is more, DTT can indicate preoperatively the possibility for total glioma removal or the maximum extent of surgical resection. The postoperative average KPS score for the seventeen patients enrolled increased by more than 10 points. CONCLUSIONS: Incorporation of fMRI driven DTT showed a maximum benefit in surgical treatment of gliomas. Our study of the assessment precision should enhance the accuracy of glioma operations with a resulting improvement in postoperative patient outcome.