Cellular and tissue defects associated with insulin resistance are coincident with transcriptional abnormalities and are improved after insulin sensitization with thiazolidinedione (TZD) PPAR␥ ligands. We characterized 72 human subjects by relating their clinical phenotypes with functional pathway alterations. We transcriptionally profiled 364 biopsies harvested before and after hyperinsulinemic-euglycemic clamp studies, at baseline and after 3-month TZD treatment. We have identified molecular and functional characteristics of insulin resistant subjects and distinctions between TZD treatment responder and nonresponder subjects. Insulin resistant subjects exhibited alterations in skeletal muscle (e.g., glycolytic flux and intramuscular adipocytes) and adipose tissue (e.g., mitochondrial metabolism and inflammation) that improved relative to TZD-induced insulin sensitization. Pre-TZD treatment expression of MLXIP in muscle and HLA-DRB1 in adipose tissue from insulin resistant subjects was linearly predictive of post-TZD insulin sensitization. We have uniquely characterized coordinated cellular and tissue functional pathways that are characteristic of insulin resistance, TZD-induced insulin sensitization, and potential TZD responsiveness. muscle and adipose tissue ͉ transcriptional mechanisms ͉ diabetes ͉ branched chain amino acid (BCAA) ͉ inflammation I nsulin resistance is a pathological state in which insulin action is impaired in target tissues including liver, skeletal muscle, and adipose tissue. Insulin resistance is a defining feature of the metabolic syndrome and the primary defect leading to type 2 diabetes (1, 2). Impaired insulin-stimulated glucose uptake in skeletal muscle and lipid metabolism in adipocytes are central characteristics of insulin-resistance. Other manifestations of the condition include elevated intramuscular fat content (3), dysregulation of adipokine secretion, and chronic lowgrade inflammation in adipose tissue (4). Macrophage infiltration in adipose tissue activates inflammatory pathways that induce insulin resistance and modulate the effects of adipose tissue on whole-body metabolism (5). Several studies have shown that decreased mitochondrial protein and oxidative phosphorylation (OXPHOS) in skeletal muscle and adipocytes are also underlying factors of insulin resistance (6, 7).Thiazolidinediones (TZDs) are insulin-sensitizing drugs used to treat type 2 diabetes. TZDs enhance insulin sensitivity by improving glucose and lipid metabolism, altering adipokine secretion, and reducing adipose tissue inflammation (4, 8). Although TZDs improve insulin sensitivity and the glycemic, lipid, and inflammatory profiles of most patients, approximately 30% of diabetic subjects do not respond to TZD treatment, as gauged by fasting plasma glucose or HbA1c levels (9, 10). TZDs are ligands of peroxisome proliferator-activated receptor gamma (PPAR␥) through which they alter the expression of hundreds of genes in skeletal muscle, adipocytes, and macrophages. PPAR␥-mediated gene regulation is the predom...

Purpose Quantification of cardiac flow and ventricular volumes comprise essential goals of many congenital heart MRI examinations, often requiring acquisition of multiple two-dimensional phase contrast (2DPC) and bright blood cine SSFP planes. Scan prescription however, is lengthy and highly reliant on an imager well-versed in structural heart disease. Though also lengthy, 3D time-resolved phase-contrast (4DPC) MRI yields global flow patterns and is simpler to prescribe. We therefore sought to accelerate 4DPC and determine whether equivalent flow and volume measurements could be extracted. Materials and Methods 4DPC was modified for higher acceleration with compressed-sensing. Custom software was developed to process 4DPC images. With IRB-approval and HIPAA-compliance, we studied 29 patients referred for congenital cardiac MRI, who underwent a routine clinical protocol including cine short-axis stack SSFP and 2DPC, followed by contrast-enhanced 4DPC. To compare quantitative measurements, Bland-Altman analysis, paired t-tests, and F-tests were used. Results Ventricular end-diastolic, end-systolic and stroke volumes obtained from 4DPC and SSFP were well-correlated (ρ=0.91–0.95, r2=0.83–0.90), with no statistically significant difference. Ejection fractions were well-correlated in a subpopulation that underwent higher-resolution compressed-sensing 4DPC (ρ=0.88, r2=0.77). 4DPC and 2DPC flow rates were also well-correlated (ρ=0.90, r2=0.82). Excluding ventricles with valvular insufficiency, cardiac outputs derived from outlet valve flow and stroke volumes were more consistent by 4DPC than by 2DPC and SSFP. Conclusion Combined parallel imaging and compressed sensing can be applied to 4DPC. With custom software, flow and ventricular volumes may be extracted with comparable accuracy to SSFP and 2DPC. Further, cardiac outputs were more consistent by 4DPC.

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Purpose:To assess the potential of compressed-sensing parallel-imaging four-dimensional (4D) phase-contrast magnetic resonance (MR) imaging and specialized imaging software in the evaluation of valvular insufficiency and intracardiac shunts in patients with congenital heart disease. Materials andMethods:Institutional review board approval was obtained for this HIPAAcompliant study. Thirty-four consecutive retrospectively identified patients in whom a compressed-sensing parallel-imaging 4D phase-contrast sequence was performed as part of routine clinical cardiac MR imaging between March 2010 and August 2011 and who had undergone echocardiography were included. Multiplanar, volume-rendered, and stereoscopic three-dimensional velocityfusion visualization algorithms were developed and implemented in Java and OpenGL. Two radiologists independently reviewed 4D phase-contrast studies for each of 34 patients (mean age, 6 years; age range, 10 months to 21 years) and tabulated visible shunts and valvular regurgitation. These results were compared with color Doppler echocardiographic and cardiac MR imaging reports, which were generated without 4D phase-contrast visualization. Cohen k statistics were computed to assess interobserver agreement and agreement with echocardiographic results. Results:The 4D phase-contrast acquisitions were performed, on average, in less than 10 minutes. Among 123 valves seen in 34 4D phasecontrast studies, 29 regurgitant valves were identified, with good agreement between observers (k = 0.85). There was also good agreement with the presence of at least mild regurgitation at echocardiography (observer 1, k = 0.76; observer 2, k = 0.77) with high sensitivity (observer 1, 75%; observer 2, 82%) and specificity (observer 1, 97%; observer 2, 95%) relative to the reference standard. Eight intracardiac shunts were identified, four of which were not visible with conventional cardiac MR imaging but were detected with echocardiography. No intracardiac shunts were found with echocardiography alone. Conclusion:With velocity-fusion visualization, the compressed-sensing parallel-imaging 4D phase-contrast sequence can augment conventional cardiac MR imaging by improving sensitivity for and depiction of hemodynamically significant shunts and valvular regurgitation.q RSNA, 2012 Supplemental material: http://radiology.rsna.org/lookup /suppl

Purpose To evaluate precision and accuracy of parallel-imaging compressed-sensing 4D phase contrast (PICS-4DPC) MRI venous flow quantification in children with patients referred for cardiac MRI at our children’s hospital. Materials and Methods With IRB approval and HIPAA compliance, 22 consecutive patients without shunts underwent 4DPC as part of clinical cardiac MRI examinations. Flow measurements were obtained in the superior and inferior vena cava, ascending and descending aorta and the pulmonary trunk. Conservation of flow to the upper, lower and whole body was used as an internal physiologic control. The arterial and venous flow rates at each location were compared with paired t-tests and F-tests to assess relative accuracy and precision. RESULTS Arterial and venous flow measurements were strongly correlated for the upper (ρ=0.89), lower (ρ=0.96) and whole body (ρ=0.97); net aortic and pulmonary trunk flow rates were also tightly correlated (ρ=0.97). There was no significant difference in the value or precision of arterial and venous flow measurements in upper, lower or whole body, though there was a trend toward improved precision with lower velocity-encoding settings. Conclusion With PICS-4DPC MRI, the accuracy and precision of venous flow quantification are comparable to that of arterial flow quantification at velocity-encodings appropriate for arterial vessels.