Chronic AMPK activity dysregulation produces myocardial insulin resistance in the human Arg302Gln-PRKAG2 glycogen storage disease mouse model

BACKGROUND: The cardiac PRKAG2 mutation in the γ2-subunit of adenosine monophosphate activated kinase (AMPK) is characterized by excessive glycogen deposition, hypertrophy, frequent arrhythmias, and progressive conduction system disease. We investigated whether myocardial glucose uptake (MGU) was augmented following insulin stimulation in a mouse model of the PRKAG2 cardiac syndrome. METHODS: Myocardial and skeletal muscle glucose uptake was assessed with 2-[(18)F]fluoro-2-deoxyglucose positron emission tomography imaging in n = 3 transgenic wildtype (TGwt) vs n = 7 PRKAG2 mutant (TGmut) mice at baseline and 1 week later, 30 min following acute insulin. Systolic function, cardiac glycogen stores, phospho-AMPK α, and insulin-receptor expression levels were analyzed to corroborate to the in vivo findings. RESULTS: TGmut Patlak Ki was reduced 56% at baseline compared to TGwt (0.3 ± 0.2 vs 0.7 ± 0.1, t test p = 0.01). MGU was augmented 71% in TGwt mice following acute insulin from baseline (0.7 ± 0.1 to 1.2 ± 0.2, t test p < 0.05). No change was observed in TGmut mice. As expected for this cardiac specific transgene, skeletal muscle was unaffected at baseline with a 33% to 38% increase (standard uptake values) for both genotypes following insulin stimulation. TGmut mice had a 47% reduction in systolic function with a fourfold increase in cardiac glycogen stores correlated with a 29% reduction in phospho-AMPK α levels. There was no difference in cardiac insulin receptor expression between mouse genotypes. CONCLUSIONS: These results demonstrate a correlation between insulin resistance and AMPK activity and provide the basis for the use of this animal model for assessing metabolic therapy in the treatment of affected PRKAG2 patients

Phase analysis of gated PET in the evaluation of mechanical ventricular synchrony:A narrative overview

Noninvasive imaging modalities offer the possibility to dynamically evaluate cardiac motion during the cardiac cycle by means of ECG-gated acquisitions. Such motion characterization along with orientation, segmentation preprocessing, and ultimately, phase analysis, can provide quantitative estimates of ventricular mechanical synchrony. Current evidence on the role of mechanical synchrony evaluation is mainly available for echocardiography and gated single-photon emission computed tomography, but less is known about the utilization of gated positron emission tomography (PET). Although data available are sparse, there is indication that mechanical synchrony evaluation can be of diagnostic and prognostic values in patients with known or suspected coronary artery disease-related myocardial ischemia, prediction of response to cardiac resynchronization therapy, and estimation of risk for adverse cardiac events in patients’ heart failure. As such, the evaluation of mechanical ventricular synchrony through phase analysis of gated acquisitions represents a value addition to modern cardiac PET imaging modality, which warrants further research and development in the evaluation of patients with cardiovascular disease

Imaging atherosclerosis with hybrid [(18)F]fluorodeoxyglucose positron emission tomography/computed tomography imaging: What Leonardo da Vinci could not see

Prodigious efforts and landmark discoveries have led toward significant advances in our understanding of atherosclerosis. Despite significant efforts, atherosclerosis continues globally to be a leading cause of mortality and reduced quality of life. With surges in the prevalence of obesity and diabetes, atherosclerosis is expected to have an even more pronounced impact upon the global burden of disease. It is imperative to develop strategies for the early detection of disease. Positron emission tomography (PET) imaging utilizing [18F]fluorodeoxyglucose (FDG) may provide a non-invasive means of characterizing inflammatory activity within atherosclerotic plaque, thus serving as a surrogate biomarker for detecting vulnerable plaque. The aim of this review is to explore the rationale for performing FDG imaging, provide an overview into the mechanism of action, and summarize findings from the early application of FDG PET imaging in the clinical setting to evaluate vascular disease. Alternative imaging biomarkers and approaches are briefly discussed. © 2012 The Author(s)

MicroRNA-133 Controls Brown Adipose Determination in Skeletal Muscle Satellite Cells by Targeting Prdm16

SummaryBrown adipose tissue (BAT) is an energy-dispensing thermogenic tissue that plays an important role in balancing energy metabolism. Lineage-tracing experiments indicate that brown adipocytes are derived from myogenic progenitors during embryonic development. However, adult skeletal muscle stem cells (satellite cells) have long been considered uniformly determined toward the myogenic lineage. Here, we report that adult satellite cells give rise to brown adipocytes and that microRNA-133 regulates the choice between myogenic and brown adipose determination by targeting the 3′UTR of Prdm16. Antagonism of microRNA-133 during muscle regeneration increases uncoupled respiration, glucose uptake, and thermogenesis in local treated muscle and augments whole-body energy expenditure, improves glucose tolerance, and impedes the development of diet-induced obesity. Finally, we demonstrate that miR-133 levels are downregulated in mice exposed to cold, resulting in de novo generation of satellite cell-derived brown adipocytes. Therefore, microRNA-133 represents an important therapeutic target for the treatment of obesity

Characterization of 3D PET systems for accurate quantification of myocardial blood flow

Three-dimensional (3D) mode imaging is the current standard for positron emission tomography-computed tomography (PET-CT) systems. Dynamic imaging for quantification of myocardial blood flow (MBF) with short-lived tracers, such as Rb-82- chloride (Rb-82), requires accuracy to be maintained over a wide range of isotope activities and scanner count-rates. We propose new performance standard measurements to characterize the dynamic range of PET systems for accurate quantitative imaging. Methods: 1100-3000 MBq of Rb-82 or N-13-ammonia was injected into the heart wall insert of an anthropomorphic torso phantom. A decaying isotope scan was performed over 5 half-lives on 9 different 3D PET-CT systems and 1 3D/twodimensional (2D) PET-only system. Dynamic images (28x15s) were reconstructed using iterative algorithms with all corrections enabled. Dynamic range was defined as the maximum activity in the myocardial wall with <10% bias, from which corresponding dead-time, count-rates and/or injected activity limits were established for each scanner. Scatter correction residual bias was estimated as the maximum cavity blood-tomyocardium activity ratio. Image quality was assessed via the coefficient of variation measuring non-uniformity of the left ventricle (LV) myocardium activity distribution. Results: Maximum recommended injected activity/body-weight, peak dead-time correction factor, count-rates and residual scatter bias for accurate cardiac MBF imaging were: 3-14 MBq/kg, 1.5-4.0, 22-64 Mcps singles and 4-14 Mcps prompt coincidence count-rates, and 2-10% on the investigated scanners. Non-uniformity of the myocardial activity distribution varied from 3-16%. Conclusion: Accurate dynamic imaging is possible on the 10 3D-PET systems if the maximum injected MBq/kg values are respected to limit peak dead-time losses during the bolus first-pass transit

Optimally Repeatable Kinetic Model Variant for Myocardial Blood Flow Measurements with 82Rb PET

Purpose. Myocardial blood flow (MBF) quantification with R b 82 positron emission tomography (PET) is gaining clinical adoption, but improvements in precision are desired. This study aims to identify analysis variants producing the most repeatable MBF measures. Methods. 12 volunteers underwent same-day test-retest rest and dipyridamole stress imaging with dynamic R b 82 PET, from which MBF was quantified usin

A Clinical Tool to Identify Candidates for Stress-First Myocardial Perfusion Imaging

Objectives: This study sought to develop a clinical model that identifies a lower-risk population for coronary artery disease that could benefit from stress-first myocardial perfusion imaging (MPI) protocols and that can be used at point of care to risk stratify patients. Background: There is an increasing interest in stress-first and stress-only imaging to reduce patient radiation exposure and improve patient workflow and experience. Methods: A secondary analysis was conducted on a single-center cohort of patients undergoing single-photon emission computed tomography (SPECT) and positron emission tomography (PET) studies. Normal MPI was defined by the absence of perfusion abnormalities and other ischemic markers and the presence of normal left ventricular wall motion and left ventricular ejection fraction. A model was derived using a cohort of 18,389 consecutive patients who underwent SPECT and was validated in a separate cohort of patients who underwent SPECT (n = 5,819), 1 internal cohort of patients who underwent PET (n=4,631), and 1 external PET cohort (n = 7,028). Results: Final models were made for men and women and consisted of 9 variables including age, smoking, hypertension, diabetes, dyslipidemia, typical angina, prior percutaneous coronary intervention, prior coronary artery bypass graft, and prior myocardial infarction. Patients with a score ≤1 were stratified as low risk. The model was robust with areas under the curve of 0.684 (95% confidence interval [CI]: 0.674 to 0.694) and 0.681 (95% CI: 0.666 to 0.696) in the derivation cohort, 0.745 (95% CI: 0.728 to 0.762) and 0.701 (95% CI: 0.673 to 0.728) in the SPECT validation cohort, 0.672 (95% CI: 0.649 to 0.696) and 0.686 (95% CI: 0.663 to 0.710) in the internal PET validation cohort, and 0.756 (95% CI: 0.740 to 0.772) and 0.737 (95% CI: 0.716 to 0.757) in the external PET validation cohort in men and women, respectively. Men and women who scored ≤1 had negative likelihood ratios of 0.48 and 0.52, respectively. Conclusions: A novel model, based on easily obtained clinical variables, is proposed to identify patients with low probability of having abnormal MPI results. This point-of-care tool may be used to identify a population that might qualify for stress-first MPI protocols

Effects of ranolazine on right ventricular function, fluid dynamics, and metabolism in patients with precapillary pulmonary hypertension: insights from a longitudinal, randomized, double-blinded, placebo controlled, multicenter study

IntroductionRight ventricular (RV) function is a major determinant of outcome in patients with precapillary pulmonary hypertension (PH). We studied the effect of ranolazine on RV function over 6 months using multi-modality imaging and biochemical markers in patients with precapillary PH (groups I, III, and IV) and RV dysfunction [CMR imaging ejection fraction (EF) &lt; 45%] in a longitudinal, randomized, double-blinded, placebo-controlled, multicenter study of ranolazine treatment.MethodsEnrolled patients were assessed using cardiac magnetic resonance (CMR) imaging, 11C-acetate and 18-F-FDG positron emission tomography (PET), and plasma metabolomic profiling, at baseline and at the end of treatment.ResultsTwenty-two patients were enrolled, and 15 patients completed all follow-up studies with 9 in the ranolazine arm and 6 in the placebo arm. RVEF and RV/Left ventricle (LV) mean glucose uptake were significantly improved after 6 months of treatment in the ranolazine arm. Metabolomic changes in aromatic amino acid metabolism, redox homeostasis, and bile acid metabolism were observed after ranolazine treatment, and several changes significantly correlated with changes in PET and CMR-derived fluid dynamic measurements.DiscussionRanolazine may improve RV function by altering RV metabolism in patients with precapillary PH. Larger studies are needed to confirm the beneficial effects of ranolazine

One-tissue compartment model for myocardial perfusion quantification with N-13 ammonia PET provides matching results: A cross-comparison between Carimas, FlowQuant, and PMOD

Purpose To cross-compare three software packages (SPs)-Carimas, FlowQuant, and PMOD-to quantify myocardial perfusion at global, regional, and segmental levels. Materials and Methods Stress N-13 ammonia PET scans of 48 patients with HCM were analyzed in three centers using Carimas, FlowQuant, and PMOD. Values agreed if they had an ICC > 0.75 and a difference < 20% of the median across all observers. Results When using 1TCM on the global level, the agreement was good, and the maximum difference between 1TCM MBF values was 17.2% (ICC = 0.83). On the regional level, the agreement was acceptable except in the LCx region (25.5% difference, ICC = 0.74) between FlowQuant and PMOD. Carimas-1TCM agreed well with PMOD-1TCM and FlowQuant-1TCM. Values obtained with FlowQuant-1TCM had a somewhat lesser agreement with PMOD-1TCM, especially at the segmental level. Conclusions The global and regional MBF values (with one exception) agree well between the different software packages. There is significant variability in segmental values, mainly located in the LCx region and segments. Out of the studied tools, Carimas can be used interchangeably with both PMOD and FlowQuant for 1TCM implementation on all levels-global, regional, and segmental.</p

Myocardial perfusion quantification with Rb-82 PET: good interobserver agreement of Carimas software on global, regional, and segmental levels

PurposeTo estimate the interobserver agreement of the Carimas software package (SP) on global, regional, and segmental levels for the most widely used myocardial perfusion PET tracer-Rb-82.Materials and methodsRest and stress Rb-82 PET scans of 48 patients with suspected or known coronary artery disease (CAD) were analyzed in four centers using the Carimas SP. We considered values to agree if they simultaneously had an intraclass correlation coefficient (ICC) > 0.75 and a difference ResultsThe median values on the segmental level were 1.08 mL/min/g for rest myocardial blood flow (MBF), 2.24 mL/min/g for stress MBF, and 2.17 for myocardial flow reserve (MFR). For the rest MBF and MFR, all the values at all the levels fulfilled were in excellent agreement. For stress MBF, at the global and regional levels, all the 24 comparisons showed excellent agreement. Only 1 out of 102 segmental comparisons (seg. 14) was over the adequate agreement limit-23.5% of the median value (ICC = 0.95).ConclusionInterobserver agreement for Rb-82 PET myocardial perfusion quantification analyzed with Carimas is good at any LV segmentation level-global, regional, and segmental. It is good for all the estimates-rest MBF, stress MBF, and MFR.</p