Acetate Positron Emission Tomography Research Articles

The grade of individual prostate cancer lesions predicted by magnetic resonance imaging and positron emission tomography

BackgroundMultiparametric magnetic resonance imaging (mpMRI) and positron emission tomography (PET) are widely used for the management of prostate cancer (PCa). However, how these modalities complement each other in PCa risk stratification is still largely unknown. We aim to provide insights into the potential of mpMRI and PET for PCa risk stratification.MethodsWe analyzed data from 55 consecutive patients with elevated prostate-specific antigen and biopsy-proven PCa enrolled in a prospective study between December 2016 and December 2019. [68Ga]PSMA-11 PET (PSMA-PET), [11C]Acetate PET (Acetate-PET) and mpMRI were co-registered with whole-mount histopathology. Lower- and higher-grade lesions were defined by International Society of Urological Pathology (ISUP) grade groups (IGG). We used PET and mpMRI data to differentiate between grades in two cases: IGG 3 vs. IGG 2 (case 1) and IGG ≥ 3 vs. IGG ≤ 2 (case 2). The performance was evaluated by receiver operating characteristic (ROC) analysis.ResultsWe find that the maximum standardized uptake value (SUVmax) for PSMA-PET achieves the highest area under the ROC curve (AUC), with AUCs of 0.72 (case 1) and 0.79 (case 2). Combining the volume transfer constant, apparent diffusion coefficient and T2-weighted images (each normalized to non-malignant prostatic tissue) results in AUCs of 0.70 (case 1) and 0.70 (case 2). Adding PSMA-SUVmax increases the AUCs by 0.09 (p < 0.01) and 0.12 (p < 0.01), respectively.ConclusionsBy co-registering whole-mount histopathology and in-vivo imaging we show that mpMRI and PET can distinguish between lower- and higher-grade prostate cancer, using partially discriminative cut-off values.

Right Ventricular Maladaptation to Pressure Overload in Fischer Rats Is Associated With Profound Deficiency in Adenylate Kinase 1 and Impaired Ventricular Energetics.

We explored the mechanism of maladaptive right ventricular (RV) remodeling in Fischer compared with Sprague-Dawley (SD) rats exposed to pressure overload. Pulmonary hypertension was induced by injection of the VEGFR antagonist, SU5416, followed by a 3-week exposure to hypoxia (Sugen chronic hypoxia). In vivo oxidative metabolism was assessed by RV/left ventricle ratio of [11C]acetate positron emission tomography clearance (kmono). Unbiased, global transcriptional and proteomic profiling was performed in Fischer and SD rats at baseline and after Sugen chronic hypoxia. All Fischer rats succumbed to RV failure by 5 weeks, whereas SD rats showed preserved RV function and 88% survival beyond 9 weeks (P<0.0001). Fischer rats exhibited increased oxidative metabolism at 4 weeks (P<0.05) and impaired RV efficiency compared with SD (work metabolic index: 52±10 versus 91±27 mmHg·mL/cm2, respectively; P<0.05), but no differences in mitochondrial complex activity. AK1 (adenylate kinase 1) was among the top 10 differentially expressed genes between Fischer and SD rats, with markedly lower RV expression in Fischer rats (FC: 3.36, P<0.05), confirmed by proteomic analysis and validated by Western blotting (>10-fold reduction, P<0.001). While whole-genome sequencing failed to reveal any coding region mutations in Fischer rats, there was a unique variant in a highly conserved upstream flanking region likely involved in the regulation of AK1 expression. Therefore, Fischer rats exhibit profound AK1 deficiency and inefficient cardiac energetics likely related to reduced adenosine triphosphate shuttling from the mitochondria to the contractile fibers. This represents a novel mechanism for RV failure in response to chronic increases in afterload.

Evaluation of Non-infarct-Related Arteries Using C-11 Acetate PET in STEMI With Multivessel Disease.

BACKGROUNDWe analyzed whether C-11 acetate positron emission tomography (PET) can be used for the evaluation of non-infarct-related artery (NIRA) in patients with ST-elevation myocardial infarction (STEMI) and multivessel disease.METHODSWe prospectively enrolled 31 patients with STEMI and at least one NIRA stenosis (diameter stenosis [DS] ≥ 50%). C-11 acetate PET was performed after successful revascularization for the infarct-related artery (IRA). Myocardial blood flow (MBF) and oxidative metabolism (kmono) were measured and compared between NIRA vs. IRA, stenotic (DS ≥ 50%) vs. non-stenotic (DS < 50%) NIRAs, and NIRAs with significant stenosis (DS ≥ 70% or fractional flow reserve [FFR] ≤ 0.80) vs. those without (neither DS ≥ 70% nor FFR ≤ 0.80). The correlations between PET and angiographic parameters were also analyzed.RESULTSMBF and kmono were significantly higher in NIRAs than those in IRAs. Stenotic NIRAs showed significantly reduced stress MBF, myocardial flow reserve (MFR), relative flow reserve (RFR) (0.72 ± 0.12 vs. 0.82 ± 0.14; p = 0.001), and stress kmono, as compared to those in non-stenotic NIRAs. NIRAs with significant stenosis had significantly lower stress MBF, MFR, and RFR (0.70 ± 0.10 vs. 0.80 ± 0.14; p = 0.001). RFR showed the best, but modest linear correlation with DS of NIRA stenosis (r = −0.429, p = 0.001). RFR > 0.81 could effectively exclude the presence of significant NIRA stenosis.CONCLUSIONSC-11 acetate PET could be a feasible alternative noninvasive modality in patients with STEMI and multivessel disease, by excluding the presence of significant NIRA stenosis.

Effects of 6 weeks of treatment with dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, on myocardial function and metabolism in patients with type 2 diabetes: A randomized, placebo-controlled, exploratory study.

To explore the early effects of dapagliflozin on myocardial function and metabolism in patients with type 2 diabetes without heart failure. Patients with type 2 diabetes on metformin treatment were randomized to double-blind, 6-week placebo or dapagliflozin 10 mg daily treatment. Investigations included cardiac function and structure with myocardial resonance imaging; cardiac oxygen consumption, perfusion and efficiency with [11 C]-acetate positron emission tomography (PET); and cardiac and hepatic fatty acid uptake with [18 F]-6-thia-heptadecanoic acid PET, analysed by ANCOVA as least square means with 95% confidence intervals. Evaluable patients (placebo: n = 24, dapagliflozin: n = 25; 53% males) had a mean age of 64.4 years, a body mass index of 30.2 kg/m2 and an HbA1c of 6.7%. Body weight and HbA1c were significantly decreased by dapagliflozin versus placebo. Dapagliflozin had no effect on myocardial efficiency, but external left ventricular (LV) work (-0.095 [-0.145, -0.043] J/g/min) and LV oxygen consumption were significantly reduced (-0.30 [-0.49, -0.12] J/g/min) by dapagliflozin, although the changes were not statistically significant versus changes in the placebo group. Change in left atrial maximal volume with dapagliflozin versus placebo was -3.19 (-6.32, -0.07) mL/m2 (p = .056). Peak global radial strain decreased with dapagliflozin versus placebo (-3.92% [-7.57%, -0.28%]; p = .035), while peak global longitudinal and circumferential strains were unchanged. Hepatic fatty acid uptake was increased by dapagliflozin versus placebo (0.024 [0.004, 0.044] μmol/g/min; p = .018), while cardiac uptake was unchanged. This exploratory study indicates reduced heart work but limited effects on myocardial function, efficiency and cardiac fatty acid uptake, while hepatic fatty acid uptake increased, after 6 weeks of treatment with dapagliflozin.

Increased Myocardial Oxygen Consumption Precedes Contractile Dysfunction in Hypertrophic Cardiomyopathy Caused by Pathogenic TNNT2 Gene Variants

BackgroundHypertrophic cardiomyopathy is caused by pathogenic sarcomere gene variants. Individuals with a thin‐filament variant present with milder hypertrophy than carriers of thick‐filament variants, although prognosis is poorer. Herein, we defined if decreased energetic status of the heart is an early pathomechanism in TNNT2 (troponin T gene) variant carriers.Methods and ResultsFourteen individuals with TNNT2 variants (genotype positive), without left ventricular hypertrophy (G+/LVH−; n=6) and with LVH (G+/LVH+; n=8) and 14 healthy controls were included. All participants underwent cardiac magnetic resonance and [11C]‐acetate positron emission tomography imaging to assess LV myocardial oxygen consumption, contractile parameters and myocardial external efficiency. Cardiac efficiency was significantly reduced compared with controls in G+/LVH− and G+/LVH+. Lower myocardial external efficiency in G+/LVH− is explained by higher global and regional oxygen consumption compared with controls without changes in contractile parameters. Reduced myocardial external efficiency in G+/LVH+ is explained by the increase in LV mass and higher oxygen consumption. Septal oxygen consumption was significantly lower in G+/LVH+ compared with G+/LVH−. Although LV ejection fraction was higher in G+/LVH+, both systolic and diastolic strain parameters were lower compared with controls, which was most evident in the hypertrophied septal wall.ConclusionsUsing cardiac magnetic resonance and [11C]‐acetate positron emission tomography imaging, we show that G+/LVH− have an initial increase in oxygen consumption preceding contractile dysfunction and cardiac hypertrophy, followed by a decline in oxygen consumption in G+/LVH+. This suggests that high oxygen consumption and reduced myocardial external efficiency characterize the early gene variant–mediated disease mechanisms that may be used for early diagnosis and development of preventive treatments.

Astrocyte metabolism in multiple sclerosis investigated by 1-C-11 acetate PET

This study was aimed at evaluating the metabolism of reactive astrocytes in the brains of patients with multiple sclerosis by quantitative 1-C-11 acetate positron emission tomography (PET). Magnetic resonance imaging and 1-C-11 quantitative PET were performed in eight patients with multiple sclerosis and 10 normal control subjects. The efflux rate (k2) of 1-C-11 acetate, which reportedly reflects the metabolic rate of 1-C-11 acetate, was calculated based on the one-tissue compartmental model. Fractional anisotropy was also determined to evaluate the integrity of the neuronal tracts. The values of k2 in the patients with multiple sclerosis were significantly higher than those in the normal control subjects, in both the white matter (p = 0.003) and the gray matter (p = 0.02). In addition, the white matter/gray matter ratio of k2 was significantly higher in the multiple sclerosis patients than in the normal control subjects (p = 0.02). Voxel-based statistical analysis revealed most prominent increase in k2 in the neuronal fiber tracts, as well as decrease in fractional anisotropy in them in the multiple sclerosis patients. The present study clarified that the pathological changes associated with astrocytic reactivation in multiple sclerosis patients could be visualized by quantitative 1-C-11 acetate PET.

Carbon Flux as a Measure of Prostate Cancer Aggressiveness: [11C]-Acetate PET/CT

Purpose: Dynamic [11C]-acetate positron emission tomography (PET) can be used to study tissue perfusion and carbon flux simultaneously. In this study, the feasibility of the quantification of prostate cancer aggressiveness using parametric methods assessing [11C]-acetate kinetics was investigated in prostate cancer subjects. The underlying uptake mechanism correlated with [11C]-acetate influx and efflux measured in real-time in vitro in cell culture.Methods: Twenty-one patients with newly diagnosed low-to-moderate risk prostate cancer underwent magnetic resonance imaging (MRI) and dynamic [11C]-acetate PET/CT examinations of the pelvis. Parametric images of K1 (extraction × perfusion), k2 (oxidative metabolism) and VT (=K1/k2, anabolic metabolism defined as carbon retention) were constructed using a one-tissue compartment model with an arterial input function derived from pelvic arteries. Regions of interest (ROIs) of the largest cancer lesion in each patient and normal prostate tissue were drawn using information from MRI (T2 and DWI images), biopsy results, and post-surgical histopathology of whole prostate sections (n=7). In vitro kinetics of [11C]-acetate were studied on DU145 and PC3 cell lines using LigandTracer® White equipment for the measurement of the radioactivity uptake in real-time at 37°C.Results: Mean prostate specific antigen (PSA) was 8.33±3.92 ng/mL and median Gleason Sum 6 (range 5-7). K1, VT and standardized uptake values (SUVs) were significantly higher in cancerous prostate tissues compared to normal ones for all patients (p<0.001), while k2 was not (p=0.26). PSA values correlated to early SUVs (r=0.50, p=0.02) and K1 (r=0.48, p=0.03). Early and late SUVs correlated to VT (r>0.76, p<0.001) and K1 (r>0.64, p<0.005). In vitro studies demonstrated higher extraction and retention (p<0.01) of [11C]-acetate in the more aggressive PC3 cells.Conclusion: Parametric images could be used to visualize the [11C]-acetate kinetics of the prostate cancer exhibiting elevated extraction associated with the cancer aggressiveness. The influx rate of [11C]-acetate studied in cell culture also showed dependence on the cancer aggressiveness associated with elevated lipogenesis. Dynamic [11C]-acetate/PET demonstrated potential for prostate cancer aggressiveness estimation using parametric-based K1 and VT values.

Seven-day overfeeding enhances adipose tissue dietary fatty acid storage and decreases myocardial and skeletal muscle dietary fatty acid partitioning in healthy subjects.

Increased myocardial partitioning of dietary fatty acids (DFA) and decreased left ventricular (LV) function is associated with insulin resistance in prediabetes. We hypothesized that enhanced myocardial DFA partitioning and reduced LV function might be induced concomitantly with reduced insulin sensitivity upon a 7-day hypercaloric (+50% in caloric intake), high-saturated fat (~11%energy), and simple carbohydrates (~54%energy) diet (HIGHCAL) versus an isocaloric diet (ISOCAL) with a moderate amount of saturated fat (~8%energy) and carbohydrates (~50%energy). Thirteen healthy subjects (7 men/6 women) underwent HIGHCAL versus ISOCAL in a randomized crossover design, with organ-specific DFA partitioning and LV function measured using the oral 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid and [11C]acetate positron emission tomography methods at the end of both interventions. HIGHCAL induced a decrease in insulin sensitivity indexes with no significant change in body composition. HIGHCAL led to increased subcutaneous abdominal (+4.2 ± 1.6%, P < 0.04) and thigh (+2.4 ± 1.2%, P < 0.08) adipose tissue storage and reduced cardiac (-0.31 ± 0.11 mean standard uptake value [(SUV), P < 0.03] and skeletal muscle (-0.17 ± 0.08 SUV, P < 0.05) DFA partitioning without change in LV function. We conclude that early increase in adipose tissue DFA storage protects the heart and skeletal muscles from potential deleterious effects of DFA.

Determination of a pharmacokinetic model for [11C]-acetate in brown adipose tissue

Background[11C]-acetate positron emission tomography is used to assess oxidative metabolism in various tissues including the heart, tumor, and brown adipose tissue. For brown adipose tissue, a monoexponential decay model is commonly employed. However, no systematic assessment of kinetic models has been performed to validate this model or others.The monoexponential decay model and various compartmental models were applied to data obtained before and during brown adipose tissue activation by cold exposure in healthy men. Quality of fit was assessed visually and by analysis of residuals, including the Akaike information criterion. Stability and accuracy of compartmental models were further assessed through simulations, along with sensitivity and identifiability of kinetic parameters.ResultsDifferences were noted in the arterial input function between the warm and cold conditions. These differences are not taken into account by the monoexponential decay model. They are accounted for by compartmental models, but most models proved too complex to be stable. Two and three-tissue models with no more than four distinct kinetic parameters, including blood volume fraction, provided the best compromise between fit quality and stability/accuracy.ConclusionFor healthy men, a three-tissue model with four kinetic parameters, similar to a heart [11C]-palmitate model seems the most appropriate based on model stability and its ability to describe the main [11C]-acetate pathways in BAT cells. Further studies are required to validate this model in women and people with metabolic disorders.

Determinants of Myocardial Strain in Experimental Chronic Myocardial Infarction

We evaluated the relationships between regional myocardial strain measured by speckle tracking echocardiography and viability, fibrosis, hypertrophy and oxygen consumption in the infarcted or remote myocardium in a pig model of chronic myocardial infarction (MI). Thirteen farm pigs with surgical occlusion of the left anterior descending coronary artery and five sham-operated pigs were studied 3 mo post-MI. Computed tomography revealed significant left ventricle remodeling. Reduced radial or circumferential strain identified areas of transmural infarction (area under the curve: 0.82 and 0.79, respectively). In the remote non-infarcted area, radial strain correlated inversely with the amount of fibrosis (r = –0.66, p = 0.04) and myocyte hypertrophy (r = –0.68, p = 0.03). Radial strain rate inversely correlated with myocardial resting oxygen consumption assessed with 11C-labeled acetate positron emission tomography (r = –0.71, p = 0.006). In conclusion, myocardial strain and strain rate reflect fibrosis, hypertrophy and oxygen consumption of the remote areas after MI.

Effects of the Acute and Chronic Ethanol Intoxication on Acetate Metabolism and Kinetics in the Rat Brain.

Ethanol (EtOH) intoxication inhibits glucose transport and decreases overall brain glucose metabolism; however, humans with long-term EtOH consumption were found to have a significant increase in [1-11 C]-acetate uptake in the brain. The relationship between the cause and effect of [1-11 C]-acetate kinetics and acute/chronic EtOH intoxication, however, is still unclear. [1-11 C]-acetate positron emission tomography (PET) with dynamic measurement of K1 and k2 rate constants was used to investigate the changes in acetate metabolism in different brain regions of rats with acute or chronic EtOH intoxication. PET imaging demonstrated decreased [1-11 C]-acetate uptake in rat brain with acute EtOH intoxication, but this increased with chronic EtOH intoxication. Tracer uptake rate constant K1 and clearance rate constant k2 were decreased in acutely intoxicated rats. No significant change was noted in K1 and k2 in chronic EtOH intoxication, although 6 of 7 brain regions showed slightly higher k2 than baseline. These results indicate that acute EtOH intoxication accelerated acetate transport and metabolism in the rat brain, whereas chronic EtOH intoxication status showed no significant effect. In vivo PET study confirmed the modulatory role of EtOH, administered acutely or chronically, in [1-11 C]-acetate kinetics and metabolism in the rat brain. Acute EtOH intoxication may inhibit the transport and metabolism of acetate in the brain, whereas chronic EtOH exposure may lead to the adaptation of the rat brain to EtOH in acetate utilization. [1-11 C]-acetate PET imaging is a feasible approach to study the effect of EtOH on acetate metabolism in rat brain.

Early Response Monitoring Following Radiation Therapy by Using [18F]FDG and [11C]Acetate PET in Prostate Cancer Xenograft Model with Metabolomics Corroboration.

We aim to characterize the metabolic changes associated with early response to radiation therapy in a prostate cancer mouse model by 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) and [11C]acetate ([11C]ACT) positron emission tomography, with nuclear magnetic resonance (NMR) metabolomics corroboration. [18F]FDG and [11C]ACT PET were performed before and following irradiation (RT, 15Gy) for transgenic adenocarcinoma of mouse prostate xenografts. The underlying metabolomics alterations of tumor tissues were analyzed by using ex vivo NMR. The [18F]FDG total lesion glucose (TLG) of the tumor significant increased in the RT group at Days 1 and 3 post-irradiation, compared with the non-RT group (p < 0.05). The [11C]ACT maximum standard uptake value (SUVmax) in RT (0.83 ± 0.02) and non-RT groups (0.85 ± 0.07) were not significantly different (p > 0.05). The ex vivo NMR analysis showed a 1.70-fold increase in glucose and a 1.2-fold increase in acetate in the RT group at Day 3 post-irradiation (p < 0.05). Concordantly, the expressions of cytoplasmic acetyl-CoA synthetase in the irradiated tumors was overexpressed at Day 3 post-irradiation (p < 0.05). Therefore, TLG of [18F]FDG in vivo PET images can map early treatment response following irradiation and be a promising prognostic indicator in a longitudinal preclinical study. The underlying metabolic alterations was not reflected by the [11C]ACT PET.

Dramatic Polarization in Genitourinary Expert Opinions Regarding the Clinical Utility of Advanced Imaging Technologies in Prostate Cancer

Advanced imaging technologies are already incorporated in national guidelines for treatment of prostate cancer (PCa), however opinions of North American genitourinary (GU) experts regarding inclusion of technologies such as prostate-specific membrane antigen (PSMA) and C-11 acetate positron emission tomography (PET) into routine practice are unknown. A survey was distributed to 88 practicing North American GU experts who serve on decision-making committees of cooperative group research organizations. Questions pertained to knowledge about and personal opinions on the role of PSMA and C-11 PET in PCa management. Demographic questions and those designed to categorize practice patterns for PCa patients were submitted. Based on responses, participants were categorized as “supporters” or “opponents” of incorporation of novel imaging techniques into routine practice. Opinions regarding novel imaging were correlated with practice patterns using Fisher’s exact test. We received 48 responses and limited analysis to 42 radiation oncologist respondents. 17 participants (40%) have been in practice for > 20 years and 38 (90%) practice at an academic center. 19 participants (45%) see > 20 patients/month in consultation. 24 (57%) were supporters of PSMA PET and 29 (69%) were supporters of C-11 PET. Supporters were more likely to routinely treat pelvic nodes in patients with high risk PCa (88% vs. 56%, p < .01) and to treat patients with low/intermediate PCa with moderate (20-28 fractions) or extreme (5-15 fractions) hypofractionation (58% vs. 28%, p = .049). Supporters also trended to being more likely to offer to patients with high risk PCa brachytherapy boost (55% vs. 23%, p = .09), favor initial observation and early salvage over adjuvant radiation in patients with high risk features after prostatectomy (77% vs. 55%, p = .09), and to consider themselves expert brachytherapists (69% vs. 39%, p = .06). Nearly all (40, 95%) recommend active surveillance for patients with Gleason 6 PCa. A majority (27, 66%) feel there is not enough evidence to determine which modality, C-11 PET or PSMA PET, is superior. There is a stark polarization among prostate cancer radiation oncology experts regarding the use of novel imaging techniques in routine practice. Moreover, there appears to be a strong correlation between support of novel imaging and adoption of treatment approaches shown in randomized trials to be either clinically superior (such as brachytherapy boost), or less expensive (such as hypofractionation). Pre-existing biases regarding novel imaging among GU experts on national treatment-decision panels and leaders of cooperative group studies may affect the design of future clinical studies and influence the adoption of these technologies in clinical practice.

Effects of exenatide on cardiac function, perfusion, and energetics in type 2 diabetic patients with cardiomyopathy: a randomized controlled trial against insulin glargine

BackgroundMultiple bloodglucose-lowering agents have been linked to cardiovascular events. Preliminary studies showed improvement in left ventricular (LV) function during glucagon-like peptide-1 receptor agonist administration. Underlying mechanisms, however, are unclear. The purpose of this study was to investigate myocardial perfusion and oxidative metabolism in type 2 diabetic (T2DM) patients with LV systolic dysfunction as compared to healthy controls. Furthermore, effects of 26-weeks of exenatide versus insulin glargine administration on cardiac function, perfusion and oxidative metabolism in T2DM patients with LV dysfunction were explored.Methods and resultsTwenty-six T2DM patients with LV systolic dysfunction (cardiac magnetic resonance (CMR) derived LV ejection fraction (LVEF) of 47 ± 13%) and 10 controls (LVEF of 59 ± 4%, P < 0.01 as compared to patients) were analyzed. Both myocardial perfusion during adenosine-induced hyperemia (P < 0.01), and coronary flow reserve (P < 0.01), measured by [15O]H2O positron emission tomography (PET), were impaired in T2DM patients as compared to healthy controls. Myocardial oxygen consumption and myocardial efficiency, measured using [11C]acetate PET and CMR derived stroke volume, were not different between the groups. Eleven patients in the exenatide group and 12 patients in the insulin glargine group completed the trial. Systemic metabolic control was improved after both treatments, although, no changes in cardiac function, perfusion and metabolism were seen after exenatide or insulin glargine.ConclusionsT2DM patients with LV systolic dysfunction did not have altered myocardial efficiency as compared to healthy controls. Exenatide or insulin glargine had no effects on cardiac function, perfusion or oxidative metabolism.Trial registration NCT00766857

Disease Stage-Dependent Changes in Cardiac Contractile Performance and Oxygen Utilization Underlie Reduced Myocardial Efficiency in Human Inherited Hypertrophic Cardiomyopathy.

Reduced myocardial efficiency represents a target for therapy in hypertrophic cardiomyopathy although therapeutic benefit may depend on disease stage. Here, we determined disease stage-dependent changes in myocardial efficiency and effects of myectomy surgery. Myocardial external efficiency (MEE) was determined in 27 asymptomatic mutation carriers (genotype positive/phenotype negative), 10 patients with hypertrophic obstructive cardiomyopathy (HOCM), 10 patients with aortic valve stenosis, and 14 healthy individuals using [11C]-acetate positron emission tomography and cardiovascular magnetic resonance imaging. Follow-up measurements were performed in HOCM and aortic valve stenosis patients 4 months after surgery. External work did not differ in HOCM compared with controls, whereas myocardial oxygen consumption was lower in HOCM. Because of a higher cardiac mass, total cardiac oxygen consumption was significantly higher in HOCM than in controls and genotype positive/phenotype negative. MEE was significantly lower in genotype positive/phenotype negative than in controls (28±6% versus 42±6%) and was further decreased in HOCM (22±5%). In contrast to patients with aortic valve stenosis, MEE was not improved in patients with HOCM after surgery, which was explained by opposite changes in the septum (decrease) and lateral (increase) wall. Different mechanisms underlie reduced MEE at the early and advanced stage of hypertrophic cardiomyopathy. The initial increase and subsequent reduction in myocardial oxygen consumption during disease progression indicates that energy deficiency is a primary mutation-related event, whereas mechanisms secondary to disease remodeling underlie low MEE in HOCM. Our data highlight that the benefit of therapies to improve energetic status of the heart may vary depending on the disease stage and that treatment should be initiated before cardiac remodeling.

(11)C]acetate PET Imaging is not Always Associated with Increased Lipogenesis in Hepatocellular Carcinoma in Mice.

Altered metabolism, including increased glycolysis and de novo lipogenesis, is one of the hallmarks of cancer. Radiolabeled nutrients, including glucose and acetate, are extensively used for the detection of various tumors, including hepatocellular carcinomas (HCCs). High signal of [(11)C]acetate positron emission tomography (PET) in tumors is often considered to be associated with increased expression of fatty acid synthase (FASN) and increased de novo lipogenesis in tumor tissues. Defining a subset of tumors with increased [(11)C]acetate PET signal and thus increased lipogenesis was suggested to help select a group of patients, who may benefit from lipogenesis-targeting therapies. To investigate whether [(11)C]acetate PET imaging is truly associated with increased de novo lipogenesis along with hepatocarcinogenesis, we performed [(11)C]acetate PET imaging in wild-type mice as well as two mouse HCC models, induced by myrAKT/Ras(V12) (AKT/Ras) and PIK3CA(1047R)/c-Met (PI3K/Met) oncogene combinations. In addition, we analyzed FASN expression and de novo lipogenesis rate in these mouse liver tissues. We found that while HCCs induced by AKT/Ras co-expression showed high levels of [(11)C]acetate PET signal compared to normal liver, HCCs induced by PI3K/Met overexpression did not. Intriguingly, elevated FASN expression and increased de novo lipogenesis rate were observed in both AKT/Ras and PI3K/Met HCCs. Altogether, our study suggests that [(11)C]acetate PET imaging can be a useful tool for imaging of a subset of HCCs. However, at molecular level, the increased [(11)C]acetate PET imaging is not always associated with increased FASN expression or de novo lipogenesis.

Cardiac remodeling in a new pig model of chronic heart failure: Assessment of left ventricular functional, metabolic, and structural changes using PET, CT, and echocardiography

AimsLarge animal models are needed to study disease mechanisms in heart failure (HF). In the present study we characterized the functional, metabolic, and structural changes of myocardium in a novel pig model of chronic myocardial infarction (MI) by using multimodality imaging and histology. Methods and ResultsMale farm pigs underwent a two-step occlusion of the left anterior descending coronary artery with concurrent distal ligation and implantation of a proximal ameroid constrictor (HF group), or sham operation (control group). Three months after the operation, cardiac output and wall stress were measured by echocardiography. Left ventricle (LV) volumes and mass were measured by computed tomography (CT). Myocardial perfusion was evaluated by [15O]water and oxygen consumption using [11C]acetate positron emission tomography, and the efficiency of myocardial work was calculated. Histological examinations were conducted to detect MI, hypertrophy, and fibrosis. Animals in the HF group had a large anterior MI scar. CT showed larger LV diastolic volume and lower ejection fraction in HF pigs than in controls. Perfusion and oxygen consumption in the remote non-infarcted myocardium were preserved in HF pigs as compared to controls. Global LV work and efficiency were significantly lower in HF than control pigs and was associated with increased wall stress. Histology showed myocyte hypertrophy but not increased interstitial fibrosis in the remote segments in HF pigs. ConclusionsThe chronic post-infarction model of HF is suitable for studies aimed to evaluate LV remodeling and changes in oxidative metabolism and can be useful for testing new therapies for HF.

¹¹C]acetate and PET/CT assessment of muscle activation in rat studies.

The purpose of the present study is to apply kinetic analysis to investigate exercise-related changes in the metabolism of the skeletal muscle of the rat hindlimb by [[Formula: see text]]acetate positron emission tomography and computed tomography (PET/CT). Contractions were induced in Wistar rats' left hindlimb by electrostimulation of the Vastus Lateralis muscle motor point. After 15min of muscle contractions, [[Formula: see text]]acetate was injected and PET/CT of both hindlimbs was acquired. The resting hindlimb was used as a control reference. The kinetic parameters [Formula: see text] and [Formula: see text] were calculated for the target muscles (exercised and control) and correlated with the corresponding standardized uptake values (SUVs). The ratio between each kinetic parameter values and the SUV extracted for the exercised muscle and the muscle at rest was computed ([Formula: see text] and [Formula: see text], respectively). Kinetic analysis quantitatively confirmed that net tracer uptake ([Formula: see text]) and washout ([Formula: see text]) were significantly higher in exercised muscles ([Formula: see text] for exercised muscles vs. [Formula: see text] for resting muscles, [Formula: see text]; [Formula: see text] for exercised muscle vs. [Formula: see text] for resting muscle, [Formula: see text]). On the other hand, SUV was not significantly different between active and inactive muscles ([Formula: see text] for exercised muscles vs. [Formula: see text] for resting muscles). Linear regression analysis revealed a good correlation ([Formula: see text]) between net tracer uptake ratio ([Formula: see text]) and the SUV ratio [Formula: see text]). A lower correlation was found between the net tracer washout ratio ([Formula: see text]) and the SUV ratio ([Formula: see text]). The present study showed that kinetic modelling can detect changes between active and inactive skeletal muscles with a higher sensitivity with respect to the SUV, when performed with [[Formula: see text]]acetate PET/CT.

Myocardial efficiency is an important determinant of functional improvement after aortic valve replacement in aortic valve stenosis patients: a combined PET and CMR study.

The pathophysiology underlying aortic valve stenosis (AVS)-induced cardiac dysfunction and reduced exercise capacity is unclear. We hypothesize that improvement of myocardial external efficiency (MEE)--the ratio between external work and myocardial oxygen consumption (MVO2)--underlies functional improvement of AVS patients after aortic valve replacement (AVR). Therefore, the aim of this proof-of-concept study was to investigate whether myocardial efficiency is reduced in patients with cardiac hypertrophy caused by AVS and to assess the effect of AVR on myocardial efficiency in relation to exercise capacity. Echocardiography, cardiopulmonary exercise test, [(11)C]-acetate positron emission tomography and cardiovascular magnetic resonance imaging were performed in 10 AVS patients prior to (pre-AVR) and 4 months after AVR (post-AVR). Fourteen healthy individuals served as control group. MEE was significantly lower in pre-AVR patients (32 ± 7%) than in controls (49 ± 6%). AVR significantly decreased left ventricle mass and MVO2. Also, external work significantly decreased post-AVR reaching similar values as in controls. AVR significantly improved MEE from 32 ± 7 to 37 ± 5% (P = 0.02). Moreover, significant correlations were present between the AVR-induced increase in MEE and changes in both exercise work (r = 0.74, P = 0.01) and peak VO2 (r = 0.67, P = 0.03). However, four AVS patients did not show improved MEE, which was associated with no or minimal improvement in exercise parameters. MEE is significantly reduced in patients with AVS-induced hypertrophy. Improved MEE is an important predictor of AVR-induced improvement of exercise capacity in AVS patients. Future investigation is needed to confirm our observations in a large prospective, multicenter clinical trial.

β2-adrenergic stress evaluation of coronary endothelial-dependent vasodilator function in mice using (11)C-acetate micro-PET imaging of myocardial blood flow and oxidative metabolism.

BackgroundEndothelial dysfunction is associated with vascular risk factors such as dyslipidemia, hypertension, and diabetes, leading to coronary atherosclerosis. Sympathetic stress using cold-pressor testing (CPT) has been used to measure coronary endothelial function in humans with positron emission tomography (PET) myocardial blood flow (MBF) imaging, but is not practical in small animal models. This study characterized coronary vasomotor function in mice with [11C]acetate micro-PET measurements of nitric-oxide-mediated endothelial flow reserve (EFRNOM) (adrenergic-stress/rest MBF) and myocardial oxygen consumption (MVO2) using salbutamol β2-adrenergic-activation.Methods[11C]acetate PET MBF was performed at rest + salbutamol (SB 0.2, 1.0 μg/kg/min) and norepinephrine (NE 3.2 μg/kg/min) stress to measure an index of MBF response. β-adrenergic specificity of NE was evaluated by pretreatment with α-adrenergic-antagonist phentolamine (PHE), and β2-selectivity was assessed using SB.ResultsAdjusting for changes in heart rate × systolic blood pressure product (RPP), the same stress/rest MBF ratio of 1.4 was measured using low-dose SB and NE in normal mice (equivalent to human CPT response). The MBF response was correlated with changes in MVO2 (p = 0.02). Nitric oxide synthase (NOS)-inhibited mice (Ng-nitro-L-arginine methyl ester (L-NAME) pretreatment and endothelial nitric oxide synthase (eNOS) knockout) were used to assess the EFRNOM, in which the low-dose SB- and NE-stress MBF responses were completely blocked (p = 0.02). With high-dose SB-stress, the MBF ratio was reduced by 0.4 following NOS inhibition (p = 0.03).ConclusionsLow-dose salbutamol β2-adrenergic-stress [11C]acetate micro-PET imaging can be used to measure coronary-specific EFRNOM in mice and may be suitable for assessment of endothelial dysfunction in small animal models of disease and evaluation of new therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-014-0068-9) contains supplementary material, which is available to authorized users.