Quantitative and qualitative comparison of Rubidium-82 and Oxygen-15 water cardiac PET.

BACKGROUND: Differences in tracer characteristics may influence the interpretation of positron emission tomography myocardial perfusion imaging (MPI). We compare the reading of MPIs with a low-extraction retention tracer (82Rb) and a high-extraction non-retention tracer (15O-water) in a selected cohort of patients with known coronary artery disease (CAD). METHODS: Thirty-nine patients with known CAD referred to 82Rb MPI due to angina underwent rest and stress imaging with both tracers and experienced MPI readers provided blinded consensus reads of all studies. In addition, a comparison of regional and global quantitative measures of perfusion was performed. RESULTS: The results showed 74 % agreement in the reading of 82Rb and 15O-water MPI for regional reversible ischemia and global disease, and 82 % agreement for regional irreversible ischemia. The 15O-water MPI identified more cases of global disease (n = 12 (15O-water) vs n = 4 (82Rb), p = 0.03), whereas differences in reversible ischemia (n = 22 vs n = 16, p = 0.11) and, irreversible ischemia (n = 8 vs n = 11, p = 0.45) were not significant. The correlation between myocardial blood flow measured using the two tracers was similar to previous studies (R2 = 0.78) with wide limits of agreement (-0.93 to 0.84 ml/g/min). CONCLUSIONS: Agreement between consensus readings of 82Rb and 15O-water MPI was good in patients with known CAD. In this limited size study, no significant differences in the identification of reversible and irreversible ischemia found, whereas 15O-water MPI had a higher positive rate for suspected global disease.

Detection and correction of patient motion in dynamic 15O-water PET MPI.

BACKGROUND: Patient motion constitutes a limitation to 15O-water cardiac PET imaging. We examined the ability of image readers to detect and correct patient motion using simulated motion data and clinical patient scans. METHODS: Simulated data consisting of 16 motions applied to 10 motion-free scans were motion corrected using two approaches, pre-analysis and post-analysis for motion identification. Both approaches employed a manual frame-by-frame correction method. In addition, a clinical cohort was analyzed for assessment of prevalence and effect of motion and motion correction. RESULTS: Motion correction was performed on 94% (pre-analysis) and 64% (post-analysis) of the scans. Large motion artifacts were corrected in 91% (pre-analysis) and 74% (post-analysis) of scans. Artifacts in MBF were reduced in 56% (pre-analysis) and 58% (post-analysis) of the scans. The prevalence of motion in the clinical patient cohort (n = 762) was 10%. Motion correction altered exam interpretation in only 10 (1.3%) clinical patient exams. CONCLUSION: Frame-by-frame motion correction after visual inspection is useful in reducing motion artifacts in cardiac 15O-water PET. Reviewing the initial results (parametric images and polar maps) as part of the motion correction process, reduced erroneous corrections in motion-free scans. In a large clinical cohort, the impact of motion correction was limited to few patients.

Exercise increases myocardial free fatty acid oxidation in subjects with metabolic dysfunction-associated fatty liver disease.

BACKGROUND AND AIMS: Metabolic dysfunction-associated fatty liver disease (MAFLD) is associated with dyslipidemia and may promote cardiac lipotoxicity. Myocardial free fatty acids (FFA) oxidation (MOFFA) is normal in pre-diabetes, but reduced in heart failure. We hypothesized that during exercise MOFFA, very low-density lipoprotein triglycerides (VLDL-TG) secretion, hepatic FFA utilization, and lactate production differ among obese subjects with and without MAFLD. METHODS: Nine obese subjects with MAFLD and 8 matched subjects without MAFLD (Control) without a history of heart failure and cardiovascular disease were compared before and after 90-min exercise at 50% Peak oxygen consumption. Basal and exercise induced cardiac and hepatic FFA oxidation, uptake and re-esterification and VLDL-TG secretion were measured using [11C]palmitate positron-emission tomography and [1-14C]VLDL-TG. RESULTS: In the heart, increased MOFFA was observed after exercise in MAFLD, whereas MOFFA decreased in Control (basal vs exercise, MAFLD: 4.1 (0.8) vs 4.8 (0.8) µmol·100 ml-1 min-1; Control: 4.9 (1.8) vs 4.0 (1.1); µmol·100 ml-1 min-1, mean (SD), p < 0.048). Hepatic FFA fluxes were significantly lower in MAFLD than Control and increased ≈ two-fold in both groups. VLDL-TG secretion was 50% greater in MAFLD at rest and similarly suppressed during exercise. Plasma lactate increased significantly less in MAFLD than Control during exercise. CONCLUSIONS: Using robust tracer-techniques we found that obese subjects with MAFLD do not downregulate MOFFA during exercise compared to Control, possibly due to diminished lactate supply. Hepatic FFA fluxes are significantly lower in MAFLD than Control, but increase similarly with exercise. VLDL-TG export remains greater in MAFLD compared to Control. Basal and post-exercise myocardial and hepatic FFA, VLDL-TG and lactate metabolism is abnormal in subjects with MAFLD compared to Control.

SGLT2 Inhibition Does Not Affect Myocardial Fatty Acid Oxidation or Uptake, but Reduces Myocardial Glucose Uptake and Blood Flow in Individuals With Type 2 Diabetes: A Randomized Double-Blind, Placebo-Controlled Crossover Trial.

Sodium-glucose cotransporter 2 (SGLT2) inhibition reduces cardiovascular morbidity and mortality in individuals with type 2 diabetes. Beneficial effects have been attributed to increased ketogenesis, reduced cardiac fatty acid oxidation, and diminished cardiac oxygen consumption. We therefore studied whether SGLT2 inhibition altered cardiac oxidative substrate consumption, efficiency, and perfusion. Thirteen individuals with type 2 diabetes were studied after 4 weeks' treatment with empagliflozin and placebo in a randomized, double-blind, placebo-controlled crossover study. Myocardial palmitate and glucose uptake were measured with 11C-palmitate and 18F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT). Oxygen consumption and myocardial external efficiency (MEE) were measured with 11C-acetate PET/CT. Resting and adenosine stress myocardial blood flow (MBF) and myocardial flow reserve (MFR) were measured using 15O-H2O PET/CT. Empagliflozin did not affect myocardial free fatty acids (FFAs) uptake but reduced myocardial glucose uptake by 57% (P < 0.001). Empagliflozin did not change myocardial oxygen consumption or MEE. Empagliflozin reduced resting MBF by 13% (P < 0.01), but did not significantly affect stress MBF or MFR. In conclusion, SGLT2 inhibition did not affect myocardial FFA uptake, but channeled myocardial substrate utilization from glucose toward other sources and reduced resting MBF. However, the observed metabolic and hemodynamic changes were modest and most likely contribute only partially to the cardioprotective effect of SGLT2 inhibition.

18Fluorodeoxyglucose Accumulation in Arterial Tissues Determined by PET Signal Analysis.

BACKGROUND: Arterial 18fluorodeoxyglucose (FDG) positron emission tomography (PET) is considered a measure of atherosclerotic plaque macrophages and is used for quantification of disease activity in clinical trials, but the distribution profile of FDG across macrophages and other arterial cells has not been fully clarified. OBJECTIVES: The purpose of this study was to analyze FDG uptake in different arterial tissues and their contribution to PET signal in normal and atherosclerotic arteries. METHODS: Wild-type and D374Y-PCSK9 transgenic Yucatan minipigs were fed a high-fat, high-cholesterol diet to induce atherosclerosis and subjected to a clinical FDG-PET and computed tomography scan protocol. Volumes of arterial media, intima/lesion, macrophage-rich, and hypoxic tissues were measured in serial histological sections. Distributions of FDG in macrophages and other arterial tissues were quantified using modeling of the in vivo PET signal. In separate transgenic minipigs, the intra-arterial localization of FDG was determined directly by autoradiography. RESULTS: Arterial FDG-PET signal appearance and intensity were similar to human imaging. The modeling approach showed high accuracy in describing the FDG-PET signal and revealed comparable FDG accumulation in macrophages and other arterial tissues, including medial smooth muscle cells. These findings were verified directly by autoradiography of normal and atherosclerotic arteries. CONCLUSIONS: FDG is taken up comparably in macrophage-rich and -poor arterial tissues in minipigs. This offers a mechanistic explanation to a growing number of observations in clinical imaging studies that have been difficult to reconcile with macrophage-selective FDG uptake.

The relationship between tumor aggressiveness and cholinergic PET imaging in prostate cancer tissue. A proof-of-concept study.

It was recently shown that high-risk prostate carcinoma (PCa) exhibited parasympathetic neurogenesis. The PET tracer 11C-donepezil is a marker of parasympathetic innervation. Therefore, we studied if parasympathetic nerve density in PCa measured with 11C-donepezil PET correlated with PCa aggressiveness and if metastases could be visualized. Twenty-six patients were included into three groups with varying tumor aggressiveness. Dynamic and static PET scans were performed. Maximal standardized uptake values (SUVmax) were determined in lesions within the prostate, lymph nodes, and bones. SUVmax in primary PCa were compared between groups, and comparisons between SUVmax and Gleason score and Prostate-specific antigen (PSA) were performed. Kinetic modelling was performed and time-activity curves of healthy tissue and tumor tissue fitted and compared. Tumor kinetic parameters were normalized to those of healthy tissue producing ratios of K1 and k2. Median SUVmax in primary PCa was higher in high-grade compared to low-grade PCa (P = 0.052). No correlation was seen between Gleason score and SUVmax (P = 0.28). A trend-level correlation was seen between PSA and SUVmax (P = 0.078). Median SUVmax was 7.7 (4.7-22.5) for suspected lymph node metastases and 8.2 (5.4-14.8) for suspected bone metastases. A significant difference was seen between time-activity tissue curves for low- and high-grade PCa (P = 0.012). Highly significant differences were seen in K1- and k2-ratios between low- and high-grade PCa (P = 0.0006 and P < 0.0001). We showed that 11C-donepezil accumulates in primary PCa and metastases. Simple SUVmax values of the cancer hot spots were higher in high-risk tumors compared to low-risk tumors. Further studies should elucidate the importance of cholinergic neurogenesis for prostate cancer biology.

Quantitative applications in positron emission tomography achieved through signal modelling.

Positron emission tomography (PET) is a valuable tool in medical imaging, but it provides limited quantitative utility in a number of important applications, such as mapping of tracer accumulation in small tissues and quantitative assessment of factors affecting tracer uptake. We aimed to develop a quantification approach based on signal modelling, to address the above limitations. Our signal modelling approach allows for a comprehensive description of target and background signals. We used in silico simulations to exemplify the quantitative utility of signal modelling in a number of applications and conducted scans of standardized PET phantoms to validate our computer simulation algorithms. The simulations showed that the modelling approach allows applications not supported by current techniques, such as estimation of activity fractions of sub-resolution small tissues and accurate quantification of the effect of biological factors, such as hypoxia, on tracer accumulation. There was strong agreement between the simulation data and actual scans of phantoms, providing support for the validity of the simulation algorithms. We conclude that the presented signal modelling approach may provide a framework for image analysis that can improve and expand the quantitative capacity of PET imaging.

Tissue volume and activity mapping using total intensity projection of PET/CT images.

Autoradiography using phosphor imaging screens is often used to characterize tissue distribution of positron emission tomography (PET) radiotracers. PET tracers emit positrons with limited penetration range, and valid quantitative autoradiography can therefore only be achieved in thin tissue slices. However, in some settings, quantitative tracer profiling in thick tissues is required. Our aim was to develop a reliable method for this purpose. In this paper, we present a method based on total intensity projections (TIPs) of PET and computed tomography (CT) images. We show theoretically and experimentally that tissue total activity and tissue volume maps can be derived from the TIPs of PET and CT images, respectively. We also show that these maps are free of signal displacement artifacts in the direction of projection. To demonstrate the utility of the approach, we obtain and compare TIP-based maps and autoradiography of ex-vivo atherosclerotic minipig aortas following in-vivo injection of 18F-fluorodeoxyglucose. We show that autoradiography of the thick aortas yields distorted results due to positron range effects, whereas TIP-mapping is free from such bias. The TIP-based maps may, thus, provide a low-resolution alternative to autoradiography, when tracer accumulation profiling in thick tissues is required.

Quantitative Tumor Perfusion Imaging with 82Rb PET/CT in Prostate Cancer: Analytic and Clinical Validation.

The aim of this work was to evaluate 82Rb PET/CT as a diagnostic tool for quantitative tumor blood flow (TBF) imaging in prostate cancer (PCa). Study 1 was performed to evaluate 82Rb as a marker of TBF, using 15O-H2O PET as a reference method. Study 2 investigated the ability of 82Rb uptake measurements to differentiate between PCa and normal prostate. Methods: Study 1: 9 PCa patients scheduled for radical prostatectomy were included. Prostate multiparametric MRI and both cardiac and pelvic 15O-H2O PET and 82Rb PET were performed. PET findings were compared with postprostatectomy Gleason grade group (GGG). Study 2: 15 primary high-risk PCa patients and 12 controls without known prostate disease were included in a clinical drug trial (EudraCT 2016-003185-26). 68Ga-prostate-specific membrane antigen PET/CT scans of PCa patients were available. Pelvic 82Rb PET was performed. Results: Study 1: both 82Rb K1 and 82Rb SUVs correlated strongly with 15O-H2O TBF (ρ = 0.95, P < 0.001, and ρ = 0.77, P = 0.015, respectively). 82Rb SUV and K1 were linearly correlated (r = 0.92, P = 0.001). 82Rb SUV correlated with postprostatectomy GGG (ρ = 0.70, P = 0.03). Study 2: 82Rb SUV in PCa (3.19 ± 0.48) was significantly higher than prostate 82Rb SUV in healthy controls (1.68 ± 0.37) (P < 0.001), with no overlap between groups. Conclusion: Study 1 shows that 82Rb PET/CT can be used for TBF quantification and that TBF can be estimated by simple SUV and suggests that 82Rb SUV is associated with postprostatectomy GGG and, hence, cancer aggressiveness. Study 2 shows that 82Rb uptake is significantly higher in PCa than in normal prostate tissue with no overlap between cohorts, confirming the primary hypothesis of the clinical trial. Consequently, 82Rb PET/CT may have potential as a noninvasive tool for evaluation of tumor aggressiveness and monitoring in nonmetastatic PCa.

Non-invasive quantification of tumor blood flow in prostate cancer using 15O-H2O PET/CT.

Tumor blood flow (TBF) measurements in prostate cancer (PCa) provide an integrative index of tumor growth, which could be important for primary diagnosis and therapy response evaluation. 15O-water PET is the non-invasive gold standard but is technically demanding. The aim of this study was to compare the accuracy of three different non-invasive strategies with an invasively measured arterial input function (BSIF): Using image-derived input functions (IDIF) from either 1) a separate heart scan or 2) the pelvic scan or 3) a populations-based input function (PBIF). Nine patients with biopsy-verified PCa scheduled for prostatectomy were included. All patients were characterized with serum levels of PSA (s-PSA), multiparametric magnetic resonance imaging (mpMRI) and post-surgical histopathology Gleason Grade. Dynamic 15O-water was performed of the heart and the pelvic area 15 minutes apart. TBF estimated from both wash-in (K1) and wash-out (k2) constants was calculated using a one-compartmental model. Results: Mean (range) s-PSA was 12 (3-27) ng/mL, Gleason Grade Group was 2.9 (1-5), k2 was 0.44 (0.007-1.2), and K1 was 0.24 (0.07-0.55) mL/mL/min. k2 (BSIF) correlated with s-PSA (r=0.86, P<0.01) and Gleason Grade Group (rho=0.78, P=0.01). BSIF, heart-IDIF and PBIF provided near-identical k2 and K1 (r>0.95, P<0.001) with slopes near unity. The correlations of BSIF and pelvic-IDIF rate constants were good (r>0.95, P<0.001), but individual errors high. In conclusion, non-invasive protocols for 15O-water PET with IDIF or PBIF accurately measures perfusion in prostate cancer and might be useful for evaluation of tumor aggressiveness and treatment response.

Automatic calculation of myocardial external efficiency using a single 11C-acetate PET scan.

BACKGROUND: Myocardial external efficiency (MEE) is defined as the ratio of kinetic energy associated with cardiac work [forward cardiac output (FCO)*mean systemic pressure] and the chemical energy from oxygen consumed (MVO2) by the left ventricular mass (LVM). We developed a fully automated method for estimating MEE based on a single 11C-acetate PET scan without ECG-gating. METHODS AND RESULTS: Ten healthy controls, 34 patients with aortic valve stenosis (AVS), and 20 patients with mitral valve regurgitation (MVR) were recruited in a dual-center study. MVO2 was calculated using washout of 11C -acetate activity. FCO and LVM were calculated automatically using dynamic PET and parametric image formation. FCO and LVM were also obtained using cardiac magnetic resonance (CMR) in all subjects. The correlation between MEEPET-CMR and MEEPET was high (r = 0.85, P < 0.001) without significant bias. MEEPET was 23.6 ± 4.2% for controls and was lowered in AVS (17.2 ± 4.3%, P < 0.001) and in MVR (18.0 ± 5.2%, P = 0.004). MEEPET was strongly associated with both NYHA class (P < 0.001) and the magnitude of valvular dysfunction (mean aortic gradient: P < 0.001, regurgitant fraction: P = 0.009). CONCLUSION: A single 11C-acetate PET yields accurate and automated MEE results on different scanners. MEE might provide an unbiased measurement of the phenotypic response to valvular disease.

Test-retest repeatability of myocardial oxidative metabolism and efficiency using standalone dynamic 11C-acetate PET and multimodality approaches in healthy controls.

BACKGROUND: Myocardial efficiency measured by 11C-acetate positron emission tomography (PET) has successfully been used in clinical research to quantify mechanoenergetic coupling. The objective of this study was to establish the repeatability of myocardial external efficiency (MEE) and work metabolic index (WMI) by non-invasive concepts. METHODS AND RESULTS: Ten healthy volunteers (63 ± 4 years) were examined twice, one week apart, using 11C-acetate PET, cardiovascular magnetic resonance (CMR), and echocardiography. Myocardial oxygen consumption from PET was combined with stroke work data from CMR, echocardiography, or PET to obtain MEE and WMI for each modality. Repeatability was estimated as the coefficient of variation (CV) between test and retest. MEECMR, MEEEcho, and MEEPET values were 21.9 ± 2.7%, 16.4 ± 3.7%, and 23.8 ± 4.9%, respectively, P < .001. WMICMR, WMIEcho, and WMIPET values were 4.42 ± 0.90, 4.07 ± 0.63, and 4.58 ± 1.13 mmHg × mL/m2 × 106, respectively, P = .45. Repeatability for MEECMR was superior compared with MEEEcho but did not differ significantly compared with MEEPET (6.3% vs 12.9% and 9.4%, P = .04 and .25). CV values for WMICMR, WMIEcho, and WMIPET were 10.0%, 14.8%, and 12.0%, respectively, (P = .53). CONCLUSIONS: Non-invasive measurements of MEE using 11C-acetate PET are highly repeatable. A PET-only approach did not differ significantly from CMR/PET and might facilitate further clinical research due to lower costs and broader applicability.

Metformin does not affect postabsorptive hepatic free fatty acid uptake, oxidation or resecretion in humans: A 3-month placebo-controlled clinical trial in patients with type 2 diabetes and healthy controls.

AIMS: To explore whether the pre-clinical findings that metformin improves lipid metabolism, possibly through modulation of intrahepatic partitioning of fatty acids towards oxidation and away from re-esterification and resecretion as triglycerides (TGs), can be translated to a human setting. MATERIALS AND METHODS: We performed a 3-month randomized, placebo-controlled, parallel-group clinical trial in patients with type 2 diabetes (T2D; n = 24) and healthy controls (n = 12). Patients with T2D received either placebo (placebo group) or 1000 mg metformin twice daily (metformin group), while healthy subjects were all treated with metformin (control group). Hepatic fatty acid metabolism was measured by [11 C]palmitate positron-emission tomography, hepatic TG secretion and peripheral oxidation by ex vivo labelled [1-14 C]VLDL-TG and VLDL particle size by TG/apolipoprotein B ratio. Body composition was assessed by dual-energy X-ray and whole-body lipid oxidation by indirect calorimetry. RESULTS: Metformin treatment for 3 months produced the anticipated decrease in fasting plasma glucose (FPG) in the metformin group (FPG 7.9 ± 1.8 mM [study day 1] vs 6.4 ± 1.1 mM [study day 2]), whereas patients in the placebo group and healthy controls had similar FPG levels before and after the trial (mixed model group vs time interaction; P = .003); however, contrary to our hypothesis, metformin treatment did not affect hepatic lipid metabolism or peripheral oxidation. CONCLUSION: The observed beneficial effects on lipid metabolism during metformin treatment in humans appear to be secondary to long-term alterations in body composition or glucose homeostasis.

Levosimendan improves cardiac function and myocardial efficiency in rats with right ventricular failure.

Levosimendan is an inotropic and vasodilator drug, which is known to improve cardiac function in animal models of right ventricular (RV) failure. The effects of levosimendan on oxygen consumption and myocardial efficiency in the failing RV is unknown. We investigated the effects of levosimendan on RV function, myocardial oxygen consumption, myocardial external efficiency (MEE), and myocardial metabolism in rats with RV hypertrophy and failure. RV hypertrophy and failure were induced by pulmonary trunk banding in rats. Rats were randomized to seven weeks of treatment with vehicle (n = 16) or levosimendan (3 mg/kg/day) (n = 13). Control animals without pulmonary banding received vehicle treatment (n = 11). RV MEE and RV metabolism were evaluated by echocardiography, 11C-acetate positron emission tomography (PET), 18F-FDG PET, and invasive pressure measurements. We found that levosimendan improved RV MEE (26 ± 3 vs. 14 ± 1%, P < 0.01) by increasing RV external work (0.62 ± 0.06 vs. 0.30 ± 0.03 mmHgcmL, P < 0.001) without affecting RV myocardial oxygen consumption ( P = 0.64). The improvement in RV MEE was not associated with a change in RV myocardial glucose uptake (1.3 ± 0.1 vs. 1.0 ± 0.1 µmol/g/min, P = 0.44). In conclusion, in the hypertrophic and failing RV of the rat, levosimendan improves RV function without increasing myocardial oxygen consumption leading to improved MEE. The improvement in RV MEE was not associated with a change in myocardial glucose uptake. This study emphasizes the potential therapeutic value of chronic levosimendan treatment RV failure. It extends previous observations on the effect profile of levosimendan and motivates clinical testing of levosimendan in RV failure.

Whole-Body Biodistribution, Dosimetry, and Metabolite Correction of [11C]Palmitate: A PET Tracer for Imaging of Fatty Acid Metabolism.

INTRODUCTION: Despite the decades long use of [11C]palmitate positron emission tomography (PET)/computed tomography in basic metabolism studies, only personal communications regarding dosimetry and biodistribution data have been published. METHODS: Dosimetry and biodistribution studies were performed in 2 pigs and 2 healthy volunteers by whole-body [11C]palmitate PET scans. Metabolite studies were performed in 40 participants (healthy and with type 2 diabetes) under basal and hyperinsulinemic conditions. Metabolites were estimated using 2 approaches and subsequently compared: Indirect [11C]CO2 release and parent [11C]palmitate measured by a solid-phase extraction (SPE) method. Finally, myocardial fatty acid uptake was calculated in a patient cohort using input functions derived from individual metabolite correction compared with population-based metabolite correction. RESULTS: In humans, mean effective dose was 3.23 (0.02) µSv/MBq, with the liver and myocardium receiving the highest absorbed doses. Metabolite correction using only [11C]CO2 estimates underestimated the fraction of metabolites in studies lasting more than 20 minutes. Population-based metabolite correction showed excellent correlation with individual metabolite correction in the cardiac PET validation cohort. CONCLUSION: First, mean effective dose of [11C]palmitate is 3.23 (0.02) µSv/MBq in humans allowing multiple scans using ∼300 MBq [11C]palmitate, and secondly, population-based metabolite correction compares well with individual correction.

Myocardial Oxygen Consumption and Efficiency in Aortic Valve Stenosis Patients With and Without Heart Failure.

BACKGROUND: Myocardial oxygen consumption (MVO2) and its coupling to contractile work are fundamentals of cardiac function and may be involved causally in the transition from compensated left ventricular hypertrophy to failure. Nevertheless, these processes have not been studied previously in patients with aortic valve stenosis (AS). METHODS AND RESULTS: Participants underwent 11C-acetate positron emission tomography, cardiovascular magnetic resonance, and echocardiography to measure MVO2 and myocardial external efficiency (MEE) defined as the ratio of left ventricular stroke work and the energy equivalent of MVO2. We studied 10 healthy controls (group A), 37 asymptomatic AS patients with left ventricular ejection fraction ≥50% (group B), 12 symptomatic AS patients with left ventricular ejection fraction ≥50% (group C), and 9 symptomatic AS patients with left ventricular ejection fraction <50% (group D). MVO2 did not differ among groups A, B, C, and D (0.105±0.02, 0.117±0.024, 0.129±0.032, and 0.104±0.026 mL/min per gram, respectively; P=0.07), whereas MEE was reduced in group D (21.0±1.6%, 22.3±3.3%, 22.1±4.2%, and 17.3±4.7%, respectively; P<0.05). Similarly, patients with global longitudinal strain greater than -12% and paradoxical low-flow, low-gradient AS had impaired MEE (P<0.05 versus controls). The ability to discriminate between symptomatic and asymptomatic patients was superior for global longitudinal strain compared with MVO2 and MEE (area under the curve 0.98, 0.48, and 0.61, respectively; P<0.05). CONCLUSIONS: AS patients display a persistent ability to maintain normal MVO2 and MEE (ie, the ability to convert energy into stroke work); however, patients with left ventricular ejection fraction <50%; global longitudinal strain greater than -12%; or paradoxical low-flow, low-gradient AS demonstrate reduced MEE. These findings suggest that mitochondrial uncoupling contributes to the dismal prognosis in patients with reduced contractile function or paradoxical low-flow, low-gradient AS.

A CT-, PET- and MR-imaging-compatible hyperbaric pressure chamber for baromedical research.

OBJECTIVES: We describe the development of a novel preclinical rodent-sized pressure chamber system compatible with computed tomography (CT), positron emission tomography (PET) and magnetic resonance imaging (MRI) that allows continuous uncompromised and minimally invasive data acquisition throughout hyperbaric exposures. The effect of various pressures on the acquired image intensity obtained with different CT, PET and MRI phantoms are characterised. MATERIAL AND METHODS: Tissue-representative phantom models were examined with CT, PET or MRI at normobaric pressure and hyperbaric pressures up to 1.013 mPa. The relationships between the acquired image signals and pressure were evaluated by linear regression analysis for each phantom. RESULTS: CT and PET showed no effect of pressure per se, except for CT of air, demonstrating an increase in Hounsfield units in proportion to the pressure. For MRI, pressurisation induced no effect on the longitudinal relaxation rate (R1), whereas the transversal relaxation rate (R2) changed slightly. The R2 data further revealed an association between pressure and the concentration of the paramagnetic nuclei gadolinium, the contrast agent used to mimic different tissues in the MRI phantoms. CONCLUSION: This study demonstrates a pressure chamber system compatible with CT, PET and MRI. We found that no correction in image intensity was required with pressurisation up to 1.013 mPa for any imaging modality. CT, PET or MRI can be used to obtain anatomical and physiological information from pressurised model animals in this chamber.

Familial hypercholesterolemia and atherosclerosis in cloned minipigs created by DNA transposition of a human PCSK9 gain-of-function mutant.

Lack of animal models with human-like size and pathology hampers translational research in atherosclerosis. Mouse models are missing central features of human atherosclerosis and are too small for intravascular procedures and imaging. Modeling the disease in minipigs may overcome these limitations, but it has proven difficult to induce rapid atherosclerosis in normal pigs by high-fat feeding alone, and genetically modified models similar to those created in mice are not available. D374Y gain-of-function mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene cause severe autosomal dominant hypercholesterolemia and accelerates atherosclerosis in humans. Using Sleeping Beauty DNA transposition and cloning by somatic cell nuclear transfer, we created Yucatan minipigs with liver-specific expression of human D374Y-PCSK9. D374Y-PCSK9 transgenic pigs displayed reduced hepatic low-density lipoprotein (LDL) receptor levels, impaired LDL clearance, severe hypercholesterolemia, and spontaneous development of progressive atherosclerotic lesions that could be visualized by noninvasive imaging. This model should prove useful for several types of translational research in atherosclerosis.