Parametric imaging of myocardial blood flow with 82Rb position emission tomography: An accuracy and image-quality analysis.

BACKGROUND: We aimed to develop a framework for generating three-dimensional (3D) myocardial blood flow (MBF) images, computing their accuracy against clinically validated two-dimensional (2D) polar MBF maps of the left ventricle, and evaluating their improvements in image quality over relative myocardial perfusion imaging (MPI). METHODS: N = 40 patients with a wide range of defect severities and uptake dynamics were retrospectively studied. The FlowQuant™ software was used to generate reference MPI and polar MBF maps and was adapted for voxel-wise MBF mapping. We evaluated agreement between parametric vs polar values for MBF at rest and stress and for reserve (stress/rest MBF). We also assessed improvements in image quality, assessed by signal-to-noise ratio, contrast-to-noise ratio, tissue-to-blood ratio, and defect severity, from relative MPI to MBF. RESULTS: There was excellent agreement between 3D parametric and 2D polar maps for all flow parameters (interclass correlation coefficient >0.96), albeit with minimal bias (<8%) for rest and stress MBF at the patient level. Image quality substantially improved from MPI to MBF in every patient for all image-quality metrics (P < 0.0001) CONCLUSIONS: We developed a robust methodology for producing highly accurate 3D MBF images exhibiting considerably improved image quality compared to relative MPI commonly used in clinical practice.

Patient body motion correction for dynamic cardiac PET-CT by attenuation-emission alignment according to projection consistency conditions.

INTRODUCTION: Patient body motion is known to cause large deviations in the determination of myocardial blood flow (MBF) with errors exceeding 300%. Accurate correction for patient whole-body motion is still a largely unsolved problem in cardiac positron emission tomography (PET) imaging. OBJECTIVE: This study evaluated the efficacy of using Natterer's formulation of the Helgason-Ludwig consistency conditions on the two-dimensional Radon transform to align computed tomography to PET projection data in multiple time frames of a dynamic sequence for the purpose of frame-by-frame correction of rigid whole-body motion. METHODS: The correction algorithm was evaluated with digital NCAT phantoms using realistic noise added by the analytical simulator. Count rates used in the simulation were derived from clinical patient data. In addition, a proof of concept test using measured data with a cardiac torso phantom was conducted. RESULTS: Motion correction resulted in significant improvement in the accuracy of MBF estimates, especially for high count-rate acquisitions. Maximum errors for 2 cm of motion dropped from 325% to 25% and from 250% to 25% using global and regional partial-volume correction, respectively. Median MBF errors dropped from 33% to 4.5% and 27% to 3.8%, respectively. Importantly, the correction algorithm performed equally well to compensate for body motion in both early and late time frames. CONCLUSION: Cardiac PET-CT data used for attenuation correction (CTAC) alignment using projection consistency conditions was effective for reducing errors in MBF measurements due to simulated patient motion, and can be integrated into the image reconstruction workflow.

Kernel-Based Reconstruction of C-11-Hydroxyephedrine Cardiac PET Images of the Sympathetic Nervous System.

Image reconstruction for positron emission tomography (PET) can be challenging and the resulting image typically has high noise. The kernel-based reconstruction method [1], incorporates prior anatomic information in the reconstruction algorithm to reduce noise while preserving resolution. Prior information is incorporated in the reconstruction algorithm by means of spatial kernels originally used in machine learning. In this paper, the kernel-based method is used to reconstruct PET images of sympathetic innervation in the heart. The resulting images are compared with standard Ordered Subset Expectation Maximization (OSEM) reconstructed images qualitatively and quantitatively using data from 6 human subjects. The kernel-based method demonstrated superior SNR with preserved contrast and accuracy compared to OSEM.

Effects of Hypercapnia on Myocardial Blood Flow in Healthy Human Subjects.

Elevation of the end-tidal partial pressure of CO2 (PETco2) increases cerebral and myocardial blood flow (MBF), suggesting that it may be a suitable alternative to pharmacologic stress or exercise for myocardial perfusion imaging. The purpose of this study was to document the pharmacodynamics of CO2 for MBF using prospective end-tidal targeting to precisely control arterial Pco2 and PET to measure the outcome variable, MBF. Methods: Ten healthy men underwent serial 82Rb PET/CT imaging. Imaging was performed at rest and during 6-min hypercapnic plateaus (baseline; PETco2 at 50, 55, and 60 mm Hg; repeat of PETco2 at 60 mm Hg; and repeat of baseline). MBF was measured using 82Rb injected 3 min after the beginning of hypercapnia and a 1-tissue-compartment model with flow-dependent extraction correction. Results were compared with those obtained during an adenosine stress test (140 µg/kg/min). Results: Baseline PETco2 was 38.9 ± 0.8 (mean ± SD) mm Hg (range, 35-43 mm Hg). All PETco2 targets were sustained, with SDs of less than 1.5 mm Hg. Heart rate, systolic blood pressure, rate × pressure product, and respiratory frequency increased with progressive hypercapnia. MBF increased significantly at each level of hypercapnia to 1.92-fold over baseline (0.86 ± 0.24 vs. 0.45 ± 0.08 mL/min/g; P = 0.002) at a PETco2 of 60 mm Hg. MBF after the administration of adenosine was significantly greater than that with the maximal hypercapnic stimulus (2.00 vs. 0.86 mL/min/g; P < 0.0001). Conclusion: To our knowledge, this study is the first to assess the response of MBF to different levels of hypercapnia in healthy humans with PET. MBF increased with increasing levels of hypercapnia; MBF at a PETco2 of 60 mm Hg was double that at baseline.

Randomized Trial Comparing the Effects of Ticagrelor Versus Clopidogrel on Myocardial Perfusion in Patients With Coronary Artery Disease.

BACKGROUND: Ticagrelor is a P2Y12 receptor inhibitor used in acute coronary syndromes to reduce platelet activity and to decrease thrombus formation. Ticagrelor is associated with a reduction in mortality incremental to that observed with clopidogrel, potentially related to its non-antiplatelet effects. Evidence from animal models indicates that ticagrelor potentiates adenosine-induced myocardial blood flow (MBF) increases. We investigated MBF at rest and during adenosine-induced hyperemia in patients with stable coronary artery disease treated with ticagrelor versus clopidogrel. METHODS AND RESULTS: This randomized double-blinded crossover study included 22 patients who received therapeutic interventions of ticagrelor 90 mg orally twice a day for 10 days and clopidogrel 75 mg orally once a day for 10 days, with a washout period of at least 10 days between the treatments. Global and regional MBF and myocardial flow reserve were measured using rubidium 82 positron emission tomography/computed tomography at baseline and during intermediate- and high-dose adenosine. Global MBF was significantly greater with ticagrelor versus clopidogrel (1.28±0.55 versus 1.13±0.47 mL/min per gram, P=0.002) at intermediate-dose adenosine and not different at baseline (0.65±0.19 versus 0.60±0.15 mL/min per gram, P=0.084) and at high-dose adenosine (1.64±0.40 versus 1.61±0.19 mL/min per gram, P=0.53). In regions with impaired myocardial flow reserve (<2.5), MBF was greater with ticagrelor compared with clopidogrel during intermediate and high doses of adenosine (P<0.0001), whereas the differences were not significant at baseline. CONCLUSIONS: Ticagrelor potentiates global and regional adenosine-induced MBF increases in patients with stable coronary artery disease. This effect may contribute to the incremental mortality benefit compared with clopidogrel. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01894789.

Characterization of 18F-FPyKYNE-Losartan for Imaging AT1 Receptors.

Most physiologic effects of the renin angiotensin system (RAS) are mediated via the angiotensin (Ang) type 1 receptor (AT1R). The 18F-FPyKYNE derivative of the clinically used AT1R blocker losartan exhibits high binding selectivity for kidney AT1R and rapid metabolism in rats. The aim of this study was to further assess the binding profile of this novel PET agent for imaging AT1R in rats and pigs. METHODS: In vitro binding assays were performed with 18F-FPyKYNE-losartan in rat kidneys. Male Sprague-Dawley rats were used to assess dosimetry, antagonistic efficacy via blood pressure measurements, and presence of labeled metabolites in kidneys. Test-retest PET imaging, blocking with AT1R antagonist candesartan (10 mg/kg), and plasma metabolism analysis were performed in female Yorkshire pigs. RESULTS: 18F-FPyKYNE-losartan bound with high affinity (dissociation constant of 49.4 ± 18.0 nM and maximal binding of 348 ± 112 fmol/mm2) to rat kidney AT1R. It bound strongly to plasma proteins in rats (97%), and its labeled metabolites displayed minimal interference on renal AT1R binding. FPyKYNE-losartan fully antagonized the Ang II pressor effect, albeit with 4-fold potency reduction (the effective dose inhibiting 50% of the Ang II-induced maximal pressor response of 25.5 mg/kg) relative to losartan. PET imaging exhibited high kidney-to-blood contrast and slow renal clearance, with an SUV of 14.1 ± 6.2. Excellent reproducibility was observed in the calculated test-retest variability (7.2% ± 0.75%). Only hydrophilic-labeled metabolites were present in plasma samples, and renal retention was reduced (-60%) at 10-15 min after blockade with candesartan. CONCLUSION: 18F-FPyKYNE-losartan has a favorable binding profile and displays high potential for translational work in humans as an AT1R PET imaging agent.

Patient motion effects on the quantification of regional myocardial blood flow with dynamic PET imaging.

PURPOSE: Patient motion is a common problem during dynamic positron emission tomography (PET) scans for quantification of myocardial blood flow (MBF). The purpose of this study was to quantify the prevalence of body motion in a clinical setting and evaluate with realistic phantoms the effects of motion on blood flow quantification, including CT attenuation correction (CTAC) artifacts that result from PET-CT misalignment. METHODS: A cohort of 236 sequential patients was analyzed for patient motion under resting and peak stress conditions by two independent observers. The presence of motion, affected time-frames, and direction of motion was recorded; discrepancy between observers was resolved by consensus review. Based on these results, patient body motion effects on MBF quantification were characterized using the digital NURBS-based cardiac-torso phantom, with characteristic time activity curves (TACs) assigned to the heart wall (myocardium) and blood regions. Simulated projection data were corrected for attenuation and reconstructed using filtered back-projection. All simulations were performed without noise added, and a single CT image was used for attenuation correction and aligned to the early- or late-frame PET images. RESULTS: In the patient cohort, mild motion of 0.5 ± 0.1 cm occurred in 24% and moderate motion of 1.0 ± 0.3 cm occurred in 38% of patients. Motion in the superior/inferior direction accounted for 45% of all detected motion, with 30% in the superior direction. Anterior/posterior motion was predominant (29%) in the posterior direction. Left/right motion occurred in 24% of cases, with similar proportions in the left and right directions. Computer simulation studies indicated that errors in MBF can approach 500% for scans with severe patient motion (up to 2 cm). The largest errors occurred when the heart wall was shifted left toward the adjacent lung region, resulting in a severe undercorrection for attenuation of the heart wall. Simulations also indicated that the magnitude of MBF errors resulting from motion in the superior/inferior and anterior/posterior directions was similar (up to 250%). Body motion effects were more detrimental for higher resolution PET imaging (2 vs 10 mm full-width at half-maximum), and for motion occurring during the mid-to-late time-frames. Motion correction of the reconstructed dynamic image series resulted in significant reduction in MBF errors, but did not account for the residual PET-CTAC misalignment artifacts. MBF bias was reduced further using global partial-volume correction, and using dynamic alignment of the PET projection data to the CT scan for accurate attenuation correction during image reconstruction. CONCLUSIONS: Patient body motion can produce MBF estimation errors up to 500%. To reduce these errors, new motion correction algorithms must be effective in identifying motion in the left/right direction, and in the mid-to-late time-frames, since these conditions produce the largest errors in MBF, particularly for high resolution PET imaging. Ideally, motion correction should be done before or during image reconstruction to eliminate PET-CTAC misalignment artifacts.

Biodistribution and radiation dosimetry of (82)Rb at rest and during peak pharmacological stress in patients referred for myocardial perfusion imaging.

PURPOSE: (82)Rb is an ultra-short-lived positron emitter used for myocardial blood flow quantification with PET imaging. The aim of this study was to quantify the biodistribution and radiation dosimetry in patients with coronary disease and in healthy normal volunteers. METHODS: A total of 30 subjects, 26 patients with known or suspected coronary artery disease (CAD) and four healthy volunteers were injected with (82)Rb chloride at 10 MBq/kg followed by a 10-min dynamic PET scan. Chest scans at rest were acquired in all subjects, as well as one additional biodistribution scan of the head, neck, abdomen, pelvis or thighs. Chest scans under stress were acquired in 25 of the CAD patients. (82)Rb time-integrated activity coefficients were determined in 22 source organs using volume of interest analysis, including corrections for partial-volume losses. The mean time-integrated activity coefficients were used to calculate the whole-body effective dose using tissue weighting factors from the International Commission on Radiological Protection (ICRP) Publications 60 and 103. RESULTS: A total of 283 organ time-integrated activity coefficients were calculated, with a minimum of four values per source organ. The rest and stress mean effective dose was 0.8 mSv/GBq, according to the most recent ICRP definition. Using 10 MBq/kg for 3D PET imaging, the effective dose to a gender-averaged reference person (60 kg female and 73 kg male) is 1.1 mSv for a complete rest and stress perfusion study. For 2D PET using a typical injected activity of 1.1 to 2.2 GBq each for rest and stress, the effective dose for a complete study is 1.8 to 3.5 mSv. CONCLUSION: The current effective dose estimate in CAD patients is four times lower than the values reported previously by the ICRP, and about 35% lower than previous in vivo studies in young healthy subjects.