Chad Hunter

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.

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.

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.

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.