Subjects with carotid webs demonstrate pro-thrombotic hemodynamics compared to subjects with carotid atherosclerosis.

Carotid artery webs (CaW) are non-atherosclerotic projections into the vascular lumen and have been linked to up to one-third of cryptogenic strokes in younger patients. Determining how CaW affects local hemodynamics is essential for understanding clot formation and stroke risk. Computational fluid dynamics simulations were used to investigate patient-specific hemodynamics in carotid artery bifurcations with CaW, bifurcations with atherosclerotic lesions having a similar degree of lumen narrowing, and with healthy carotid bifurcations. Simulations were conducted using segmented computed tomography angiography geometries with inlet boundary conditions extracted from 2D phase contrast MRI scans. The study included carotid bifurcations with CaW (n = 13), mild atherosclerosis (n = 7), and healthy bifurcation geometries (n = 6). Hemodynamic parameters associated with vascular dysfunction and clot formation, including shear rate, oscillatory shear index (OSI), low velocity, and flow stasis were calculated and compared between the subject groups. Patients with CaW had significantly larger regions containing low shear rate, high OSI, low velocity, and flow stasis in comparison to subjects with mild atherosclerosis or normal bifurcations. These abnormal hemodynamic metrics in patients with CaW are associated with clot formation and vascular dysfunction and suggest that hemodynamic assessment may be a tool to assess stroke risk in these patients.

Assessment of Complex Flow Patterns in Patients With Carotid Webs, Patients With Carotid Atherosclerosis, and Healthy Subjects Using 4D Flow MRI.

BACKGROUND: Carotid webs (CaWs) are fibromuscular projections in the internal carotid artery (ICA) that cause mild luminal narrowing (<50%), but may be causative in up to one-third of seemingly cryptogenic strokes. Understanding hemodynamic alterations caused by CaWs is imperative to assessing stroke risk. Time-Average Wall Shear Stress (TAWSS) and Oscillatory Shear Index (OSI) are hemodynamic parameters linked to vascular dysfunction and thrombosis. PURPOSE: To test the hypothesis: "CaWs are associated with lower TAWSS and higher OSI than mild atherosclerosis or healthy carotid bifurcation." STUDY TYPE: Prospective study. POPULATION: A total of 35 subjects (N = 14 bifurcations with CaW, 11F, age: 49 ± 10, 10 mild atherosclerosis 6F, age: 72 ± 9, 11 healthy 9F, age: 42 ± 13). FIELD STRENGTH/SEQUENCE: 4D flow/STAR-MATCH/3D TOF/3T MRI, CTA. ASSESSMENT: 4D Flow velocity data were analyzed in two ways: 1) 3D ROI in the ICA bulbar segment (complex flow patterns are expected) was used to quantify the regions with low TAWSS and high OSI. 2) 2D planes were placed perpendicular to the centerline of the carotid bifurcation for detailed analysis of TAWSS and OSI. STATISTICAL TESTS: Independent-samples Kruskal-Wallis-H test with 0.05 used for statistical significance. RESULTS: The percent surface area where low TAWSS was present in the ICA bulb was 12.3 ± 8.0% (95% CI: 7.6-16.9) in CaW subjects, 1.6 ± 1.9% (95% CI: 0.2-2.9) in atherosclerosis, and 8.5 ± 7.7% (95% CI: 3.6-13.4) in healthy subjects, all differences were statistically significant (ƞ2 = 0.3 [95% CI: 0.05-0.5], P-value CaW vs. healthy = 0.2). OSI had similar values in the CCA between groups (ƞ2 = 0.07 [95% CI: 0.0-0.2], P-value = 0.5), but OSI was significantly higher downstream of the bifurcation in CaW subjects compared to atherosclerosis and normal subjects. OSI returned to similar values between groups 1.5 diameters distal to the bifurcation (ƞ2 = 0.03 [95% CI: 0.0-0.2], P-value = 0.7). CONCLUSION: Lower TAWSS and higher OSI are present in the ICA bulb in patients with CaW when compared to patients with atherosclerotic or healthy subjects. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Optimization of 4D Flow MRI Spatial and Temporal Resolution for Examining Complex Hemodynamics in the Carotid Artery Bifurcation.

BACKGROUND: Three-dimensional, ECG-gated, time-resolved, three-directional, velocity-encoded phase-contrast MRI (4D flow MRI) has been applied extensively to measure blood velocity in great vessels but has been much less used in diseased carotid arteries. Carotid artery webs (CaW) are non-inflammatory intraluminal shelf-like projections into the internal carotid artery (ICA) bulb that are associated with complex flow and cryptogenic stroke. PURPOSE: Optimize 4D flow MRI for measuring the velocity field of complex flow in the carotid artery bifurcation model that contains a CaW. METHODS: A 3D printed phantom model created from computed tomography angiography (CTA) of a subject with CaW was placed in a pulsatile flow loop within the MRI scanner. 4D Flow MRI images of the phantom were acquired with five different spatial resolutions (0.50-2.00  mm3) and four different temporal resolutions (23-96 ms) and compared to a computational fluid dynamics (CFD) solution of the flow field as a reference. We examined four planes perpendicular to the vessel centerline, one in the common carotid artery (CCA) and three in the internal carotid artery (ICA) where complex flow was expected. At these four planes pixel-by-pixel velocity values, flow, and time average wall shear stress (TAWSS) were compared between 4D flow MRI and CFD. HYPOTHESIS: An optimized 4D flow MRI protocol will provide a good correlation with CFD velocity and TAWSS values in areas of complex flow within a clinically feasible scan time (~ 10 min). RESULTS: Spatial resolution affected the velocity values, time average flow, and TAWSS measurements. Qualitatively, a spatial resolution of 0.50  mm3 resulted in higher noise, while a lower spatial resolution of 1.50-2.00  mm3 did not adequately resolve the velocity profile. Isotropic spatial resolutions of 0.50-1.00  mm3 showed no significant difference in total flow compared to CFD. Pixel-by-pixel velocity correlation coefficients between 4D flow MRI and CFD were > 0.75 for 0.50-1.00  mm3 but were < 0.5 for 1.50 and 2.00  mm3. Regional TAWSS values determined from 4D flow MRI were generally lower than CFD and decreased at lower spatial resolutions (larger pixel sizes). TAWSS differences between 4D flow and CFD were not statistically significant at spatial resolutions of 0.50-1.00  mm3 but were different at 1.50 and 2.00 mm3. Differences in temporal resolution only affected the flow values when temporal resolution was > 48.4 ms; temporal resolution did not affect TAWSS values. CONCLUSION: A spatial resolution of 0.74-1.00  mm3 and a temporal resolution of 23-48 ms (1-2 k-space segments) provides a 4D flow MRI protocol capable of imaging velocity and TAWSS in regions of complex flow within the carotid bifurcation at a clinically acceptable scan time.

A New Method for Quantifying Abdominal Aortic Wall Shear Stress Using Phase Contrast Magnetic Resonance Imaging and the Womersley Solution.

Wall shear stress (WSS) is an important mediator of cardiovascular pathologies and there is a need for its reliable evaluation as a potential prognostic indicator. The purpose of this work was to develop a method that quantifies WSS from two-dimensional (2D) phase contrast magnetic resonance (PCMR) imaging derived flow waveforms, apply this method to PCMR data acquired in the abdominal aorta of healthy volunteers, and to compare PCMR-derived WSS values to values predicted from a computational fluid dynamics (CFD) simulation. The method uses PCMR-derived flow versus time waveforms constrained by the Womersley solution for pulsatile flow in a cylindrical tube. The method was evaluated for sensitivity to input parameters, intrastudy repeatability and was compared with results from a patient-specific CFD simulation. 2D-PCMR data were acquired in the aortas of healthy men (n = 12) and women (n = 15) and time-averaged WSS (TAWSS) was compared. Agreement was observed when comparing TAWSS between CFD and the PCMR flow-based method with a correlation coefficient of 0.88 (CFD: 15.0 ± 1.9 versus MRI: 13.5 ± 2.4 dyn/cm2) though comparison of WSS values between the PCMR-based method and CFD predictions indicate that the PCMR method underestimated instantaneous WSS by 3.7 ± 7.6 dyn/cm2. We found no significant difference in TAWSS magnitude between the sexes; 8.19 ± 2.25 versus 8.07 ± 1.71 dyn/cm2, p = 0.16 for men and women, respectively.

Carotid webs produce greater hemodynamic disturbances than atherosclerotic disease: a DSA time-density curve study.

BACKGROUND: Carotid webs (CaWs) are associated with ischemic strokes in younger patients without degrees of stenosis that are traditionally considered clinically significant. OBJECTIVE: To compare the hemodynamic parameters in the internal carotid artery (ICA) bulbar segment in patients with CaW with those in patients with atherosclerotic lesions using time-density curve (TDC) analysis of digital subtraction angiography (DSA) images. METHODS: We retrospectively assessed DSA images of 47 carotid arteries in 41 adult patients who underwent ICA catheter angiography for evaluation after ischemic stroke. Hemodynamic parameters, including full width at half maximum (FWHM) and area under the time-density curve (AUC) as proxies for increased flow stasis, were calculated using TDC analyses of a region of interest (ROI) in the ICA bulb immediately rostral to the web/atherosclerotic plaque, relative to a standardized ROI in the ipsilateral distal common carotid artery (eg, relative FWHM (rFWHM)). Hemodynamic parameters were compared using non-parametric Kruskal-Wallis tests. Logistic regression was used to predict CaW versus mild/moderate atherosclerosis for each hemodynamic parameter, adjusting for degree of stenosis. RESULTS: Mean age of patients was 56.0±13 years, with 22 (53.7%) women. 17 CaWs, 22 atherosclerotic plaques (15 mild/moderate and 7 severe), and eight normal carotid arteries were assessed. Significant between-group differences were present in the relative total AUC (p<0.001), relative AUC at wash out (p=0.031), and relative FWHM (p=0.001). Logistic regression to predict CaW versus mild/moderate atherosclerosis showed that rAUC total had the highest predictive value (pAUC=0.96, 95% CI 0.90 to 1.00), followed by rFWHM (0.87, 95% CI 0.74 to 1.00), and rAUC WO (0.74, 95% CI (0.57 to 0.91). CONCLUSION: CaW results in larger local hemodynamic disruption, characterized by flow stasis, than mild/moderate carotid atherosclerotic lesions, suggesting that CaWs may produce larger regions of thrombogenic flow stasis.

Effect of Patient-Specific Coronary Flow Reserve Values on the Accuracy of MRI-Based Virtual Fractional Flow Reserve.

The purpose of this study is to investigate the effect of varying coronary flow reserve (CFR) values on the calculation of computationally-derived fractional flow reserve (FFR). CFR reflects both vessel resistance due to an epicardial stenosis, and resistance in the distal microvascular tissue. Patients may have a wide range of CFR related to the tissue substrate that is independent of epicardial stenosis levels. Most computationally based virtual FFR values such as FFRCT do not measure patient specific CFR values but use a population-average value to create hyperemic flow conditions. In this study, a coronary arterial computational geometry was constructed using magnetic resonance angiography (MRA) data acquired in a patient with moderate CAD. Coronary flow waveforms under rest and stress conditions were acquired in 13 patients with phase-contrast magnetic resonance (PCMR) to calculate CFR, and these flow waveforms and CFR values were applied as inlet flow boundary conditions to determine FFR based on computational fluid dynamics (CFD) simulations. The stress flow waveform gave a measure of the functional significance of the vessel when evaluated with the physiologically-accurate behavior with the patient-specific CFR. The resting flow waveform was then scaled by a series of CFR values determined in the 13 patients to simulate how hyperemic flow and CFR affects FFR values. We found that FFR values calculated using non-patient-specific CFR values did not accurately predict those calculated with the true hyperemic flow waveform. This indicates that both patient-specific anatomic and flow information are required to accurately non-invasively assess the functional significance of coronary lesions.

New 55Co-labeled Albumin-Binding Folate Derivatives as Potential PET Agents for Folate Receptor Imaging.

Overexpression of folate receptors (FRs) on different tumor types (e.g., ovarian, lung) make FRs attractive in vivo targets for directed diagnostic/therapeutic agents. Currently, no diagnostic agent suitable for positron emission tomography (PET) has been adopted for clinical FR imaging. In this work, two 55Co-labeled albumin-binding folate derivatives-[55Co]Co-cm10 and [55Co]Co-rf42-with characteristics suitable for PET imaging have been developed and evaluated. High radiochemical yields (≥95%) and in vitro stabilities (≥93%) were achieved for both compounds, and cell assays demonstrated FR-mediated uptake. Both 55Co-labeled folate conjugates demonstrated high tumor uptake of 17% injected activity per gram of tissue (IA/g) at 4 h in biodistribution studies performed in KB tumor-bearing mice. Renal uptake was similar to other albumin-binding folate derivatives, and liver uptake was lower than that of previously reported [64Cu]Cu-rf42. Small animal PET/CT images confirmed the biodistribution results and showed the clear delineation of FR-expressing tumors.

Manganese-52 production cross-section measurements via irradiation of natural chromium targets up to 20 MeV.

Manganese-52g, 54 and Chromium-51 production cross-section measurements were conducted using natural chromium foils and copper monitor foils. Proton beam energies between 10 and 20 MeV were used for target bombardment. After bombardment, the irradiated foils were allowed to decay for at least 48 h and radioactivity was quantified using a high-purity germanium detector. The maximum 52gMn cross-section was 90.8 ±â€¯16.0 mb at 14.3 ±â€¯0.8 MeV. These data contribute to the existing nuclear data for cyclotron production of 52gMn at low to medium proton energies.

Imaging of HER2 with [89Zr]pertuzumab in Response to T-DM1 Therapy.

Background: The success of human epidermal growth factor receptor 2 (HER2)-targeted therapy depends on accurate characterization of HER2 expression, but current methods available have several limitations. This study aims to investigate the feasibility of [89Zr]pertuzumab imaging to monitor early response to Ado-trastuzumab emtansine (T-DM1) therapy in mice bearing xenografts of HER2-positive breast cancer (BCa). Materials and Methods: Pertuzumab was conjugated to DFO-Bz-NCS and labeled with 89Zr. Mice bearing BT-474 tumors were imaged with [89Zr]pertuzumab and [18F]FDG before and after T-DM1 therapy. Results: Pertuzumab was successfully labeled with 89Zr with a specific activity of 0.740 MBq/µg. Overall [18F]FDG images showed poor delineation of tumors. Using [18F]FDG-PET to measure tumor volume, the volume remained unchanged from 107.6 ± 20.7 mm3 before treatment to 89.87 ± 66.55 mm3 after treatment. In contrast, [89Zr]pertuzumab images showed good delineation of HER2-positive tumors, allowing accurate detection of changes in tumor volume (from 243.80 ± 40.91 mm3 before treatment to 78.4 ± 40.43 mm3 after treatment). Conclusion: [89Zr]pertuzumab may be an imaging probe for monitoring the response of HER2-positive BCa patients to T-DM1 therapy.

Production of Zr-89 using sputtered yttrium coin targets 89Zr using sputtered yttrium coin targets.

An increasing interest in zirconium-89 (89Zr) can be attributed to the isotope's half-life which is compatible with antibody imaging using positron emission tomography (PET). The goal of this work was to develop an efficient means of production for 89Zr that provides this isotope with high radionuclidic purity and specific activity. We investigated the irradiation of yttrium sputtered niobium coins and compared the yields and separation efficiency to solid yttrium coins. The sputtered coins were irradiated with an incident beam energy of 17.5MeV or 17.8MeV providing a degraded transmitted energy through an aluminum degrader of 12.5MeV or 12.8MeV, respectively, with various currents to determine optimal cyclotron conditions for 89Zr production. Dissolution of the solid yttrium coin took 2h with 50mL of 2M HCl and dissolution of the sputtered coin took 15-30min with 4mL of 2M HCl. During the separation of 89Zr from the solid yttrium coins, 77.9 ± 11.2% of the activity was eluted off in an average of 7.3mL of 1M oxalic acid whereas for the sputtered coins, 91 ± 6% was eluted off in an average of 1.2mL of 1M oxalic acid with 100% radionuclidic purity. The effective specific activity determined via DFO-SCN titration from the sputtered coins was 108±7mCi/µmol as compared to 20.3mCi/µmol for the solid yttrium coin production. ICP-MS analysis of the yttrium coin and the sputtered coins showed 99.99% yttrium removed with 178µg of yttrium in the final solution and 99.93-100% of yttrium removed with remaining range of 0-42µg of yttrium in the final solution, respectively. The specific activity calculated for the solid coin and 3 different sputtered coins using the concentration of Zr found via ICP-MS was 140±2mCi/µmol, 300±30mCi/µmol, 410±60mCi/µmol and 1719±5mCi/µmol, respectively. Labeling yields of the 89Zr produced via sputtered targets for 89Zr- DFO-trastuzumab were >98%. Overall, these results show the irradiation of yttrium sputtered niobium coins is a highly effective means for the production of 89Zr.