Measurement of enhanced vasa vasorum density in a porcine carotid model using photon counting detector CT.

Purpose: The onset of atherosclerosis is preceded by changes in blood perfusion within the arterial wall due to localized proliferation of the vasa vasorum. The purpose of this study was to quantify these changes in spatial density of the vasa vasorum using a research whole-body photon-counting detector CT (PCD-CT) scanner and a porcine model. Approach: Vasa vasorum angiogenesis was stimulated in the left carotid artery wall of anesthetized pigs ( n = 5 ) while the right carotid served as a control. After a 6-week recovery period, the animals were scanned on the PCD-CT prior to and after injection of iodinated contrast. Annular regions of interest were used to measure wall enhancement in the injured and control arteries. The exact Wilcoxon-signed rank test was used to determine whether a significant difference in contrast enhancement existed between the injured and control arterial walls. Results: The greatest arterial wall enhancement was observed following contrast recirculation. The wall enhancement measurements made over these time points revealed that the enhancement was greater in the injured artery for 13/16 scanned arterial regions. Using an exact Wilcoxon-signed rank test, a significantly increased enhancement ratio was found in injured arteries compared with control arteries ( p = 0.013 ). Vasa vasorum angiogenesis was confirmed in micro-CT scans of excised arteries. Conclusions: Whole-body PCD-CT scanners can be used to detect and quantify the increased perfusion occurring within the porcine carotid arterial wall resulting from an increased density of vasa vasorum.

Overcoming calcium blooming and improving the quantification accuracy of percent area luminal stenosis by material decomposition of multi-energy computed tomography datasets.

Purpose: Conventional stenosis quantification from single-energy computed tomography (SECT) images relies on segmentation of lumen boundaries, which suffers from partial volume averaging and calcium blooming effects. We present and evaluate a method for quantifying percent area stenosis using multienergy CT (MECT) images. Approach: We utilize material decomposition of MECT images to measure stenosis based on the ratio of iodine mass between vessel locations with and without a stenosis, thereby eliminating the requirement for segmentation of iodinated lumen. The method was first assessed using simulated MECT images created with different spatial resolutions. To experimentally assess this method, four phantoms with different stenosis severity (30% to 51%), vessel diameters (5.5 to 14 mm), and calcification densities (700 to 1100 mgHA / cc ) were fabricated. Conventional SECT images were acquired using a commercial CT system and were analyzed with commercial software. MECT images were acquired using a commercial dual-energy CT (DECT) system and also from a research photon-counting detector CT (PCD-CT) system. Three-material-decomposition was performed on MECT data, and iodine density maps were used to quantify stenosis. Clinical radiation doses were used for all data acquisitions. Results: Computer simulation verified that this method reduced partial volume and blooming effects, resulting in consistent stenosis measurements. Phantom experiments showed accurate and reproducible stenosis measurements from MECT images. For DECT and two-threshold PCD-CT images, the estimation errors were 4.0% to 7.0%, 2.0% to 9.0%, 10.0% to 18.0%, and - 1.0 % to - 5.0 % (ground truth: 51%, 51%, 51%, and 30%). For four-threshold PCD-CT images, the errors were 1.0% to 3.0%, 4.0% to 6.0%, - 1.0 % to 9.0%, and 0.0% to 6.0%. Errors using SECT were much larger, ranging from 4.4% to 46%, and were especially worse in the presence of dense calcifications. Conclusions: The proposed approach was shown to be insensitive to acquisition parameters, demonstrating the potential to improve the accuracy and precision of stenosis measurements in clinical practice.

Probing the Depth of the Myocardium: Vasculature, Transit Time, and Perfusion Within the Left Ventricular Wall.

The branching architecture of arterial trees traversing the thickness of the left ventricular wall is studied to determine the way in which adequate blood supply is provided to myocardial tissue at different depths within the wall thickness from arterial trees originating at the epicardial surface. The study is based on micro-CT images of tissue biopsies, coupled with a dedicated vascular tree analysis program. The results show that this combination of methodologies allows a more detailed and much more accurate exploration of the vasculature within the sampled tissue than is possible by histological means. The spatial density of the smallest resolvable "end" arterioles is found to be higher in the sub-endocardial region than in the sub-epicardial region, with vascular branching architecture consistent with a fractal structure. The concept of "transit time" is introduced as an approximate measure of the time it takes bulk flow to reach different regions of the myocardium. Our data suggest that a transit time differential is a major contributor to the equalization of transmural perfusion gradient against unequal distribution of "end' arteriolar density.

Impact of Effective Detector Pixel and CT Voxel Size on Accurate Estimation of Blood Volume in Opacified Microvasculature.

RATIONALE AND OBJECTIVES: The purpose of this study was to determine the impact of effective detector-pixel-size and image voxel size on the accurate estimation of microvessel density (ratio of microvascular lumen volume/tissue volume) in an excised porcine myocardium specimen using microcomputed tomography (CT), and the ability of whole-body energy-integrating-detector (EID) CT and photon-counting-detector (PCD) CT to measure microvessel density in the same ex vivo specimen. MATERIALS AND METHODS: Porcine myocardial tissue in which the microvessels contained radio-opaque material was scanned using a micro-CT scanner and data were generated with a range of detector pixel sizes and image voxel sizes from 20 to 260 microns, to determine the impact of these parameters on the accuracy of microvessel density estimates. The same specimen was scanned in a whole-body EID CT and PCD CT system and images reconstructed with 600 and 250 micron slice thicknesses, respectively. Fraction of tissue volume that is filled with opacified microvessels was determined by first subtracting the mean background attenuation value from all voxels, and then by summing the remaining attenuation. RESULTS: Microvessel density data were normalized to the value measured at 20 µm voxel size, which was considered reference truth for this study. For emulated micro-CT voxels up to 260 µm, the microvessel density was underestimated by at most 11%. For whole-body EID CT and PCD CT, microvessel density was underestimated by 9.5% and overestimated by 0.1%, respectively. CONCLUSION: Our data indicate that microvessel density can be accurately calculated from the larger detector pixels used in clinical CT scanners by measuring the increase of CT attenuation caused by these opacified microvessels.

Evaluation of a photon counting Medipix3RX cadmium zinc telluride spectral x-ray detector.

We assess the performance of a cadmium zinc telluride (CZT)-based Medipix3RX energy-resolving and photon-counting x-ray detector as a candidate for spectral microcomputed tomography (micro-CT) imaging. It features an array of 128 × 128 , 110 - µ m 2 pixels, each with four simultaneous threshold counters that utilize real-time charge summing. Each pixel's response is assessed by imaging with a range of incident x-ray intensities and detector integration times. Energy-related assessments are made by exposing the detector to the emission from an I-125 radioisotope brachytherapy seed. Long-term stability is assessed by repeating identical exposures over the course of 1 h. The high yield of properly functioning pixels (98.8%), long-term stability (linear regression of whole-chip response over 1 h of acquisitions: y = - 0.0038 x + 2284 ; standard deviation: 3.7 counts), and energy resolution [2.5 keV full-width half-maximum (FWHM) (single pixel), 3.7 keV FWHM (across the full image)] make this device suitable for spectral micro-CT.

Measuring arterial wall perfusion using photon-counting computed tomography (CT): improving CT number accuracy of artery wall using image deconvolution.

Changes in arterial wall perfusion mark the onset of atherosclerosis. A characteristic change is the increased spatial density of vasa vasorum (VV), the microvessels in the arterial walls. Measuring this increased VV (IVV) density using contrast-enhanced computed tomography (CT) has had limited success due to blooming effects from contrast media. If the system point-spread function (PSF) is known, then the blooming effect can be modeled as a convolution between the true signal and the PSF. We report the application of image deconvolution to improve the CT number accuracy in the arterial wall of a phantom and in a porcine model of IVV density, both scanned using a whole-body research photon-counting CT scanner. A 3D-printed carotid phantom filled with three concentrations of iodinated contrast material was scanned to assess blooming and its effect on wall CT number accuracy. The results showed a reduction in blooming effects following image deconvolution, and, consequently, a better delineation between lumen and wall was achieved. Results from the animal experiment showed improved CT number difference between the carotid with IVV density and the normal carotid artery after deconvolution, enabling the detection of VV proliferation, which may serve as an early indicator of atherosclerosis.

Detection of increased vasa vasorum in artery walls: Improving CT number accuracy using image deconvolution.

Changes in arterial wall perfusion are an indicator of early atherosclerosis. This is characterized by an increased spatial density of vasa vasorum (VV), the micro-vessels that supply oxygen and nutrients to the arterial wall. Detection of increased VV during contrast-enhanced computed tomography (CT) imaging is limited due to contamination from blooming effect from the contrast-enhanced lumen. We report the application of an image deconvolution technique using a measured system point-spread function, on CT data obtained from a photon-counting CT system to reduce blooming and to improve the CT number accuracy of arterial wall, which enhances detection of increased VV. A phantom study was performed to assess the accuracy of the deconvolution technique. A porcine model was created with enhanced VV in one carotid artery; the other carotid artery served as a control. CT images at an energy range of 25-120 keV were reconstructed. CT numbers were measured for multiple locations in the carotid walls and for multiple time points, pre and post contrast injection. The mean CT number in the carotid wall was compared between the left (increased VV) and right (control) carotid arteries. Prior to deconvolution, results showed similar mean CT numbers in the left and right carotid wall due to the contamination from blooming effect, limiting the detection of increased VV in the left carotid artery. After deconvolution, the mean CT number difference between the left and right carotid arteries was substantially increased at all the time points, enabling detection of the increased VV in the artery wall.

Evaluation of a photon counting Medipix3RX CZT spectral x-ray detector.

We assessed the performance of a cadmium zinc telluride (CZT)-based Medipix3RX x-ray detector as a candidate for micro-computed tomography (micro-CT) imaging. This technology was developed at CERN for the Large Hadron Collider. It features an array of 128 by 128, 110 micrometer square pixels, each with eight simultaneous threshold counters, five of which utilize real-time charge summing, significantly reducing the charge sharing between contiguous pixels. Pixel response curves were created by imaging a range of x-ray intensities by varying x-ray tube current and by varying the exposure time with fixed x-ray current. Photon energy-related assessments were made by flooding the detector with the tin foil filtered emission of an I-125 radioisotope brachytherapy seed and sweeping the energy threshold of each of the four charge-summed counters of each pixel in 1 keV steps. Long term stability assessments were made by repeating exposures over the course of one hour. The high properly-functioning pixel yield (99%), long term stability (linear regression of whole-chip response over one hour of acquisitions: y = -0.0038x + 2284; standard deviation: 3.7 counts) and energy resolution (2.5 keV FWHM (single pixel), 3.7 keV FWHM across the full image) make this device suitable for spectral micro-CT. The charge summing performance effectively reduced the measurement corruption caused by charge sharing which, when unaccounted for, shifts the photon energy assignment to lower energies, degrading both count and energy accuracy. Effective charge summing greatly improves the potential for calibrated, energy-specific material decomposition and K edge difference imaging approaches.

Arterial Wall Perfusion Measured with Photon Counting Spectral X-ray CT.

Early atherosclerosis changes perfusion of the arterial wall due to localized proliferation of the vasa vasorum. When contrast agent passes through the artery, some enters the vasa vasorum and increases radiopacity of the arterial wall. Technical challenges to detecting changes in vasa vasorum density include the thin arterial wall, partial volume averaging at the arterial lumen/wall interface and calcification within the wall. We used a photon-counting spectral CT scanner to study carotid arteries of anesthetized pigs and micro-CT of these arteries to quantify vasa vasorum density. The left carotid artery wall was injected with autologous blood to stimulate vasa vasorum angiogenesis. The scans were performed at 25-120 keV; the tube-current-time product was 550 mAs. A 60 mL bolus of iodine contrast agent was injected into the femoral vein at 5mL/s. Two seconds post injection, an axial scan was acquired at every 3 s over 60 s (i.e., 20 time points). Each time point acquired 28 contiguous transaxial slices with reconstructed voxels 0.16 × 0.16 × 1 mm3. Regions-of-interest in the outer 2/3 of the arterial wall and in the middle 2/3 of the lumen were drawn and their enhancements plotted versus time. Lumenal CT values peaked several seconds after injection and then returned towards baseline. Arterial wall CT values peaked concurrent to the lumen. The peak arterial wall enhancement in the left carotid arterial wall correlated with increased vasa vasorum density observed in micro-CT images of the isolated arteries.

A Three-Dimensional Micro-Computed Tomographic Study of the Intraosseous Lunate Vasculature: Implications for Surgical Intervention and the Development of Avascular Necrosis.

BACKGROUND: The purpose of this study was to use micro-computed tomography to demonstrate the intraosseous vascularity of the lunate within a three-dimensional orientation to identify areas of greatest perfusion and define vascular "safe zones" for surgical intervention. METHODS: Fourteen upper extremities were injected with a lead-based contrast agent. The lunates were harvested and scanned using a micro-computed tomography scanner. The intraosseous vascularity was incorporated into a three-dimensional image. Vessel number, diameter, distribution, and pattern were evaluated and analyzed. Vascularity of all specimens was projected onto one representative lunate to identity areas of higher and lower vascularity. RESULTS: Twelve specimens had nutrient vessels entering the bone from volar and dorsal; two specimens had no dorsal vessels. The intraosseous vascularity could be classified according to the Y, I, and X patterns described by Gelberman et al. Average number and diameter of vessels were 2.3 and 118.1 µm, respectively, for volar; and 1.4 and 135.8 µm, respectively, for dorsal. The long axis of the lunate showed the highest vascularity on both axial and lateral views. Lower vascularity was observed in the dorsoradial and volar-ulnar quadrants on the axial view, and in the proximal part on the lateral view. Lunate shape was not associated with an increase or decrease in nutrient vessels or vascular pattern. CONCLUSIONS: Vascular safe zones were identified, allowing for potentially safer surgical interventions to the lunate. Volar approaches to the lunate may result in localized ischemia in a subset of patients with absent dorsal nutrient vessels. This study may help to better define patients at risk for Kienböck disease.

How Low Can We Go in Radiation Dose for the Data-Completion Scan on a Research Whole-Body Photon-Counting Computed Tomography System.

PURPOSE: A research photon-counting computed tomography (CT) system that consists of an energy-integrating detector (EID) and a photon-counting detector (PCD) was installed in our laboratory. The scanning fields of view of the EID and PCD at the isocenter are 500 and 275 mm, respectively. When objects are larger than the PCD scanning field of view, a data-completion scan (DCS) using the EID subsystem is needed to avoid truncation artifacts in PCD images. The goals of this work were to (1) find the impact of a DCS on noise of PCD images and (2) determine the lowest possible dose for a DCS such that truncation artifacts are negligible in PCD images. METHODS: First, 2 semianthropomorphic abdomen phantoms were scanned on the PCD subsystem. For each PCD scan, we acquired 1 DCS with the maximum effective mAs and 5 with lower effective mAs values. The PCD image reconstructed using the maximum effective mAs was considered as the reference image, and those using the lower effective mAs as the test images. The PCD image reconstructed without a DCS was considered the baseline image. Each PCD image was assessed in terms of noise and CT number uniformity; the results were compared among the baseline, test, and reference images. Finally, the impact of a DCS on PCD image quality was qualitatively assessed for other body regions using an anthropomorphic torso phantom. RESULTS: The DCS had a negligible impact on the noise magnitude in the PCD images. The PCD images with the minimum available dose (CTDIvol < 2 mGy) showed greatly enhanced CT number uniformity compared with the baseline images without noticeable truncation artifacts. Further increasing the effective mAs of a DCS did not yield noticeable improvement in CT number uniformity. CONCLUSIONS: A DCS using the minimum available dose had negligible effect on image noise and was sufficient to maintain satisfactory CT number uniformity for the PCD scans.

Evaluation of conventional imaging performance in a research whole-body CT system with a photon-counting detector array.

This study evaluated the conventional imaging performance of a research whole-body photon-counting CT system and investigated its feasibility for imaging using clinically realistic levels of x-ray photon flux. This research system was built on the platform of a 2nd generation dual-source CT system: one source coupled to an energy integrating detector (EID) and the other coupled to a photon-counting detector (PCD). Phantom studies were conducted to measure CT number accuracy and uniformity for water, CT number energy dependency for high-Z materials, spatial resolution, noise, and contrast-to-noise ratio. The results from the EID and PCD subsystems were compared. The impact of high photon flux, such as pulse pile-up, was assessed by studying the noise-to-tube-current relationship using a neonate water phantom and high x-ray photon flux. Finally, clinical feasibility of the PCD subsystem was investigated using anthropomorphic phantoms, a cadaveric head, and a whole-body cadaver, which were scanned at dose levels equivalent to or higher than those used clinically. Phantom measurements demonstrated that the PCD subsystem provided comparable image quality to the EID subsystem, except that the PCD subsystem provided slightly better longitudinal spatial resolution and about 25% improvement in contrast-to-noise ratio for iodine. The impact of high photon flux was found to be negligible for the PCD subsystem: only subtle high-flux effects were noticed for tube currents higher than 300 mA in images of the neonate water phantom. Results of the anthropomorphic phantom and cadaver scans demonstrated comparable image quality between the EID and PCD subsystems. There were no noticeable ring, streaking, or cupping/capping artifacts in the PCD images. In addition, the PCD subsystem provided spectral information. Our experiments demonstrated that the research whole-body photon-counting CT system is capable of providing clinical image quality at clinically realistic levels of x-ray photon flux.

Human Imaging With Photon Counting-Based Computed Tomography at Clinical Dose Levels: Contrast-to-Noise Ratio and Cadaver Studies.

OBJECTIVES: The purpose of this work was to measure and compare the iodine contrast-to-noise ratio (CNR) between a commercial energy-integrating detector (EID) computed tomography (CT) system and a photon-counting detector (PCD) CT scanner capable of human imaging at clinical dose rates, as well as to determine clinical feasibility using human cadavers. MATERIALS AND METHODS: A research dual-source PCD-CT scanner was used, where the "A" tube/detector subsystem used an EID and the "B" tube/detector subsystem used a PCD. Iodine CNR was measured in 4 anthropomorphic phantoms, simulating 4 patient sizes, at 4 tube potential settings. After biospecimen committee approval, PCD scans were performed on a fresh-frozen human head and a whole-body cadaver using clinical dose rates. Scans were repeated using the EID and identical parameters, and qualitative side-by-side comparisons were performed. RESULTS: For the same photon fluence, phantom measurements demonstrated a mean increase in CNR of 11%, 23%, 31%, 38% for the PCD system, relative to the EID system, at 80, 100, 120, and 140 kV, respectively. Photon-counting detector CT additionally provided energy-selective imaging, where low- and high-energy images reflected the energy dependence of the iodine signal. Photon-counting detector images of cadaveric anatomy demonstrated decreased beam hardening and calcium blooming in the high-energy bin images and increased contrast in the low-energy bins images relative to the EID images. Threshold-based PCD images were qualitatively deemed equivalent in other aspects. CONCLUSIONS: The evaluated research PCD-CT system was capable of clinical levels of image quality at clinical dose rates. It further provided improved CNR relative to state-of-the-art EID-CT. The energy-selective bin images provide further opportunity for dual-energy and multienergy analyses.

Myocardial Perfusion: Characteristics of Distal Intramyocardial Arteriolar Trees.

A combination of experimental, theoretical, and imaging methodologies is used to examine the hierarchical structure and function of intramyocardial arteriolar trees in porcine hearts to provide a window onto a region of myocardial microvasculature which has been difficult to fully explore so far. A total of 66 microvascular trees from 6 isolated myocardial specimens were analyzed, with a cumulative number of 2438 arteriolar branches greater than or equal to 40 µm lumen diameter. The distribution of flow rates within each tree was derived from an assumed power law relationship for that tree between the diameter of vessel segments and flow rates that are consistent with that power law and subject to conservation of mass along hierarchical structure of the tree. The results indicate that the power law index increases at levels of arteriolar vasculature closer to the capillary level, consistent with a concomitant decrease in shear stress acting on endothelial tissue. These results resolve a long standing predicament which could not be resolved previously because of lack of data about the 3D, interconnected, arterioles. In the context of myocardial perfusion, the results indicate that the coefficient of variation of flow rate in pre-capillary distal arterioles is high, suggesting that heterogeneity of flow rate in these arterioles is not entirely random but may be due at least in part to active control.

Coronary microcirculation changes in non-ischemic dilated cardiomyopathy identified by novel perfusion CT.

Intramyocardial microvessels demonstrate functional changes in cardiomyopathies. However, clinical computed tomography (CT) does not have adequate spatial resolution to assess the microvessels. Our hypothesis is that these functional changes manifest as altered heterogeneity of the spatial distribution of arteriolar perfusion territories. Our goal was to determine whether the spatial analysis of perfusion CT could clinically detect changes in the function and structure of the intramyocardial microcirculation in a non-ischemic dilated cardiomyopathy (DCM). Two groups were studied: (1) a Control group (12 male plus 12 female) with no risk factors nor evidence of coronary artery disease, and (2) a DCM group (12 male plus 12 female) with left ventricular ejection fraction ≤40% and no evidence of coronary artery disease. Using the CT scan, the LV free wall thickness and its radius of curvature were measured. The DCM group was sub divided into those with LV free wall thickness <11.5 mm and those with thickness ≥11.5 mm. In the myocardial opacification phase of the CT scan sequence, myocardial perfusion (F) and intramyocardial blood volume (Bv) for multiple intramyocardial regions were computed. No significant differences between the groups were demonstrable in overall myocardial F or Bv. However, the myocardial regional data showed significantly increased spatial heterogeneity in the DCM group when compared to the Control group. The findings demonstrate that altered function of the subresolution intramyocardial microcirculation can be quantified with myocardial perfusion CT and that significant changes in these parameters occur in the DCM subjects with LV wall thickness greater than 11.5 mm.

Evaluation of coronary adventitial vasa vasorum using 3D optical coherence tomography--animal and human studies.

OBJECTIVES: This study sought to evaluate adventitial vasa vasorum (VV) in vivo with novel imaging technique of optical coherence tomography (OCT). METHODS: To verify OCT methods for quantification of VV, we first studied 2 swine carotid arteries in a model of focal angiogenesis by autologous blood injection, and compared microchannel volume (MCV) by OCT and VV by m-CT, and counts of those. In OCT images, adventitial MC was identified as signal-voiding areas which were located within 1 mm from the lumen-intima border. After manually tracing microchannel areas and the boundaries of lumen-intima and media-adventitial in all slices, we reconstructed 3D images. Moreover, we performed with OCT imaging in 8 recipients referred for evaluation of cardiac allograft vasculopathy at 1 year after heart transplantation. MCV and plaque volume (PV) were assessed with 3D images in each 10-mm-segment. RESULTS: In the animal study, among the 16 corresponding 1-mm-segments, there were significant correlations of count and volume between both the modalities (count r(2) = 0.80, P < 0.01; volume r(2) = 0.50, P < 0.01) and a good agreement with a systemic bias toward underestimation with m-CT. In the human study, there was a significant positive correlation between MCV and PV (segment number = 24, r(2) = 0.63, P < 0.01). CONCLUSION: Our results suggest that evaluation of MCV with 3D OCT imaging might be a novel method to estimate the amount of adventitial VV in vivo, and further has the potential to provide a pathophysiological insight into a role of the VV in allograft vasculopathy.

Earl Wood--a research career noted for development of novel instruments driven by the power of the indicator dilution concept.

During World War 2, Earl Wood was charged with elucidating the biomedical factors in acceleration-induced loss of consciousness experienced by pilots in high-performance aircraft. For this, he developed devices for measurement and recording of blood pressure and tissue blood content. Those data lead to the design and fabrication of successful countermeasures to acceleration-induced loss of consciousness with an inflatable "G-suit" and "M1" breath-holding maneuver. After World War 2, he utilized and modified these instruments and made use of indicator dilution techniques by continuous intracardiac blood sampling to greatly increase the specificity and sensitivity of diagnosis of intracardiac anatomic and functional abnormalities in patients with congenital heart disease. This contributed to the greatly increased success rate of open-heart surgery in the 1950s. In the 1960s, he built on the then recently available video-coupled electronic X-ray image intensifier to develop X-ray fluoroscopy-based recording of indicator dilution signals in all cardiac chambers and surrounding great vessels without the need for placing catheter tips at those locations for blood sampling. However, these blood flow-related data were of limited value, as they were not measured concurrent with myocardial functional demand for perfusion. In the 1970s, he overcame this limitation by developing a high-speed multislice X-ray imaging scanner to provide tomographic images of concurrent dynamic cardiac anatomy and the indicator dilution-based estimates of blood flow distributions. On his retirement at age 70 in 1982, he had accomplished his 2 decade-old goal of the ability to make accurate concurrent, minimally invasive, and indicator dilution-based measurement of cardiovascular structure to function relationships.