Design and development of the DE-SPECT system: a clinical SPECT system for broadband multi-isotope imaging of peripheral vascular disease.

Objective. Peripheral Vascular Disease (PVD) affects more than 230 million people worldwide and is one of the leading causes of disability among people over age 60. Nowadays, PVD remains largely underdiagnosed and undertreated, and requires the development of tailored diagnostic approaches. We present the full design of the Dynamic Extremity SPECT (DE-SPECT) system, the first organ-dedicated SPECT system for lower extremity imaging, based on 1 cm thick Cadmium Zinc Telluride (CZT) spectrometers and a dynamic dual field-of-view (FOV) synthetic compound-eye (SCE) collimator.Approach. The proposed DE-SPECT detection system consists of 48 1 cm thick 3D-position-sensitive CZT spectrometers arranged in a partial ring of 59 cm in diameter in a checkerboard pattern. The detection system is coupled with a compact dynamic SCE collimator that allows the user to select between two different FOVs at any time during an imaging study: a wide-FOV (28 cm diameter) configuration for dual-leg or scout imaging or a high-resolution and high-sensitivity (HR-HS) FOV (16 cm diameter) for single-leg or focused imaging.Main results.The preliminary experimental data show that the CZT spectrometer achieves a 3D intrinsic spatial resolution of <0.75 mm FWHM and an excellent energy resolution over a broad energy range (2.6 keV FWHM at 218, 3.3 keV at 440 keV). From simulations, the wide-FOV configuration offers a 0.034% averaged sensitivity at 140 keV and <8 mm spatial resolution, whereas the HR-HS configuration presents a peak central sensitivity of 0.07% at 140 keV and a ∼5 mm spatial resolution. The dynamic SCE collimator enables the capability to perform joint reconstructions that would ensure an overall improvement in imaging performance.Significance. The DE-SPECT system is a stationary and high-performance SPECT system that offers an excellent spectroscopic performance with a unique computer-controlled dual-FOV imaging capability, and a relatively high sensitivity for multi-tracer and multi-functional SPECT imaging of the extremities.

CineCT platform for in vivo and ex vivo measurement of 3D high resolution Lagrangian strains in the left ventricle following myocardial infarction and intramyocardial delivery of theranostic hydrogel.

Myocardial infarction (MI) produces acute changes in strain and stiffness within the infarct that can affect remote areas of the left ventricle (LV) and drive pathological remodeling. We hypothesized that intramyocardial delivery of a hydrogel within the MI region would lower wall stress and reduce adverse remodeling in Yorkshire pigs (n = 5). 99mTc-Tetrofosmin SPECT imaging defined the location and geometry of induced MI and border regions in pigs, and in vivo and ex vivo contrast cine computed tomography (cineCT) quantified deformations of the LV myocardium. Serial in vivo cineCT imaging provided data in hearts from control pigs (n = 3) and data from pigs (n = 5) under baseline conditions before MI induction, post-MI day 3, post-MI day 7, and one hour after intramyocardial delivery of a hyaluronic acid (HA)-based hydrogel with shear-thinning and self-healing properties to the central infarct area. Isolated, excised hearts underwent similar cineCT imaging using an ex vivo perfused heart preparation with cyclic LV pressurization. Deformations were evaluated using nonlinear image registration of cineCT volumes between end-diastole (ED) and end-systole (ES), and 3D Lagrangian strains were calculated from the displacement gradients. Post-MI day 3, radial, circumferential, maximum principal, and shear strains were reduced within the MI region (p < 0.04) but were unchanged in normal regions (p > 0.6), and LV end diastolic volume (LV EDV) increased (p = 0.004), while ejection fraction (EF) and stroke volume (SV) decreased (p < 0.02). Post-MI day 7, radial strains in MI border zones increased (p = 0.04) and dilation of LV EDV continued (p = 0.052). There was a significant negative linear correlation between regional radial and maximum principal/shear strains and percent infarcted tissue in all hearts (R2 > 0.47, p < 0.004), indicating that cineCT strain measures could predict MI location and degree of injury. Post-hydrogel day 7 post-MI, LV EDV was significantly reduced (p = 0.009), EF increased (p = 0.048), and radial (p = 0.021), maximum principal (p = 0.051), and shear strain (p = 0.047) increased within regions bordering the infarct. A smaller strain improvement within the infarct and normal regions was also noted on average along with an improvement in SV in 4 out of 5 hearts. CineCT provides a reliable method to assess regional changes in strains post-MI and the therapeutic effects of intramyocardial hydrogel delivery.

Magnetically Coated Bioabsorbable Stents for Renormalization of Arterial Vessel Walls after Stent Implantation.

The insertion of a stent in diseased arteries is a common endovascular procedure that can be compromised by the development of short- and long-term inflammatory responses leading to restenosis and thrombosis, respectively. While treatment with drugs, either systemic or localized, has decreased the incidence of restenosis and thrombosis these complications persist and are associated with a high mortality in those that present with stent thrombosis. We reasoned that if stents could be made to undergo accelerated endothelialization in the deployed region, then such an approach would further decrease the occurrence of stent thrombosis and restenosis thereby improving clinical outcomes. Toward that objective, the first step necessitated efficient capture of progenitor stem cells, which eventually would become the new endothelium. To achieve this objective, we engineered intrinsic ferromagnetism within nonmagnetizable, biodegradable magnesium (Mg) bare metal stents. Mg stents were coated with biodegradable polylactide (PLA) polymer embedding magnetizable iron-platinum (FePt) alloy nanoparticles, nanomagnetic particles, nMags, which increased the surface area and hence magnetization of the stent. nMags uniformly distributed on stents enabled capture, under flow, up to 50 mL/min, of systemically injected iron-oxide-labeled (IO-labeled) progenitor stem cells. Critical parameters enhancing capture efficiency were optimized, and we demonstrated the generality of the approach by showing that nMag-coated stents can capture different cell types. Our work is a potential paradigm shift in engineering stents because implants are rendered as tissue in the body, and this "natural stealthiness" reduces or eliminates issues associated with pro-inflammatory immune responses postimplantation.

Application of BOLD Magnetic Resonance Imaging for Evaluating Regional Volumetric Foot Tissue Oxygenation: A Feasibility Study in Healthy Volunteers.

OBJECTIVE/BACKGROUND: To evaluate the feasibility and repeatability of applying blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) in the feet to quantify regional dynamic changes in tissue oxygenation during proximal cuff occlusion and reactive hyperemia. METHODS: Ten healthy male subjects underwent BOLD and T1-weighted imaging of the feet on two separate occasions, using a 3-T scanner. Dynamic changes in BOLD signal intensity were assessed before and during proximal cuff occlusion of the thigh and during reactive hyperemia, and BOLD time course data were evaluated for the time-to-half ischemic minimum, minimum ischemic value, peak hyperemic value, time-to-peak hyperemia, time-to-half peak hyperemia, and end value. T1-weighted images were used for segmentation of volumes of interest (VOI) in anatomical regions of the foot (heel, toes, dorsal foot, medial and lateral plantar foot). Repeatability of vascular responses was assessed for each foot VOI using semiautomated image registration and quantification of serial BOLD images. RESULTS: The heel VOI demonstrated a significantly higher peak hyperemic response, expressed as percent change from baseline BOLD signal intensity, compared with all other VOIs of the foot (heel, 7.4 ± 1.2%; toes, 5.6 ± 0.8%; dorsal foot, 5.7 ± 1.6%; medial plantar, 5.6 ± 1.7%; lateral plantar, 5.6 ± 1.5% [p < .05]). Additionally, the lateral plantar VOI had a significantly lower terminal signal intensity value (i.e., end value) when compared with all foot VOIs (p < .05). BOLD MRI was repeatable between visits in all foot VOIs, with no significant differences between study visits for any of the evaluated functional indices. CONCLUSION: BOLD MRI offers a repeatable technique for volumetric assessment of regional foot tissue oxygenation. Future application of BOLD imaging in the feet of patients with peripheral vascular disease may permit serial evaluation of regional tissue oxygenation and allow for improved assessment of therapeutic interventions targeting specific sites of the foot.

Segmentation of 3D radio frequency echocardiography using a spatio-temporal predictor.

This paper presents an algorithm for segmenting left ventricular endocardial boundaries from RF ultrasound. Our method incorporates a computationally efficient linear predictor that exploits short-term spatio-temporal coherence in the RF data. Segmentation is achieved jointly using an independent identically distributed (i.i.d.) spatial model for RF intensity and a multiframe conditional model that relates neighboring frames in the image sequence. Segmentation using the RF data overcomes challenges due to image inhomogeneities often amplified in B-mode segmentation and provides geometric constraints for RF phase-based speckle tracking. The incorporation of multiple frames in the conditional model significantly increases the robustness and accuracy of the algorithm. Results are generated using between 2 and 5 frames of RF data for each segmentation and are validated by comparison with manual tracings and automated B-mode boundary detection using standard (Chan and Vese-based) level sets on echocardiographic images from 27 3D sequences acquired from six canine studies.

WHOLE BODY NONRIGID CT-PET REGISTRATION USING WEIGHTED DEMONS.

We present a new registration method for whole-body rat computed tomography (CT) image and positron emission tomography (PET) images using a weighted demons algorithm. The CT and PET images are acquired in separate scanners at different times and the inherent differences in the imaging protocols produced significant nonrigid changes between the two acquisitions in addition to heterogeneous image characteristics. In this situation, we utilized both the transmission-PET and the emission-PET images in the deformable registration process emphasizing particular regions of the moving transmission-PET image using the emission-PET image. We validated our results with nine rat image sets using M-Hausdorff distance similarity measure. We demonstrate improved performance compared to standard methods such as Demons and normalized mutual information-based non-rigid FFD registration.

Molecular imaging in nuclear cardiology: translating research concepts into clinical applications.

Molecular imaging provides a novel approach for the early non-invasive detection of critical molecular or cellular processes associated with initiation of disease, before the manifestation of anatomical changes or late physiological consequences. This article reviews the current and future role of molecular imaging in evaluation of cardiovascular diseases, including the early detection of atherosclerosis, ischemia-induced angiogenesis, and post-infarction left ventricular remodeling. Cardiovascular molecular imaging with radiolabeled probes has already translated into clinical practice in the evaluation of critical metabolic and receptor mediated process in the heart, however, the true clinical impact of targeted molecular imaging has not yet been realized. The advancement of cardiovascular molecular imaging will require the development of novel targeted probes, hybrid high-sensitivity and high-resolution imaging systems, and the collaboration of basic and clinical imaging communities. The application of molecular imaging in combination with conventional anatomical and physiological imaging should provide new insights into the pathophysiology of disease that may allow a more personalized approach to the evaluation and management of cardiovascular diseases.

SERIAL NONRIGID VASCULAR REGISTRATION USING WEIGHTED NORMALIZED MUTUAL INFORMATION.

Vascular registration is a challenging problem with many potential applications. However, registering vessels accurately is difficult as they often occupy a small portion of the image and their relative motion/deformation is swamped by the displacements seen in large organs such as the heart and the liver. Our registration method uses a vessel detection algorithm to generate a vesselness image (probability of having a vessel at any given voxel) which is used to construct a weighting factor that is used to modify the intensity metric to give preference to vascular structures while maintaining the larger context. Therefore, our proposing method uses fully data-driven calculated weights and needs no prior knowledge for the weight calculation. We applied our method to the registration of serial MRI lamb images obtained from studies on tissue engineered vascular grafts and demonstrate encouraging performance as compared to non-weighted registration methods.

Regional hypoxia correlates with the uptake of a radiolabeled targeted marker of angiogenesis in rat model of myocardial hypertrophy and ischemic injury.

BACKGROUND: Non-invasive imaging strategies play a critical role for assessment of the efficacy of angiogenesis therapies. Hypoxia resulting from deficient blood flow is a potent stimulator of angiogenesis which is marked by upregulated alphavbeta3 integrin receptor. METHODS AND RESULTS: The use of dual-isotope radiotracers targeted at alphavbeta3 and myocardial hypoxia has been demonstrated to non-invasively track hypoxia-induced angiogenesis in ischemic rat model of myocardial hypertrophy, which was induced by non-occlusive abdominal aortic banding followed by myocardial infarction at 6 weeks after the banding procedure. The pressure overload-induced myocardial hypertrophy was confirmed by 2D echocardiography. Two radiotracers; 111In-labeled agent targeted at the alphavbeta3 (RP748) and 99mTc-labeled nitroimidazole retained in hypoxic myocardium (BRU-5921) have been used. Gamma well counting analysis demonstrated an inverse linear relationship (R2=0.5) between BRU-5921 myocardial uptake and the degree of hypoperfusion assessed by 201Tl chloride. 111In-RP748 was found to be preferentially retained in hypoxic myocardium identified by increased BRU-5921 uptake and localized to anterior-lateral wall as assessed by dual-isotope microautoradiography. There was a significant (P<0.01) almost four-fold increase in RP748 uptake in myocardial segments with highest relative BRU-5921 retention (200-600% non-ischemic). Immunohistochemical staining confirmed that increased RP748 uptake is associated with an augmented alphav and beta3 integrin expression within infarcted myocardium. CONCLUSIONS: Angiogenesis in the rodent model of combined myocardial hypertrophy and infarction was successfully assessed with alphavbeta3-targeted agent in relation to tissue hypoxia measured with 99mTc -labeled nitroimidazole retained in hypoxic myocardium. Regional retention of RP748 correlated well with BRU-5921 retention, supporting the role of RP748 as a targeted marker of hypoxia-stimulated angiogenesis with a potential clinical use to track naturally occurring and therapeutic angiogenesis and to predict the left ventricular remodeling in patients following myocardial infarction.

LV segmentation through the analysis of radio frequency ultrasonic images.

LV segmentation is often an important part of many automated cardiac diagnosis strategies. However, the segmentation of echocardiograms is a difficult task because of poor image quality. In echocardiography, we note that radio-frequency (RF) signal is a rich source of information about the moving LV as well. In this paper, first, we will investigate currently used, important RF derived parameters: integrated backscatter coefficient (IBS), mean central frequency (MCF) and the maximum correlation coefficients (MCC) from speckle tracking. Second, we will develop a new segmentation algorithm for the segmentation of the LV boundary, which can avoid local minima and leaking through uncompleted boundary. Segmentations are carried out on the RF signal acquired from a Sonos7500 ultrasound system. The results are validated by comparing to manual segmentation results.

On the dark rim artifact in dynamic contrast-enhanced MRI myocardial perfusion studies.

A dark band or rim along parts of the subendocardial border of the left ventricle (LV) and the myocardium has been noticed in some dynamic contrast-enhanced MR perfusion studies. The artifact is thought to be due to susceptibility effects from the gadolinium bolus, motion, or resolution, or a combination of these. Here motionless ex vivo hearts in which the cavity was filled with gadolinium are used to show that dark rim artifacts can be consistent with resolution effects alone.

Molecular imaging. A new approach to nuclear cardiology.

Nuclear cardiology has historically played an important role in detection of cardiovascular disease as well as risk stratification. With the growth of molecular biology have come new therapeutic interventions and the requirement for new diagnostic imaging approaches. Noninvasive targeted radiotracer based as well as transporter gene imaging strategies are evolving to meet these new needs, but require the development of an interdisciplinary approach which focuses on molecular processes, as well as the pathogenesis and progression of disease. This progress has been made possible with the availability of transgenic animal models along with many technological advances. Future adaptations of the developing experimental procedures and instrumentation will allow for the smooth translation and application to clinical practice. This review is intended as a brief overview on the subject molecular imaging. Basic concepts and historical perspective of molecular imaging will be reviewed first, followed by description of current technology, and concluding with current applications in cardiology. The emphasis will be on the use of both single photon emission computed tomography (SPECT) and positron emission tomography (PET) radiotracers, although other imaging modalities will be also briefly discussed. The specific approaches presented here will include receptor-based and reporter gene imaging of natural and therapeutic angiogenesis.

Vascular cell adhesion molecule-1-targeted detection of endothelial activation in human microvasculature.

The hallmark of endothelial activation, an early and critical step in many alloimmune and inflammatory responses, is the transcriptional induction and expression of endothelial adhesion molecules (eg, vascular cell adhesion molecule-1 [VCAM-1]). We assessed the feasibility of VCAM-1-targeted in vivo detection of endothelial activation using I-125-labeled-F(ab')2 fragments of E1/6, a monoclonal antibody against human but not murine VCAM-1. The Kd and Bmax, determined by saturation binding in tumor necrosis factor (TNF)-activated human endothelial cells (ECs), were 3.2 +/- 0.6 nmol/L and 5600 +/- 300 binding sites per EC, respectively. Biodistribution and in vivo binding characteristics of I-125-E1/6 F(ab')2 were assessed in a novel chimeric human/mouse model, in which human skin (as a source of human microvasculature) is grafted onto SCID/beige mice. I-125-E1/6 F(ab')2 localized to TNF-activated human skin grafts as detected by autoradiography and gamma well-counting. Relative uptakes (uptake in human skin graft/uptake in the surrounding mouse skin) were, respectively, 2.6 +/- 0.8 (n = 14) and 1.6 +/- 0.3 (n = 12) for E1/6 and MOPC-21, an isotype-matched control antibody (P < .01). The preferential uptake in human skin graft was not due to differences in tissue vascularity assessed by Tc-99m-labeled murine red blood cells. In conclusion, the chimeric human/mouse model is a novel experimental tool for in vivo evaluation of human endothelial cell-specific radiopharmaceuticals. Although I-125-E1/6 F(ab')2 localized to human skin grafts, the limited number of VCAM-1 molecules/endothelial cell adversely affects its suitability as a target for in vivo imaging of endothelial activation.

Quantification of 3-D regional myocardial deformation: shape-based analysis of magnetic resonance images.

A comprehensive three-dimensional (3-D) shape-based approach for quantification of regional myocardial deformations was evaluated in a canine model (n = 8 dogs) with the use of cine magnetic resonance imaging. The shape of the endocardial and epicardial surfaces was used to track the 3-D trajectories of a dense field of points over the cardiac cycle. The shape-based surface displacements are integrated with a continuum biomechanics model incorporating myofiber architecture to estimate both cardiac- and fiber-specific endocardial and epicardial strains and shears for 24 left ventricular regions. Whereas radial and circumferential end-systolic strains were fairly uniform, there was a significant apex-to-base gradient in longitudinal strain and radial-longitudinal shear. We also observed transmural epicardial-to-endocardial gradients in both cardiac- and fiber-specific strains. The increase in endocardial strain was accompanied by increases in radial-longitudinal shear and radial-fiber shears in the endocardium, supporting previous theories of regional myocardial deformation that predict considerable sliding between myocardial fibers.

Technetium-99m-labeled myocardial perfusion agents: Are they better than thallium-201?

Currently, thallium-201 (201Tl)- and technetium-99m (99mTc)-labeled tracers are used interchangeably for the detection of coronary artery disease, the assessment of myocardial viability, and risk stratification. This article reviews some of the potential advantages and disadvantages of the 99mTc-labeled tracers relative to 201Tl. The basic myocardial kinetic properties and biodistribution of the commonly used 99mTc-labeled perfusion tracers are compared with those of 201Tl. The clinical value of the 99mTc-labeled perfusion tracers is then compared with that of 201Tl imaging. With regard to imaging physics and radiation safety, the 99mTc-labeled tracers are superior to 201Tl. Cost and tracer availability also may favor 99mTc-labeled perfusion tracers rather than 201Tl imaging. However, the most widely used 99mTc-labeled perfusion tracers currently approved for clinical use-99mTc-sestamibi and 99mTc-tetrofosmin-do not track myocardial flow as well as 201Tl does. This shortcoming of 99mTc-labeled perfusion tracers may reduce the sensitivity of these agents in detecting subcritical coronary artery disease. The most notable new perfusion agent is 99mTc-labeled bis(N-ethoxy, N-ethyl dithiocarbamato) nitrido technetium(v), which is considered to be the 99mTc-labeled equivalent of 201Tl. However, 99mTc-labeled bis(N-ethoxy, N-ethyl dithiocarbamato) nitrido technetium(v) is a neutral compound with kinetic properties that are very different from those of 201Tl. Myocardial perfusion imaging is often conducted in conjunction with exercise or with different pharmacologic stressors, both of which augment regional flow heterogeneity. Each of these stressors has unique effects on the coronary vasculature and influences the behavior of the radiolabeled perfusion agents. The substantial differences in myocardial uptake, clearance kinetics, and biodistribution between each of the 99mTc-labeled perfusion tracers and 201Tl should be considered in the clinical application of perfusion imaging. The myocardial retention of all of the agents is affected by myocardial viability. However, 201Tl demonstrates greater differential clearance from normal and ischemic regions (redistribution), making 201Tl a better agent for assessment of viability, particularly in patients with extremely low flow. In contrast, agents that do not redistribute, such as 99mTc-tetrofosmin, might be better for acute assessment of "risk areas" or of chest pain. Each of the available perfusion tracers has unique advantages and disadvantages that must be considered to ensure its optimal application.

A new method for quantification of spatial and temporal parameters of endocardial motion: evaluation of experimental infarction using magnetic resonance imaging.

BACKGROUND: With the development of high-resolution myocardial imaging there has evolved a need for automated techniques that can accurately quantify regional function. OBJECTIVE: To develop a new method for quantification of spatial and temporal parameters of endocardial motion. DESIGN: Magnetic resonance images were analyzed using a unique, shape-based approach that tracks endocardial surface motion at defined points through the cardiac cycle by minimizing the bending energy. SETTING: Animal instrumentation was performed in the Nuclear Cardiology Experimental Research Laboratory at Yale University, New Haven, Connecticut. Magnetic resonance imaging was performed at the Yale New Haven Hospital Center. ANIMALS: Eight mongrel canines were used. INTERVENTIONS: Electrocardiograph-gated gradient-echo magnetic resonance images were obtained before and after occlusion of the left anterior descending coronary. Thirty-two points along automatically defined endocardial contours were tracked. Average displacements and cumulative path lengths were computed from end-diastole for each point over the entire cardiac cycle. The average cumulative path length was computed for each of four quarters of systole for the normal, border and infarct zones. Shape-based parameters of systolic motion were compared with the centreline approach. Infarct zone was defined by postmortem histochemical staining. MAIN RESULTS: Displacement and cumulative path length over the cardiac cycle decreased significantly in the infarct and border zones (P<0.05), but did not change in the normal zone (P was not significant). Temporal changes in motion were observed in all zones. Displacement measured using the shape-based algorithm was more consistent than cumulative path length when compared with systolic motion measured using the centreline method. CONCLUSIONS: An automated, shape-based approach permits quantitative evaluation of both spatial and temporal parameters of regional endocardial motion from high-resolution electrocardiograph-gated images. Analysis of endocardial motion and cumulative motion over the entire cardiac cycle discriminated infarcted from normal and border regions.

Estimation of 3D left ventricular deformation from echocardiography.

The quantitative estimation of regional cardiac deformation from 3D image sequences has important clinical implications for the assessment of viability in the heart wall. Such estimates have so far been obtained almost exclusively from Magnetic Resonance (MR) images, specifically MR tagging. In this paper we describe a methodology for estimating cardiac deformations from 3D echocardiography (3DE). The images are segmented interactively and then initial correspondence is established using a shape-tracking approach. A dense motion field is then estimated using a transversely isotropic linear elastic model, which accounts for the fiber directions in the left ventricle. The dense motion field is in turn used to calculate the deformation of the heart wall in terms of strain in cardiac specific directions. The strains obtained using this approach in open-chest dogs before and after coronary occlusion, show good agreement with previously published results in the literature. They also exhibit a high correlation with strains produced in the same animals using implanted sonomicrometers. This proposed method provides quantitative regional 3D estimates of heart deformation from ultrasound images.