Donald P. Dione

Noninvasive imaging of myocardial angiogenesis following experimental myocardial infarction.

Noninvasive imaging strategies will be critical for defining the temporal characteristics of angiogenesis and assessing efficacy of angiogenic therapies. The alphavbeta3 integrin is expressed in angiogenic vessels and represents a potential novel target for imaging myocardial angiogenesis. We demonstrated the localization of an indium-111-labeled ((111)In-labeled) alphavbeta3-targeted agent in the region of injury-induced angiogenesis in a chronic rat model of infarction. The specificity of the targeted alphavbeta3-imaging agent for angiogenesis was established using a nonspecific control agent. The potential of this radiolabeled alphavbeta3-targeted agent for in vivo imaging was then confirmed in a canine model of postinfarction angiogenesis. Serial in vivo dual-isotope single-photon emission-computed tomographic (SPECT) imaging with the (111)In-labeled alphavbeta3-targeted agent demonstrated focal radiotracer uptake in hypoperfused regions where angiogenesis was stimulated. There was a fourfold increase in myocardial radiotracer uptake in the infarct region associated with histological evidence of angiogenesis and increased expression of the alphavbeta3 integrin. Thus, angiogenesis in the heart can be imaged noninvasively with an (111)In-labeled alphavbeta3-targeted agent. The noninvasive evaluation of angiogenesis may have important implications for risk stratification of patients following myocardial infarction. This approach may also have significant clinical utility for noninvasively tracking therapeutic myocardial angiogenesis.

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.

Noninvasive Targeted Imaging of Matrix Metalloproteinase Activation in a Murine Model of Postinfarction Remodeling

Background— Time-dependent activation of matrix metalloproteinases (MMPs) after myocardial infarction (MI) contributes to adverse left ventricular (LV) remodeling; however, noninvasive methods to monitor this process serially are needed. Methods and Results— MMP-targeted radiotracers were developed that displayed selective binding kinetics to the active MMP catalytic domain. Initial nonimaging studies were performed with a 111In-labeled MMP-targeted radiotracer (111In-RP782) and negative control compound (111In-RP788) in control mice (Ctrl) and in mice 1 week after surgically induced MI. Localization of 111In-RP782 was demonstrated within the MI by microautoradiography. A 334±44% increase (P<0.001 versus Ctrl) in relative retention of 111In-RP782 was confirmed by gamma well counting of myocardium. Subsequent high-resolution dual-isotope planar and hybrid micro–single-photon emission computed tomography/CT imaging studies with an analogous 99mTc-labeled MMP-targeted radiotracer (99mTc-RP805) and 201Tl demonstrated favorable biodistribution and clearance kinetics of 99mTc-RP805 for in vivo cardiac imaging, with robust retention 1 to 3 weeks after MI in regions of decreased 201Tl perfusion. Gamma well counting yielded a similar ≈300% increase in relative myocardial retention of 99mTc-RP805 in MI regions (Ctrl, 102±9%; 1 week, 351±77%; 2 weeks, 291±45%; 3 weeks, 292±41%; P<0.05 versus Ctrl). Myocardial uptake in the MI region was also significantly increased ≈5-fold when expressed as percentage injected dose per gram tissue. There was also a significant 2-fold increase in myocardial activity in remote regions relative to control mice, suggesting activation of MMPs in regions remote from the MI. Conclusions— This novel noninvasive targeted MMP radiotracer imaging approach holds significant diagnostic potential for in vivo localization of MMP activation and tracking of MMP-mediated post-MI remodeling.

Targeted imaging of the spatial and temporal variation of matrix metalloproteinase activity in a porcine model of postinfarct remodeling: relationship to myocardial dysfunction.

Background—Matrix metalloproteinases (MMPs) are known to modulate left ventricular (LV) remodeling after a myocardial infarction (MI). However, the temporal and spatial variation of MMP activation and their relationship to mechanical dysfunction after MI remain undefined. Methods and Results—MI was surgically induced in pigs (n=23) and cine magnetic resonance (MR) and dual-isotope hybrid single-photon emission CT (SPECT)/CT imaging obtained using thallium-201 and a technetium-99m-labeled MMP targeted tracer (99mTc-RP805) at 1, 2, and 4 weeks post-MI along with controls (n=5). Regional myocardial strain was computed from MR images and related to MMP zymography and ex vivo myocardial 99mTc-RP805 retention. MMP activation as assessed by in vivo and ex vivo 99mTc-RP805 imaging and retention studies was increased nearly 4-fold within the infarct region at 1 week post-MI and remained elevated up to 1 month post-MI. The post-MI change in LV end-diastolic volumes was correlated with MMP activity (y=31.34e0.48x, P=0.04). MMP activity was increased within the border and remote regions early post-MI, but declined over 1 month. There was a high concordance between regional 99mTc-RP805 uptake and ex vivo MMP-2 activity. Conclusions—A novel, multimodality, noninvasive hybrid SPECT/CT imaging approach was validated and applied for in vivo evaluation of MMP activation in combination with cine MR analysis of LV deformation. Increased 99mTc-RP805 retention was seen throughout the heart early post-MI and was not purely a reciprocal of thallium-201 perfusion. The 99mTc-RP805 SPECT/CT imaging may provide unique information regarding regional myocardial MMP activation and predict late post-MI LV remodeling.

A non-parametric vessel detection method for complex vascular structures

Modern medical imaging techniques enable the acquisition of in vivo high resolution images of the vascular system. Most common methods for the detection of vessels in these images, such as multiscale Hessian-based operators and matched filters, rely on the assumption that at each voxel there is a single cylinder. Such an assumption is clearly violated at the multitude of branching points that are easily observed in all, but the most focused vascular image studies. In this paper, we propose a novel method for detecting vessels in medical images that relaxes this single cylinder assumption. We directly exploit local neighborhood intensities and extract characteristics of the local intensity profile (in a spherical polar coordinate system) which we term as the polar neighborhood intensity profile. We present a new method to capture the common properties shared by polar neighborhood intensity profiles for all the types of vascular points belonging to the vascular system. The new method enables us to detect vessels even near complex extreme points, including branching points. Our method demonstrates improved performance over standard methods on both 2D synthetic images and 3D animal and clinical vascular images, particularly close to vessel branching regions.

3D Cardiac Deformation from Ultrasound Images

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 ultrasound images. The images are segmented interactively and then initial correspondence is established using a shape-tracking approach. A dense motion field is then estimated using an anisotropic 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 related to changes in blood flow, show good agreement with previously published results in the literature. This proposed method provides quantitative regional 3D estimates of heart deformation from ultrasound images.

Refraction corrected transmission ultrasound computed tomography for application in breast imaging.

PURPOSE We present an iterative framework for CT reconstruction from transmission ultrasound data which accurately and efficiently models the strong refraction effects that occur in our target application: Imaging the female breast. METHODS Our refractive ray tracing framework has its foundation in the fast marching method (FNMM) and it allows an accurate as well as efficient modeling of curved rays. We also describe a novel regularization scheme that yields further significant reconstruction quality improvements. A final contribution is the development of a realistic anthropomorphic digital breast phantom based on the NIH Visible Female data set. RESULTS Our system is able to resolve very fine details even in the presence of significant noise, and it reconstructs both sound speed and attenuation data. Excellent correspondence with a traditional, but significantly more computationally expensive wave equation solver is achieved. CONCLUSIONS Apart from the accurate modeling of curved rays, decisive factors have also been our regularization scheme and the high-quality interpolation filter we have used. An added benefit of our framework is that it accelerates well on GPUs where we have shown that clinical 3D reconstruction speeds on the order of minutes are possible.

Contour tracking in echocardiographic sequences via sparse representation and dictionary learning.

This paper presents a dynamical appearance model based on sparse representation and dictionary learning for tracking both endocardial and epicardial contours of the left ventricle in echocardiographic sequences. Instead of learning offline spatiotemporal priors from databases, we exploit the inherent spatiotemporal coherence of individual data to constraint cardiac contour estimation. The contour tracker is initialized with a manual tracing of the first frame. It employs multiscale sparse representation of local image appearance and learns online multiscale appearance dictionaries in a boosting framework as the image sequence is segmented frame-by-frame sequentially. The weights of multiscale appearance dictionaries are optimized automatically. Our region-based level set segmentation integrates a spectrum of complementary multilevel information including intensity, multiscale local appearance, and dynamical shape prediction. The approach is validated on twenty-six 4D canine echocardiographic images acquired from both healthy and post-infarct canines. The segmentation results agree well with expert manual tracings. The ejection fraction estimates also show good agreement with manual results. Advantages of our approach are demonstrated by comparisons with a conventional pure intensity model, a registration-based contour tracker, and a state-of-the-art database-dependent offline dynamical shape model. We also demonstrate the feasibility of clinical application by applying the method to four 4D human data sets.

Targeted imaging of hypoxia-induced integrin activation in myocardium early after infarction

The alphavbeta3-integrin is expressed in angiogenic vessels in response to hypoxia and represents a potential novel target for imaging myocardial angiogenesis. This study evaluated the feasibility of noninvasively tracking hypoxia-induced alphavbeta3-integrin activation within the myocardium as a marker of angiogenesis early after myocardial infarction. Acute myocardial infarction was produced by coronary artery occlusion in rodent and canine studies. A novel (111)In-labeled radiotracer targeted at the alphavbeta3-integrin ((111)In-RP748) was used to localize regions of hypoxia-induced angiogenesis early after infarction. In rodent studies, the specificity of (111)In-RP748 for alphavbeta3-integrin was confirmed with a negative control compound ((111)In-RP790), and regional uptake of these compounds correlated with (201)Tl perfusion and a (99m)Tc-labeled nitroimidazole (BRU59-21), which was used as a quantitative marker of myocardial hypoxia. The ex vivo analysis demonstrated that only (111)In-RP748 was selectively retained in infarcted regions with reduced (201)Tl perfusion and correlated with uptake of BRU59-21. In canine studies, myocardial uptake of (111)In-RP748 was assessed using in vivo single-photon-emission computed tomography (SPECT), ex vivo planar imaging, and gamma well counting of myocardial tissue and correlated with (99m)Tc-labeled 2-methoxy-2-methyl-propyl-isonitrile ((99m)Tc-sestamibi) perfusion. Dual-radiotracer in vivo SPECT imaging of (111)In-RP748 and (99m)Tc-sestamibi provided visualization of (111)In-RP748 uptake within the infarct region, which was confirmed by ex vivo planar imaging of excised myocardial slices. Myocardial (111)In-RP748 retention was associated with histological evidence of alphavbeta3-integrin expression/activation in the infarct region. (111)In-RP748 imaging provides a novel noninvasive approach for evaluation of hypoxia-induced alphavbeta3-integrin activation in myocardium early after infarction and may prove useful for directing and evaluating angiogenic therapies in patients with ischemic heart disease.

Articulated rigid registration for serial lower-limb mouse imaging

This paper describes a new piecewise rotational transformation model for capturing the articulation of joints such as the hip and the knee. While a simple piecewise rigid model can be applied, such models suffer from discontinuities at the motion boundary leading to both folding and stretching. Our model avoids both of these problems by constructing a provably continuous transformation along the motion interface. We embed this transformation model within the robust point matching framework and demonstrate its successful application to both synthetic data, and to serial x-ray CT mouse images. In the later case, our model captures the articulation of six joints, namely the left/right hip, the left/right knee and the left/right ankle. In the future such a model could be used to initialize non-rigid registrations of images from different subjects, as well as, be embedded in intensity-based and integrated registration algorithms. It could also be applied to human data in cases where articulated motion is an issue (e.g. image guided prostate radiotherapy, lower extremity CT angiography).