Biomedical subjects

Albert J Sinusas

Publications and source records attributed to Albert J Sinusas.

At least 19 recordsLinked to original sources

PubMed2006

Critical function of Bmx/Etk in ischemia-mediated arteriogenesis and angiogenesis.

Bmx/Etk non-receptor tyrosine protein kinase has been implicated in endothelial cell migration and tube formation in vitro. However, the role of Bmx in vivo is not known. Bmx is highly induced in the vasculature of ischemic hind limbs. We used both mice with a genetic deletion of Bmx (Bmx-KO mice) and transgenic mice expressing a constitutively active form of Bmx under the endothelial Tie-2 enhancer/promoter (Bmx-SK-Tg mice) to study the role of Bmx in ischemia-mediated arteriogenesis/angiogenesis. In response to ischemia, Bmx-KO mice had markedly reduced, whereas Bmx-SK-Tg mice had enhanced, clinical recovery, limb perfusion, and ischemic reserve capacity when compared with nontransgenic control mice. The functional outcomes in these mice were correlated with ischemia-initiated arteriogenesis, capillary formation, and vessel maturation as well as Bmx-dependent expression/activation of TNF receptor 2- and VEGFR2-mediated (TNFR2/VEGFR2-mediated) angiogenic signaling in both hind limb and bone marrow. More importantly, results of bone marrow transplantation studies showed that Bmx in bone marrow-derived cells plays a critical role in the early phase of ischemic tissue remodeling. Our study provides the first demonstration to our knowledge that Bmx in endothelium and bone marrow plays a critical role in arteriogenesis/angiogenesis in vivo and suggests that Bmx may be a novel target for the treatment of vascular diseases such as coronary artery disease and peripheral arterial disease.

Animals↗

PubMed2006

Activation of AMPK alpha- and gamma-isoform complexes in the intact ischemic rat heart.

AMP-activated protein kinase (AMPK) plays a key role in modulating cellular metabolic processes. AMPK, a serine-threonine kinase, is a heterotrimeric complex of catalytic alpha-subunits and regulatory beta- and gamma-subunits with multiple isoforms. Mutations in the cardiac gamma(2)-isoform have been associated with hypertrophic cardiomyopathy and pre-excitation syndromes. However, physiological regulation of AMPK complexes containing different subunit isoforms is not well defined and is important for an understanding of the function of this signaling pathway in the intact heart. We evaluated the kinase activity associated with heart AMPK complexes containing specific alpha- and gamma-subunit isoforms of AMPK in an in vivo rat model of regional ischemia. Left coronary artery occlusion activated the immunoprecipitated alpha(1)-isoform (6-fold, P < 0.01) and alpha(2)-isoform (9-fold, P < 0.01) in the ischemic left ventricle compared with sham controls. The degree of alpha-subunit activation depended on the extent of ischemia and paralleled echocardiographic contractile dysfunction. The regulatory gamma(1)- and gamma(2)-isoforms were expressed in the heart. The gamma(1)- and gamma(2)-isoforms coimmunoprecipitated with alpha(1)- and alpha(2)-isoforms in proportion to alpha-subunit content. gamma(1)-Isoform immunocomplexes accounted for 70% of AMPK activity and AMPK phosphorylation (Thr(172)) in hearts. Ischemia similarly increased AMPK activity associated with the gamma(1)- and gamma(2)-isoform complexes threefold (P < 0.01 for each). Thus AMPK catalytic alpha(1)- and alpha(2)-isoforms are activated by regional ischemia in vivo in the heart, irrespective of the regulatory gamma(1)- or gamma(2)-isoforms to which they are complexed. Despite the pathophysiological importance of gamma(2)-isoform mutations, gamma(1)-isoform complexes account for most of the AMPK activity in the ischemic heart.

AMP-Activated Protein Kinases↗

PubMed2006

Towards pointwise motion tracking in echocardiographic image sequences--comparing the reliability of different features for speckle tracking.

In this paper, we studied the problem of feature-based motion tracking in echocardiographic image sequences. We described the relation between possible feature variations and different kinds of tissue motion using a linear convolution model. We also showed that motion-feature decorrelation (which means that the motion parameters estimated using feature tracking fail to represent the underlying tissue motion) compensation is an ill-posed inverse problem. Instead of finding a method that may provide better compensation results than previous approaches, we used an quantitative measure to compare the reliability of tracking features. Experiment results showed that the use of the reliability measure improved the robustness of displacement estimation. With the help of the reliability measure, we compared the performance of different features using simulations and phantom examples. While we noticed that the radio frequency (RF) signal outperforms the B-mode (BM) signal in the analysis of small deformation (e.g., less than 0.1% compression), we also found out that the BM signal works better than the RF signal in the analysis of large deformation (e.g., larger than 2% compression). The use of a band-passed filtered feature does not result in significant improvement in tracking.

Algorithms↗

PubMed2005

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 (111)In-labeled MMP-targeted radiotracer ((111)In-RP782) and negative control compound ((111)In-RP788) in control mice (Ctrl) and in mice 1 week after surgically induced MI. Localization of (111)In-RP782 was demonstrated within the MI by microautoradiography. A 334+/-44% increase (P<0.001 versus Ctrl) in relative retention of (111)In-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 approximately 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 approximately 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.

Animals↗

PubMed2005

Alphavbeta3-targeted detection of arteriopathy in transplanted human coronary arteries: an autoradiographic study.

Graft arteriopathy (GA), characterized by diffuse concentric narrowing of coronary arteries, is the major cause of late graft failure in cardiac transplantation. alphavbeta3 Integrin is up-regulated in proliferating vascular cells and may constitute an appropriate target for imaging GA. We used a human/mouse chimeric model of GA, in which segments of human coronary artery were transplanted to severe combined immunodeficiency mice, followed by reconstitution with allogeneic human peripheral blood mononuclear cells (PBMC). This led to vascular remodeling characterized by neointima formation over a period of 4 wk. alphavbeta3 expression in the graft was minimal in animals without PBMC, considerably increased by 2 wk, and decreased toward baseline by 4 wk after PBMC reconstitution. Cell proliferation was maximal at 2 wk, correlating with peak alphavbeta3 expression. RP748, an 111In-labeled alphavbeta3 (active conformation)-targeted radiotracer was injected into groups of 5 recipients at 0, 2, and 4 wk after PBMC reconstitution. Relative uptakes, defined as autoradiographic intensity in the graft/native aortas closely tracked the proliferative process. Specificity of uptake was demonstrated using excess nonlabeled tracer. In conclusion, alphavbeta3 integrin is transiently up-regulated (and activated) in GA and may be targeted by RP748 for detection of the proliferative process in early GA.

Animals↗

PubMed2005

Matrix metalloproteinase-9 gene deletion facilitates angiogenesis after myocardial infarction.

Matrix metalloproteinases (MMPs) are postulated to be necessary for neovascularization during wound healing. MMP-9 deletion alters remodeling postmyocardial infarction (post-MI), but whether and to what degree MMP-9 affects neovascularization post-MI is unknown. Neovascularization was evaluated in wild-type (WT; n = 63) and MMP-9 null (n = 55) mice at 7-days post-MI. Despite similar infarct sizes, MMP-9 deletion improved left ventricular function as evaluated by hemodynamic analysis. Blood vessel quantity and quality were evaluated by three independent studies. First, vessel density was increased in the infarct of MMP-9 null mice compared with WT, as quantified by Griffonia (Bandeiraea) simplicifolia lectin I (GSL-I) immunohistochemistry. Second, preexisting vessels, stained in vivo with FITC-labeled GSL-I pre-MI, were present in the viable but not MI region. Third, a technetium-99m-labeled peptide (NC100692), which selectively binds to activated alpha(v)beta3-integrin in angiogenic vessels, was injected into post-MI mice. Relative NC100692 activity in myocardial segments with diminished perfusion (0-40% nonischemic) was higher in MMP-9 null than in WT mice (383 +/- 162% vs. 250 +/- 118%, respectively; P = 0.002). The unique finding of this study was that MMP-9 deletion stimulated, rather than impaired, neovascularization in remodeling myocardium. Thus targeted strategies to inhibit MMP-9 early post-MI will likely not impair the angiogenic response.

Animals↗

PubMed2005

Noninvasive imaging of angiogenesis with a 99mTc-labeled peptide targeted at alphavbeta3 integrin after murine hindlimb ischemia.

BACKGROUND: Noninvasive imaging strategies play a critical role in assessment of the efficacy of angiogenesis therapies. The alpha(v)beta3 integrin is activated in angiogenic vessels and represents a potential target for noninvasive imaging of angiogenesis. METHODS AND RESULTS: We evaluated a 99mTc-labeled peptide (NC100692) targeted at alpha(v)beta3 integrin for imaging in an established murine model of angiogenesis induced by hindlimb ischemia. Control mice (n=9) or mice with surgical right femoral artery occlusion (n=29) were injected with NC100692 (1.5+/-0.2 mCi IV) at different times after femoral occlusion (1, 3, 7, and 14 days) for in vivo pinhole planar gamma camera imaging. Tissue from hindlimb proximal and distal to occlusion was excised for gamma well counting and for immunostaining. On in vivo pinhole images, increased focal NC100692 activity was seen distal to the occlusion at days 3 and 7. This increase in relative NC100692 activity was confirmed by gamma well counting. Lectin staining confirmed increased angiogenesis in the ischemic hindlimb at these time points. A fluorescent analogue of NC100692 was used to confirm specificity and localization of the targeted tracer in cultured endothelial cells. In addition, endothelial cell specificity was confirmed on tissue sections with the use of dual immunofluorescent staining of endothelium and the fluorescent analogue targeted at the alpha(v)beta3 integrin. CONCLUSIONS: A 99mTc-labeled peptide (NC100692) targeted at alpha(v)beta3 integrin selectively localized to endothelial cells in regions of increased angiogenesis and could be used for noninvasive serial "hot spot" imaging of angiogenesis. This targeted radiotracer imaging approach is a major advance in tracking therapeutic myocardial angiogenesis and has an important clinical potential.

Animals↗

PubMed2005

A boundary element-based approach to analysis of LV deformation.

Quantification of left ventricular (LV) deformation from 3D image sequences (4D data) is important for the assessment of myocardial viability, which can have important clinical implications. To date, feature information from either Magnetic Resonance, computed tomographic or echocardiographic image data has been assembled with the help of different interpolative models to estimate LV deformation. These models typically are designed to be computationally efficient (e.g. regularizing strategies using B-splines) or more physically realistic (e.g. finite element approximations to biomechanical models), but rarely incorporate both notions. In this paper, we combine an approach to the extraction and matching of image-derived point features based on local shape properties with a boundary element model. This overall scheme is intended to be both computationally efficient and physically realistic. In order to illustrate this, we compute strains using our method on canine 4D MR image sequences and compare the results to those found from a B-spline-based method (termed extended free-form deformation (EFFD)) and a method based on finite elements (FEM). All results are compared to displacements found using implanted markers, taken to be agold standard.

Algorithms↗

PubMed2005

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).

Algorithms↗

PubMed2005

A new method for SPECT quantification of targeted radiotracers uptake in the myocardium.

We developed a new method for absolute quantification of targeted radiotracers uptake in the myocardium using hybrid SPECT/CT and an external reference point source. A segmentation algorithm based on the level set was developed to determine the endocardial edges from CT, which were subsequently applied to the physically co-registered SPECT. A 3-D Gaussian fitting method was applied for quantification of the external point source. The total targeted radiotracer activity in the myocardium was normalized to that in the point source to calculate the absolute uptake of targeted radiotracer in the myocardium. Preliminary validation was performed in rats with ischemia-induced angiogenesis. The quantified in vivo radiotracer uptake was compared to the postmortem tissue radioactive well-counting of the myocardium. Our methods worked well for identification of the endocardial edges. Quantification of the focal uptake was consistent with the well-counting data. Our methods may have the potential of providing precise absolute quantification of targeted radiotracer uptake in the myocardium.

Animals↗

PubMed2005

Characterizing vascular connectivity from microCT images.

X-ray microCT (computed tomography) has become a valuable tool in the analysis of vascular architecture in small animals. Because of its high resolution, a detailed assessment of blood vessel physiology and pathology is possible. Vascular measurement from noninvasive imaging is important for the study and quantification of vessel disease and can aid in diagnosis, as well as measure disease progression and response to therapy. The analysis of tracked vessel trajectories enables the derivation of vessel connectivity information, lengths between vessel junctions as well as level of ramification, contributing to a quantitative analysis of vessel architecture. In this paper, we introduce a new vessel tracking methodology based on wave propagation in oriented domains. Vessel orientation and vessel likelihood are estimated based on an eigenanalysis of gray-level Hessian matrices computed at multiple scales. An anisotropic wavefront then propagates through this vector field with a speed modulated by the maximum vesselness response at each location. Putative vessel trajectories can be found by tracing the characteristics of the propagation solution between different points. We present preliminary results from both synthetic and mouse microCT image data.

Algorithms↗

PubMed2005

Molecular cardiovascular imaging.

Imaging with radionuclides has historically played an important role in detection of cardiovascular disease as well as in risk stratification and prognostication. With the growth of molecular biology have come new therapeutic interventions and the requirement for new diagnostic imaging approaches. Noninvasive targeted radiotracer-based strategies require the development of new instrumentation to meet these needs. This progress has been made possible with the availability of many technologic advances, which include dedicated micro single-photon emission computed tomography (SPECT) and micro positron emission tomography (PET) hybrid systems for small animal imaging. This review is a brief overview on the subject of molecular imaging. Basic concepts of molecular imaging are reviewed, followed by description of current technologic advances, and current applications to evaluate ischemic heart disease and potential therapeutic intervention. The emphasis is on the use of both SPECT and PET radiotracers, although other imaging modalities are also briefly discussed.

Angiogenesis Inducing Agents↗

PubMed2005

Cardiovascular molecular imaging.

The recent introduction of novel gene therapies for treatment of cardiac and noncardiac diseases has caused a remarkable need for noninvasive imaging approaches to evaluate and track the progress of these therapies. In the past we have relied on the evaluation of the physiological consequences of therapeutic interventions. With advances in targeted molecular imaging we now have the ability to evaluate early molecular effects of these therapies. The development of dedicated high resolution small animal imaging systems and the establishment of transgenic animal models has enhanced our understanding of cardiovascular disease and has expedited the development of new gene therapies. Noninvasive targeted molecular imaging will allow us to directly track biochemical processes and signaling events that precede the pathophysiological changes. The examples of targeted molecular imaging outlined in this seminar provide some insight into the bright and growing future of cardiovascular molecular imaging. The success of this new field rests on the development of targeted biological markers of molecular and physiological processes, development of new instruments with improved sensitivity and resolution, and the establishment of multidisciplinary teams of experimental and clinical investigators with a wide range of expertise. Molecular imaging already plays a critical role in the experimental laboratory. We expect that, in the near future, targeted molecular imaging will be routinely used in clinical cardiovascular nuclear medicine laboratories in conjunction with existing imaging modalities for both diagnostic and prognostic purposes, as well as for evaluation of new genetic based therapeutic strategies.

Animals↗

PubMed2004

Detection of injury-induced vascular remodeling by targeting activated alphavbeta3 integrin in vivo.

BACKGROUND: The alpha(v)beta3 integrin plays a critical role in cell proliferation and migration. We hypothesized that vascular cell proliferation, a hallmark of injury-induced remodeling, can be tracked by targeting alpha(v)beta3 integrin expression in vivo. METHODS AND RESULTS: RP748, a novel 111In-labeled alpha(v)beta3-specific radiotracer, was evaluated for its cell-binding characteristics and ability to track injury-induced vascular proliferation in vivo. Three groups of experiments were performed. In cultured endothelial cells (ECs), TA145, a cy3-labeled homologue of RP748, localized to alpha(v)beta3 at focal contacts. Activation of alpha(v)beta3 by Mn2+ led to increased EC binding of TA145. Left common carotid artery wire injury in apolipoprotein E-/- mice led to vascular wall expansion over a period of 4 weeks. RP748 (7.4 MBq) was injected into groups of 9 mice at 1, 3, or 4 weeks after left carotid injury, and carotids were harvested for autoradiography. Relative autographic intensity, defined as counts/pixel of the injured left carotid area divided by counts/pixel of the uninjured right carotid area, was higher at 1 and 3 weeks (1.8+/-0.1 and 1.9+/-0.2, respectively) and decreased significantly by 4 weeks after injury (1.4+/-0.1, P<0.05). Carotid alpha(v) and beta3 integrin expression was maximal at 1 week and decreased by 4 weeks after injury. The proliferation index, as determined by Ki67 staining, followed a temporal pattern similar to that of RP748 uptake. Dynamic gamma imaging demonstrated rapid renal clearance of RP748. CONCLUSIONS: RP748 has preferential binding to activated alpha(v)beta3 integrin and can track the injury-induced vascular proliferative process in vivo.

Animals↗

PubMed2004

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.

Animals↗

PubMed2003

Simultaneous optical coherence tomography imaging and beta particle detection.

A prototype hybrid catheter device designed for imaging and detection of vascular diseases is introduced. The prototype device integrates a high-resolution optical coherent tomography probe and a high-sensitivity beta detector into a single unit. With this prototype device we demonstrate the feasibility of simultaneous optical coherence tomography imaging and detection of beta particles.

Beta Particles↗

PubMed2002

Estimation of 3-D left ventricular deformation from medical images using biomechanical models.

The quantitative estimation of regional cardiac deformation from three-dimensional (3-D) image sequences has important clinical implications for the assessment of viability in the heart wall. We present here a generic methodology for estimating soft tissue deformation which integrates image-derived information with biomechanical models, and apply it to the problem of cardiac deformation estimation. The method is image modality independent. 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 muscle 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, exhibit a high correlation with strains produced in the same animals using implanted markers. Further, they show good agreement with previously published results in the literature. This proposed method provides quantitative regional 3-D estimates of heart deformation.

Algorithms↗

PubMed2002

Correlation of myocardial p-(123)I-iodophenylpentadecanoic acid retention with (18)F-FDG accumulation during experimental low-flow ischemia.

UNLABELLED: Myocardial ischemia is associated with reduced free fatty acid (FFA) beta-oxidation and increased glucose utilization. This study evaluated the potential of dynamic SPECT imaging of a FFA analog, p-(123)I-iodophenylpentadecanoic acid (IPPA), for detection of ischemia and compares retention of IPPA with (18)F-FDG accumulation. METHODS: In a canine model of regional low-flow ischemia (n = 9), serial IPPA SPECT images (2 min per image) were acquired over 52--90 min. In a subset of dogs (n = 6), (18)F-FDG was injected after completing SPECT imaging and allowed to accumulate for 40 min before killing the animals. Flow was assessed with radiolabeled microspheres. Myocardial metabolism was evaluated independently by selective coronary arterial and venous sampling. RESULTS: Serial IPPA SPECT images showed an initial defect in the ischemic region (0.70% plus minus 0.03% ischemic-to-nonischemic ratio), which normalized within 48 min because of the slower IPPA clearance from the ischemic region (t(1/2) = 54.2 plus minus 3.3 min) relative to the nonischemic region (t(1/2) = 36.7 plus minus 5.6 min) (P < 0.05). Delayed myocardial IPPA and (18)F-FDG activities were correlated (r = 0.70; n = 576 segments), and both were maximally increased in segments with a moderate flow reduction (IPPA, 151% of nonischemic; (18)F-FDG, 450% of nonischemic; P < 0.05). CONCLUSION: Serial SPECT imaging showed delayed myocardial clearance of IPPA in ischemic regions with moderate flow reduction, which lead to increased late myocardial retention of IPPA. Retention of IPPA correlated with (18)F-FDG accumulation, supporting the potential of IPPA as a noninvasive marker of ischemic myocardium.

Animals↗