Background: Single photon emission computed tomography (SPECT)/computed tomography (CT) imaging a... more Background: Single photon emission computed tomography (SPECT)/computed tomography (CT) imaging allows for assessment of skeletal muscle microvascular perfusion but has not been quantitatively assessed in angiosomes, or 3-dimensional vascular territories, of the foot. This study assessed and compared resting angiosome foot perfusion between healthy subjects and diabetic patients with critical limb ischemia (CLI). Additionally, the relationship between SPECT/CT imaging and the ankle–brachial index—a standard tool for evaluating peripheral artery disease—was assessed. Methods and Results: Healthy subjects (n=9) and diabetic patients with CLI and nonhealing ulcers (n=42) underwent SPECT/CT perfusion imaging of the feet. CT images were segmented into angiosomes for quantification of relative radiotracer uptake, expressed as standardized uptake values. Standardized uptake values were assessed in ulcerated angiosomes of patients with CLI and compared with whole-foot standardized uptake va...
The goal of this review is to highlight how molecular imaging will impact the management and impr... more The goal of this review is to highlight how molecular imaging will impact the management and improved understanding of the major cardiovascular diseases that have substantial clinical impact and research interest. These topics include atherosclerosis, myocardial ischemia, myocardial viability, heart failure, gene therapy, and stem cell transplantation. Traditional methods of evaluation for these diseases will be presented first, followed by methods that incorporate conventional and molecular imaging approaches.
Arteriosclerosis, Thrombosis, and Vascular Biology, 2011
Objective— Inflammation plays a key role in the development of vascular diseases. Monocytes and m... more Objective— Inflammation plays a key role in the development of vascular diseases. Monocytes and macrophages express α v β 3 integrin. We used an α v integrin-specific tracer, 99m Tc-NC100692, to investigate integrin-targeted imaging for detection vessel wall inflammation. Methods and Results— The binding of a fluorescent homologue of NC100692 to α v β 3 on human monocytes and macrophages was shown by flow cytometry. Vessel wall inflammation and remodeling was induced in murine carotid arteries through adventitial exposure to CaCl 2 . NC100692 micro single photon computed tomography/CT imaging was performed after 2 and 4 weeks and showed significantly higher uptake of the tracer in CaCl 2 -exposed left carotids compared with sham-operated contralateral arteries. Histological analysis at 4 weeks demonstrated significant remodeling of left carotid arteries and considerable macrophage infiltration, which was confirmed by real-time polymerase chain reaction. There was no significant diff...
Cancer mortality has improved due to earlier detection via screening, as well as due to novel can... more Cancer mortality has improved due to earlier detection via screening, as well as due to novel cancer therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitions. However, similarly to older cancer therapies such as anthracyclines, these therapies have also been documented to cause cardiotoxic events including cardiomyopathy, myocardial infarction, myocarditis, arrhythmia, hypertension, and thrombosis. Imaging modalities such as echocardiography and magnetic resonance imaging (MRI) are critical in monitoring and evaluating for cardiotoxicity from these treatments, as well as in providing information for the assessment of function and wall motion abnormalities. MRI also allows for additional tissue characterization using T1, T2, extracellular volume (ECV), and delayed gadolinium enhancement (DGE) assessment. Furthermore, emerging technologies may be able to assist with these efforts. Nuclear imaging using targeted radiotracers, some of which are already clinically u...
BackgroundQuantitative gated single photon emission computed tomography (SPECT [QGS]) software is... more BackgroundQuantitative gated single photon emission computed tomography (SPECT [QGS]) software is widely used for the assessment of left ventricular ejection fraction (LVEF). Potentially confounding variables that may affect the accuracy of quantitative analysis of LVEF remain undefined. This study evaluated the accuracy of QGS as a means of determining LVEF in a wide range of LVEF values; evaluated the effect of extracardiac activity, count statistics, heart size, and perfusion defects on the accuracy of QGS LVEF; and compared QGS LVEF obtained at rest with that obtained after stress.Methods and ResultsQGS-derived LVEF was compared with rest first-pass radionuclide angiography (FPRNA) LVEF in 400 electrocardiographic-gated SPECT studies. The overall correlation between QGS and FPRNA LVEF was only fair (r = 0.66, SEE = 11.85%). In 35 of the patient studies (9%) with high extracardiac activity, the automated software failed, and no correlation was obtained. In the remaining 365 patie...
Journal of Clinical and Translational Science, 2021
IMPACT: Advanced cardiac magnetic resonance imaging techniques can help to protect cancer patient... more IMPACT: Advanced cardiac magnetic resonance imaging techniques can help to protect cancer patients from cardiotoxicity from immunotherapy with a more sensitive assessment of cardiac function with strain imaging for detection of abnormal cardiac function in the setting of normal left ventricular ejection fraction. OBJECTIVES/GOALS: Immune checkpoint inhibitors (ICI) are associated with fatal cardiotoxicity. Cardiac magnetic resonance (CMR) imaging can assess ICI-associated cardiotoxicity, but the utility of CMR strain imaging is unknown. We present a study of patients with ICI-associated cardiotoxicity evaluated with fast strain-encoded (fast-SENC) CMR. METHODS/STUDY POPULATION: This prospective study was approved by the institutional IRB and informed consent was obtained from 15 patients (5 patients with ICI-associated cardiotoxicity, 10 controls patients) between August 2018 and January 2020. All patients with ICI-associated cardiotoxicity had abnormal troponin values and evidence ...
BACKGROUND Doxorubicin (DOX) induces cardiotoxicity in part by activation of matrix metalloprotei... more BACKGROUND Doxorubicin (DOX) induces cardiotoxicity in part by activation of matrix metalloproteinases (MMPs). Sacubitril/valsartan (Sac/Val) exerts additive cardioprotective actions over renin-angiotensin-aldosterone inhibitors in preclinical models of myocardial infarction and in heart failure patients. We hypothesized that Sac/Val would be more cardioprotective than Val in a rodent model of progressive DOX-induced cardiotoxicity, and this benefit would be associated with modulation of MMP activation. OBJECTIVES We sought to investigate the efficacy of Sac/Val for the treatment of anthracycline-induced cardiotoxicity. METHODS Male Wistar rats received DOX intraperitoneally (15 mg/kg cumulative) or saline over 3 weeks. Following the first treatment, control animals were gavaged daily with water (n ¼ 25), while DOX-treated animals were gavaged daily with water (n ¼ 25), Val (31 mg/kg; n ¼ 25) or Sac/Val (68 mg/kg; n ¼ 25) for either 4 or 6 weeks. Echocardiography was performed at baseline, and 4 and 6 weeks after DOX initiation. In addition, myocardial MMP activity was assessed with 99m Tc-RP805, and cardiotoxicity severity was assessed by histology at these time points in a subgroup of animals. RESULTS Left ventricular ejection fraction decreased by 10% at 6 weeks in DOX and DOX þ Val rats (both p < 0.05), while this reduction was attenuated in DOX þ Sac/Val rats. MMP activity was increased at 6 weeks by 76% in DOX-alone rats, and tended to increase in DOX þ Val rats (36%; p ¼ 0.051) but was similar in DOX þ Sac/Val rats as compared with time-matched control animals. Both therapies attenuated histological evidence of cellular toxicity and fibrosis (p < 0.05). CONCLUSIONS Sac/Val offers greater protection against left ventricular remodeling and dysfunction compared with standard angiotensin receptor blocker therapy in a rodent model of progressive DOX-induced cardiotoxicity.
Reliable motion estimation and strain analysis using 3D+ time echocardiography (4DE) for localiza... more Reliable motion estimation and strain analysis using 3D+ time echocardiography (4DE) for localization and characterization of myocardial injury is valuable for early detection and targeted interventions. However, motion estimation is difficult due to the low-SNR that stems from the inherent image properties of 4DE, and intelligent regularization is critical for producing reliable motion estimates. In this work, we incorporated the notion of domain adaptation into a supervised neural network regularization framework. We first propose a semi-supervised Multi-Layered Perceptron (MLP) network with biomechanical constraints for learning a latent representation that is shown to have more physiologically plausible displacements. We extended this framework to include a supervised loss term on synthetic data and showed the effects of biomechanical constraints on the network's ability for domain adaptation.
Background. We have set out to develop a catheter-based theranostic system that: (a) identifies d... more Background. We have set out to develop a catheter-based theranostic system that: (a) identifies diseased and at-risk myocardium via endocardial detection of systemically delivered b-emitting radiotracers and (b) utilizes molecular signals to guide delivery of therapeutics to appropriate tissue via direct intramyocardial injection. Methods. Our prototype device consists of a miniature b-radiation detector contained within the tip of a flexible intravascular catheter. The catheter can be adapted to incorporate an injection port and retractable needle for therapeutic delivery. The performance of the b-detection catheter was assessed in vitro with various b-emitting radionuclides and ex vivo in hearts of pigs following systemic injection of 18 F-fluorodeoxyglucose (18 F-FDG) at 1-week post-myocardial infarction. Regional catheter-based endocardial measurements of 18 F activity were compared to regional tissue activity from PET/CT images and gamma counting. Results. The b-detection catheter demonstrated sensitive in vitro detection of b-radiation from 22 Na (b 1), 18 F (b 1), and 204 Tl (b-), with minimal sensitivity to c-radiation. For 18 F, the catheter demonstrated a sensitivity of 4067 counts/s/lCi in contact and a spatial resolution of 1.1 mm FWHM. Ex vivo measurements of endocardial 18 F activity with the b-detection catheter in the chronic pig infarct model demonstrated good qualitative and quantitative correlation with regional tissue activity from PET/CT images and gamma counting. Conclusion. The prototype b-detection catheter demonstrates sensitive and selective detection of band b 1 emissions over a wide range of energies and enables high-fidelity ex vivo characterization of endocardial activity from systemically delivered 18 F-FDG. (J Nucl Cardiol 2020) Key Words: Image guided application AE instrumentation AE molecular imaging myocardial ischemia and infarction AE PET Electronic supplementary material The online version of this article (
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2015
Nanoparticulate imaging agents and therapeutics have proven to be valuable tools in preclinical c... more Nanoparticulate imaging agents and therapeutics have proven to be valuable tools in preclinical cardiovascular disease research. Because of their distinct properties and significant functional versatility, nanoparticulate imaging agents afford certain capabilities that are typically not provided by traditional small molecule agents. This review is the second in a two-part series covering nanoparticulate imaging agents and theranostics. It highlights current examples of radiolabeled nanoparticulate probes in preclinical cardiovascular research and demonstrates their utility in applications such as blood pool imaging and molecular imaging of ischemia, angiogenesis, atherosclerosis, and inflammation. These agents provide valuable insight into the molecular and cellular mechanisms of cardiovascular disease and illustrate both the limitations and the significant potential of nanoparticles in diagnostic and therapeutic applications. Further technologic development to improve performance, ...
Background— Noninvasive imaging strategies play a critical role in assessment of the efficacy of ... more Background— Noninvasive imaging strategies play a critical role in assessment of the efficacy of angiogenesis therapies. The α v β 3 integrin is activated in angiogenic vessels and represents a potential target for noninvasive imaging of angiogenesis. Methods and Results— We evaluated a 99m Tc-labeled peptide (NC100692) targeted at α v β 3 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 stai...
Background— Time-dependent activation of matrix metalloproteinases (MMPs) after myocardial infarc... more 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 99m Tc-labeled MMP-targeted radi...
A variety of contrast mechanisms is available for imaging molecular processes in vivo by optical ... more A variety of contrast mechanisms is available for imaging molecular processes in vivo by optical methods. At the core of molecular imaging is the need for in-depth understanding of key molecular processes involved in pathologic conditions of interest. This then allows for a logical design of molecular probes for detecting or reporting the functional status of specific molecular targets. Today, many molecular probes have been developed for preclinical and clinical studies using this scientific approach. Despite our best efforts to use scientific methods in the lab, unexpected results frequently occur. Although many such results are discarded, sometimes they give rise to the discovery of important molecular reporter systems. Two examples of recent unexpected but exciting findings in our lab will be used to illustrate the concept of serendipity in molecular optical imaging research. Multimodal imaging of remodeling post myocardial infarction: anatomy, physiology, and molecular targets
V ascular dysfunction is causally contributing to many diseases, including but not limited to car... more V ascular dysfunction is causally contributing to many diseases, including but not limited to cardiovascular disease, which is still the leading cause of death in the Western world. The endothelium that lines the inner wall of the blood vessels plays a critical role in the pathobiology of these illnesses. Particularly after ischemia or injury, the growth of new blood vessels, driven by endothelial expansion, is essential to maintain oxygen supply to the ischemic or injured tissue. Recent studies additionally suggest that the endothelium acts as a paracrine source for signals that determine tissue regeneration versus fibrosis after injury. Excessive vascularization, however, might also be unwanted, as in the case of cancer, neovascular eye diseases including diabetic retinopathy, atheroma growth, or the expansion of vasa vasorum, which leads to adverse vessel wall remodeling. Neovascularization is a tightly regulated and essential process that results in the formation of new blood vessels. Specific types of neovascularization include angiogenesis, the formation of new capillaries from existing capillaries, and arteriogenesis, the formation of new arteries from preexisting collaterals or de novo. Although endothelial cells (ECs) certainly are essential for both processes, the formation of functionally active vessels requires a complex molecular cross-talk of ECs with perivascular cells such as pericytes, smooth muscle cells, and macrophages. Simple in vitro models are 1. In Vitro Assays Considerable progress has been made over the past 20 years in the development of in vitro strategies to investigate the complex processes of vascular morphogenesis and maturation events in
Background: Single photon emission computed tomography (SPECT)/computed tomography (CT) imaging a... more Background: Single photon emission computed tomography (SPECT)/computed tomography (CT) imaging allows for assessment of skeletal muscle microvascular perfusion but has not been quantitatively assessed in angiosomes, or 3-dimensional vascular territories, of the foot. This study assessed and compared resting angiosome foot perfusion between healthy subjects and diabetic patients with critical limb ischemia (CLI). Additionally, the relationship between SPECT/CT imaging and the ankle–brachial index—a standard tool for evaluating peripheral artery disease—was assessed. Methods and Results: Healthy subjects (n=9) and diabetic patients with CLI and nonhealing ulcers (n=42) underwent SPECT/CT perfusion imaging of the feet. CT images were segmented into angiosomes for quantification of relative radiotracer uptake, expressed as standardized uptake values. Standardized uptake values were assessed in ulcerated angiosomes of patients with CLI and compared with whole-foot standardized uptake va...
The goal of this review is to highlight how molecular imaging will impact the management and impr... more The goal of this review is to highlight how molecular imaging will impact the management and improved understanding of the major cardiovascular diseases that have substantial clinical impact and research interest. These topics include atherosclerosis, myocardial ischemia, myocardial viability, heart failure, gene therapy, and stem cell transplantation. Traditional methods of evaluation for these diseases will be presented first, followed by methods that incorporate conventional and molecular imaging approaches.
Arteriosclerosis, Thrombosis, and Vascular Biology, 2011
Objective— Inflammation plays a key role in the development of vascular diseases. Monocytes and m... more Objective— Inflammation plays a key role in the development of vascular diseases. Monocytes and macrophages express α v β 3 integrin. We used an α v integrin-specific tracer, 99m Tc-NC100692, to investigate integrin-targeted imaging for detection vessel wall inflammation. Methods and Results— The binding of a fluorescent homologue of NC100692 to α v β 3 on human monocytes and macrophages was shown by flow cytometry. Vessel wall inflammation and remodeling was induced in murine carotid arteries through adventitial exposure to CaCl 2 . NC100692 micro single photon computed tomography/CT imaging was performed after 2 and 4 weeks and showed significantly higher uptake of the tracer in CaCl 2 -exposed left carotids compared with sham-operated contralateral arteries. Histological analysis at 4 weeks demonstrated significant remodeling of left carotid arteries and considerable macrophage infiltration, which was confirmed by real-time polymerase chain reaction. There was no significant diff...
Cancer mortality has improved due to earlier detection via screening, as well as due to novel can... more Cancer mortality has improved due to earlier detection via screening, as well as due to novel cancer therapies such as tyrosine kinase inhibitors and immune checkpoint inhibitions. However, similarly to older cancer therapies such as anthracyclines, these therapies have also been documented to cause cardiotoxic events including cardiomyopathy, myocardial infarction, myocarditis, arrhythmia, hypertension, and thrombosis. Imaging modalities such as echocardiography and magnetic resonance imaging (MRI) are critical in monitoring and evaluating for cardiotoxicity from these treatments, as well as in providing information for the assessment of function and wall motion abnormalities. MRI also allows for additional tissue characterization using T1, T2, extracellular volume (ECV), and delayed gadolinium enhancement (DGE) assessment. Furthermore, emerging technologies may be able to assist with these efforts. Nuclear imaging using targeted radiotracers, some of which are already clinically u...
BackgroundQuantitative gated single photon emission computed tomography (SPECT [QGS]) software is... more BackgroundQuantitative gated single photon emission computed tomography (SPECT [QGS]) software is widely used for the assessment of left ventricular ejection fraction (LVEF). Potentially confounding variables that may affect the accuracy of quantitative analysis of LVEF remain undefined. This study evaluated the accuracy of QGS as a means of determining LVEF in a wide range of LVEF values; evaluated the effect of extracardiac activity, count statistics, heart size, and perfusion defects on the accuracy of QGS LVEF; and compared QGS LVEF obtained at rest with that obtained after stress.Methods and ResultsQGS-derived LVEF was compared with rest first-pass radionuclide angiography (FPRNA) LVEF in 400 electrocardiographic-gated SPECT studies. The overall correlation between QGS and FPRNA LVEF was only fair (r = 0.66, SEE = 11.85%). In 35 of the patient studies (9%) with high extracardiac activity, the automated software failed, and no correlation was obtained. In the remaining 365 patie...
Journal of Clinical and Translational Science, 2021
IMPACT: Advanced cardiac magnetic resonance imaging techniques can help to protect cancer patient... more IMPACT: Advanced cardiac magnetic resonance imaging techniques can help to protect cancer patients from cardiotoxicity from immunotherapy with a more sensitive assessment of cardiac function with strain imaging for detection of abnormal cardiac function in the setting of normal left ventricular ejection fraction. OBJECTIVES/GOALS: Immune checkpoint inhibitors (ICI) are associated with fatal cardiotoxicity. Cardiac magnetic resonance (CMR) imaging can assess ICI-associated cardiotoxicity, but the utility of CMR strain imaging is unknown. We present a study of patients with ICI-associated cardiotoxicity evaluated with fast strain-encoded (fast-SENC) CMR. METHODS/STUDY POPULATION: This prospective study was approved by the institutional IRB and informed consent was obtained from 15 patients (5 patients with ICI-associated cardiotoxicity, 10 controls patients) between August 2018 and January 2020. All patients with ICI-associated cardiotoxicity had abnormal troponin values and evidence ...
BACKGROUND Doxorubicin (DOX) induces cardiotoxicity in part by activation of matrix metalloprotei... more BACKGROUND Doxorubicin (DOX) induces cardiotoxicity in part by activation of matrix metalloproteinases (MMPs). Sacubitril/valsartan (Sac/Val) exerts additive cardioprotective actions over renin-angiotensin-aldosterone inhibitors in preclinical models of myocardial infarction and in heart failure patients. We hypothesized that Sac/Val would be more cardioprotective than Val in a rodent model of progressive DOX-induced cardiotoxicity, and this benefit would be associated with modulation of MMP activation. OBJECTIVES We sought to investigate the efficacy of Sac/Val for the treatment of anthracycline-induced cardiotoxicity. METHODS Male Wistar rats received DOX intraperitoneally (15 mg/kg cumulative) or saline over 3 weeks. Following the first treatment, control animals were gavaged daily with water (n ¼ 25), while DOX-treated animals were gavaged daily with water (n ¼ 25), Val (31 mg/kg; n ¼ 25) or Sac/Val (68 mg/kg; n ¼ 25) for either 4 or 6 weeks. Echocardiography was performed at baseline, and 4 and 6 weeks after DOX initiation. In addition, myocardial MMP activity was assessed with 99m Tc-RP805, and cardiotoxicity severity was assessed by histology at these time points in a subgroup of animals. RESULTS Left ventricular ejection fraction decreased by 10% at 6 weeks in DOX and DOX þ Val rats (both p < 0.05), while this reduction was attenuated in DOX þ Sac/Val rats. MMP activity was increased at 6 weeks by 76% in DOX-alone rats, and tended to increase in DOX þ Val rats (36%; p ¼ 0.051) but was similar in DOX þ Sac/Val rats as compared with time-matched control animals. Both therapies attenuated histological evidence of cellular toxicity and fibrosis (p < 0.05). CONCLUSIONS Sac/Val offers greater protection against left ventricular remodeling and dysfunction compared with standard angiotensin receptor blocker therapy in a rodent model of progressive DOX-induced cardiotoxicity.
Reliable motion estimation and strain analysis using 3D+ time echocardiography (4DE) for localiza... more Reliable motion estimation and strain analysis using 3D+ time echocardiography (4DE) for localization and characterization of myocardial injury is valuable for early detection and targeted interventions. However, motion estimation is difficult due to the low-SNR that stems from the inherent image properties of 4DE, and intelligent regularization is critical for producing reliable motion estimates. In this work, we incorporated the notion of domain adaptation into a supervised neural network regularization framework. We first propose a semi-supervised Multi-Layered Perceptron (MLP) network with biomechanical constraints for learning a latent representation that is shown to have more physiologically plausible displacements. We extended this framework to include a supervised loss term on synthetic data and showed the effects of biomechanical constraints on the network's ability for domain adaptation.
Background. We have set out to develop a catheter-based theranostic system that: (a) identifies d... more Background. We have set out to develop a catheter-based theranostic system that: (a) identifies diseased and at-risk myocardium via endocardial detection of systemically delivered b-emitting radiotracers and (b) utilizes molecular signals to guide delivery of therapeutics to appropriate tissue via direct intramyocardial injection. Methods. Our prototype device consists of a miniature b-radiation detector contained within the tip of a flexible intravascular catheter. The catheter can be adapted to incorporate an injection port and retractable needle for therapeutic delivery. The performance of the b-detection catheter was assessed in vitro with various b-emitting radionuclides and ex vivo in hearts of pigs following systemic injection of 18 F-fluorodeoxyglucose (18 F-FDG) at 1-week post-myocardial infarction. Regional catheter-based endocardial measurements of 18 F activity were compared to regional tissue activity from PET/CT images and gamma counting. Results. The b-detection catheter demonstrated sensitive in vitro detection of b-radiation from 22 Na (b 1), 18 F (b 1), and 204 Tl (b-), with minimal sensitivity to c-radiation. For 18 F, the catheter demonstrated a sensitivity of 4067 counts/s/lCi in contact and a spatial resolution of 1.1 mm FWHM. Ex vivo measurements of endocardial 18 F activity with the b-detection catheter in the chronic pig infarct model demonstrated good qualitative and quantitative correlation with regional tissue activity from PET/CT images and gamma counting. Conclusion. The prototype b-detection catheter demonstrates sensitive and selective detection of band b 1 emissions over a wide range of energies and enables high-fidelity ex vivo characterization of endocardial activity from systemically delivered 18 F-FDG. (J Nucl Cardiol 2020) Key Words: Image guided application AE instrumentation AE molecular imaging myocardial ischemia and infarction AE PET Electronic supplementary material The online version of this article (
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2015
Nanoparticulate imaging agents and therapeutics have proven to be valuable tools in preclinical c... more Nanoparticulate imaging agents and therapeutics have proven to be valuable tools in preclinical cardiovascular disease research. Because of their distinct properties and significant functional versatility, nanoparticulate imaging agents afford certain capabilities that are typically not provided by traditional small molecule agents. This review is the second in a two-part series covering nanoparticulate imaging agents and theranostics. It highlights current examples of radiolabeled nanoparticulate probes in preclinical cardiovascular research and demonstrates their utility in applications such as blood pool imaging and molecular imaging of ischemia, angiogenesis, atherosclerosis, and inflammation. These agents provide valuable insight into the molecular and cellular mechanisms of cardiovascular disease and illustrate both the limitations and the significant potential of nanoparticles in diagnostic and therapeutic applications. Further technologic development to improve performance, ...
Background— Noninvasive imaging strategies play a critical role in assessment of the efficacy of ... more Background— Noninvasive imaging strategies play a critical role in assessment of the efficacy of angiogenesis therapies. The α v β 3 integrin is activated in angiogenic vessels and represents a potential target for noninvasive imaging of angiogenesis. Methods and Results— We evaluated a 99m Tc-labeled peptide (NC100692) targeted at α v β 3 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 stai...
Background— Time-dependent activation of matrix metalloproteinases (MMPs) after myocardial infarc... more 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 99m Tc-labeled MMP-targeted radi...
A variety of contrast mechanisms is available for imaging molecular processes in vivo by optical ... more A variety of contrast mechanisms is available for imaging molecular processes in vivo by optical methods. At the core of molecular imaging is the need for in-depth understanding of key molecular processes involved in pathologic conditions of interest. This then allows for a logical design of molecular probes for detecting or reporting the functional status of specific molecular targets. Today, many molecular probes have been developed for preclinical and clinical studies using this scientific approach. Despite our best efforts to use scientific methods in the lab, unexpected results frequently occur. Although many such results are discarded, sometimes they give rise to the discovery of important molecular reporter systems. Two examples of recent unexpected but exciting findings in our lab will be used to illustrate the concept of serendipity in molecular optical imaging research. Multimodal imaging of remodeling post myocardial infarction: anatomy, physiology, and molecular targets
V ascular dysfunction is causally contributing to many diseases, including but not limited to car... more V ascular dysfunction is causally contributing to many diseases, including but not limited to cardiovascular disease, which is still the leading cause of death in the Western world. The endothelium that lines the inner wall of the blood vessels plays a critical role in the pathobiology of these illnesses. Particularly after ischemia or injury, the growth of new blood vessels, driven by endothelial expansion, is essential to maintain oxygen supply to the ischemic or injured tissue. Recent studies additionally suggest that the endothelium acts as a paracrine source for signals that determine tissue regeneration versus fibrosis after injury. Excessive vascularization, however, might also be unwanted, as in the case of cancer, neovascular eye diseases including diabetic retinopathy, atheroma growth, or the expansion of vasa vasorum, which leads to adverse vessel wall remodeling. Neovascularization is a tightly regulated and essential process that results in the formation of new blood vessels. Specific types of neovascularization include angiogenesis, the formation of new capillaries from existing capillaries, and arteriogenesis, the formation of new arteries from preexisting collaterals or de novo. Although endothelial cells (ECs) certainly are essential for both processes, the formation of functionally active vessels requires a complex molecular cross-talk of ECs with perivascular cells such as pericytes, smooth muscle cells, and macrophages. Simple in vitro models are 1. In Vitro Assays Considerable progress has been made over the past 20 years in the development of in vitro strategies to investigate the complex processes of vascular morphogenesis and maturation events in
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