National Heart, Lung, and Blood Institute

Research Corner

National Heart, Lung, and Blood Institute The following abstracts of diagnostic radiology research and training grants funded by the National Institutes of Health (NIH) were awarded to principal investigators (PIs) whose primary appointments are in medical school departments of radiology. These abstracts are listed on the NIH Web page (http://www-commons.cit.nih.gov/crisp/) and are printed here verbatim. The grant identification number (eg, 1R01AI12345-01) contains a three-digit activity code (in the previous example, R01) that identifies a specific category of extramural activity. All current NIH activity code titles and definitions can be obtained at the NIH Web page http://silk.nih.gov/silk/brownbooks/actcod. IRG (Internal Review Group) refers to the study section that reviewed the application. ICD (Institute, Center, Division) refers to the NIH funding source. The abstracts of the funded grants are printed alphabetically by author according to the funding institute or center.

HEART IMAGING AGENTS: A STRUCTURAL-MECHANISTIC STUDY Grant Number: 5R01HL079540-26 Raffel, David M. Abstract: Description (provided by applicant): The main focus of this project has been the development of radiotracers for the noninvasive assessment of cardiac sympathetic nerve function using scintigraphic imaging. Our laboratory has previously developed several successful tracers for cardiac sympathetic neurons, including [123I]meta-iodobenzylguanidine (MIBG) for SPECT imaging and [11C]meta-hydroxyephedrine (HED) and [11C]epinephrine (EPI) for PET imaging. All of these tracers are rapidly transported into cardiac sympathetic neurons as substrates of the norepinephrine transporter (NET), and then taken up into vesicles by the vesicular monoamine transporter (VMAT2). While the rapid neuronal uptake of these agents results in high quality heart images, their neuronal uptake rates are so fast that compartmental modeling of their kinetics fails. This also causes measures of tracer retention to be insensitive to nerve losses until those losses become severe. We believe this obstacle to accurate quantification can only be overcome with new kinetically superior, more information-rich tracers that possess optimal kinetics for tracer kinetic analyses. Such tracers would provide more accurate and sensitive measures of regional nerve density, allowing detection of denervation earlier in the course of diseases that cause nerve damage, such as diabetic autonomic neuropathy and heart failure. Early detection of denervation may be clinically important in terms of providing patients with effective therapies to halt or reverse denervation. In the last project period, we hypothesized that a radiolabeled NET substrate must possess two kinetic properties to be ‘ideal’ for tracer kinetic analyses: (1) a slower neuronal uptake rate, and (2) a very long neuronal retention time, through efficient vesicular

storage. We had further hypothesized that a tracer with these properties could be found among the many guanidines known to exert potent pharmacological effects on sympathetic neurons. Studies of 11C-phenethylguanidines yielded several compounds with the desired kinetic properties. N[11C]guanyl-( )-meta-octopamine (GMO) emerged as the most promising 11C-labeled agent, while encouraging results with 4-fluoro- and 6-fluoro-meta-hydroxyphenethylguanidine (4F-MHPG, 6F-MHPG) support the development of these compounds into 18F-labeled tracers. In the current proposal, a major goal is to perform imaging studies of GMO in monkeys with microPET to assess its suitability for quantitative PET studies in humans. A second major goal is to prepare and evaluate 18F-labeled 4F-MHPG and 6F-MHPG. Also, work on radiolabeled guanidines will extend to two new series based on 2-(2-pyrindinyl)ethylguanidine and guanoxan. These new series include structures with ring fluorine substitutions as part of ongoing efforts to develop an optimal 18F-labeled tracer. Tracer bioevaluation methods will include kinetic studies in isolated rat heart, biodistribution and metabolism studies in rats, assays of NET and VMAT2 transport kinetics in cells, and metabolism and microPET studies in monkeys. This systematic study of 11C- and 18F-guanidines should result in the development of a tracer with optimal kinetics for quantifying cardiac sympathetic nerve density with PET. PUBLIC HEALTH RELEVANCE Many diseases, including diabetes, heart failure, heart attacks (infarction) and Parkinson’s disease are known to cause severe damage to the nerves of the heart, which may contribute to sudden cardiac death. The main goal of this project is to develop nuclear medicine imaging studies that can be used by doctors to take pictures of the damage to the nerves of the heart in patients with these diseases. These imaging studies will help doctors understand how the nerves of the heart are damaged in diseases, and also can be used to study if the nerve damage can be stopped or reversed with new drug therapies. e163

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Public Health Relevance: This Public Health Relevance is not available.

Public Health Relevance: This Public Health Relevance is not available.

Thesaurus Terms: There are no thesaurus terms on file for this project. Institution: University Of Michigan At Ann Arbor 3003 South State Street, Room 1040 Ann Arbor, MI 481091274 Fiscal Year: 2009 Department: Radiology Project Start: 01-Aug-1981 Project End: 30-May-2012 ICD: National Heart, Lung, And Blood Institute IRG: ZRG1

Thesaurus Terms: diagnosis quality /standard, disease /disorder etiology, emphysema, lung, noninvasive diagnosis, respiratory disorder diagnosis, respiratory function disease /disorder model, inflammation, longitudinal animal study, microcapsule, oxygen tension, plethysmography, pulmonary respiration, vascular endothelial growth factor laboratory rat Institution: University Of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Fiscal Year: 2009 Department: Radiology Project Start: 01-Apr-2000 Project End: 31-Mar-2012 ICD: National Heart, Lung, And Blood Institute IRG: MEDI

ASSESSMENT OF LUNG FUNCTION IN SAMLL ANIMALS Grant Number: 5R01HL064741-06 Rizi, Rahim R. Abstract: Description (provided by applicant): Non-invasive, regional assessment of lung function has the potential to markedly enhance early diagnosis and management of disease, to accelerate drug discovery and trials, and to provide fundamental insights into the root causes of disease. In this proposal, we aim to address a fundamental question of emphysema pathogenesis thorough a systematic study of lung function and structure using techniques developed over the first funding cycle. These techniques include measurements of pulmonary ventilation and perfusion, alveolar oxygen tension, and a sensitive measure of lung microstructure using hyperpolarized magnetic tracers, as well as several well-established methods in pulmonary medicine. The proposed research is designed specifically to corroborate or refute a molecular model of emphysema progression that is currently under widespread debate. Despite extensive investigation, it is still not clear which of the numerous and varied presentations of emphysema corresponds to the fundamental cause of the disease, or even if one principal cause can be identified. Nonetheless, a large body of current research suggests that altered expression of one or more mediators of angiogenesis may be the first step in the disease. This alteration degrades the capillary endothelium’s ability to repair itself, resulting in cell death, reduced perfusion, and ultimately tissue destruction. Although in vivo imaging methods cannot replace the powerful molecular techniques in use today, they can provide a more complete picture of the action of disease or therapy on the body. In this study, we first demonstrate a comprehensive, self-consistent, and validated set of pulmonary measurements and evaluate sensitivity to disease. We then apply these measurements to three animal models of emphysema in order to evaluate time ordering and spatial correlation of the various aspects of pulmonary dysfunction. By comparing these measurements to testable predictions of the disease model, we hope to elucidate the first stages of this devastating disease. e164

IMAGING REGIONAL PHYSIOLOGIC PARAMETERS OF LUNG FUNCTION Grant Number: 2R01HL077241-05 Rizi, Rahim R Abstract: Description (provided by applicant): The longterm goal of this project is to develop hyperpolarized MRI methods for the prediction and characterization of chronic obstructive pulmonary disease (COPD), a prevalent pulmonary disorder that is projected to become the third leading cause of death in the U.S. by 2020. Recent publications, including our, suggest that hyperpolarized gas MRI techniques are uniquely sensitive to the early onset of COPD in both human subjects and animal models. Our approach has been to develop noninvasive hyperpolarized MRI techniques to detect this disease in its early stages and to identify new therapeutic agents. During the first funding cycle we designed and implemented various methods to accurately measure regional alveolar partial pressure of oxygen, ventilation, perfusion, and ventilation-to-perfusion ratio, as well as oxygen depletion rate and diffusivity of helium-3 in the lung. We have evaluated the utility of these regional parameters in the quantitative assessment of lung function and structure. The most exciting results are: 1) significant changes in regional ventilation in emphysematous lungs that precede histological findings; 2) significant changes in the regional partial pressure of oxygen and regional ventilation-to-perfusion ratio in lungs with perfusion defects; 3) an elevated value of regional apparent diffusion coefficient of helium-3 in emphysematous lungs that correlates well with histology; 4) design and fabrication of a state-of-the-art programmable ventilator capable of delivering an accurate mixture of oxygen, nitrogen, and hyperpolarized helium-3 to both small and large animals; 5) development of hyperpolarized carbon-13 technology for the quantitative measurement of regional perfusion. These methods were developed in animal models and have now

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been translated to clinical use at several sites to comprehensively assess lung function and structure. However, these non-invasive methods have not, as yet, been used to characterize the underlying mechanisms of emphysema. The objectives of the current proposal are to use these non-invasive hyperpolarized helium-3 MRI parameters for studying the underlying mechanisms that lead to the development of emphysema. Specifically, we will 1) induce emphysema in a rat model using chronic exposure to cigarette smoke; 2) trace the progression of emphysematous changes with hyperpolarized helium-3 MRI markers, established CT parameters, pulmonary function tests, and histology; 3) measure the regional concentration of the molecular signatures of apoptosis and identify the onset of the disease through hyperpolarized helium-3 markers; and 4) further the understanding of disease pathogenesis and evaluate possible interventions in emphysema progression by disrupting specific apoptosis pathways We will employ a number of sophisticated and novel methods, including hyperpolarized helium-3 MRI parameters to quantitatively assess lung function and immunohistological staining methods to measure molecular signatures responsible for apoptosis in lung tissue, to achieve these goals. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: There are no thesaurus terms on file for this project. Institution: University Of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Fiscal Year: 2008 Department: Radiology Project Start: 01-Aug-2004 Project End: 31-Jul-2012 ICD: National Heart, Lung, And Blood Institute IRG: BMIT

NMR DETECTION OF GENE EXPRESSION Grant Number: 5R01HL069961-05 Roman, Brian B. Abstract: DESCRIPTION (provided by applicant): Noninvasive monitoring of transient and stable gene expression would be a potent technique to evaluate normal and pathological processes as well as the efficacy of disease treatment. The ‘‘biosensor’’ proposed will take advantage of well known early patterns of gene transcription which occur in response to pathologic stimuli. Promoter sequences of native genes that are transcriptionally activated in ventricular myocardium under pathologic conditions will drive expression of an NMR sensitive reporter gene. This DNA sequence will be transfected and characterized in isolated cells to establish its patho-sensitivity. Subsequently, these constructs will be used to create transgenic mice for in vivo studies. Detection of the biosensor will require novel NMR RF microcoils of

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two general designs: 1)planar or cylindrical geometry amenable to isolated cell conditions and 2) an interventricular catheter coil of solenoid or Maxwell design. Since both the reporter and detectors are being developed simultaneously, the result will be a truly integrated detection system. Specific Aim I. - NMR Sensitive Reporter Genes and Transfection into Cardiocytes: Hypothesis 1: Endogenous genes and gene products can be combined to non-invasively monitor cellular status. Hypothesis 2: Specifically engineered cells can act as endogenous biosensors of physiological stress. Specific Aim II. - Mouse Cardiac Catheter MR Microcoil: Hypothesis: A MR cardiac catheter microcoil can detect localized 31P NMR spectra from inside the mouse ventricle. Specific Aim II1. - Cell Culture Microcoil: Hypothesis: A MR microcoil can detect gene expression defined 31P NMR spectra from isolated cells or cell lines. Specific Aim IV. - Endogenous Biosensors Expressed in Hearts of Transgenic Mice: Hypothesis: NMR sensitive reporters (Biosensors) can be expressed and detected in the heart of a mouse in response to transient and stable hypertrophic stimuli. The importance of this approach suggests it is now possible to provide a very early detection of intracellular events prior to tissue remodeling or mechanical failure. This opens the window to early treatments such that a reversal of the process is possible. This system will also be able to evaluate therapeutic regimens as the activity of the biosensor (CK) will modulate with the disease process. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: biomedical equipment development, biosensor device, gene expression, genetic transcription genetic promoter element, heart cell, heart ventricle, nucleic acid sequence, physiologic stressor, radiowave radiation, reporter gene bioengineering /biomedical engineering, fusion gene, genetically modified animal, heart catheterization, nuclear magnetic resonance spectroscopy, spectrometry, tissue /cell culture, transfection /expression vector Institution: University Of Chicago 5801 S Ellis Ave Chicago, IL 60637 Fiscal Year: 2007 Department: Radiology Project Start: 01-Aug-2003 Project End: 31-Jul-2009 ICD: National Heart, Lung, And Blood Institute IRG: DMG

SICKLE-CELL DISEASE: NEUROIMAGING AND COGNITIVE DECLINE Grant Number: 5K01HL073152-05 Rule, Randall R. Abstract: Description (provided by applicant): The overall goal of this neuroimaging project is to determine the e165

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anatomical basis of reduced cognition in sickle cell disease (SCD). Specifically to test the hypothesis that impaired cognition is closely associated with decreased cortical gray matter and hippocampal volumes, and is less associated with the extent of subcortical ischemia/infarction. This will be accomplished by quantitative magnetic resonance imaging (MRI), long TE proton magnetic resonance spectroscopic imaging (1H MRSI), and neuropsychological testing that will include test of executive function and memory. These tests will include the California Card Sorting Task (CCST), the Self Ordered Pointing Task, tests of written and verbal fluency and the this study will focus on adult SCD patients with Wechsler Memory Scale (WMS). no history of overt clinical stroke. Overt infarcts are known to be associated with cognitive deficits. However, SCD patients with no history of CVAs are known suffer from impairment of memory and executive function. This study is designed to test whether cortical and hippocampal degeneration subsequent to subcortical ischemia is a marker of cognitive decline in these patients with no history of stroke. The ischemia that can occur in subcortical ischemic vascular disease (SIVD) is similar to the silent infarcts seen in SCD. In SIVD it has been determined that cognitive decline is associated with decreased cortical gray matter and hippocampal volumes. This project is designed to look for similar relationships in SCD. The primary hypotheses are: 1.) Gray matter volume and gray matter NAA are significantly decreased in SCD versus control subjects. 2.) Comical gray matter and hippocampal volume and NAA will correlate highly with cognition while white matter lesions, lacunars infarcts, and white matter NAA will be less correlated with cognition. Secondary hypotheses are: 1.) Gray matter volume and NAA reductions in SCD compared with controls will be greater in the frontal lobe than in posterior areas. 2) Hippocampal volume will correlate with memory function. And frontal cortical gray matter volume will correlate with executive function. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: cognition, entorhinal cortex, hippocampus, neural degeneration, neuroimaging, neuropathology, neuropsychology, sickle cell anemia aspartate, brain morphology, cerebrospinal fluid, executive function, frontal lobe /cortex, functional ability, ischemia, memory adult human (21+), bioimaging /biomedical imaging, clinical research, human subject, magnetic resonance imaging, morphometry, neuropsychological test Institution: University Of California San Francisco 3333 California St., Ste 315 San Francisco, CA 941430962 Fiscal Year: 2007 Department: Radiology And Biomedical Imaging Project Start: 20-Jun-2003 Project End: 28-Feb-2009 ICD: National Heart, Lung, And Blood Institute IRG: ZHL1

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MR GUIDED TRANSENDOCARDIAL ANGIOGENIC AGENTS Grant Number: 3R01HL072956-04S1 Saeed, Maythem M. Abstract: The overall aim of this project is to investigate the response of ischemic myocardium to injections of angiogenic growth factors using a system that provides a substantially reduced level of invasiveness compared to alternative treatment methods. The rationale behind the proposed project is that accurate targeting and focal delivery are essential to achieve optimal therapeutic effects. Delivery of angiogenic factors will be performed using a unique dual x-ray fluoroscopy-MRI unit that permits real-time imaging during procedures. Improvements in MRI pulse sequence design and the use of recently developed MR contrast media will be pursued to evaluate the effects of angiogenic growth factors on ischemically injured myocardium. High-resolution MRI will be performed to obtain quantitative data about global and regional wall motion and blood flow at rest and stress (dobutamine and adenosine). MRI in conjunction with novel contrast media will be used to assess microvascular integrity, myocardial perfusion and viability. In vivo (physiologic and pharmacologic) and ex vivo (histopathologic and quantitative analytical) studies will be performed to confirm and support MRI findings. These studies will be conducted in dogs but rapid high-resolution MR sequences suitable for use in humans will also be developed. Effects of the most widely used angiogenic growth factors, namely vascular endothelial growth factor (VEGF) for angiogenesis and fibroblast growth factor (FGF) for arteriogenesis, will be investigated in 3 dog models of ischemia. Since the evolution of angiogenesis and arteriogenesis differs in hypoperfused, occlusive and reperfused infarction models, dynamic vascular, cellular and morphologic changes will be longitudinally monitored and compared. This project is a collaborative effort between scientists and clinicians in the field of cardiac MRI. The potential clinical benefits of focal MRI-guided treatment are to: 1) reduce morbidity caused by open-chest surgery, 2) accomplish rapid recovery due to minimal invasiveness, 3) potentially provide treatment on an outpatient basis and 4) reduce treatment costs. The key elements of this project are: 1) development of minimally invasive MRI-guided method for focal therapies and 2) chronological evaluation of new therapies on an admixture of stunned and infarcted myocardium in coronary artery disease. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: There are no thesaurus terms on file for this project. Institution:

Fiscal Year:

University Of California San Francisco 3333 California St., Ste 315 San Francisco, CA 941430962 2007

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Department: RADIOLOGY AND BIOMEDICAL IMAGING Project Start: 15-DEC-2003 Project End: 30-JUN-2007 ICD: National Heart, Lung, And Blood Institute IRG: CVA

PULMONARY TRANSGENE EXPRESSION IMAGING WITH PET Grant Number: 5R01HL076488-03 Schuster, Daniel P. Abstract: Description (provided by applicant): Although it is already clear that positron emission tomographic (PET) imaging can be used to follow transgene expression in whole animals, no studies to date have yet demonstrated the utility of using molecular imaging methods, such as PET, to follow transgene expression in experimental models of disease. We propose to address this important issue by administering, to rats, adenoviral vectors carrying biologically relevant genes (shown previously by collaborators to affect the pathophysiology of different disease models of the acute respiratory distress syndrome, ARDS, and of pulmonary hypertension) and a ‘‘PET reporter gene’’ (e.g. viral thymidine kinase, tk), both under the control of the same promoter. Imaging will be performed to follow the location (within the lungs), timing (onset and duration), and magnitude of reporter transgene expression in relation to the physiologic effects (also studied with non-invasive imaging) of the disease modifying genes. Thus, our proposal has the following specific aims: Specific Aim 1: using PET imaging, determine the timing, magnitude, duration, and functional effects of beta-2 adrenergic receptor (beta2AR) transgene expression during experimental lung injury. 1.a Measure changes with PET and in vitro assays of beta2AR and tk expression as a function of viral dose. 1.b Determine the time course of gene expression with PET in normal animals. 1.c Correlate (temporally and geographically, i.e. within the lungs) PET reporter gene expression, beta-2 adrenergic receptor transgene expression, and functional effects of the beta2AR transgene (also evaluated with PET imaging) in acute hyperoxic lung injury (a lung injury model of ARDS). Specific Aim 2: using PET imaging and echocardiography, determine the timing, magnitude, duration, and functional effects of prostaglandin I2 synthase transgene expression during experimental pulmonary hypertension. An analogous series of studies (Specific Aims2.a, 2.b and 2.c) will be implemented in two variants of the monocrotaline model of pulmonary hypertension, a model of sub-acute pulmonary vascular disease. The results will demonstrate how PET imaging can be used to study the impact of changes in gene expression on the natural history of disease or to develop therapeutic protocols to alter disease outcome. Public Health Relevance: This Public Health Relevance is not available.

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Thesaurus Terms: disease /disorder model, gene expression, gene therapy, lung injury, nonhuman therapy evaluation, pulmonary hypertension, respiratory imaging /visualization, transfection /expression vector Adenoviridae, beta adrenergic receptor, disease /therapy duration, genetic promoter element, genetic transcription, monocrotaline, pathologic process, prostaglandin endoperoxide synthase, reporter gene echocardiography, laboratory rat, positron emission tomography Institution: Washington University 1 Brookings Dr, Campus Box 1054 Saint Louis, MO 631304899 Fiscal Year: 2007 Department: Radiology Project Start: 15-Dec-2004 Project End: 30-Nov-2008 ICD: National Heart, Lung, And Blood Institute IRG: MEDI

GENETIC ANALYSIS OF NEOINTIMAL HYPERPLASIA Grant Number: 1R01HL082881-01A2 Shi, Weibin Abstract: Description (provided by applicant): Restenosis remains the most significant clinical challenge limiting the success of angioplasty and/or stenting. Neointimal hyperplasia is the primary reason for in-stent restenosis. The objective of this proposal is to use variations among mouse strains in injury-induced neointimal hyperplasia to identify genetic factors that contribute to the development of post-angioplasty/stent restenosis. On the apolipoprotein E-deficient (apoE-/-) background, inbred mouse strains C57BL/6 J (B6) and C3H/HeJ (C3H) differ markedly in injury-induced neointimal hyperplasia. B6.apoE-/- mice readily develop neointimal hyperplasia whereas CSH.apoE-/- mice are totally resistant to lesion formation despite the fact that the two strains have comparable hyperlipidemia on a chow diet. The F1 hybrids are intermediate in the phenotype, indicating a codominant control of the phenotype in the mice. Immediately following arterial injury is deposition of a layer of platelets at sites of vascular injury. Subsequently, leukocyte recruitment and infiltration occur. Recruited macrophages and lymphocytes and damaged endothelial cells and vascular smooth muscle cells (SMC) release cytokines, growth factors, and matrix metalloproteinases (MMP) that stimulate SMC in the medial wall to proliferate and migrate into the damaged intima. We hypothesize that genetic factors that influence the induction of cytokines and growth factors or that modulate the proliferation of vascular smooth muscle cells contribute to the variation in neointimal hyperplasia of the two strains. To test this hypothesis, B6.apoE-/- mice will be mated with CSH.apoE-/- mice to generate F1 mice, which will be subsequently intercrossed to generate a cohort of F2 e167

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mice. The male F2 mice, together with male F1 and two parental strains, will be subject to endothelial denudation of the left common carotid artery. Neointimal thickening will be quantitated by light microscopy. Blood will be collected for assessment of fasting lipid and inflammatory marker levels. Genome-wide scans will be performed using microsatellite markers to define the genetic loci that are linked to differences in the phenotypes between B6 and C3H strains. After the genome screen has detected chromosomal regions that show linkage with neointimal lesions, we will type additional closely spaced polymorphic markers to narrow the regions. One to two major QTLs for neointimal hyperplasia will be dissected through construction and analysis of congenic strains. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: apolipoprotein E, genetic regulation, hyperplasia, restenosis, vascular endothelium blood vessel prosthesis, cardiovascular injury, genetic strain, genetic susceptibility, hyperlipidemia, inflammation, intraluminal angioplasty, medical complication, quantitative trait loci laboratory mouse, linkage mapping nstitution: University Of Virginia Charlottesville Box 400195 Charlottesville, VA 229044195 Fiscal Year: 2007 Department: Radiology Project Start: 06-Jun-2007 Project End: 31-May-2010 ICD: National Heart, Lung, And Blood Institute IRG: GHD

QTL ANALYSIS OF CAROTID ATHEROSCLEROSIS Grant Number: 5R01HL075433-04 Shi, Weibin Abstract: Description (provided by applicant): Stroke is the third leading cause of mortality and the leading cause of disability in the United States, and a significant fraction of ischemic strokes are caused by carotid atherosclerosis, which results in stenosis of the vessels and blocks the blood flow to the brain. The goal of this proposal is to identify genetic factors that contribute to the development of carotid atherosclerosis, using the novel apolipoprotein E-deficient (apoE-/) mouse model. ApoE-/- mice on the C57BL/6 (B6) genetic background develop all phases of atherosclerotic lesions seen in humans in carotid arteries. Our recent studies show that the lesions can be dramatically diminished by outcross with C3H/HeJ (C3H) mice, demonstrating the genetic control of the disease process in the mice. In vitro, endothelial cells of C3H mice are not as responsive to oxidized LDL as B6 endothelial cells. We hypothesize that a genetic alteration that influences the response to oxidized LDL contributes to e168

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the resistance of C3H mice to carotid atherosclerosis. To test this hypothesis, B6.apoE-/- mice will be crossed with C3H.apoE-/- mice to generate F1 mice, which will be subsequently intercrossed to generate F2 mice. Starting at 6 weeks of age, the F2 mice, together with the F1 and the two parental strains, will be fed a Western diet for 12 weeks. Atherosclerotic lesions in carotid arteries will be measured by light microscopy. Blood will be collected for fasting lipid profiles and inflammatory markers. Genome wide scan will be performed using microsatellite markers to define the genetic loci that are linked to differences in phenotypes between B6 and C3H strains. Statistical associations of the markers and the phenotypes will be performed to identify loci underlying the traits. After the genome screen has detected chromosomal regions that show linkage with atherosclerotic lesions, we will type additional closely spaced polymorphic markers. One to two major QTLs for atherosclerotic lesions will be dissected through construction of congenic strains. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: atherosclerosis, carotid artery, genetic susceptibility, quantitative trait loci, stroke CD40 molecule, acute phase protein, apolipoprotein E, artery stenosis, genome, ischemia, low density lipoprotein, restriction fragment length polymorphism enzyme linked immunosorbent assay, genetically modified animal, laboratory mouse, light microscopy, microarray technology, polymerase chain reaction Institution: University Of Virginia Charlottesville Box 400195 Charlottesville, VA 229044195 Fiscal Year: 2007 Department: Radiology Project Start: 01-Jul-2004 Project End: 30-Apr-2009 ICD: National Heart, Lung, And Blood Institute IRG: MGN

NON-INVASIVE MEASURES OF REGIONAL CORONARY ENDOTHELIAL FUNCTION BY 3T MRI Grant Number: 5R01HL084186-04 Stuber, Matthias Abstract: Description (provided by applicant): The endothelium plays a pivotal role in maintaining vasodilation and acting as a permeability barrier. Impaired coronary endothelial function likely contributes to plaque progression and instability and predicts cardiovascular events. Systemic endothelium-dependent vasoreactivity is commonly measured in peripheral arteries like the brachial. Although brachial reactivity predicts cardiovascular event rates in population studies, coronary endothelial dysfunction is likely more

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closely linked to coronary atherosclerosis and cardiac events. Unfortunately, there is currently no non-invasive means for assessing endothelial function of the coronary arteries. We propose to develop, integrate, and test new non-invasive procedures for the evaluation of regional coronary artery endothelial function using high-field (3 T) magnetic resonance imaging (MRI) to investigate the premise that local coronary endothelial function affects the progression of coronary atheroslcerosis, a regionally heterogeneous process. MRI offers high soft-tissue contrast images that can be used to measure arterial dimensions and blood flow. In addition, recent studies indicate that abnormal endothelial permeability can be detected as vessel wall enhancement in atherosclerotic regions with MRI. The PI has extensive experience in developing coronary MRI techniques and proposes here new procedures that include motion-suppressed high-resolution coronary lumen, flow, and vessel wall imaging, together with imaging of coronary artery endothelial permeability using contrast agents. The Specific Aims include defining endothelium-dependent and -independent coronary vasoreactivity in low- and high-risk populations. In patients with coronary artery disease, we propose to establish the spatial and temporal range of coronary endothelial permeability as assessed by delayed hyperenhancement of the normal and abnormal coronary artery vessel wall. Finally, we will test the hypothesis that coronary arterial endothelial dysfunction in a given coronary arterial segment relates to the subsequent development and progression of atherosclerotic disease in that segment. By the end of this grant period, we will have developed and optimized MRI methods for the truly non-invasive assessment of regional coronary artery endothelial function for the first time. The ability to noninvasively measure regional coronary vasoreactivity offers a greater fundamental understanding of the progression of atherosclerosis and may also lead to a true clinical paradigm shift. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: cardiovascular disorder diagnosis, cardiovascular imaging /visualization, coronary disorder, diagnosis design /evaluation, magnetic resonance imaging, noninvasive diagnosis atherosclerosis, blood flow measurement, cardiovascular disorder risk, coronary artery, method development, vascular endothelium permeability bioimaging /biomedical imaging, clinical research, human subject, patient oriented research Institution:

Johns Hopkins University W400 Wyman Park Building Baltimore, MD 21218 Fiscal Year: 2009 Department: Radiology And Radiological Sciences Project Start: 01-May-2006 Project End: 30-Apr-2011 ICD: National Heart, Lung, And Blood Institute IRG: MEDI

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SEGMENTATION OF ULTRASOUND IMAGES Grant Number: 5R01HL077810-02 Tagare, Hemant D. Abstract: Description (provided by applicant): Segmentation, which is the task of finding boundaries in an image, is an important stage in quantifying information in ultrasound images. The proposed research seeks to build a computational framework for segmenting human and animal cardiac ultrasound images. It is based on two ideas: the first uses a probabilistic model for the ultrasound signal and poses segmentation as a MAP estimation problem. The second uses a new optimization strategy called tunneling descent to calculate the MAP estimate. Tunneling descent has the capacity to escape from local maxima of the MAP log-likelihood function. Preliminary results, which compare tunneling descent results to manual segmentation, clearly show that tunneling descent outperforms classical active contours in segmenting shortaxis ultrasound images. Experimental evaluation also shows that it is robust with respect to initialization and works reliably without tweaking. This research seeks to extend these ideas to segment more complex boundaries, boundaries with specularities, boundaries with data dropout, moving boundaries in ultrasound image sequences, 3-D ultrasound images, and r.f. ultrasound images. These extensions will be used to jointly segment the endo and epi-cardium in short axis and apical four-chamber views. Human as well as laboratory animal images will be segmented. These images will be made available by the co-investigators. Two cardiac ultrasound phantoms will be built and used for evaluating the accuracy of segmentation as well as accuracy of volume and thickening calculations that are based on segmentation. R.F. data from the phantom will also be collected and systematically manipulated in software to create B-mode images. The segmentation of the r.f. images will be compared to the segmentation of the B-mode images to understand the effect of machine processing on segmentation. The human and animal image segmentations will be compared to manual segmentation. The performance of tunneling descent will also be compared to simulated annealing. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: computer program /software, heart imaging /visualization /scanning, image processing, mathematical model, three dimensional imaging /topography, ultrasonography echocardiography, endocardium, image enhancement, pericardium, phantom model animal data, bioimaging /biomedical imaging, human data Institution: Yale University 47 College Street, Ste 203 New Haven, CT 065208047 Fiscal Year: 2007 Department: Diagnostic Radiology Project Start: 01-Aug-2006 e169

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Project End: 30-Jun-2010 ICD: National Heart, Lung, And Blood Institute IRG: BMIT

MOLECULAR UBM AND MRI OF VASCULAR DEVELOPMENT Grant Number: 5R01HL078665-04 Turnbull, Daniel H. Abstract: Description (provided by applicant): Over the past decade, investigations using genetically-engineered mice have led to new insights into the genetic control of embryonic vascular development, which has also had a major impact on our understanding of neovascularization in diseases such as cancer and diabetic retinopathy. Noninvasive microimaging methods such as ultrasound biomicroscopy (UBM) and high-resolution magnetic resonance imaging (MRI) can play an important role in this research, enabling direct in utero visualization of the developing mouse embryo. We have pioneered the use of UBM and UBM-guided Doppler ultrasound for in vivo anatomical and functional cardiovascular development in normal and mutant mouse embryos. MRI of live embryos has been more difficult, but several groups have shown the utility of contrast-perfusion for high resolution MRI analysis of vascular structures in fixed mouse embryos. Lacking in these studies has been the ability to image molecular targets directly, to better understand and correlate gene expression patterns with morphological and functional data provided by UBM and MRI. Recent advances indicate that cell-specific vascular imaging should be possible using ultrasound and MRI contrast agents targeted to specific endothelial cell receptors. This strategy is likely to be successful first in transgenic mice that over-express defined receptors from endothelial cell-specific promoters, although similar approaches may enable future imaging of endogenous receptors in mice and men. Targeted ultrasound contrast agents have the additional advantage of potentiating in vivo cellspecific gene delivery, via ultrasound-mediated transfection, or sonoporation. The specific aims are: 1) To produce transgenic mice over-expressing Transferrin Receptor (TfR) from endothelial promoters. 2) To determine optimal conditions for sonoporation in the mouse embryonic cardiovascular system. 3) To develop and test TfR-specific contrast agents for in utero targeted UBM imaging and sonoporation of the mouse embryonic cardiovascular system. 4) To develop and test TfR-specific contrast agents for targeted vascular MRI in fixed mouse embryos. The approaches developed in this project will provide powerful new tools for direct analysis of vascular development in living mouse embryos. Significantly, these new molecular imaging methods will provide, for the first time, the ability to detect gene expression in utero in normal and genetically-engineered mice. (End of Abstract) Public Health Relevance: This Public Health Relevance is not available. e170

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Thesaurus Terms: angiogenesis, cardiovascular imaging /visualization, developmental genetics, gene delivery system, magnetic resonance imaging, technology /technique development, ultrasound contrast media, gene expression, genetically modified animal, mammalian embryology, molecular probe, receptor expression, transferrin receptor bioimaging /biomedical imaging, laboratory mouse Institution: New York University School Of Medicine 550 1st Ave New York, NY 10016 Fiscal Year: 2007 Department: Radiology Project Start: 22-Sep-2004 Project End: 31-Aug-2009 ICD: National Heart, Lung, And Blood Institute IRG: ZHL1

REAL-TIME MRI-GUIDED RF ABLATION OF CARDIAC TACHYARRHYTHMIAS Grant Number: 5R01HL086975-02 Unal, Orhan Abstract: Description (provided by applicant): Atrial fibrillation (AF) is the most common adult cardiac tachyarrhythmia affecting more than 2,200,000 people in the US. AF also accounts for 15% of all strokes. Ectopic electrical impulses originating in the pulmonary veins initiate AF in many patients. Surgical or catheter-based procedures that isolate pulmonary veins from the remaining atrial tissue may be offered to those patients who fail from medical therapy or suffer intolerable side effects. Surgery is invasive, risks morbidity and mortality and requires long recovery. In response, novel minimally invasive, catheter-based radiofrequency (RF) ablation approaches are being developed. However, catheter ablation guided by X-ray fluoroscopy (XRF) with adjunctive electroanatomic/ mechanical mapping (EMM) is challenging and time-consuming. Limitations with XRF include poor soft-tissue contrast and poor depth perception due to 2D projection imaging. Catheters are ‘‘blindly’’ steered in the heart chambers without visualization of endocardial surfaces or wall thickness, risking inappropriate ablation, life-threatening perforation or valve trauma. EMM requires expert skill and can take hours to obtain a low-resolution static roadmap. Cardiac, respiratory or random patient movements are not resolved with this or other roadmap techniques. For these reasons, catheter-based pulmonary vein ablation using conventional imaging is not widely attempted. Alternatively, magnetic resonance imaging (MRI) offers superior soft-tissue contrast with imaging in any arbitrary plane. Recent advances in novel therapeutic devices and rapid imaging techniques have made catheter-based interventions possible. Specific advantages for real-time MRIguided cardiac ablation over conventional image guidance include: 1) real-time, high tissue contrast, high resolution

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visualization of heart chambers and pulmonary veins in any arbitrary spatial perspective 2) real-time catheter navigation and positioning overcoming respiratory, cardiac and random patient movement (like non-roadmap imaging), 3) spatial and temporal tracking and visual assessment of ablation zones, 4) functional imaging to evaluate atrial and cardiac physiology, and flow dynamics during therapy, 5) elimination of radiation exposure to both patients and operators. We propose to design, develop, and validate a novel catheter-based pulmonary vein ablation approach using catheters modified with ‘‘multi-mode’’ intravascular MR probes with tracking, imaging, wireless marker, and RF ablation features integrated into a 3D real-time MRI guidance system. Successful completion of this project is expected to improve safety, simplicity, and efficacy catheter ablation procedure to treat AF. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: cardiovascular imaging /visualization, catheterization, fluoroscopy, functional magnetic resonance imaging, method development arrhythmia, atrial fibrillation, blood flow measurement, disease /disorder model, image enhancement, pulmonary vein, radiowave radiation, stroke, tachycardia, three dimensional imaging /topography cardiography, swine Institution: University Of Wisconsin Madison 21 N. Park Street, Suite 6401 Madison, WI 537151218 Fiscal Year: 2008 Department: Radiology Project Start: 01-Aug-2007 Project End: 30-Jun-2011 ICD: National Heart, Lung, And Blood Institute IRG: BMIT

DEVELOPMENT OF NAVIGATOR CORONARY MRI Grant Number: 5R01HL062994-09 Wang, Yi Abstract: Description (provided by applicant): The broad objective of this research is to develop magnetic resonance imaging (MRJ) techniques that will accurately detect significant lesions in the coronary arteries. MRI offers many advantages over CT and x- ray angiography for imaging coronary artery disease, including rich and adjustable contrasts between different tissues, noninvasive procedures, no use of ionizing radiation, and no risk of nephrotoxicity. Prior studies have demonstrated the feasibility of imaging both the coronary lumen and wall, but diagnostic accuracy is still impaired by motion artifacts. Coronary MR Angiography (MRA) technology is rapidly evolving. Studies in the prior funding cycle have led to several key findings. SSFP has been identified as the best sequence for coronary MRA because of its high SNR efficiency and fast imaging speed. Real time navigator

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gating provides higher spatial resolution and image quality than breath-holding for coronary MRA. There is still inconsistency in coronary MRA quality because of the use of electrocardiogram and the diaphragm navigator echo, neither of which directly measures coronary motion. We have recently developed the coronary fat navigator method that allows direct and accurate monitoring of coronary motion. Accordingly, we propose here to develop the coronary fat navigator for SSFP coronary MRA to achieve effective motion suppression. We have also developed a simultaneous multiple volume (SMV) algorithm for efficient navigator gating. Preliminary data demonstrate that the SMV algorithm shortens navigator gated scan time by 2-3 fold. Accordingly, we propose to incorporate SMV gating into navigator coronary MRA to shorten scan time. We have also obtained preliminary experience in imaging coronary vessel walls. The navigator technology can be directly employed to reduce motion blurring artifacts in high resolution plaque imaging, which would provide valuable information for characterizing atherosclerotic plaque in coronary arteries. This research consists of two specific aims: 1) develop an efficient and effective navigator method for imaging the coronary lumen and wall; and 2) evaluate the developed coronary MRI in patients with coronary artery disease by comparing to conventional x-ray angiography and intravascular ultrasound. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: There are no thesaurus terms on file for this project. Institution: Weill Medical College Of Cornell Univ 1300 York Avenue New York, NY 10065 Fiscal Year: 2009 Department: Radiology Project Start: 30-Sep-2000 Project End: 31-May-2011 ICD: National Heart, Lung, And Blood Institute IRG: ZRG1

MR DIGITAL SUBTRACTION ANGIOGRAPHY OF LOWER EXTREMITY Grant Number: 5R01HL060879-08 Wang, Yi Abstract: Description (provided by applicant): The broad objective of this research is to develop and evaluate contrast enhanced magnetic resonance angiography (MRA) for accurately diagnosing peripheral vascular disease. The successful outcome of this research will overcome the inaccuracy problem of current MRA and catheter-based x-ray angiography (XRA) in detecting lesions in small distal arteries in the lower calf and feet. The specific aims are 1) develop SNR efficient pulse sequences for peripheral MRA, 2) optimize RF coil for signal reception of the lower extremity, e171

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3) evaluate the accuracy of improved peripheral MRA in patients with peripheral vascular disease. Current contrast enhanced MRA acquisition is based on the Cartesian spoiled gradient echo (SPGR) sequence. The spiral SPGR and the fully refocused gradient echo sequence (steady state free precession, SSFP) can potentially provide much greater SNR than the Cartesian SPGR. Accordingly, spiral and SSFP sequence will be developed for data acquisition of peripheral MRA to provide > 50% increase in SNR. Current RF coils are not optimized for signal reception from the leg and feet. The multiple RF channels in recently disseminated MR scanners offer an opportunity to reduce noise using smaller coils. Accordingly, coil pants consisting of 8 channel orthogonal coil arrays and birdcage arrays will be developed to provide > 100% increase in SNR. Peripheral MRA using spiral/SSFP sequence and optimized coil will have a 200% increase in SNR over current peripheral MRA. The accuracy of this improved peripheral MRA will be evaluated in a group of patients with peripheral vascular disease, using intraoperative x-ray angiography as the gold standard. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: angiography, biomedical equipment development, cardiovascular disorder diagnosis, diagnosis design /evaluation, limb, magnetic resonance imaging, peripheral blood vessel disorder aorta, contrast media, noninvasive diagnosis, rapid diagnosis X ray, bioimaging /biomedical imaging, clinical research, human subject Institution: Weill Medical College Of Cornell Univ 1300 York Avenue New York, NY 10065 Fiscal Year: 2007 Department: Radiology Project Start: 01-Apr-1999 Project End: 31-Aug-2008 ICD: National Heart, Lung, And Blood Institute IRG: ZRG1

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1256 patients with suspected acute PE will be recruited at 7 clinical centers. All patients will undergo clinically indicated tests to diagnose or exclude PE. This includes a validated clinical assessment, D-dimer by rapid enzyme-linked immunosorbent assay (ELIS A), compression ultrasound of the lower extremities, ventilation/perfusion (V/Q) lung scan, contrast enhanced spiral computed tomography (CT), and ultimately may include pulmonary digital subtraction angiography (DSA). It is expected that 317 patients will have PE and they will undergo gadolinium enhanced MRA. It is expected that 939 patients will be shown to have no PE. From among this group with no PE, 317 patients will be randomized for MRA (and venous ultrasound as well). All MRA images and all images used for the diagnosis or exclusion of PE in patients who had an MRA will be sent for blinded central readings by two readers. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: cardiovascular disorder diagnosis, diagnosis design /evaluation, diagnosis quality /standard, diagnostic test, gadolinium, magnetic resonance imaging, pulmonary circulation obstruction, radiodiagnosis, respiratory disorder diagnosis cardiovascular imaging /visualization, cooperative study, pulmonary artery, pulmonary circulation, respiratory imaging /visualization, thromboembolism, venography adult human (21+), angiography, bioimaging /biomedical imaging, clinical research, human subject, patient oriented research Institution: Washington University 1 Brookings Dr, Campus Box 1054 Saint Louis, MO 631304899 Fiscal Year: 2008 Department: Radiology Project Start: 01-Aug-2005 Project End: 31-May-2010 ICD: National Heart, Lung, And Blood Institute IRG: ZHL1

PROSPECTIVE INVESTIGATION OF PULMONARY EMBOLISM DX-III

NANOSTRUCTURING AND MOLECULAR IMAGING OF ENGINEERED CARDIOVASCULAR TISSUES

Grant Number: 5U01HL077154-04 Woodard, Pamela K.

Grant Number: 1R21HL089027-01 Wu, Joseph C.

Abstract: Description (provided by applicant): The Prospective Investigation of Pulmonary Embolism Diagnosis in (PIOPED ffl) is a multicenter prospective investigation designed to give a quantitative assessment of the sensitivity and specificity of gadolinium enhanced magnetic resonance angiography (MRA) for the diagnosis of acute pulmonary embolism (PE). The study design is a prospective study of consecutive patients incorporating standardized inclusion/ exclusion criteria, complete ascertainment of patient characteristics and outcomes, uniform diagnostic criteria, and unbiased central reading of imaging studies. Over a period of two years,

Abstract: Description (provided by applicant): Ischemic heart disease (IHD) is the number one cause of morbidity and mortality in the US. With an estimated 1.6 million new or recurrent myocardial infarctions, the total economic burden of IHD on our health care system is tremendous. Although conventional pharmacotherapy and surgical interventions often improve cardiac function and quality of life, many patients continue to develop refractory symptoms. Thus, the development of new therapeutic strategies is urgently needed. ‘‘Tissue engineering’’ can be broadly defined as the application of novel engineering methods toward

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understanding structure-function relationships in normal or pathological conditions and the development of biological substitutes to restore, maintain, or improve function. It is different from ‘‘cell therapy’’ which intends to improve the function of an injured tissue by simply injecting suspensions of isolated cells. To date, two of the main limitations have been the lack of available methodology for scaling up the number of cells for potential clinical application and the inability to track the functionality of either cells or tissues after transplantation. Thus, the application of nanotechnology for development of novel techniques that address both deficits will provide a new catalyst for the entire field of investigation. The aims of our R21 proposal are to (1) significantly enhance the in vitro and in vivo performance of differentiated cardiomyocytes by electromechanical conditioning in an integrated stretchable microelectrode array-bioreactor system and (2) to engineer safe, durable, and biodegradable nanostructured scaffold sheets that can improve survival of conditioned cardiomyocytes. Once validated, we will transition into the R33 phase in years 3-5. The goals are (1) to scale-up nanostructured sheets from a single cell layer to a large area, multi-cell layer tissue graft, (2) to perform small animal in vivo assessment using molecular imaging techniques comparing the durability of injected cells alone versus our nanostructured tissue graft, and (3) to demonstrate safety and efficacy of our nanostructured tissue graft in a pre-clinical large animal model. We are confident that these developments will contribute substantially and help merge the fields of nanotechnology, tissue engineering, and molecular imaging. Progress in the field of cell therapy has been hindered by the lack of long-term engraftment and inability to monitor cell fate reliably post transplantation. Tissue engineering, by delivering cells with electrical and mechanical conditioning coupled to a supporting nanostructured scaffold may be a more promising and logical alternative. Our proposal uses multi-layers of conditioned cardiomyocytes patterned on a nanostructured scaffold to form a tissue graft that will be more durable, biodegradable, and safe. Concurrently, the application of molecular imaging modalities in small and large animal models will help us validate their functionality in vivo. With a multi-disciplinary team approach, we are confident that these combined efforts will accelerate the translation of nanotechnology-based tissue engineering to the clinical arena in the future. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: cardiac myocyte, ischemic preconditioning, nanotechnology, tissue engineering biodegradable product, biomechanics, cell differentiation, cytotoxicity, electrostimulus, tissue support frame bioengineering /biomedical engineering, human embryonic stem cell line, human genetic material tag, microarray technology, molecular /cellular imaging Institution: Fiscal Year:

Stanford University Stanford, CA 94305 2007

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Department: Project Start: Project End: ICD: IRG:

Radiology 01-Sep-2007 31-Jul-2012 National Heart, Lung, And Blood Institute ZRG1

MOLECULAR IMAGING OF CARDIAC CELL TRANSPLANTATION Grant Number: 5K08HL074883-03 Wu, Joseph C. Abstract: Description (provided by applicant): Cell transplantation shows potential promise for treating ischemic heart disease. Several elegant studies have demonstrated that implantation of skeletal myoblasts and bone marrow stem cells into the scarred myocardium can result in improved function. However, longitudinal analysis of cell survival remains problematic, because the current methodology relies on postmortem histology. Recently, we have established the feasibility of monitoring transplanted embryonic cardiomyoblasts expressing reporter genes in living animals using optical bioluminescence charged coupled device (CCD) and micro positron emission tomography (microPET) imaging. The specific aims of this proposal are well- thought-out extensions of our initial findings. This proposal will test the following multi-leveled hypothesis. In Aim 1, we will continue to develop an in vivo imaging model for monitoring the location, magnitude, and survival duration of transplanted human mesenchymal stem cells (hMSCs). Equally important, cell survival will be correlated with changes in contractility, perfusion, and metabolism, as determined by echocardiography, [13 N]-NH3, and [18F]-FDG imaging, respectively. In Aim 2, imaging results will be validated with traditional ex vivo and in vitro assays, such as morphometric analysis, immunocytochemistry, TaqMan PCR, TUNEL apoptosis stain, Westerns, and enzyme assays. Afterwards, we will focus on more fundamental questions related to stem cell physiology. In particular, Aim 3 will evaluate the optimal cell type, cell dosage, delivery route, timing of transplant, and efficacy of repeated injections. Finally, we will examine the causes of early cell death post transplant in Aim 4, and then screen for pharmaceutical, gene, and cell-based therapies aimed at preventing cell death and apoptosis. The overall significance of this proposal is to understand the real-time physiologic state of transplanted cells in an intact whole-body system. These studies will add further insights to the field of stem cell biology. As PET imaging is readily transferable from small animals to humans, our findings should have direct clinical impact in the near future. The goal is to use molecular imaging to guide stem cell therapy, which should translate into transplant protocols that are more reproducible, quantifiable, and beneficial. Public Health Relevance: This Public Health Relevance is not available. e173

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Thesaurus Terms: cardiovascular disorder therapy, heart imaging /visualization /scanning, mesenchyme, molecular /cellular imaging, myocardial ischemia /hypoxia, nonhuman therapy evaluation, stem cell transplantation, therapy design /development blood circulation, cell biology, cell death, chemotherapy, disease /disorder model, gene therapy, heart contraction, heart metabolism, pharmacology bioimaging /biomedical imaging, bioluminescence, deoxyglucose, echocardiography, human genetic material tag, laboratory rat, positron emission tomography, tissue /cell culture, transfection Institution: Stanford University Stanford, CA 94305 Fiscal Year: 2007 Department: Radiology Project Start: 01-Jan-2005 Project End: 31-Dec-2009 ICD: National Heart, Lung, And Blood Institute IRG: ZHL1

QUANTITATION OF LUNG VENTILATION AND STRUCTURE BY 3HE MR Grant Number: 5R01HL070037-05 Yablonskiy, Dmitriy A. Abstract: Emphysema is a major medical problem in the US and worldwide. Diagnostic methods for the evaluation of emphysema should be sensitive to regional lung structure at the alveolar level. Diffusion MRI with hyperpolarized 3He gas that evaluates the 3He-gas ADC (apparent diffusion coefficient) can provide this sensitivity. It offers information on lung microstructure and function not provided by traditional imaging modalities and pulmonary function tests. With 3He diffusion MRI, alveolar size and the integrity of alveolar walls can be evaluated, even though the alveoli are too small to be resolved by direct imaging. This points to the large potential for clinical application of ADC measurements with hyperpolarized 3He gas. However, until recently it was not clear what specific features of lung structure are probed by 3He gas ADC measurements. Recently we proposed a theoretical model based on a large body of histology data that provides this explanation. However, substantial questions must be answered if we are to understand the 3He ADC measurement and optimally exploit its diagnostic potential. In this proposal we will extend our mathematical model that relates anisotropic ADC measurements in lung to lung microstructural parameters. The mathematical model is based on a realistic structure of lung at the acinar level described in terms of acinar airways covered with alveolar sleeves. The theory of gas diffusion in lung is based on our key concept of anisotropic diffusion in lung acinar airways. We will conduct sophisticated multi-dimensional MR experiments on sacrificed mice with healthy lungs to test the fundamental feature of our mathematical model, the anisotropy of ADC. We will develop further and test our new diffusion e174

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3He MRI technique for tomographic ‘‘lung biopsy’’ on a canine model of emphysema with physiology similar to human and establish a quantitative relationship between the severity of emphysema as determined by CT and the 3He anisotropic diffusivities. We will use 3He diffusion and ventilation MRI together with CT to study normal human subjects and patients with emphysema. Inter-comparison of these three techniques will establish quantitative relationships between CT, lung ventilation and anisotropic ADC measurements and will open up possibilities for new interpretations of results obtained by each modality. The potential implications are significant. A comprehensive clinical picture of emphysema progression, from initial onset of the alveolar deformation to the final stage, characterized by dramatic loss of lung function, will be established. New methods will be sensitive enough to allow early diagnosis of emphysema that will improve patient treatment. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: diagnosis design /evaluation, emphysema, lung imaging /visualization /scanning, magnetic resonance imaging, pulmonary respiration, respiratory disorder diagnosis computed axial tomography, mathematical model, pulmonary diffusion bioimaging /biomedical imaging, clinical research, dog, human subject, laboratory mouse, patient oriented research Institution: Washington University 1 Brookings Dr, Campus Box 1054 Saint Louis, MO 631304899 Fiscal Year: 2007 Department: Radiology Project Start: 15-Dec-2002 Project End: 30-Nov-2009 ICD: National Heart, Lung, And Blood Institute IRG: DMG

MR IMAGING OF STEM CELL-GENE THERAPY OF ATHEROSCLEROSES Grant Number: 5R01HL078672-05 Yang, Xiaoming Abstract: Description (provided by applicant): Atherosclerotic cardiovascular disease is a unique illness with multiplylocated and diffusely-fashioned, as well as differently-staged plaques, that can involve the entire body. To date, there are no established methods available for either early diagnosis or efficient treatment of multiple/diffuse atheroscleroses. Recent studies have confirmed that the migration of bone marrow cells can give rise to vascular progenitor cells that home in the damaged vessels and differentiate into either endothelial cells or smooth muscle cells in various models of atherosclerotic lesions. The transfused hematopoietic stem-progenitor cells (SC) are strictly restricted to atherosclerotic plaques, which accelerates re-endothelialization and thereby reduces

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neointima formation. This concept, ‘‘plaque-specific trafficking of hematopoietic SCs,’’ motivated us to develop a new technology using MR imaging to monitor and guide plaque-specific, stem cell-mediated early diagnosis and therapy of multiple/diffuse atheroscleroses. In the current proposal, we will develop two novel techniques: (a) plaquespecific, SC-mediated MR imaging of early multiple/diffuse atheroscleroses by creating magnetically-labeled stem cells that traffic/target specifically the multiple/diffuse plaques; and (b) MR imaging-guided, plaque-specific, SC-mediated gene therapy of multiple/diffuse atheroscleroses by transducing a therapeutic gene to the magnetically-labeled stem cells that traffic/target specifically the multiple/diffuse plaques. The principles of these two novel technical developments will be first tested and proved in a series of in vitro and in vivo experiments with hematopoietic bone marrow stem cells of donor mice and atherosclerotic models of recipient mice using molecular MR imaging. Subsequently, the two novel techniques will be validated in a preclinical setting using near human-sized Yucatan pig models with multiple/ diffuse atheroscleroses under clinical MR imaging. We firmly believe that the success of this project will open up new avenues for the future efficient management of cardiovascular ischemic disorders in humans using MR imaging-based, stem cell-mediated vascular gene/drug therapy. (End of Abstract) Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: atherosclerosis, cardiovascular imaging /visualization, gene therapy, magnetic resonance imaging, stem cell transplantation, technology /technique development cardiovascular disorder diagnosis, diagnosis design /evaluation, hematopoietic stem cell, therapy design /development bioimaging /biomedical imaging, laboratory mouse, swine Institution: University Of Washington Office Of Sponsored Programs Seattle, WA 981959472 Fiscal Year: 2007 Department: Radiology Project Start: 22-Sep-2004 Project End: 31-Aug-2009 ICD: National Heart, Lung, And Blood Institute IRG: ZHL1

3T ATHEROSCLEROTIC MRI AND CAROTID SCORING SYSTEM Grant Number: 5R01HL056874-13 Yuan, Chun Abstract: Description (provided by applicant): According to the National Center for Health Statistics, cardiovascular disease is the leading cause of death in the U.S. Over 70% of these deaths are related to atherosclerosis, and atherosclerotic cerebrovascular disease is a leading cause of death and major disability among adults. Thrombolic events originating in the

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bifurcation region of the carotid artery are a major cause of stroke. Currently some 140,000 carotid endarterectomy (CEA) surgeries are performed annually in the U.S. to prevent these events. A non-invasive, lower-cost alternative will be developed at University of Washington’s Vascular Imaging Lab (VIL). The purpose of our research is to develop such a non-invasive imaging tool that can identify and characterize the features of carotid atherosclerotic plaque that signal imminent rapid lesion progression and ischemic complications. The specific aims are to: 1. Optimize MRI techniques for probing the luminal surface conditions and tissue composition of atherosclerotic carotid arteries on 3 T. 2. Develop an MRIbased carotid artery scoring (CAS) system based on luminal and juxtaluminal surface conditions. 3. Optimize the weightings applied to various juxtaluminal characteristics in the CAS system. 4. Test the CAS for predicting progression or ischemic events within enrolled atherosclerotic patients in a prospective study. We will test the hypothesis that juxtaluminal characteristics are the primary determinants of carotid plaque progression and vulnerability to rupture. MRI imaging in combination with non-invasive in vivo histology will provide accurate information on plaque morphology and tissue composition, especially at the boundaries of the vessel wall and lumen. Improved methods of identifying high-risk plaques will result in: 1) better selection of patients for intervention; 2) development of an accurate, reproducible, and quantitative technique for directly assessing the status and progression of atherosclerotic lesions, significantly reducing the cost of clinical trials; 3) a unique opportunity to examine the processes involved in the progression from a stable lesion to vulnerable plaque. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: There are no thesaurus terms on file for this project. Institution: University Of Washington Office Of Sponsored Programs Seattle, Wa 981959472 Fiscal Year: 2009 Department: Radiology Project Start: 01-Aug-1996 Project End: 31-May-2010 ICD: National Heart, Lung, And Blood Institute IRG: MEDI

QUANTIFICATION OF REGIONAL MYOCARDIAL OXYGENATION BY MRI Grant Number: 5R01HL074019-04 Zheng, Jie Abstract: Description (provided by applicant): Coronary artery disease (CAD) is the leading cause of death in industrialized nations. Under normal physiological conditions, myocardial blood flow, oxygen consumption (MVO2), myocardial blood volume, and myocardial mechanical e175

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function are intimately related. CAD manifests as imbalances between myocardial oxygen supply and demand. Myocardial oxygen extraction fraction (OEF) and MVO2 directly reflects the balance of oxygen supply and demand of myocardium. Accurate assessment of myocardial ischemic status, particularly myocardial viability, is of paramount importance for selection of patients likely to benefit from coronary revascularization. However, detection of this status in myocardium remains an important clinical problem, partially owning to the inherent difficulty of direct measurement of OEF and MVO2 in vivo, particularly on a non-invasive and regional basis. In this proposal, it is hypothesized that myocardial OEF and MVO2 can be quantified using non-invasive magnetic resonance imaging (MRI) techniques and the BOLD (Blood Oxygen Level Dependent) effect. The later can be characterized by transverse relaxation time T2 contrast in MRI. Therefore, our overall objective is to optimize and validate a series of clinically viable MRI techniques to measure myocardial OEF and MVO2 reliably and consistently. Measurement of MVO2 is based on Pick’s law: MVO2 is proportional to the product of myocardial OEF and blood flow. To validate the proposed techniques by invasive methods, we propose to use a closed-chest canine model. The goal of the application will be accomplished by pursuing the following three specific aims. In Aim 1, a first-pass perfusion method will be further optimized with an established mathematical modeling. This MRI method will be used to measure myocardial blood flow and volume at rest and during pharmacologically induced stress. Accuracy will be determined by comparing with gold standards such as microsphere for blood flow measurements and 99mTc-labeled red blood cells for blood volume measurement. In Aim 2, established techniques for measuring myocardial OEF will be further optimized and validated in vivo. The gold standard will be simultaneous blood sampling from artery and coronary sinus. These optimized techniques will be integrated in Aim 3 to calculate myocardial OEF and MVO2 in dogs with and without coronary artery stenosis, at rest and during pharmacological stress. Validation will be performed by comparison to PET imaging. This MRI research will provide an important tool for better understanding the physiology and pathophysiology underlying the myocardial ischemia and viability. In addition, this direct measurement may offer an objective and convenient means to assess the efficacy of cardiac therapies. Ultimately, the proposed methods may facilitate more comprehensive MRI assessments of CAD and other cardiac diseases. Public Health Relevance: This Public Health Relevance is not available. Thesaurus Terms: blood volume, heart disorder diagnosis, heart imaging /visualization /scanning, magnetic resonance imaging, method development, myocardial ischemia /hypoxia, oxygen consumption artery stenosis, coronary artery, disease /disorder model, mathematical model, radiotracer bioimaging /biomedical imaging, blood flow measurement, dog, perfusion, positron emission tomography

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Institution:

Washington University 1 Brookings Dr, Campus Box 1054 Saint Louis, MO 631304899 Fiscal Year: 2008 Department: Radiology Project Start: 01-Apr-2005 Project End: 31-Mar-2010 ICD: National Heart, Lung, And Blood Institute IRG: MEDI

IMAGING STEM CELL GRAFTED IN THE INFARCTED MYOCARDIUM Grant Number: 5R01HL081185-02 Zhou, Rong Abstract: Description (provided by applicant): Stem cell therapy for myocardial infarction has been proposed as a restorative therapy to limit progressive remodeling. However, its therapeutic benefit is still controversial largely because most studies failed to account for the variations in the initial infarct size and the extent of ventricular remodeling on the therapeutic outcome; the fate (survival and differentiation status) of the grafted cells is not clear either. Therefore, the overall goal of this proposal is to develop a multi-modality non-invasive imaging approach to best assess these critical parameters. This system would allow assessment of the survival and differentiation of grafted stem cells longitudinally in the same animals, on which the extent of initial impairment and experimental recovery are evaluated. Specifically, two reporter genes (one for cell survival and the other for differentiation) will be introduced: the survival marker is always ‘‘on’’ as long as the cell is alive, whereas the differentiation marker is NOT turned on until the cardiac differentiation occurs in the cell. After stem cells are grafted, survival fraction will be quantified by the expression of the reporter gene associated with the surviving cells, using radionuclide imaging (PET) while cardiac differentiation of these cells will be detected / monitored by optical imaging. Tagged or displacement encoded MRI will be used to quantify the regional myocardial contractile function and to document the functional loss or gain during LV remodeling in response to stem cell grafting. This strategy aims to maximize the sensitivity and spatial resolution necessary for specific measurements. By using these imaging modalities in concert, a cohesive picture of stem cell survival, differentiation in the infarcted myocardium and their therapeutic benefits will be obtained to address critical issues regarding the fate and therapeutic mechanism of stem cells, i.e., do the grafted cells contribute to the improvement of contractile function or they primarily provide structural support to ‘‘stiffen’’ the infarcted heart wall, thus reduce the wall-stress? Public Health Relevance: This Public Health Relevance is not available.

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Thesaurus Terms: cardiovascular disorder diagnosis, cardiovascular disorder therapy, heart imaging /visualization /scanning, molecular /cellular imaging, myocardial infarction, nonhuman therapy evaluation, noninvasive diagnosis, stem cell transplantation cardiac myocyte, cell differentiation, cell population study, disease /disorder model, embryonic stem cell, functional ability, heart contraction, hematopoietic stem cell, image processing, postoperative state, reporter gene bioimaging /biomedical imaging, laboratory rat, magnetic resonance imaging, positron emission tomography

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Institution:

University Of Pennsylvania 3451 Walnut Street Philadelphia, PA 19104 Fiscal Year: 2007 Department: Radiology Project Start: 01-Apr-2006 Project End: 31-Mar-2010 ICD: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE IRG: MEDI

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