Michael V. McConnell, MD, MSEE

All Publications

• CANDI: an R package and Shiny app for annotating radiographs and evaluating Computer-Aided Diagnosis. Bioinformatics (Oxford, England) Badgeley, M. A., Liu, M., Glicksberg, B. S., Shervey, M., Zech, J., Shameer, K., Lehar, J., Oermann, E. K., McConnell, M. V., Snyder, T. M., Dudley, J. T. 2018

  Abstract

  Motivation: Radiologists have used algorithms for Computer-Aided Diagnosis (CAD) for decades. These algorithms use machine learning with engineered features, and there have been mixed findings on whether they improve radiologists' interpretations. Deep learning offers superior performance, but requires more training data and has not been evaluated in joint algorithm-radiologist decision systems.Results: We developed the Computer-Aided Note and Diagnosis Interface (CANDI) for collaboratively annotating radiographs and evaluating how algorithms alter human interpretation. The annotation app collects classification, segmentation, and image captioning training data, and the evaluation app randomizes the availability of CAD tools to facilitate clinical trials on radiologist enhancement.Availability: Demonstrations and source code are hosted at {{https://candi.nextgenhealthcare.org}}, and {{https://github.com/mbadge/candi}}, respectively, under GPL-3 license.Supplementary information: We demonstrate CANDI with chest x-ray datasets and deep learning models for cardiopulmonary diseases. In the online Supplement we describe these datasets, data security, and model training and performance evaluation.

  View details for DOI 10.1093/bioinformatics/bty855

  View details for PubMedID 30304439

• Mobile Health Advances in Physical Activity, Fitness, and Atrial Fibrillation Moving Hearts JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY McConnell, M. V., Turakhia, M. P., Harrington, R. A., King, A. C., Ashley, E. A. 2018; 71 (23): 2691–2701

  Abstract

  The growing recognition that "health" takes place outside of the hospital and clinic, plus recent advances in mobile and wearable devices, have propelled the field of mobile health (mHealth). Cardiovascular disease and prevention are major opportunities for mHealth, as mobile devices can monitor key physiological signals (e.g., physical activity, heart rate and rhythm) for promoting healthy behaviors, detecting disease, and aid in ongoing care. In this review, the authors provide an update on cardiovascular mHealth by highlighting recent progress and challenges with mobile and wearable devices for assessing and promoting physical activity and fitness, and for monitoring heart rate and rhythm for the detection and management of atrial fibrillation.

  View details for DOI 10.1016/j.jacc.2018.04.030

  View details for Web of Science ID 000434924500013

  View details for PubMedID 29880130

• A Dual-Modality Hybrid Imaging System Harnesses Radioluminescence and Sound to Reveal Molecular Pathology of Atherosclerotic Plaques SCIENTIFIC REPORTS Zaman, R. T., Yousefi, S., Long, S. R., Saito, T., Mandella, M., Qiu, Z., Chen, R., Contag, C. H., Gambhir, S. S., Chin, F. T., Khuri-Yakub, B. T., McConnell, M. V., Shung, K., Xing, L. 2018; 8: 8992

  Abstract

  Atherosclerosis is a progressive inflammatory condition caused by an unstable lesion, called thin-cap fibro atheromata (TCFA) that underlies coronary artery disease (CAD)-one of the leading causes of death worldwide. Therefore, early clinical diagnosis and effective risk stratification is important for CAD management as well as preventing progression to catastrophic events. However, early detection could be difficult due to their small size, motion, obscuring 18F-FDG uptake by adjacent myocardium, and complex morphological/biological features. To overcome these limitations, we developed a catheter-based Circumferential-Intravascular-Radioluminescence-Photoacoustic-Imaging (CIRPI) system that can detect vulnerable plaques in coronary arteries and characterizes them with respect to pathology and biology. Our CIRPI system combined two imaging modalities: Circumferential Radioluminescence Imaging (CRI) and PhotoAcoustic Tomography (PAT) within a novel optical probe. The probe's CaF2:Eu based scintillating imaging window provides a 360° view of human (n = 7) and murine carotid (n = 10) arterial plaques by converting β-particles into visible photons during 18F-FDG decay. A 60× and 63× higher radioluminescent signals were detected from the human and murine plaque inflammations, respectively, compared to the control. The system's photoacoustic imaging provided a comprehensive analysis of the plaque compositions and its morphologic information. These results were further verified with IVIS-200, immunohistochemical analysis, and autoradiography.

  View details for DOI 10.1038/s41598-018-26696-8

  View details for Web of Science ID 000434921300001

  View details for PubMedID 29895966

  View details for PubMedCentralID PMC5997702

• Prediction of cardiovascular risk factors from retinal fundus photographs via deep learning NATURE BIOMEDICAL ENGINEERING Poplin, R., Varadarajan, A. V., Blumer, K., Liu, Y., McConnell, M. V., Corrado, G. S., Peng, L., Webster, D. R. 2018; 2 (3): 158–64

  View details for DOI 10.1038/s41551-018-0195-0

  View details for Web of Science ID 000435464800008

• Imaging cellular pharmacokinetics of F-18-FDG and 6-NBDG uptake by inflammatory and stem cells PLOS ONE Zaman, R. T., Tuerkcan, S., Mahmoudi, M., Saito, T., Yang, P. C., Chin, F. T., McConnell, M. V., Xing, L. 2018; 13 (2): e0192662

  Abstract

  Myocardial infarction (MI) causes significant loss of cardiomyocytes, myocardial tissue damage, and impairment of myocardial function. The inability of cardiomyocytes to proliferate prevents the heart from self-regeneration. The treatment for advanced heart failure following an MI is heart transplantation despite the limited availability of the organs. Thus, stem-cell-based cardiac therapies could ultimately prevent heart failure by repairing injured myocardium that reverses cardiomyocyte loss. However, stem-cell-based therapies lack understanding of the mechanisms behind a successful therapy, including difficulty tracking stem cells to provide information on cell migration, proliferation and differentiation. In this study, we have investigated the interaction between different types of stem and inflammatory cells and cell-targeted imaging molecules, 18F-FDG and 6-NBDG, to identify uptake patterns and pharmacokinetics in vitro.Macrophages (both M1 and M2), human induced pluripotent stem cells (hiPSCs), and human amniotic mesenchymal stem cells (hAMSCs) were incubated with either 18F-FDG or 6-NBDG. Excess radiotracer and fluorescence were removed and a 100 μm-thin CdWO4 scintillator plate was placed on top of the cells for radioluminescence microscopy imaging of 18F-FDG uptake, while no scintillator was needed for fluorescence imaging of 6-NBDG uptake. Light produced following beta decay was imaged with a highly sensitive inverted microscope (LV200, Olympus) and an Electron Multiplying Charge-Couple Device (EM-CCD) camera. Custom-written software was developed in MATLAB for image processing.The average cellular activity of 18F-FDG in a single cell of hAMSCs (0.670±0.028 fCi/μm2, P = 0.001) was 20% and 36% higher compared to uptake in hiPSCs (0.540±0.026 fCi/μm2, P = 0.003) and macrophages (0.430±0.023 fCi/μm2, P = 0.002), respectively. hAMSCs exhibited the slowest influx (0.210 min-1) but the fastest efflux (0.327 min-1) rate compared to the other tested cell lines for 18F-FDG. This cell line also has the highest phosphorylation but exhibited the lowest rate of de-phosphorylation. The uptake pattern for 6-NBDG was very different in these three cell lines. The average cellular activity of 6-NBDG in a single cell of macrophages (0.570±0.230 fM/μm2, P = 0.004) was 38% and 14% higher compared to hiPSCs (0.350±0.160 fM/μm2, P = 0.001) and hAMSCs (0.490±0.028 fM/μm2, P = 0.006), respectively. The influx (0.276 min-1), efflux (0.612 min-1), phosphorylation (0.269 min-1), and de-phosphorylation (0.049 min-1) rates were also highest for macrophages compared to the other two tested cell lines.hAMSCs were found to be 2-3× more sensitive to 18F-FDG molecule compared to hiPSCs/macrophages. However, macrophages exhibited the most sensitivity towards 6-NBDG. Based on this result, hAMSCs targeted with 18F-FDG could be more suitable for understanding the mechanisms behind successful therapy for treating MI patients by gathering information on cell migration, proliferation and differentiation.

  View details for DOI 10.1371/journal.pone.0192662

  View details for Web of Science ID 000425554200021

  View details for PubMedID 29462173

  View details for PubMedCentralID PMC5819797

• Dose-Dependent Cardioprotection of Moderate (32°C) Versus Mild (35°C) Therapeutic Hypothermia in Porcine Acute Myocardial Infarction. JACC. Cardiovascular interventions Dash, R., Mitsutake, Y., Pyun, W. B., Dawoud, F., Lyons, J., Tachibana, A., Yahagi, K., Matsuura, Y., Kolodgie, F. D., Virmani, R., McConnell, M. V., Illindala, U., Ikeno, F., Yeung, A. 2018; 11 (2): 195–205

  Abstract

  The study investigated whether a dose response exists between myocardial salvage and the depth of therapeutic hypothermia.Cardiac protection from mild hypothermia during acute myocardial infarction (AMI) has yielded equivocal clinical trial results. Rapid, deeper hypothermia may improve myocardial salvage.Swine (n = 24) undergoing AMI were assigned to 3 reperfusion groups: normothermia (38°C) and mild (35°C) and moderate (32°C) hypothermia. One-hour anterior myocardial ischemia was followed by rapid endovascular cooling to target reperfusion temperature. Cooling began 30 min before reperfusion. Target temperature was reached before reperfusion and was maintained for 60 min. Infarct size (IS) was assessed on day 6 using cardiac magnetic resonance, triphenyl tetrazolium chloride, and histopathology.Triphenyl tetrazolium chloride area at risk (AAR) was equivalent in all groups (p = 0.2), but 32°C exhibited 77% and 91% reductions in IS size per AAR compared with 35°C and 38°C, respectively (AAR: 38°C, 45 ± 12%; 35°C, 17 ± 10%; 32°C, 4 ± 4%; p < 0.001) and comparable reductions per LV mass (LV mass: 38°C, 14 ± 5%; 35°C, 5 ± 3%; 32°C 1 ± 1%; p < 0.001). Importantly, 32°C showed a lower IS AAR (p = 0.013) and increased immunohistochemical granulation tissue versus 35°C, indicating higher tissue salvage. Delayed-enhancement cardiac magnetic resonance IS LV also showed marked reduction at 32°C (38°C: 10 ± 4%, p < 0.001; 35°C: 8 ± 3%; 32°C: 3 ± 2%, p < 0.001). Cardiac output on day 6 was only preserved at 32°C (reduction in cardiac output: 38°C, -29 ± 19%, p = 0.041; 35°C: -17 ± 33%; 32°C: -1 ± 28%, p = 0.041). Using linear regression, the predicted IS reduction was 6.7% (AAR) and 2.1% (LV) per every 1°C reperfusion temperature decrease.Moderate (32°C) therapeutic hypothermia demonstrated superior and near-complete cardioprotection compared with 35°C and control, warranting further investigation into clinical applications.

  View details for DOI 10.1016/j.jcin.2017.08.056

  View details for PubMedID 29348013

  View details for PubMedCentralID PMC5777183

• RGD targeting of human ferritin iron oxide nanoparticles enhances in vivo MRI of vascular inflammation and angiogenesis in experimental carotid disease and abdominal aortic aneurysm JOURNAL OF MAGNETIC RESONANCE IMAGING Kitagawa, T., Kosuge, H., Uchida, M., Iida, Y., Dalman, R. L., Douglas, T., McConnell, M. V. 2017; 45 (4): 1144-1153

  View details for DOI 10.1002/jmri.25459

  View details for Web of Science ID 000397489100020

• The Changing Face of Informed Consent NEW ENGLAND JOURNAL OF MEDICINE Grady, C., Cummings, S. R., Rowbotham, M. C., McConnell, M. V., Ashley, E. A., Kang, G. 2017; 376 (9): 856-867

  View details for Web of Science ID 000395627500009

• The Use of Smartphones for Health Research ACADEMIC MEDICINE Dorsey, E. R., Chan, Y. Y., McConnell, M. V., Shaw, S. Y., Trister, A. D., Friend, S. H. 2017; 92 (2): 157-160

  View details for DOI 10.1097/ACM.0000000000001205

  View details for Web of Science ID 000393677800015

• Investigating the value of right heart echocardiographic metrics for detection of pulmonary hypertension in patients with advanced lung disease. The international journal of cardiovascular imaging Amsallem, M., Boulate, D., Kooreman, Z., Zamanian, R. T., Fadel, G., Schnittger, I., Fadel, E., McConnell, M. V., Dhillon, G., Mercier, O., Haddad, F. 2017

  Abstract

  This study determined whether novel right heart echocardiography metrics help to detect pulmonary hypertension (PH) in patients with advanced lung disease (ALD). We reviewed echocardiography and catheterization data of 192 patients from the Stanford ALD registry and echocardiograms of 50 healthy controls. Accuracy of echocardiographic right heart metrics to detect PH was assessed using logistic regression and area under the ROC curves (AUC) analysis. Patients were divided into a derivation (n = 92) and validation cohort (n = 100). Experimental validation was assessed in a piglet model of mild PH followed longitudinally. Tricuspid regurgitation (TR) was not interpretable in 52% of patients. In the derivation cohort, right atrial maximal volume index (RAVI), ventricular end-systolic area index (RVESAI), free-wall longitudinal strain and tricuspid annular plane systolic excursion (TAPSE) differentiated patients with and without PH; 20% of patients without PH had moderate to severe RV enlargement by RVESAI. On multivariate analysis, RAVI and TAPSE were independently associated with PH (AUC = 0.77, p < 0.001), which was confirmed in the validation cohort (0.78, p < 0.001). Presence of right heart metrics abnormalities did not improve detection of PH in patients with interpretable TR (p > 0.05) and provided moderate detection value in patients without TR. Only two patients with more severe PH (mean pulmonary pressure 35 and 36 mmHg) were missed. The animal model confirmed that right heart enlargement discriminated best pigs with PH from shams. This study highlights the frequency of right heart enlargement and dysfunction in ALD irrespectively from presence of PH, therefore limiting their use for detection of PH.

  View details for DOI 10.1007/s10554-017-1069-3

  View details for PubMedID 28120156

• Dual-Modality Activity-Based Probes as Molecular Imaging Agents for Vascular Inflammation JOURNAL OF NUCLEAR MEDICINE Withana, N. P., Saito, T., Ma, X., Garland, M., Liu, C., Kosuge, H., Amsallem, M., Verdoes, M., Ofori, L. O., Fischbein, M., Arakawa, M., Cheng, Z., McConnell, M. V., Bogyo, M. 2016; 57 (10): 1583-1590

  Abstract

  Macrophages are cellular mediators of vascular inflammation and are involved in the formation of atherosclerotic plaques. These immune cells secrete proteases such as matrix metalloproteinases and cathepsins that contribute to disease formation and progression. Here, we demonstrate that activity-based probes (ABPs) targeting cysteine cathepsins can be used in murine models of atherosclerosis to noninvasively image activated macrophage populations using both optical and PET/CT methods. The probes can also be used to topically label human carotid plaques demonstrating similar specific labeling of activated macrophage populations.Macrophage-rich carotid lesions were induced in FVB mice fed on a high-fat diet by streptozotocin injection followed by ligation of the left common carotid artery. Mice with carotid atherosclerotic plaques were injected with the optical or dual-modality probes BMV109 and BMV101, respectively, via the tail vein and noninvasively imaged by optical and small-animal PET/CT at different time points. After noninvasive imaging, the murine carotid arteries were imaged in situ and ex vivo, followed by immunofluorescence staining to confirm target labeling. Additionally, human carotid plaques were topically labeled with the probe and analyzed by both sodium dodecyl sulfate polyacrylamide gel electrophoresis and immunofluorescence staining to confirm the primary targets of the probe.Quantitative analysis of the signal intensity from both optical and PET/CT imaging showed significantly higher levels of accumulation of BMV109 and BMV101 (P < 0.005 and P < 0.05, respectively) in the ligated left carotid arteries than the right carotid or healthy arteries. Immunofluorescence staining for macrophages in cross-sectional slices of the murine artery demonstrated substantial infiltration of macrophages in the neointima and adventitia of the ligated left carotid arteries compared with the right. Analysis of the human plaque tissues by sodium dodecyl sulfate polyacrylamide gel electrophoresis confirmed that the primary targets of the probe were cathepsins X, B, S, and L. Immunofluorescence labeling of the human tissue with the probe demonstrated colocalization of the probe with CD68, elastin, and cathepsin S, similar to that observed in the experimental carotid inflammation murine model.We demonstrate that ABPs targeting the cysteine cathepsins can be used in murine models of atherosclerosis to noninvasively image activated macrophage populations using both optical and PET/CT methods. The probes could also be used to topically label human carotid plaques demonstrating similar specific labeling of activated macrophage populations. Therefore, ABPs targeting the cysteine cathepsins are potentially valuable new reagents for rapid and noninvasive imaging of atherosclerotic disease progression and plaque vulnerability.

  View details for DOI 10.2967/jnumed.115.171553

  View details for Web of Science ID 000384961900024

  View details for PubMedID 27199363

  View details for PubMedCentralID PMC5367444

• RGD targeting of human ferritin iron oxide nanoparticles enhances in vivo MRI of vascular inflammation and angiogenesis in experimental carotid disease and abdominal aortic aneurysm. Journal of magnetic resonance imaging : JMRI Kitagawa, T., Kosuge, H., Uchida, M., Iida, Y., Dalman, R. L., Douglas, T., McConnell, M. V. 2016

  Abstract

  To evaluate Arg-Gly-Asp (RGD)-conjugated human ferritin (HFn) iron oxide nanoparticles for in vivo magnetic resonance imaging (MRI) of vascular inflammation and angiogenesis in experimental carotid disease and abdominal aortic aneurysm (AAA).HFn was genetically engineered to express the RGD peptide and Fe3 O4 nanoparticles were chemically synthesized inside the engineered HFn (RGD-HFn). Macrophage-rich left carotid lesions were induced by ligation in FVB mice made hyperlipidemic and diabetic (n = 14), with the contralateral right carotid serving as control. Murine AAAs were created by continuous angiotensin II infusion in ApoE-deficient mice (n = 12), while control mice underwent saline infusion (n = 8). All mice were imaged before and after intravenous injection with either RGD-HFn-Fe3 O4 or HFn-Fe3 O4 using a gradient-echo sequence on a whole-body 3T clinical scanner, followed by histological analysis. The nanoparticle accumulation was assessed by the extent of T2*-induced carotid lumen reduction (% lumen loss) or aortic T2*-weighted signal intensity reduction (% SI [signal intensity] loss).RGD-HFn-Fe3 O4 was taken up more than HFn-Fe3 O4 in both the ligated left carotid arteries (% lumen loss; 69 ± 9% vs. 36 ± 7%, P = 0.01) and AAAs (% SI loss; 47 ± 6% vs. 20 ± 5%, P = 0.01). The AAA % SI loss correlated positively with AAA size (r = 0.89, P < 0.001). Histology confirmed the greater accumulation and colocalization of RGD-HFn-Fe3 O4 to both vascular macrophages and endothelial cells.RGD-HFn-Fe3 O4 enhances in vivo MRI by targeting both vascular inflammation and angiogenesis, and provides a promising translatable MRI approach to detect high-risk atherosclerotic and aneurysmal vascular diseases.1 J. Magn. Reson. Imaging 2016.

  View details for DOI 10.1002/jmri.25459

  View details for PubMedID 27689830

• Multimodality Molecular Imaging of Cardiac Cell Transplantation: Part I. Reporter Gene Design, Characterization, and Optical in Vivo Imaging of Bone Marrow Stromal Cells after Myocardial Infarction. Radiology Parashurama, N., Ahn, B., Ziv, K., Ito, K., Paulmurugan, R., Willmann, J. K., Chung, J., Ikeno, F., Swanson, J. C., Merk, D. R., Lyons, J. K., Yerushalmi, D., Teramoto, T., Kosuge, H., Dao, C. N., Ray, P., Patel, M., Chang, Y., Mahmoudi, M., Cohen, J. E., Goldstone, A. B., Habte, F., Bhaumik, S., Yaghoubi, S., Robbins, R. C., Dash, R., Yang, P. C., Brinton, T. J., Yock, P. G., McConnell, M. V., Gambhir, S. S. 2016; 280 (3): 815-825

  Abstract

  Purpose To use multimodality reporter-gene imaging to assess the serial survival of marrow stromal cells (MSC) after therapy for myocardial infarction (MI) and to determine if the requisite preclinical imaging end point was met prior to a follow-up large-animal MSC imaging study. Materials and Methods Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. Mice (n = 19) that had experienced MI were injected with bone marrow-derived MSC that expressed a multimodality triple fusion (TF) reporter gene. The TF reporter gene (fluc2-egfp-sr39ttk) consisted of a human promoter, ubiquitin, driving firefly luciferase 2 (fluc2), enhanced green fluorescent protein (egfp), and the sr39tk positron emission tomography reporter gene. Serial bioluminescence imaging of MSC-TF and ex vivo luciferase assays were performed. Correlations were analyzed with the Pearson product-moment correlation, and serial imaging results were analyzed with a mixed-effects regression model. Results Analysis of the MSC-TF after cardiac cell therapy showed significantly lower signal on days 8 and 14 than on day 2 (P = .011 and P = .001, respectively). MSC-TF with MI demonstrated significantly higher signal than MSC-TF without MI at days 4, 8, and 14 (P = .016). Ex vivo luciferase activity assay confirmed the presence of MSC-TF on days 8 and 14 after MI. Conclusion Multimodality reporter-gene imaging was successfully used to assess serial MSC survival after therapy for MI, and it was determined that the requisite preclinical imaging end point, 14 days of MSC survival, was met prior to a follow-up large-animal MSC study. (©) RSNA, 2016 Online supplemental material is available for this article.

  View details for DOI 10.1148/radiol.2016140049

  View details for PubMedID 27308957

  View details for PubMedCentralID PMC5006716

• Multimodality Molecular Imaging of Cardiac Cell Transplantation: Part II. In Vivo Imaging of Bone Marrow Stromal Cells in Swine with PET/CT and MR Imaging. Radiology Parashurama, N., Ahn, B., Ziv, K., Ito, K., Paulmurugan, R., Willmann, J. K., Chung, J., Ikeno, F., Swanson, J. C., Merk, D. R., Lyons, J. K., Yerushalmi, D., Teramoto, T., Kosuge, H., Dao, C. N., Ray, P., Patel, M., Chang, Y., Mahmoudi, M., Cohen, J. E., Goldstone, A. B., Habte, F., Bhaumik, S., Yaghoubi, S., Robbins, R. C., Dash, R., Yang, P. C., Brinton, T. J., Yock, P. G., McConnell, M. V., Gambhir, S. S. 2016; 280 (3): 826-836

  Abstract

  Purpose To quantitatively determine the limit of detection of marrow stromal cells (MSC) after cardiac cell therapy (CCT) in swine by using clinical positron emission tomography (PET) reporter gene imaging and magnetic resonance (MR) imaging with cell prelabeling. Materials and Methods Animal studies were approved by the institutional administrative panel on laboratory animal care. Seven swine received 23 intracardiac cell injections that contained control MSC and cell mixtures of MSC expressing a multimodality triple fusion (TF) reporter gene (MSC-TF) and bearing superparamagnetic iron oxide nanoparticles (NP) (MSC-TF-NP) or NP alone. Clinical MR imaging and PET reporter gene molecular imaging were performed after intravenous injection of the radiotracer fluorine 18-radiolabeled 9-[4-fluoro-3-(hydroxyl methyl) butyl] guanine ((18)F-FHBG). Linear regression analysis of both MR imaging and PET data and nonlinear regression analysis of PET data were performed, accounting for multiple injections per animal. Results MR imaging showed a positive correlation between MSC-TF-NP cell number and dephasing (dark) signal (R(2) = 0.72, P = .0001) and a lower detection limit of at least approximately 1.5 × 10(7) cells. PET reporter gene imaging demonstrated a significant positive correlation between MSC-TF and target-to-background ratio with the linear model (R(2) = 0.88, P = .0001, root mean square error = 0.523) and the nonlinear model (R(2) = 0.99, P = .0001, root mean square error = 0.273) and a lower detection limit of 2.5 × 10(8) cells. Conclusion The authors quantitatively determined the limit of detection of MSC after CCT in swine by using clinical PET reporter gene imaging and clinical MR imaging with cell prelabeling. (©) RSNA, 2016 Online supplemental material is available for this article.

  View details for DOI 10.1148/radiol.2016151150

  View details for PubMedID 27332865

  View details for PubMedCentralID PMC5006717

• Defining a Mobile Health Roadmap for Cardiovascular Health and Disease. Journal of the American Heart Association Eapen, Z. J., Turakhia, M. P., McConnell, M. V., Graham, G., Dunn, P., Tiner, C., Rich, C., Harrington, R. A., Peterson, E. D., Wayte, P. 2016; 5 (7)

  View details for DOI 10.1161/JAHA.115.003119

  View details for PubMedID 27405809

  View details for PubMedCentralID PMC5015362

• Magnetic Resonance Imaging and Positron Emission Tomography Approaches to Imaging Vascular and Cardiac Inflammation CIRCULATION JOURNAL Amsallem, M., Saito, T., Tada, Y., Dash, R., McConnell, M. V. 2016; 80 (6): 1269-1277

  Abstract

  Inflammation plays a significant role in a wide range of cardiovascular diseases (CVDs). The numerous implications of inflammation in all steps of CVDs, including initiation, progression and complications, have prompted the emergence of noninvasive imaging modalities as diagnostic, prognostic and monitoring tools. In this review, we first synthesize the existing evidence on the role of inflammation in vascular and cardiac diseases, in order to identify the main targets used in noninvasive imaging. We chose to focus on positron emission tomographic (PET) and magnetic resonance imaging (MRI) studies, which offer the greatest potential of translation and clinical application. We detail the main preclinical and clinical studies in the following CVDs: coronary and vascular atherosclerosis, abdominal aortic aneurysms, myocardial infarction, myocarditis, and acute heart transplant rejection. We highlight the potential complementary roles of these imaging modalities, which are currently being studied in the emerging technology of PET/MRI. Finally, we provide a perspective on innovations and future applications of noninvasive imaging of cardiovascular inflammation. (Circ J 2016; 80: 1269-1277).

  View details for DOI 10.1253/circj.CJ-16-0224

  View details for Web of Science ID 000377143200001

  View details for PubMedID 27151335

• Inflammatory Markers Associated With Subclinical Coronary Artery Disease: The Multicenter AIDS Cohort Study. Journal of the American Heart Association Bahrami, H., Budoff, M., Haberlen, S. A., Rezaeian, P., Ketlogetswe, K., Tracy, R., Palella, F., Witt, M. D., McConnell, M. V., Kingsley, L., Post, W. S. 2016; 5 (6)

  Abstract

  Despite evidence for higher risk of coronary artery disease among HIV+ individuals, the underlying mechanisms are not well understood. We investigated associations of inflammatory markers with subclinical coronary artery disease in 923 participants of the Multicenter AIDS Cohort Study (575 HIV+ and 348 HIV- men) who underwent noncontrast computed tomography scans for coronary artery calcification, the majority (n=692) also undergoing coronary computed tomography angiography.Outcomes included presence and extent of coronary artery calcification, plus computed tomography angiography analysis of presence, composition, and extent of coronary plaques and severity of coronary stenosis. HIV+ men had significantly higher levels of interleukin-6 (IL-6), intercellular adhesion molecule-1, C-reactive protein, and soluble-tumor necrosis factor-α receptor (sTNFαR) I and II (all P<0.01) and a higher prevalence of noncalcified plaque (63% versus 54%, P=0.02) on computed tomography angiography. Among HIV+ men, for every SD increase in log-interleukin-6 and log intercellular adhesion molecule-1, there was a 30% and 60% increase, respectively, in the prevalence of coronary stenosis ≥50% (all P<0.05). Similarly, sTNFαR I and II in HIV+ participants were associated with an increase in prevalence of coronary stenosis ≥70% (P<0.05). Higher levels of interleukin-6, sTNFαR I, and sTNFαR II were also associated with greater coronary artery calcification score in HIV+ men (P<0.01).Higher inflammatory marker levels are associated with greater prevalence of coronary stenosis in HIV+ men. Our findings underscore the need for further study to elucidate the relationships of inflammatory pathways with coronary artery disease in HIV+ individuals.

  View details for DOI 10.1161/JAHA.116.003371

  View details for PubMedID 27353609

• The Wild Wild West: A Framework to Integrate mHealth Software Applications and Wearables to Support Physical Activity Assessment, Counseling and Interventions for Cardiovascular Disease Risk Reduction PROGRESS IN CARDIOVASCULAR DISEASES Lobelo, F., Kelli, H. M., Tejedor, S. C., Pratt, M., McConnell, M. V., Martin, S. S., Welk, G. J. 2016; 58 (6): 584-594

  Abstract

  Physical activity (PA) interventions constitute a critical component of cardiovascular disease (CVD) risk reduction programs. Objective mobile health (mHealth) software applications (apps) and wearable activity monitors (WAMs) can advance both assessment and integration of PA counseling in clinical settings and support community-based PA interventions. The use of mHealth technology for CVD risk reduction is promising, but integration into routine clinical care and population health management has proven challenging. The increasing diversity of available technologies and the lack of a comprehensive guiding framework are key barriers for standardizing data collection and integration. This paper reviews the validity, utility and feasibility of implementing mHealth technology in clinical settings and proposes an organizational framework to support PA assessment, counseling and referrals to community resources for CVD risk reduction interventions. This integration framework can be adapted to different clinical population needs. It should also be refined as technologies and regulations advance under an evolving health care system landscape in the United States and globally.

  View details for DOI 10.1016/j.pcad.2016.02.007

  View details for Web of Science ID 000376552200003

  View details for PubMedID 26923067

• Characterizing Cathepsin Activity and Macrophage Subtypes in Excised Human Carotid Plaques STROKE Abd-Elrahman, I., Meir, K., Kosuge, H., Ben-Nun, Y., Sadan, T. W., Rubinstein, C., Samet, Y., McConnell, M. V., Blum, G. 2016; 47 (4): 1101-1108

  View details for DOI 10.1161/STROKEAHA.115.011573

  View details for Web of Science ID 000372853200029

• Regional right ventricular dysfunction in acute pulmonary embolism: relationship with clot burden and biomarker profile INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING Tuzovic, M., Adigopula, S., Amsallem, M., Kobayashi, Y., Kadoch, M., Boulate, D., Krishnan, G., Liang, D., Schnittger, I., Fleischmann, D., McConnell, M. V., Haddad, F. 2016; 32 (3): 389-398

  Abstract

  Regional right ventricular (RV) dysfunction (RRVD) is an echocardiographic feature in acute pulmonary embolism (PE), primarily reported in patients with moderate-to-severe RV dysfunction. This study investigated the clinical importance of RRVD by assessing its relationship with clot burden and biomarkers. We identified consecutive patients admitted to the emergency department between 1999 and 2014 who underwent computed tomographic angiography, echocardiography, and biomarker testing (troponin and NT-proBNP) for suspected acute PE. RRVD was defined as normal excursion of the apex contrasting with hypokinesis of the mid-free wall segment. RV assessment included measurements of ventricular dimensions, fractional area change, free-wall longitudinal strain and tricuspid annular plane systolic excursion. Clot burden was assessed using the modified Miller score. Of 82 patients identified, 51 had acute PE (mean age 66 ± 17 years, 43 % male). No patient had RV myocardial infarction. RRVD was present in 41 % of PEs and absent in all patients without PE. Among patients with PE, 86 % of patients with RRVD had central or multi-lobar PE. Patients with RRVD had higher prevalence of moderate-to-severe RV dilation (81 vs. 30 %, p < 0.01) and dysfunction (86 vs. 23 %, p < 0.01). There was a strong trend for higher troponin level in PE patients with RRVD (38 vs. 13 % in PE patients without RRVD, p = 0.08), while there was no significant difference for NT-proBNP (67 vs. 73 %, p = 0.88). RRVD showed good concordance between readers (87 %). RRVD is associated with an increased clot burden in acute PE and is more prevalent among patients with moderate-to-severe RV enlargement and dysfunction.

  View details for DOI 10.1007/s10554-015-0780-1

  View details for Web of Science ID 000370166100003

  View details for PubMedID 26428674

• Twenty-four Hours of Sleep, Sedentary Behavior, and Physical Activity with Nine Wearable Devices. Medicine and science in sports and exercise Rosenberger, M. E., Buman, M. P., Haskell, W. L., McConnell, M. V., Carstensen, L. L. 2016; 48 (3): 457-465

  Abstract

  Getting enough sleep, exercising, and limiting sedentary activities can greatly contribute to disease prevention and overall health and longevity. Measuring the full 24-h activity cycle-sleep, sedentary behavior (SED), light-intensity physical activity (LPA), and moderate-to-vigorous physical activity (MVPA)-may now be feasible using small wearable devices.This study compared nine devices for accuracy in a 24-h activity measurement.Adults (n = 40, 47% male) wore nine devices for 24 h: ActiGraph GT3X+, activPAL, Fitbit One, GENEactiv, Jawbone Up, LUMOback, Nike Fuelband, Omron pedometer, and Z-Machine. Comparisons (with standards) were made for total sleep time (Z-machine), time spent in SED (activPAL), LPA (GT3X+), MVPA (GT3X+), and steps (Omron). Analysis included mean absolute percent error, equivalence testing, and Bland-Altman plots.Error rates ranged from 8.1% to 16.9% for sleep, 9.5% to 65.8% for SED, 19.7% to 28.0% for LPA, 51.8% to 92% for MVPA, and 14.1% to 29.9% for steps. Equivalence testing indicated that only two comparisons were significantly equivalent to standards: the LUMOback for SED and the GT3X+ for sleep. Bland-Altman plots indicated GT3X+ had the closest measurement for sleep, LUMOback for SED, GENEactiv for LPA, Fitbit for MVPA, and GT3X+ for steps.Currently, no device accurately captures activity data across the entire 24-h day, but the future of activity measurement should aim for accurate 24-h measurement as a goal. Researchers should continue to select measurement devices on the basis of their primary outcomes of interest.

  View details for DOI 10.1249/MSS.0000000000000778

  View details for PubMedID 26484953

  View details for PubMedCentralID PMC4760880

• Addressing the Controversy of Estimating Pulmonary Arterial Pressure by Echocardiography JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Amsallem, M., Sternbach, J. M., Adigopula, S., Kobayashi, Y., Vu, T. A., Zamanian, R., Liang, D., Dhillon, G., Schnittger, I., McConnell, M. V., Haddad, F. 2016; 29 (2): 93-102

  Abstract

  There is currently controversy over whether echocardiography provides reliable estimations of pulmonary pressures. The objective of this study was to determine the factors influencing the accuracy and reliability of estimating right ventricular systolic pressure (RVSP) using echocardiography in patients with advanced lung disease or pulmonary arterial hypertension.Between January 2001 and December 2012, 667 patients with advanced lung disease or pulmonary arterial hypertension underwent right heart catheterization and transthoracic echocardiography. Of those, 307 had both studies within 5 days of each other. The correlation and bias in estimating RVSP according to tricuspid regurgitation (TR) signal quality and reader expertise were retrospectively determined. Reasons for under- and overestimation were analyzed. The diagnostic performance of estimated RVSP, relative right ventricular size, eccentricity index, and tricuspid annular plane systolic excursion was compared for classifying patients with pulmonary hypertension (mean pulmonary artery pressure ≥ 25 mm Hg).Invasive mean and systolic pulmonary artery pressures were strongly correlated (R(2) = 0.95, P < .001), with mean pulmonary artery pressure = 0.60 × systolic pulmonary artery pressure + 2.1 mm Hg. Among patients undergoing right heart catheterization and transthoracic echocardiography within 5 days, level 3 readers considered only 61% of TR signals interpretable, compared with 72% in clinical reports. Overestimation in the clinical report was related mainly to not assigning peak TR velocity at the modal frequency and underestimation to overreading of uninterpretable signals. When the TR signal was interpretable, the areas under the curve for classifying pulmonary hypertension were 0.97 for RVSP and 0.98 for RVSP and eccentricity index (P > .05). When TR signals were uninterpretable, eccentricity index and right ventricular size were independently associated with pulmonary hypertension (area under the curve, 0.77).Echocardiography reliably estimates RVSP when attention is given to simple quality metrics.

  View details for DOI 10.1016/j.echo.2015.11.001

  View details for Web of Science ID 000369168700003

• Telmisartan in the diabetic murine model of acute myocardial infarction: dual contrast manganese-enhanced and delayed enhancement MRI evaluation of the peri-infarct region. Cardiovascular diabetology Toma, I., Kim, P. J., Dash, R., McConnell, M. V., Nishimura, D., Harnish, P., Yang, P. C. 2016; 15 (1): 24-?

  Abstract

  A novel MRI technique, employing dual contrast manganese-enhanced MRI (MEMRI) and delayed enhancement MRI (DEMRI), can evaluate the physiologically unstable peri-infarct region. Dual contrast MEMRI-DEMRI enables comprehensive evaluation of telmisartan to salvage the peri-infarct injury to elucidate the underlying mechanism of restoring the ischemic cardiomyopathy in the diabetic mouse model.Dual contrast MEMRI-DEMRI was performed on weeks 1, 2, and 4 following initiation of telmisartan treatment in 24 left anterior descendent artery ligated diabetic mice. The MRI images were analyzed for core infarct, peri-infarct, left ventricular end-diastolic, end-systolic volumes, and the left ventricular ejection fraction (LVEF). Transmission electron microscopy (TEM) and real-time PCR were used for ex vivo analysis of the myocardium. Telmisartan vs. control groups demonstrated significantly improved LVEF at weeks 1, 2, and 4, respectively (33 ± 7 %*** vs. 19 ± 5 %, 29 ± 3 %*** vs. 22 ± 4 %, and 31 ± 2 %*** vs 18 ± 6 %, ***p < 0.001). The control group demonstrated significant differences in the scar volume measured by MEMRI and DEMRI, demonstrating peri-infarct injury. Telmisartan group significantly salvaged the peri-infarct injury. The myocardial effects were validated by TEM, which confirmed the presence of the injured but viable cardiomyocyte morphology in the peri-infarct region and by flow cytometry of venous blood, which demonstrated significantly increased circulating endothelial progenitor cells (EPCs).The improved cardiac function in ischemic cardiomyopathy of diabetic mice by telmisartan is attributed to the attenuation of the peri-infarct injury by the angiogenic effects of EPCs to salvage the injured cardiomyocytes. Dual-contrast MEMRI-DEMRI technique tracked the therapeutic effects of telmisartan on the injured myocardium longitudinally.

  View details for DOI 10.1186/s12933-016-0348-y

  View details for PubMedID 26846539

• Cathepsin Activity-Based Probes and Inhibitor for Preclinical Atherosclerosis Imaging and Macrophage Depletion. PloS one Abd-Elrahman, I., Kosuge, H., Wises Sadan, T., Ben-Nun, Y., Meir, K., Rubinstein, C., Bogyo, M., McConnell, M. V., Blum, G. 2016; 11 (8)

  Abstract

  Cardiovascular disease is the leading cause of death worldwide, mainly due to an increasing prevalence of atherosclerosis characterized by inflammatory plaques. Plaques with high levels of macrophage infiltration are considered "vulnerable" while those that do not have significant inflammation are considered stable; cathepsin protease activity is highly elevated in macrophages of vulnerable plaques and contributes to plaque instability. Establishing novel tools for non-invasive molecular imaging of macrophages in plaques could aid in preclinical studies and evaluation of therapeutics. Furthermore, compounds that reduce the macrophage content within plaques should ultimately impact care for this disease.We have applied quenched fluorescent cathepsin activity-based probes (ABPs) to a murine atherosclerosis model and evaluated their use for in vivo imaging using fluorescent molecular tomography (FMT), as well as ex vivo fluorescence imaging and fluorescent microscopy. Additionally, freshly dissected human carotid plaques were treated with our potent cathepsin inhibitor and macrophage apoptosis was evaluated by fluorescent microscopy.We demonstrate that our ABPs accurately detect murine atherosclerotic plaques non-invasively, identifying cathepsin activity within plaque macrophages. In addition, our cathepsin inhibitor selectively induced cell apoptosis of 55%±10% of the macrophage within excised human atherosclerotic plaques.Cathepsin ABPs present a rapid diagnostic tool for macrophage detection in atherosclerotic plaque. Our inhibitor confirms cathepsin-targeting as a promising approach to treat atherosclerotic plaque inflammation.

  View details for DOI 10.1371/journal.pone.0160522

  View details for PubMedID 27532109

• Acquisition, Analysis, and Sharing of Data in 2015 and Beyond: A Survey of the Landscape A Conference Report From the American Heart Association Data Summit 2015 JOURNAL OF THE AMERICAN HEART ASSOCIATION Antman, E. M., Benjamin, E. J., Harrington, R. A., Houser, S. R., Peterson, E. D., Bauman, M. A., Brown, N., Bufalino, V., Califf, R. M., Creager, M. A., Daugherty, A., DeMets, D. L., Dennis, B. P., Ebadollahi, S., Jessup, M., Lauer, M. S., Lo, B., MacRae, C. A., McConnell, M. V., McCray, A. T., Mello, M. M., Mueller, E., Newburger, J. W., Okun, S., Packer, M., Philippakis, A., Ping, P., Prasoon, P., Roger, V. L., Singer, S., Temple, R., Turner, M. B., Vigilante, K., Warner, J., Wayte, P. 2015; 4 (11)

  View details for DOI 10.1161/JAHA.115.002810

  View details for Web of Science ID 000366615600032

  View details for PubMedID 26541391

• Clinician Innovator: A Novel Career Path in Academic Medicine A Presidentially Commissioned Article From the American Heart Association JOURNAL OF THE AMERICAN HEART ASSOCIATION Majmudar, M. D., Harrington, R. A., Brown, N. J., Graham, G., McConnell, M. V. 2015; 4 (10)

  View details for DOI 10.1161/JAHA.115.001990

  View details for Web of Science ID 000364153000009

  View details for PubMedID 26450117

• Manganese-Enhanced Magnetic Resonance Imaging Enables In Vivo Confirmation of Peri-Infarct Restoration Following Stem Cell Therapy in a Porcine Ischemia-Reperfusion Model. Journal of the American Heart Association Dash, R., Kim, P. J., Matsuura, Y., Ikeno, F., Metzler, S., Huang, N. F., Lyons, J. K., Nguyen, P. K., Ge, X., Foo, C. W., McConnell, M. V., Wu, J. C., Yeung, A. C., Harnish, P., Yang, P. C. 2015; 4 (7)

  Abstract

  The exact mechanism of stem cell therapy in augmenting the function of ischemic cardiomyopathy is unclear. In this study, we hypothesized that increased viability of the peri-infarct region (PIR) produces restorative benefits after stem cell engraftment. A novel multimodality imaging approach simultaneously assessed myocardial viability (manganese-enhanced magnetic resonance imaging [MEMRI]), myocardial scar (delayed gadolinium enhancement MRI), and transplanted stem cell engraftment (positron emission tomography reporter gene) in the injured porcine hearts.Twelve adult swine underwent ischemia-reperfusion injury. Digital subtraction of MEMRI-negative myocardium (intrainfarct region) from delayed gadolinium enhancement MRI-positive myocardium (PIR and intrainfarct region) clearly delineated the PIR in which the MEMRI-positive signal reflected PIR viability. Human amniotic mesenchymal stem cells (hAMSCs) represent a unique population of immunomodulatory mesodermal stem cells that restored the murine PIR. Immediately following hAMSC delivery, MEMRI demonstrated an increased PIR viability signal compared with control. Direct PIR viability remained higher in hAMSC-treated hearts for >6 weeks. Increased PIR viability correlated with improved regional contractility, left ventricular ejection fraction, infarct size, and hAMSC engraftment, as confirmed by immunocytochemistry. Increased MEMRI and positron emission tomography reporter gene signal in the intrainfarct region and the PIR correlated with sustained functional augmentation (global and regional) within the hAMSC group (mean change, left ventricular ejection fraction: hAMSC 85±60%, control 8±10%; P<0.05) and reduced chamber dilatation (left ventricular end-diastole volume increase: hAMSC 24±8%, control 110±30%; P<0.05).The positron emission tomography reporter gene signal of hAMSC engraftment correlates with the improved MEMRI signal in the PIR. The increased MEMRI signal represents PIR viability and the restorative potential of the injured heart. This in vivo multimodality imaging platform represents a novel, real-time method of tracking PIR viability and stem cell engraftment while providing a mechanistic explanation of the therapeutic efficacy of cardiovascular stem cells.

  View details for DOI 10.1161/JAHA.115.002044

  View details for PubMedID 26215972

• Self-Gated Fat-Suppressed Cardiac Cine MRI MAGNETIC RESONANCE IN MEDICINE Ingle, R. R., Santos, J. M., Overall, W. R., McConnell, M. V., Hu, B. S., Nishimura, D. G. 2015; 73 (5): 1764-1774

  Abstract

  To develop a self-gated alternating repetition time balanced steady-state free precession (ATR-SSFP) pulse sequence for fat-suppressed cardiac cine imaging.Cardiac gating is computed retrospectively using acquired magnetic resonance self-gating data, enabling cine imaging without the need for electrocardiogram (ECG) gating. Modification of the slice-select rephasing gradients of an ATR-SSFP sequence enables the acquisition of a one-dimensional self-gating readout during the unused short repetition time (TR). Self-gating readouts are acquired during every TR of segmented, breath-held cardiac scans. A template-matching algorithm is designed to compute cardiac trigger points from the self-gating signals, and these trigger points are used for retrospective cine reconstruction. The proposed approach is compared with ECG-gated ATR-SSFP and balanced steady-state free precession in 10 volunteers and five patients.The difference of ECG and self-gating trigger times has a variability of 13 ± 11 ms (mean ± SD). Qualitative reviewer scoring and ranking indicate no statistically significant differences (P > 0.05) between self-gated and ECG-gated ATR-SSFP images. Quantitative blood-myocardial border sharpness is not significantly different among self-gated ATR-SSFP ( 0.61±0.15 mm -1), ECG-gated ATR-SSFP ( 0.61±0.15 mm -1), or conventional ECG-gated balanced steady-state free precession cine MRI ( 0.59±0.15 mm -1).The proposed self-gated ATR-SSFP sequence enables fat-suppressed cardiac cine imaging at 1.5 T without the need for ECG gating and without decreasing the imaging efficiency of ATR-SSFP. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.

  View details for DOI 10.1002/mrm.25291

  View details for Web of Science ID 000353240600008

  View details for PubMedID 24806049

• Scintillating balloon-enabled fiber-optic system for radionuclide imaging of atherosclerotic plaques. Journal of nuclear medicine Zaman, R. T., Kosuge, H., Carpenter, C., Sun, C., McConnell, M. V., Xing, L. 2015; 56 (5): 771-777

  Abstract

  Atherosclerosis underlies coronary artery disease, the leading cause of death in the United States and worldwide. Detection of coronary plaque inflammation remains challenging. In this study, we developed a scintillating balloon-enabled fiber-optic radionuclide imaging (SBRI) system to improve the sensitivity and resolution of plaque imaging using (18)F-FDG, a marker of vascular inflammation, and tested it in a murine model.The fiber-optic system uses a Complementary Metal-Oxide Silicon (CMOS) camera with a distal ferrule terminated with a wide-angle lens. The novelty of this system is a scintillating balloon in the front of the wide-angle lens to image light from the decay of (18)F-FDG emission signal. To identify the optimal scintillating materials with respect to resolution, we calculated the modulation transfer function of yttrium-aluminum-garnet doped with cerium, anthracene, and calcium fluoride doped with europium (CaF2:Eu) phosphors using an edge pattern and a thin-line optical phantom. The scintillating balloon was then fabricated from 10 mL of silicone RTV catalyst mixed with 1 mL of base and 50 mg of CaF2:Eu per mL. The addition of a lutetium oxyorthosilicate scintillating crystal (500 μm thick) to the balloon was also investigated. The SBRI system was tested in a murine atherosclerosis model: carotid-ligated mice (n = 5) were injected with (18)F-FDG, followed by ex vivo imaging of the macrophage-rich carotid plaques and nonligated controls. Confirmatory imaging of carotid plaques and controls was also performed by an external optical imaging system and autoradiography.Analyses of the different phosphors showed that CaF2:Eu enabled the best resolution of 1.2 μm. The SBRI system detected almost a 4-fold-higher radioluminescence signal from the ligated left carotid artery than the nonligated right carotid: 1.63 × 10(2) ± 4.01 × 10(1) vs. 4.21 × 10(1) ± 2.09 × 10(0) (photon counts), P = 0.006. We found no significant benefit to adding a scintillating crystal to the balloon: 1.65 × 10(2) ± 4.07 × 10(1) vs. 4.44 × 10(1) ± 2.17 × 10(0) (photon counts), P = 0.005. Both external optical imaging and autoradiography confirmed the high signal from the (18)F-FDG in carotid plaques versus controls.This SBRI system provides high-resolution and sensitive detection of (18)F-FDG uptake by murine atherosclerotic plaques.

  View details for DOI 10.2967/jnumed.114.153239

  View details for PubMedID 25858046

• Direct evaluation of myocardial viability and stem cell engraftment demonstrates salvage of the injured myocardium. Circulation research Kim, P. J., Mahmoudi, M., Ge, X., Matsuura, Y., Toma, I., Metzler, S., Kooreman, N. G., Ramunas, J., Holbrook, C., McConnell, M. V., Blau, H., Harnish, P., Rulifson, E., Yang, P. C. 2015; 116 (7): e40-50

  Abstract

  Rationale: The mechanism of functional restoration by stem cell therapy remains poorly under-stood. Novel manganese-enhanced MRI and bioluminescence reporter gene imaging (BLI) were applied to follow myocardial viability and cell engraftment, respectively. Human-placenta-derived amniotic mesenchymal stem cells (AMCs) demonstrate unique immunoregulatory and pre-cardiac properties. In this study, the restorative effects of three AMC-derived sub-populations were exam-ined in a murine myocardial injury model: 1) unselected AMCs (uAMCs), 2) ckit+AMCs (c+AMCs), and 3) AMC-derived iPSCs (MiPSCs). Objective: Determine the differential restorative effects of the AMC-derived sub-populations in the murine myocardial injury model using multi-modality imaging. Methods and Results: SCID mice underwent left anterior descending artery ligation and were divid-ed into 4 treatment arms: 1) normal saline control (n=14), 2) uAMCs (n=10), 3) c+AMCs (n=13), and 4) MiPSCs (n=11). Cardiac MRI assessed myocardial viability and left ventricular (LV) func-tion while BLI assessed stem cell engraftment over a four-week period. Immunohistological label-ing and RT-PCR of the explanted myocardium were performed. The uAMC and c+AMC treated mice demonstrated transient LV functional improvement. However, the MiPSCs exhibited a signifi-cantly greater increase in LV function compared to all the other groups during the entire four-week period. LV functional improvement correlated with increased myocardial viability and sustained stem cell engraftment. The MiPSCs treated animals lacked any evidence of de novo cardiac differ-entiation. Conclusions: The functional restoration seen in MiPSCs was characterized by increased myocardial viability and sustained engraftment without de novo cardiac differentiation, indicating salvage of the injured myocardium.

  View details for DOI 10.1161/CIRCRESAHA.116.304668

  View details for PubMedID 25654979

• A Crack in the Wall: Evolution of a Left Ventricular Apical Pseudoaneurysm. The Canadian journal of cardiology Parikh, R. V., Ahmadi-Kashani, M., Fleischmann, D., Woo, Y. J., McConnell, M. V. 2015

  View details for DOI 10.1016/j.cjca.2015.07.009

  View details for PubMedID 26514751

• miR-24 limits aortic vascular inflammation and murine abdominal aneurysm development NATURE COMMUNICATIONS Maegdefessel, L., Spin, J. M., Raaz, U., Eken, S. M., Toh, R., Azuma, J., Adam, M., Nagakami, F., Heymann, H. M., Chernugobova, E., Jin, H., Roy, J., Hultgren, R., Caidahl, K., Schrepfer, S., Hamsten, A., Eriksson, P., McConnell, M. V., Dalman, R. L., Tsao, P. S. 2014; 5

  Abstract

  Identification and treatment of abdominal aortic aneurysm (AAA) remain among the most prominent challenges in vascular medicine. MicroRNAs (miRNAs) are crucial regulators of cardiovascular pathology and represent intriguing targets to limit AAA expansion. Here we show, by using two established murine models of AAA disease along with human aortic tissue and plasma analysis, that miR-24 is a key regulator of vascular inflammation and AAA pathology. In vivo and in vitro studies reveal chitinase 3-like 1 (Chi3l1) to be a major target and effector under the control of miR-24, regulating cytokine synthesis in macrophages as well as their survival, promoting aortic smooth muscle cell migration and cytokine production, and stimulating adhesion molecule expression in vascular endothelial cells. We further show that modulation of miR-24 alters AAA progression in animal models, and that miR-24 and CHI3L1 represent novel plasma biomarkers of AAA disease progression in humans.

  View details for DOI 10.1038/ncomms6214

  View details for Web of Science ID 000343982800003

  View details for PubMedCentralID PMC4217126

• Continuous wireless pressure monitoring and mapping with ultra-small passive sensors for health monitoring and critical care NATURE COMMUNICATIONS Chen, L. Y., Tee, B. C., Chortos, A. L., Schwartz, G., Tse, V., Lipomi, D. J., Wong, H. P., McConnell, M. V., Bao, Z. 2014; 5

  Abstract

  Continuous monitoring of internal physiological parameters is essential for critical care patients, but currently can only be practically achieved via tethered solutions. Here we report a wireless, real-time pressure monitoring system with passive, flexible, millimetre-scale sensors, scaled down to unprecedented dimensions of 1 × 1 × 0.1 cubic millimeters. This level of dimensional scaling is enabled by novel sensor design and detection schemes, which overcome the operating frequency limits of traditional strategies and exhibit insensitivity to lossy tissue environments. We demonstrate the use of this system to capture human pulse waveforms wirelessly in real time as well as to monitor in vivo intracranial pressure continuously in proof-of-concept mice studies using sensors down to 2.5 × 2.5 × 0.1 cubic millimeters. We further introduce printable wireless sensor arrays and show their use in real-time spatial pressure mapping. Looking forward, this technology has broader applications in continuous wireless monitoring of multiple physiological parameters for biomedical research and patient care.

  View details for DOI 10.1038/ncomms6028

  View details for Web of Science ID 000343935600001

• Fiber-Optic System for Dual-Modality Imaging of Glucose Probes F-18-FDG and 6-NBDG in Atherosclerotic Plaques PLOS ONE Zaman, R. T., Kosuge, H., Pratx, G., Carpenter, C., Xing, L., McConnell, M. V. 2014; 9 (9)

  View details for DOI 10.1371/journal.pone.0108108

  View details for Web of Science ID 000342921200083

• Outcomes after coronary artery calcium and other cardiovascular biomarker testing among asymptomatic medicare beneficiaries. Circulation. Cardiovascular imaging Shreibati, J. B., Baker, L. C., McConnell, M. V., Hlatky, M. A. 2014; 7 (4): 655-662

  Abstract

  Biomarkers improve cardiovascular disease (CVD) risk prediction, but their comparative effectiveness in clinical practice is not known. We sought to compare the use, spending, and clinical outcomes in asymptomatic Medicare beneficiaries evaluated for CVD with coronary artery calcium (CAC) or other cardiovascular risk markers.We used a 20% sample of 2005 to 2011 Medicare claims to identify fee-for-service beneficiaries aged ≥65.5 years with no CVD claims in the previous 6 months. We matched patients with CAC with patients who received high-sensitivity C-reactive protein (hs-CRP; n=8358) or lipid screening (n=6250) using propensity-score methods. CAC was associated with increased noninvasive cardiac testing within 180 days (hazard ratio, 2.22, 95% confidence interval, 1.68-2.93, P<0.001, versus hs-CRP; hazard ratio, 4.30, 95% confidence interval, 3.04-6.06, P<0.001, versus lipid screening) and increased coronary angiography and revascularization. During 3-year follow-up, CAC was associated with higher CVD-related spending ($6525 versus $4432 for hs-CRP, P<0.001; and $6500 versus $3073 for lipid screening, P<0.001) and fewer CVD-related events when compared with hs-CRP (hazard ratio, 0.74, 95% confidence interval, 0.58-0.94, P=0.017) but not compared with lipid screening (hazard ratio, 0.84, 95% confidence interval, 0.64-1.11, P=0.23).CAC testing among asymptomatic Medicare beneficiaries was associated with increased use of cardiac tests and procedures, higher spending, and slightly improved clinical outcomes when compared with hs-CRP testing.

  View details for DOI 10.1161/CIRCIMAGING.113.001869

  View details for PubMedID 24777939

• Assessment of elastin deficit in a marfan mouse aneurysm model using an elastin-specific magnetic resonance imaging contrast agent. Circulation. Cardiovascular imaging Okamura, H., Pisani, L. J., Dalal, A. R., Emrich, F., Dake, B. A., Arakawa, M., Onthank, D. C., Cesati, R. R., Robinson, S. P., Milanesi, M., Kotek, G., Smit, H., Connolly, A. J., Adachi, H., McConnell, M. V., Fischbein, M. P. 2014; 7 (4): 690-696

  Abstract

  -Ascending aortic dissection and rupture remain a life-threatening complication in patients with Marfan syndrome (MFS). The extracellular matrix provides strength and elastic recoil to the aortic wall, thereby preventing radial expansion. We have previously shown that ascending aortic aneurysm formation in Marfan mice (Fbn1(C1039G/+)) is associated with decreased aortic wall elastogenesis and increased elastin breakdown. In this study, we test the feasibility of quantifying aortic wall elastin content using magnetic resonance imaging (MRI) with a gadolinium-based elastin-specific contrast agent (ESMA) in Fbn1(C1039G/+) mice.-Ascending aorta elastin content was measured in 32-week-old Fbn1(C1039G/+) mice and wild-type (WT) (n=9 and n=10, respectively) using 7T MRI with a T1-mapping sequence. Significantly lower enhancement (i.e., lower R1 values, where R1=1/T1) was detected post-ESMA in Fbn1(C1039G/+) compared to WT ascending aortas (1.15±0.07 vs. 1.36±0.05, p<0.05). Post-ESMA R1 values correlated with ascending aortic wall gadolinium content directly measured by inductively coupled mass spectroscopy (p=0.006).-Herein, we demonstrate that MRI with ESMA accurately measures elastin bound gadolinium within the aortic wall and detects a decrease in aortic wall elastin in Marfan mice compared to WT controls. This approach has translational potential for non-invasively assessing aneurysm tissue changes and risk, as well as monitoring elastin content in response to therapeutic interventions.

  View details for DOI 10.1161/CIRCIMAGING.114.001658

  View details for PubMedID 24814820

• Relationship between Echocardiographic and Magnetic Resonance Derived Measures of Right Ventricular Size and Function in Patients with Pulmonary Hypertension. Journal of the American Society of Echocardiography Shiran, H., Zamanian, R. T., McConnell, M. V., Liang, D. H., Dash, R., Heidary, S., Sudini, N. L., Wu, J. C., Haddad, F., Yang, P. C. 2014; 27 (4): 405-412

  Abstract

  Transthoracic echocardiographic (TTE) imaging is the mainstay of clinical practice for evaluating right ventricular (RV) size and function, but its accuracy in patients with pulmonary hypertension has not been well validated.Magnetic resonance imaging (MRI) and TTE images were retrospectively reviewed in 40 consecutive patients with pulmonary hypertension. RV and left ventricular volumes and ejection fractions were calculated using MRI. TTE areas and indices of RV ejection fraction (RVEF) were compared.The average age was 42 ± 12 years, with a majority of women (85%). There was a wide range of mean pulmonary arterial pressures (27-81 mm Hg) and RV end-diastolic volumes (111-576 mL), RVEFs (8%-67 %), and left ventricular ejection fractions (26%-72%) by MRI. There was a strong association between TTE and MRI-derived parameters: RV end-diastolic area (by TTE imaging) and RV end-diastolic volume (by MRI), R(2) = 0.78 (P < .001); RV fractional area change by TTE imaging and RVEF by MRI, R(2) = 0.76 (P < .001); and tricuspid annular plane systolic excursion by TTE imaging and RVEF by MRI, R(2) = 0.64 (P < .001). By receiver operating characteristic curve analysis, an RV fractional area change < 25% provided excellent discrimination of moderate systolic dysfunction (RVEF < 35%), with an area under the curve of 0.97 (P < .001). An RV end-diastolic area index of 18 cm(2)/m(2) provided excellent discrimination for moderate RV enlargement (area under the curve, 0.89; P < .001).Echocardiographic estimates of RV volume (by RV end-diastolic area) and function (by RV fractional area change and tricuspid annular plane systolic excursion) offer good approximations of RV size and function in patients with pulmonary hypertension and allow the accurate discrimination of normal from abnormal.

  View details for DOI 10.1016/j.echo.2013.12.011

  View details for PubMedID 24444659

• ACC/AHA/ASE/ASNC/HRS/IAC/Mended Hearts/NASCI/RSNA/SAIP/SCAI/SCCT/SCMR/SNMMI 2014 health policy statement on use of noninvasive cardiovascular imaging: a report of the American College of Cardiology Clinical Quality Committee. Journal of the American College of Cardiology Mark, D. B., Anderson, J. L., Brinker, J. A., Brophy, J. A., Casey, D. E., Cross, R. R., Edmundowicz, D., Hachamovitch, R., Hlatky, M. A., Jacobs, J. E., Jaskie, S., Kett, K. G., Malhotra, V., Masoudi, F. A., McConnell, M. V., Rubin, G. D., Shaw, L. J., Sherman, M. E., Stanko, S., Ward, R. P. 2014; 63 (7): 698-721

  View details for DOI 10.1016/j.jacc.2013.02.002

  View details for PubMedID 24556329

• miR-24 limits aortic vascular inflammation and murine abdominal aneurysm development. Nature communications Maegdefessel, L., Spin, J. M., Raaz, U., Eken, S. M., Toh, R., Azuma, J., Adam, M., Nakagami, F., Heymann, H. M., Chernogubova, E., Jin, H., Roy, J., Hultgren, R., Caidahl, K., Schrepfer, S., Hamsten, A., Eriksson, P., McConnell, M. V., Dalman, R. L., Tsao, P. S. 2014; 5: 5214-?

  Abstract

  Identification and treatment of abdominal aortic aneurysm (AAA) remain among the most prominent challenges in vascular medicine. MicroRNAs (miRNAs) are crucial regulators of cardiovascular pathology and represent intriguing targets to limit AAA expansion. Here we show, by using two established murine models of AAA disease along with human aortic tissue and plasma analysis, that miR-24 is a key regulator of vascular inflammation and AAA pathology. In vivo and in vitro studies reveal chitinase 3-like 1 (Chi3l1) to be a major target and effector under the control of miR-24, regulating cytokine synthesis in macrophages as well as their survival, promoting aortic smooth muscle cell migration and cytokine production, and stimulating adhesion molecule expression in vascular endothelial cells. We further show that modulation of miR-24 alters AAA progression in animal models, and that miR-24 and CHI3L1 represent novel plasma biomarkers of AAA disease progression in humans.

  View details for DOI 10.1038/ncomms6214

  View details for PubMedID 25358394

  View details for PubMedCentralID PMC4217126

• Fiber-optic system for dual-modality imaging of glucose probes 18F-FDG and 6-NBDG in atherosclerotic plaques. PloS one Zaman, R. T., Kosuge, H., Pratx, G., Carpenter, C., Xing, L., McConnell, M. V. 2014; 9 (9)

  Abstract

  Atherosclerosis is a progressive inflammatory condition that underlies coronary artery disease (CAD)-the leading cause of death in the United States. Thus, the ultimate goal of this research is to advance our understanding of human CAD by improving the characterization of metabolically active vulnerable plaques within the coronary arteries using a novel catheter-based imaging system. The aims of this study include (1) developing a novel fiber-optic imaging system with a scintillator to detect both 18F and fluorescent glucose probes, and (2) validating the system on ex vivo murine plaques.A novel design implements a flexible fiber-optic catheter consisting of both a radio-luminescence and a fluorescence imaging system to detect radionuclide 18F-fluorodeoxyglucose (18F-FDG) and the fluorescent analog 6-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-6-Deoxyglucose (6-NBDG), respectively. Murine macrophage-rich atherosclerotic carotid plaques were imaged ex vivo after intravenous delivery of 18F-FDG or 6-NBDG. Confirmatory optical imaging by IVIS-200 and autoradiography were also performed.Our fiber-optic imaging system successfully visualized both 18F-FDG and 6-NBDG probes in atherosclerotic plaques. For 18F-FDG, the ligated left carotid arteries (LCs) exhibited 4.9-fold higher radioluminescence signal intensity compared to the non-ligated right carotid arteries (RCs) (2.6 × 10(4) ± 1.4 × 10(3) vs. 5.4 × 10(3) ± 1.3 × 10(3) A.U., P = 0.008). Similarly, for 6-NBDG, the ligated LCs emitted 4.3-fold brighter fluorescent signals than the control RCs (1.6 × 10(2) ± 2.7 × 10(1) vs. 3.8 × 10(1) ± 5.9 A.U., P = 0.002). The higher uptake of both 18F-FDG and 6-NBDG in ligated LCs were confirmed with the IVIS-200 system. Autoradiography further verified the higher uptake of 18F-FDG by the LCs.This novel fiber-optic imaging system was sensitive to both radionuclide and fluorescent glucose probes taken up by murine atherosclerotic plaques. In addition, 6-NBDG is a promising novel fluorescent probe for detecting macrophage-rich atherosclerotic plaques.

  View details for DOI 10.1371/journal.pone.0108108

  View details for PubMedID 25233472

• Histological characteristics of myocardial bridge with an ultrasonic echolucent band. Comparison between intravascular ultrasound and histology. Circulation journal Yamada, R., Turcott, R. G., Connolly, A. J., Ikeno, F., McConnell, M. V., Schnittger, I., Fitzgerald, P. J., Honda, Y. 2014; 78 (2): 502-504

  View details for PubMedID 24172077

• Integrin-Targeted Molecular Imaging of Experimental Abdominal Aortic Aneurysms by 18F-labeled Arg-Gly-Asp Positron-Emission Tomography. Circulation. Cardiovascular imaging Kitagawa, T., Kosuge, H., Chang, E., James, M. L., Yamamoto, T., Shen, B., Chin, F. T., Gambhir, S. S., Dalman, R. L., McConnell, M. V. 2013; 6 (6): 950-956

  Abstract

  Background- Both inflammation and neoangiogenesis contribute to abdominal aortic aneurysm (AAA) disease. Arg-Gly-Asp-based molecular imaging has been shown to detect the integrin αvβ3. We studied a clinical dimeric (18)F-labeled Arg-Gly-Asp positron-emission tomography (PET) agent ((18)F-FPPRGD2) for molecular imaging of experimental AAAs. Methods and Results- Murine AAAs were induced in Apo-E-deficient mice by angiotensin II infusion, with monitoring of aortic diameter on ultrasound. AAA (n=10) and saline-infused control mice (n=7) were injected intravenously with (18)F-FPPRGD2, as well as an intravascular computed tomography contrast agent, then scanned using a small-animal PET/computed tomography scanner. Aortic uptake of (18)F-FPPRGD2 was quantified by percentage-injected dose per gram and target-to-=0.003; median target-to-=0.0008). Ex vivo autoradiography demonstrated high uptake of (18)F-FPPRGD2 into the AAA wall, with immunohistochemistry showing substantial cluster of differentiation (CD)-11b(+) macrophages and CD-31(+) neovessels. Target-to-=-0.29, P=0.41) but did strongly correlate with both mural macrophage density (r=0.79, P=0.007) and neovessel counts (r=0.87, P=0.001) on immunohistochemistry. Conclusions- PET imaging of experimental AAAs using (18)F-FPPRGD2 detects biologically active disease, correlating to the degree of vascular inflammation and neoangiogenesis. This may provide a clinically translatable molecular imaging approach to characterize AAA biology to predict risk beyond size alone.

  View details for DOI 10.1161/CIRCIMAGING.113.000234

  View details for PubMedID 23995363

• Mass fabrication and delivery of 3D multilayer mu Tags into living cells SCIENTIFIC REPORTS Chen, L. Y., Parizi, K. B., Kosuge, H., Milaninia, K. M., McConnell, M. V., Wong, H. P., Poon, A. S. 2013; 3

  Abstract

  Continuous monitoring of in vivo biological processes and their evolution at the cellular level would enable major advances in our understanding of biology and disease. As a stepping stone towards chronic cellular monitoring, we demonstrate massively parallel fabrication and delivery of 3D multilayer micro-Tags (μTags) into living cells. Both 10 μm × 10 μm × 1.5 μm and 18 μm × 7 μm × 1.5 μm devices containing inductive and capacitive structures were designed and fabricated as potential passive radio-frequency identification tags. We show cellular internalization and persistence of μTags over a 5-day period. Our results represent a promising advance in technologies for studying biology and disease at the cellular level.

  View details for DOI 10.1038/srep02295

  View details for Web of Science ID 000322308900002

  View details for PubMedID 23887586

  View details for PubMedCentralID PMC3724179

• Reproducibility study for free-breathing measurements of pyruvate metabolism using hyperpolarized 13C in the heart MAGNETIC RESONANCE IN MEDICINE Wu, H. H., Gurney, P. T., Hu, B. S., Nishimura, D. G., McConnell, M. V. 2013; 69 (4): 1083-1093

  Abstract

  Noninvasive visualization of the coronary arteries in vivo is one of the most important goals in cardiovascular imaging. Compared to other paradigms for coronary MR angiography, a free-breathing three-dimensional whole-heart iso-resolution approach simplifies prescription effort, requires less patient cooperation, reduces overall exam time, and supports retrospective reformats at arbitrary planes. However, this approach requires a long continuous acquisition and must account for respiratory and cardiac motion throughout the scan. In this work, a new free-breathing coronary MR angiography technique that reduces scan time and improves robustness to motion is developed. Data acquisition is accomplished using a three-dimensional cones non-Cartesian trajectory, which can reduce the number of readouts 3-fold or more compared to conventional three-dimensional Cartesian encoding and provides greater robustness to motion/flow effects. To further enhance robustness to motion, two-dimensional navigator images are acquired to directly track respiration-induced displacement of the heart and enable retrospective compensation of all acquired data (none discarded) for image reconstruction. In addition, multiple cardiac phases are imaged to support retrospective selection of the best phase(s) for visualizing each coronary segment. Experimental results demonstrate that whole-heart coronary angiograms can be obtained rapidly and robustly with this proposed technique.

  View details for DOI 10.1002/mrm.24342

  View details for Web of Science ID 000316629300020

• A novel stress echocardiography pattern for myocardial bridge with invasive structural and hemodynamic correlation. Journal of the American Heart Association Lin, S., Tremmel, J. A., Yamada, R., Rogers, I. S., Yong, C. M., Turcott, R., McConnell, M. V., Dash, R., Schnittger, I. 2013; 2 (2)

  View details for DOI 10.1161/JAHA.113.000097

  View details for PubMedID 23591827

• Three-dimensional first-pass myocardial perfusion MRI using a stack-of-spirals acquisition MAGNETIC RESONANCE IN MEDICINE Shin, T., Nayak, K. S., Santos, J. M., Nishimura, D. G., Hu, B. S., McConnell, M. V. 2013; 69 (3): 839-844

  Abstract

  Three-dimensional cardiac magnetic resonance perfusion imaging is promising for the precise sizing of defects and for providing high perfusion contrast, but remains an experimental approach primarily due to the need for large-dimensional encoding, which, for traditional 3DFT imaging, requires either impractical acceleration factors or sacrifices in spatial resolution. We demonstrated the feasibility of rapid three-dimensional cardiac magnetic resonance perfusion imaging using a stack-of-spirals acquisition accelerated by non-Cartesian k-t SENSE, which enables entire myocardial coverage with an in-plane resolution of 2.4 mm. The optimal undersampling pattern was used to achieve the largest separation between true and aliased signals, which is a prerequisite for k-t SENSE reconstruction. Flip angle and saturation recovery time were chosen to ensure negligible magnetization variation during the transient data acquisition. We compared the proposed three-dimensional perfusion method with the standard 2DFT approach by consecutively acquiring both data during each R-R interval in cardiac patients. The mean and standard deviation of the correlation coefficients between time intensity curves of three-dimensional versus 2DFT were 0.94 and 0.06 across seven subjects. The linear correlation between the two sets of upslope values was significant (r = 0.78, P < 0.05).

  View details for DOI 10.1002/mrm.24303

  View details for Web of Science ID 000315331300026

  View details for PubMedID 22556062

• Respiratory-Mode Display of Echocardiographic Images Highlights Effects of Pericardial Disease. JACC. Cardiovascular imaging McConnell, M. V., Wu, H. H. 2013

  View details for DOI 10.1016/j.jcmg.2012.12.013

  View details for PubMedID 23769491

• Imaging Atherosclerotic Plaques In Vivo using Peptide-Functionalized Iron Oxide Nanoparticles International Workshop on Magnetic Particle Imaging (IWMPI) Drews, L. B., Croft, L. R., Kosuge, H., Saritas, E. U., Goodwill, P. W., McConnell, M. V., Conolly, S. M., Tirrell, M. V. IEEE. 2013

  View details for Web of Science ID 000325950400067

• Mass fabrication and delivery of 3D multilayer µTags into living cells. Scientific reports Chen, L. Y., Parizi, K. B., Kosuge, H., Milaninia, K. M., McConnell, M. V., Wong, H. P., Poon, A. S. 2013; 3: 2295-?

  Abstract

  Continuous monitoring of in vivo biological processes and their evolution at the cellular level would enable major advances in our understanding of biology and disease. As a stepping stone towards chronic cellular monitoring, we demonstrate massively parallel fabrication and delivery of 3D multilayer micro-Tags (μTags) into living cells. Both 10 μm × 10 μm × 1.5 μm and 18 μm × 7 μm × 1.5 μm devices containing inductive and capacitive structures were designed and fabricated as potential passive radio-frequency identification tags. We show cellular internalization and persistence of μTags over a 5-day period. Our results represent a promising advance in technologies for studying biology and disease at the cellular level.

  View details for DOI 10.1038/srep02295

  View details for PubMedID 23887586

  View details for PubMedCentralID PMC3724179

• Near infrared imaging and photothermal ablation of vascular inflammation using single-walled carbon nanotubes. Journal of the American Heart Association Kosuge, H., Sherlock, S. P., Kitagawa, T., Dash, R., Robinson, J. T., Dai, H., McConnell, M. V. 2012; 1 (6)

  Abstract

  Macrophages are critical contributors to atherosclerosis. Single-walled carbon nanotubes (SWNTs) show promising properties for cellular imaging and thermal therapy, which may have application to vascular macrophages.In vitro uptake and photothermal destruction of mouse macrophage cells (RAW264.7) were performed with SWNTs (14.7 nmol/L) exposed to an 808-nm light source. SWNTs were taken up by 94 ± 6% of macrophages, and light exposure induced 93 ± 3% cell death. In vivo vascular macrophage uptake and ablation were then investigated in carotid-ligated FVB mice (n=33) after induction of hyperlipidemia and diabetes. Two weeks postligation, near-infrared fluorescence (NIRF) carotid imaging (n=12) was performed with SWNT-Cy5.5 (8 nmol of Cy5.5) given via the tail vein. Photothermal heating and macrophage apoptosis were evaluated on freshly excised carotid arteries (n=21). NIRF of SWNTs showed higher signal intensity in ligated carotids compared with sham, confirmed by both in situ and ex vivo NIRF imaging (P<0.05, ligation versus sham). Immunofluorescence staining showed colocalization of SWNT-Cy5.5 and macrophages in atherosclerotic lesions. Light (808 nm) exposure of freshly excised carotids showed heating and induction of macrophage apoptosis in ligated left carotid arteries with SWNTs, but not in control groups without SWNTs or without light exposure.Carbon nanotubes accumulate in atherosclerotic macrophages in vivo and provide a multifunctional platform for imaging and photothermal therapy of vascular inflammation.

  View details for DOI 10.1161/JAHA.112.002568

  View details for PubMedID 23316318

• Randomized Trial of Personal Genomics for Preventive Cardiology Design and Challenges CIRCULATION-CARDIOVASCULAR GENETICS Knowles, J. W., Assimes, T. L., Kiernan, M., Pavlovic, A., Goldstein, B. A., Yank, V., McConnell, M. V., Absher, D., Bustamante, C., Ashley, E. A., Ioannidis, J. P. 2012; 5 (3): 368-376

  View details for DOI 10.1161/CIRCGENETICS.112.962746

  View details for Web of Science ID 000309884900017

  View details for PubMedID 22715281

  View details for PubMedCentralID PMC3394683

• RGD-Conjugated Human Ferritin Nanoparticles for Imaging Vascular Inflammation and Angiogenesis in Experimental Carotid and Aortic Disease MOLECULAR IMAGING AND BIOLOGY Kitagawa, T., Kosuge, H., Uchida, M., Dua, M. M., Iida, Y., Dalman, R. L., Douglas, T., McConnell, M. V. 2012; 14 (3): 315-324

  Abstract

  Inflammation and angiogenesis are important contributors to vascular disease. We evaluated imaging both of these biological processes, using Arg-Gly-Asp (RGD)-conjugated human ferritin nanoparticles (HFn), in experimental carotid and abdominal aortic aneurysm (AAA) disease.Macrophage-rich carotid lesions were induced by ligation in hyperlipidemic and diabetic FVB mice (n = 16). AAAs were induced by angiotensin II infusion in apoE(-/-) mice (n=10). HFn, with or without RGD peptide, was labeled with Cy5.5 and injected intravenously for near-infrared fluorescence imaging.RGD-HFn showed significantly higher signal than HFn in diseased carotids and AAAs relative to non-diseased regions, both in situ (carotid: 1.88 ± 0.30 vs. 1.17 ± 0.10, p = 0.04; AAA: 2.59 ± 0.24 vs. 1.82 ± 0.16, p = 0.03) and ex vivo. Histology showed RGD-HFn colocalized with macrophages in carotids and both macrophages and neoangiogenesis in AAA lesions.RGD-HFn enhances vascular molecular imaging by targeting both vascular inflammation and angiogenesis, and allows more comprehensive detection of high-risk atherosclerotic and aneurysmal vascular diseases.

  View details for DOI 10.1007/s11307-011-0495-1

  View details for Web of Science ID 000303884400006

  View details for PubMedID 21638084

• Infection of pregnant mice with Listeria monocytogenes induces fetal bradycardia PEDIATRIC RESEARCH Hardy, J., Kirkendoll, B., Zhao, H., Pisani, L., Luong, R., Switzer, A., McConnell, M. V., Contag, C. H. 2012; 71 (5): 539-545

  Abstract

  Listeriosis is one of the most lethal bacterial diseases for fetuses and infants. However, pregnant women who get infected with Listeria may experience only mild symptoms, making the diagnosis difficult, even when the fetus is fatally infected.To reveal features of this infection, we conducted a multimodality imaging study of Listeria-induced miscarriage, using a pregnant mouse model. In this model, fetal morbidity and mortality can be observed in utero, noninvasively, and the timing and extent of infection can be carefully controlled. By employing in vivo bioluminescence imaging (BLI), perinatal infections were localized over time such that a correlation of infection to outcome could be determined without the need to kill the animal subject. The morbidity and viability of fetuses were assessed with ultrasound, and fetal morphology was imaged using magnetic resonance imaging (MRI).The ultrasound revealed sustained fetal bradycardia, the slowing of the fetal heartbeat, in infected fetuses, with an association between slowed fetal heart rate and strong bioluminescent signal.Uninfected fetuses showing no bioluminescent signal in the same uterine horn exhibited normal heartbeats. Thus, fetal bradycardia during infection was localized to the infected fetus and was not systemic or disseminated.

  View details for DOI 10.1038/pr.2012.2

  View details for Web of Science ID 000303373300003

  View details for PubMedID 22314663

• Bioluminescence and Magnetic Resonance Imaging of Macrophage Homing to Experimental Abdominal Aortic Aneurysms MOLECULAR IMAGING Miyama, N., Dua, M. M., Schultz, G. M., Kosuge, H., Terashima, M., Pisani, L. J., Dalman, R. L., McConnell, M. V. 2012; 11 (2): 126-134

  Abstract

  Macrophage infiltration is a prominent feature of abdominal aortic aneurysm (AAA) progression. We used a combined imaging approach with bioluminescence (BLI) and magnetic resonance imaging (MRI) to study macrophage homing and accumulation in experimental AAA disease. Murine AAAs were created via intra-aortic infusion of porcine pancreatic elastase. Mice were imaged over 14 days after injection of prepared peritoneal macrophages. For BLI, macrophages were from transgenic mice expressing luciferase. For MRI, macrophages were labeled with iron oxide particles. Macrophage accumulation during aneurysm progression was observed by in situ BLI and by in vivo 7T MRI. Mice were sacrificed after imaging for histologic analysis. In situ BLI (n  =  32) demonstrated high signal in the AAA by days 7 and 14, which correlated significantly with macrophage number and aortic diameter. In vivo 7T MRI (n  =  13) at day 14 demonstrated T₂* signal loss in the AAA and not in sham mice. Immunohistochemistry and Prussian blue staining confirmed the presence of injected macrophages in the AAA. BLI and MRI provide complementary approaches to track macrophage homing and accumulation in experimental AAAs. Similar dual imaging strategies may aid the study of AAA biology and the evaluation of novel therapies.

  View details for DOI 10.2310/7290.2011.00033

  View details for Web of Science ID 000307645900004

  View details for PubMedID 22469240

• MicroRNA-21 Blocks Abdominal Aortic Aneurysm Development and Nicotine-Augmented Expansion SCIENCE TRANSLATIONAL MEDICINE Maegdefessel, L., Azuma, J., Toh, R., Deng, A., Merk, D. R., Raiesdana, A., Leeper, N. J., Raaz, U., Schoelmerich, A. M., McConnell, M. V., Dalman, R. L., Spin, J. M., Tsao, P. S. 2012; 4 (122)

  Abstract

  Identification and treatment of abdominal aortic aneurysm (AAA) remains among the most prominent challenges in vascular medicine. MicroRNAs are crucial regulators of cardiovascular pathology and represent possible targets for the inhibition of AAA expansion. We identified microRNA-21 (miR-21) as a key modulator of proliferation and apoptosis of vascular wall smooth muscle cells during development of AAA in two established murine models. In both models (AAA induced by porcine pancreatic elastase or infusion of angiotensin II), miR-21 expression increased as AAA developed. Lentiviral overexpression of miR-21 induced cell proliferation and decreased apoptosis in the aortic wall, with protective effects on aneurysm expansion. miR-21 overexpression substantially decreased expression of the phosphatase and tensin homolog (PTEN) protein, leading to increased phosphorylation and activation of AKT, a component of a pro-proliferative and antiapoptotic pathway. Systemic injection of a locked nucleic acid-modified antagomir targeting miR-21 diminished the pro-proliferative impact of down-regulated PTEN, leading to a marked increase in the size of AAA. Similar results were seen in mice with AAA augmented by nicotine and in human aortic tissue samples from patients undergoing surgical repair of AAA (with more pronounced effects observed in smokers). Modulation of miR-21 expression shows potential as a new therapeutic option to limit AAA expansion and vascular disease progression.

  View details for DOI 10.1126/scitranslmed.3003441

  View details for Web of Science ID 000300952100004

  View details for PubMedID 22357537

• Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development JOURNAL OF CLINICAL INVESTIGATION Maegdefessel, L., Azuma, J., Toh, R., Merk, D. R., Deng, A., Chin, J. T., Raaz, U., Schoelmerich, A. M., Raiesdana, A., Leeper, N. J., McConnell, M. V., Dalman, R. L., Spin, J. M., Tsao, P. S. 2012; 122 (2): 497-506

  Abstract

  MicroRNAs (miRs) regulate gene expression at the posttranscriptional level and play crucial roles in vascular integrity. As such, they may have a role in modifying abdominal aortic aneurysm (AAA) expansion, the pathophysiological mechanisms of which remain incompletely explored. Here, we investigate the role of miRs in 2 murine models of experimental AAA: the porcine pancreatic elastase (PPE) infusion model in C57BL/6 mice and the AngII infusion model in Apoe-/- mice. AAA development was accompanied by decreased aortic expression of miR-29b, along with increased expression of known miR-29b targets, Col1a1, Col3a1, Col5a1, and Eln, in both models. In vivo administration of locked nucleic acid anti-miR-29b greatly increased collagen expression, leading to an early fibrotic response in the abdominal aortic wall and resulting in a significant reduction in AAA progression over time in both models. In contrast, overexpression of miR-29b using a lentiviral vector led to augmented AAA expansion and significant increase of aortic rupture rate. Cell culture studies identified aortic fibroblasts as the likely vascular cell type mediating the profibrotic effects of miR-29b modulation. A similar pattern of reduced miR-29b expression and increased target gene expression was observed in human AAA tissue samples compared with that in organ donor controls. These data suggest that therapeutic manipulation of miR-29b and its target genes holds promise for limiting AAA disease progression and protecting from rupture.

  View details for DOI 10.1172/JCI61598

  View details for Web of Science ID 000299765800016

  View details for PubMedID 22269326

• In Vivo Bioluminescence Imaging of Inducible Nitric Oxide Synthase Gene Expression in Vascular Inflammation MOLECULAR IMAGING AND BIOLOGY Terashima, M., Ehara, S., Yang, E., Kosuge, H., Tsao, P. S., Quertermous, T., Contag, C. H., McConnell, M. V. 2011; 13 (6): 1061-1066

  Abstract

  Inflammation plays a critical role in atherosclerosis and is associated with upregulation of inducible nitric oxide synthase (iNOS). We studied bioluminescence imaging (BLI) to track iNOS gene expression in a murine model of vascular inflammation.Macrophage-rich vascular lesions were induced by carotid ligation plus high-fat diet and streptozotocin-induced diabetes in 18 iNOS-luc reporter mice. In vivo iNOS expression was imaged serially by BLI over 14 days, followed by in situ BLI and histology.BLI signal from ligated carotids increased over 14 days (9.7 ± 4.4 × 10(3 ) vs. 4.4 ± 1.7 × 10(3) photons/s/cm(2)/sr at baseline, p < 0.001 vs. baseline, p < 0.05 vs. sham controls). Histology confirmed substantial macrophage infiltration, with iNOS and luciferase expression, only in ligated left carotid arteries and not controls.BLI allows in vivo detection of iNOS expression in murine carotid lesions and may provide a valuable approach for monitoring vascular gene expression and inflammation in small animal models.

  View details for DOI 10.1007/s11307-010-0451-5

  View details for Web of Science ID 000296794400002

  View details for PubMedID 21057879

• Dual Manganese-Enhanced and Delayed Gadolinium-Enhanced MRI Detects Myocardial Border Zone Injury in a Pig Ischemia-Reperfusion Model CIRCULATION-CARDIOVASCULAR IMAGING Dash, R., Chung, J., Ikeno, F., Hahn-Windgassen, A., Matsuura, Y., Bennett, M. V., Lyons, J. K., Teramoto, T., Robbins, R. C., McConnell, M. V., Yeung, A. C., Brinton, T. J., Harnish, P. P., Yang, P. C. 2011; 4 (5): 574-582

  Abstract

  Gadolinium (Gd)-based delayed-enhancement MRI (DEMRI) identifies nonviable myocardium but is nonspecific and may overestimate nonviable territory. Manganese (Mn(2+))-enhanced MRI (MEMRI) denotes specific Mn(2+) uptake into viable cardiomyocytes. We performed a dual-contrast myocardial assessment in a porcine ischemia-reperfusion (IR) model to test the hypothesis that combined DEMRI and MEMRI identifies viable infarct border zone (BZ) myocardium in vivo.Sixty-minute left anterior descending coronary artery IR injury was induced in 13 adult swine. Twenty-one days post-IR, 3-T cardiac MRI was performed. MEMRI was obtained after injection of 0.7 mL/kg Mn(2+) contrast agent. DEMRI was then acquired after injection of 0.2 mmol/kg Gd. Left ventricular (LV) mass, infarct, and function were analyzed. Subtraction of MEMRI defect from DEMRI signal identified injured BZ myocardium. Explanted hearts were analyzed by 2,3,5-triphenyltetrazolium chloride stain and tissue electron microscopy to compare infarct, BZ, and remote myocardium. Average LV ejection fraction was reduced (30±7%). MEMRI and DEMRI infarct volumes correlated with 2,3,5-triphenyltetrazolium chloride stain analysis (MEMRI, r=0.78; DEMRI, r=0.75; P<0.004). MEMRI infarct volume percentage was significantly lower than that of DEMRI (14±4% versus 23±4%; P<0.05). BZ MEMRI signal-to-noise ratio (SNR) was intermediate to remote and core infarct SNR (7.5±2.8 versus 13.2±3.4 and 2.9±1.6; P<0.0001), and DEMRI BZ SNR tended to be intermediate to remote and core infarct SNR (8.4±5.4 versus 3.3±0.6 and 14.3±6.6; P>0.05). Tissue electron microscopy analysis exhibited preserved cell structure in BZ cardiomyocytes despite transmural DEMRI enhancement.The dual-contrast MEMRI-DEMRI detects BZ viability within DEMRI infarct zones. This approach may identify injured, at-risk myocardium in ischemic cardiomyopathy.

  View details for DOI 10.1161/CIRCIMAGING.110.960591

  View details for Web of Science ID 000295030600017

  View details for PubMedID 21719779

  View details for PubMedCentralID PMC3178667

• In Vitro Validation of Finite Element Analysis of Blood Flow in Deformable Models ANNALS OF BIOMEDICAL ENGINEERING Kung, E. O., Les, A. S., Figueroa, C. A., Medina, F., Arcaute, K., Wicker, R. B., McConnell, M. V., Taylor, C. A. 2011; 39 (7): 1947-1960

  Abstract

  The purpose of this article is to validate numerical simulations of flow and pressure incorporating deformable walls using in vitro flow phantoms under physiological flow and pressure conditions. We constructed two deformable flow phantoms mimicking a normal and a restricted thoracic aorta, and used a Windkessel model at the outlet boundary. We acquired flow and pressure data in the phantom while it operated under physiological conditions. Next, in silico numerical simulations were performed, and velocities, flows, and pressures in the in silico simulations were compared to those measured in the in vitro phantoms. The experimental measurements and simulated results of pressure and flow waveform shapes and magnitudes compared favorably at all of the different measurement locations in the two deformable phantoms. The average difference between measured and simulated flow and pressure was approximately 3.5 cc/s (13% of mean) and 1.5 mmHg (1.8% of mean), respectively. Velocity patterns also showed good qualitative agreement between experiment and simulation especially in regions with less complex flow patterns. We demonstrated the capabilities of numerical simulations incorporating deformable walls to capture both the vessel wall motion and wave propagation by accurately predicting the changes in the flow and pressure waveforms at various locations down the length of the deformable flow phantoms.

  View details for DOI 10.1007/s10439-011-0284-7

  View details for Web of Science ID 000291479600010

  View details for PubMedID 21404126

  View details for PubMedCentralID PMC4404701

• Physical Activity in Older Subjects Is Associated With Increased Coronary Vasodilation The ADVANCE Study JACC-CARDIOVASCULAR IMAGING Nguyen, P. K., Terashima, M., Fair, J. M., Varady, A., Taylor-Piliae, R. E., Iribarren, C., Go, A. S., Haskell, W. L., Hlatky, M. A., Fortmann, S. P., McConnell, M. V. 2011; 4 (6): 622-629

  Abstract

  We investigated the association between physical activity and coronary vasodilation to nitroglycerin (NTG) in the ADVANCE (Atherosclerotic Disease, Vascular Function, and Genetic Epidemiology) cohort of older healthy subjects.Physical activity may exert its beneficial effects by augmenting coronary responsiveness to nitric oxide. The relationship between physical activity and coronary vasodilatory response to NTG, an exogenous nitric oxide donor, has not been studied in a community-based population with typical activity levels.In 212 older adults (ages 60 to 72 years) without cardiovascular disease, we measured the coronary vasodilatory response to NTG using magnetic resonance angiography and physical activity using the Stanford Seven-Day Physical Activity Recall Questionnaire. The primary predictor measure was total physical activity (kcal/kg/day). The primary outcome measure was coronary vasodilatory response (percent increase of cross-sectional area post-NTG).Coronary vasodilation was 27.6% in more active subjects (>35 kcal/kg/day, e.g., 1 h of walking per day) compared to 18.9% in less active subjects (p=0.03). Regression analysis showed a significant positive correlation between coronary vasodilation and physical activity (p=0.003), with a slope (beta) of 1.2% per kcal/kg/day. This finding remained significant after adjustment for cardiac risk factors, coronary calcium, the use of vasoactive or statin medications, and analysis of physical activity by quintiles (p < 0.05). Coronary vasodilation was also associated with physical activity intensity (p = 0.03).In an asymptomatic, community-based cohort of older adults, increased coronary vasodilatory response was independently associated with greater physical activity, supporting the benefits of exercise on the order of 1 h of walking per day.

  View details for DOI 10.1016/j.jcmg.2011.05.001

  View details for Web of Science ID 000292042900009

  View details for PubMedID 21679897

• In Vitro Validation of Finite-Element Model of AAA Hemodynamics Incorporating Realistic Outlet Boundary Conditions JOURNAL OF BIOMECHANICAL ENGINEERING-TRANSACTIONS OF THE ASME Kung, E. O., Les, A. S., Medina, F., Wicker, R. B., McConnell, M. V., Taylor, C. A. 2011; 133 (4)

  Abstract

  The purpose of this study is to validate numerical simulations of flow and pressure in an abdominal aortic aneurysm (AAA) using phase-contrast magnetic resonance imaging (PCMRI) and an in vitro phantom under physiological flow and pressure conditions. We constructed a two-outlet physical flow phantom based on patient imaging data of an AAA and developed a physical Windkessel model to use as outlet boundary conditions. We then acquired PCMRI data in the phantom while it operated under conditions mimicking a resting and a light exercise physiological state. Next, we performed in silico numerical simulations and compared experimentally measured velocities, flows, and pressures in the in vitro phantom to those computed in the in silico simulations. There was a high degree of agreement in all of the pressure and flow waveform shapes and magnitudes between the experimental measurements and simulated results. The average pressures and flow split difference between experiment and simulation were all within 2%. Velocity patterns showed good agreement between experimental measurements and simulated results, especially in the case of whole-cycle averaged comparisons. We demonstrated methods to perform in vitro phantom experiments with physiological flows and pressures, showing good agreement between numerically simulated and experimentally measured velocity fields and pressure waveforms in a complex patient-specific AAA geometry.

  View details for DOI 10.1115/1.4003526

  View details for Web of Science ID 000288706600004

  View details for PubMedID 21428677

  View details for PubMedCentralID PMC4404703

• Protein Cage Nanoparticles Bearing the LyP-1 Peptide for Enhanced Imaging of Macrophage-Rich Vascular Lesions ACS NANO Uchida, M., Kosuge, H., Terashima, M., Willits, D. A., Liepold, L. O., Young, M. J., McConnell, M. V., Douglas, T. 2011; 5 (4): 2493-2502

  Abstract

  Cage-like protein nanoparticles are promising platforms for cell- and tissue-specific targeted delivery of imaging and therapeutic agents. Here, we have successfully modified the 12 nm small heat shock protein from Methanococcus jannaschii (MjHsp) to detect atherosclerotic plaque lesions in a mouse model system. As macrophages are centrally involved in the initiation and progression of atherosclerosis, targeted imaging of macrophages is valuable to assess the biologic status of the blood vessel wall. LyP-1, a nine residue peptide, has been shown to target tumor-associated macrophages. Thus, LyP-1 was genetically incorporated onto the exterior surface of MjHsp, while a fluorescent molecule (Cy5.5) was conjugated on the interior cavity. This bioengineered protein cage, LyP-Hsp, exhibited enhanced affinity to macrophage in vitro. Furthermore, in vivo injection of LyP-Hsp allowed visualization of macrophage-rich murine carotid lesions by in situ and ex vivo fluorescence imaging. These results demonstrate the potential of LyP-1-conjugated protein cages as nanoscale platforms for delivery of imaging agents for the diagnosis of atherosclerosis.

  View details for DOI 10.1021/nn102863y

  View details for Web of Science ID 000289742100011

  View details for PubMedID 21391720

• Human ferritin cages for imaging vascular macrophages BIOMATERIALS Terashima, M., Uchida, M., Kosuge, H., Tsao, P. S., Young, M. J., Conolly, S. M., Douglas, T., McConnell, M. V. 2011; 32 (5): 1430-1437

  Abstract

  Atherosclerosis is a leading cause of death worldwide. Macrophages are key components of vascular inflammation, which contributes to the development and complications of atherosclerosis. Ferritin, an iron storage and transport protein, has been found to accumulate in macrophages in human atherosclerotic plaques. We hypothesized that ferritin could serve as an intrinsic nano-platform to target delivery of imaging agents to vascular macrophages to detect high-risk atherosclerotic plaques. Here we show that engineered human ferritin protein cages, either conjugated to the fluorescent Cy5.5 molecule or encapsulating a magnetite nanoparticle, are taken up in vivo by macrophages in murine atherosclerotic carotid arteries and can be imaged by fluorescence and magnetic resonance imaging. These results indicate that human ferritin can serve as a nanoparticle platform to image vascular inflammation in vivo.

  View details for DOI 10.1016/j.biomaterials.2010.09.029

  View details for Web of Science ID 000287073000020

  View details for PubMedID 21074263

• FeCo/Graphite Nanocrystals for Multi-Modality Imaging of Experimental Vascular Inflammation PLOS ONE Kosuge, H., Sherlock, S. P., Kitagawa, T., Terashima, M., Barral, J. K., Nishimura, D. G., Dai, H., McConnell, M. V. 2011; 6 (1)

  Abstract

  FeCo/graphitic-carbon nanocrystals (FeCo/GC) are biocompatible, high-relaxivity, multi-functional nanoparticles. Macrophages represent important cellular imaging targets for assessing vascular inflammation. We evaluated FeCo/GC for vascular macrophage uptake and imaging in vivo using fluorescence and MRI.Hyperlipidemic and diabetic mice underwent carotid ligation to produce a macrophage-rich vascular lesion. In situ and ex vivo fluorescence imaging were performed at 48 hours after intravenous injection of FeCo/GC conjugated to Cy5.5 (n = 8, 8 nmol of Cy5.5/mouse). Significant fluorescence signal from FeCo/GC-Cy5.5 was present in the ligated left carotid arteries, but not in the control (non-ligated) right carotid arteries or sham-operated carotid arteries (p = 0.03 for ligated vs. non-ligated). Serial in vivo 3T MRI was performed at 48 and 72 hours after intravenous FeCo/GC (n = 6, 270 µg Fe/mouse). Significant T2* signal loss from FeCo/GC was seen in ligated left carotid arteries, not in non-ligated controls (p = 0.03). Immunofluorescence staining showed colocalization of FeCo/GC and macrophages in ligated carotid arteries.FeCo/GC accumulates in vascular macrophages in vivo, allowing fluorescence and MR imaging. This multi-functional high-relaxivity nanoparticle platform provides a promising approach for cellular imaging of vascular inflammation.

  View details for DOI 10.1371/journal.pone.0014523

  View details for Web of Science ID 000286516500005

  View details for PubMedID 21264237

• Assessment of Elastase-Induced Murine Abdominal Aortic Aneurysms: Comparison of Ultrasound Imaging with In Situ Video Microscopy JOURNAL OF BIOMEDICINE AND BIOTECHNOLOGY Azuma, J., Maegdefessel, L., Kitagawa, T., Dalman, R. L., McConnell, M. V., Tsao, P. S. 2011

  Abstract

  The aim of this study was to definitively assess the validity of noninvasive high-frequency ultrasound (US) measurements of aortic luminal diameter (ALD) in a murine model of elastase-induced abdominal aortic aneurysm in comparison with in situ video microscopy (VM).C57BL/6 mice underwent transient perfusion of the aorta with either elastase (n = 20: Elastase group) or saline (n = 10: Sham). Unoperated mice (n = 10) were also studied.ALD measurements by US had excellent linear correlation and absolute agreement with that by VM in both Control (unoperated or sham-operated mice) and elastase groups (r = 0.96, intraclass correlation coefficient (ICC) = 0.88 and r = 0.93, ICC = 0.92, resp.). Bland-Altman analysis of US compared with VM measurements in both groups indicated good agreement, however US measurements were slightly but significantly higher than VM measurements in the control group (mean bias 0.039 mm, P < .05). Linear regression analysis revealed excellent correlation between US and VM measurements in both groups. (R² = 0.91 in Control group, R² = 0.85 in elastase group.) The reliability of US measurements was also confirmed by ex vivo histological measurements.High-frequency US provides reliable ALD measurements in developing murine abdominal aortic aneurysms.

  View details for DOI 10.1155/2011/252141

  View details for Web of Science ID 000289091200001

  View details for PubMedID 21331328

• Right coronary wall cmr in the older asymptomatic advance cohort: positive remodeling and associations with type 2 diabetes and coronary calcium JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE Terashima, M., Nguyen, P. K., Rubin, G. D., Meyer, C. H., Shimakawa, A., Nishimura, D. G., Ehara, S., Iribarren, C., Courtney, B. K., Go, A. S., Hlatky, M. A., Fortmann, S. P., McConnell, M. V. 2010; 12

  Abstract

  Coronary wall cardiovascular magnetic resonance (CMR) is a promising noninvasive approach to assess subclinical atherosclerosis, but data are limited in subjects over 60 years old, who are at increased risk. The purpose of the study was to evaluate coronary wall CMR in an asymptomatic older cohort.Cross-sectional images of the proximal right coronary artery (RCA) were acquired using spiral black-blood coronary CMR (0.7 mm resolution) in 223 older, community-based patients without a history of cardiovascular disease (age 60-72 years old, 38% female). Coronary measurements (total vessel area, lumen area, wall area, and wall thickness) had small intra- and inter-observer variabilities (r = 0.93~0.99, all p < 0.0001), though one-third of these older subjects had suboptimal image quality. Increased coronary wall thickness correlated with increased coronary vessel area (p < 0.0001), consistent with positive remodeling. On multivariate analysis, type 2 diabetes was the only risk factor associated with increased coronary wall area and thickness (p = 0.03 and p = 0.007, respectively). Coronary wall CMR measures were also associated with coronary calcification (p = 0.01-0.03).Right coronary wall CMR in asymptomatic older subjects showed increased coronary atherosclerosis in subjects with type 2 diabetes as well as coronary calcification. Coronary wall CMR may contribute to the noninvasive assessment of subclinical coronary atherosclerosis in older, at-risk patient groups.

  View details for DOI 10.1186/1532-429X-12-75

  View details for Web of Science ID 000286371000001

  View details for PubMedID 21192815

  View details for PubMedCentralID PMC3022803

• Nasal continuous positive airway pressure improves myocardial perfusion reserve and endothelial-dependent vasodilation in patients with obstructive sleep apnea JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE Nguyen, P. K., Katikireddy, C. K., McConnell, M. V., Kushida, C., Yang, P. C. 2010; 12

  Abstract

  Obstructive sleep apnea (OSA) has been associated with cardiovascular disease (CVD), but whether OSA is an independent risk factor for CVD is controversial. The purpose of this study is to determine if patients with OSA have subclinical cardiovascular disease that is detectable by multi-modality cardiovascular imaging and whether these abnormalities improve after nasal continuous positive airway pressure (nCPAP).Of the 35 consecutive subjects with newly diagnosed moderate to severe OSA recruited from the Stanford Sleep Disorders Clinic, 20 patients were randomized to active vs. sham nCPAP. Active nCPAP was titrated to pressures that would prevent sleep disordered breathing based on inpatient polysomnography. OSA patients had baseline vascular function abnormalities including decreased myocardial perfusion reserve (MPR), brachial flow mediated dilation (FMD) and nitroglycerin-induced coronary vasodilation. Patients randomized to active nCPAP had improvement of MPR (1.5 ± 0.5 vs. 3.0 ± 1.3, p = 0.02) and brachial FMD (2.5% ± 5.7% vs. 9.0% ± 6.5%, p = 0.03) after treatment, but those randomized to sham nCPAP showed no significant improvement. There were no significant changes seen in chamber sizes, systolic and diastolic function, valvular function and coronary vasodilation to nitroglycerin.Patients with moderate to severe OSA had decreased MPR and brachial FMD that improved after 3 months of nCPAP. These findings suggest that relief of apnea in OSA may improve microvascular disease and endothelial dysfunction, which may prevent the development of overt cardiovascular disease. Further study in a larger patient population may be warranted.

  View details for DOI 10.1186/1532-429X-12-50

  View details for Web of Science ID 000282342300001

  View details for PubMedID 20815898

  View details for PubMedCentralID PMC2945335

• Hybrid referenceless and multibaseline subtraction MR thermometry for monitoring thermal therapies in moving organs MEDICAL PHYSICS Grissom, W. A., Rieke, V., Holbrook, A. B., Medan, Y., Lustig, M., Santos, J., McConnell, M. V., Pauly, K. B. 2010; 37 (9): 5014-5026

  Abstract

  Magnetic resonance thermometry using the proton resonance frequency (PRF) shift is a promising technique for guiding thermal ablation. For temperature monitoring in moving organs, such as the liver and the heart, problems with motion must be addressed. Multi-baseline subtraction techniques have been proposed, which use a library of baseline images covering the respiratory and cardiac cycle. However, main field shifts due to lung and diaphragm motion can cause large inaccuracies in multi-baseline subtraction. Referenceless thermometry methods based on polynomial phase regression are immune to motion and susceptibility shifts. While referenceless methods can accurately estimate temperature within the organ, in general, the background phase at organ/tissue interfaces requires large polynomial orders to fit, leading to increased danger that the heated region itself will be fitted by the polynomial and thermal dose will be underestimated. In this paper, a hybrid method for PRF thermometry in moving organs is presented that combines the strengths of referenceless and multi-baseline thermometry.The hybrid image model assumes that three sources contribute to image phase during thermal treatment: Background anatomical phase, spatially smooth phase deviations, and focal, heat-induced phase shifts. The new model and temperature estimation algorithm were tested in the heart and liver of normal volunteers, in a moving phantom HIFU heating experiment, and in numerical simulations of thermal ablation. The results were compared to multi-baseline and referenceless methods alone.The hybrid method allows for in vivo temperature estimation in the liver and the heart with lower temperature uncertainty compared to multi-baseline and referenceless methods. The moving phantom HIFU experiment showed that the method accurately estimates temperature during motion in the presence of smooth main field shifts. Numerical simulations illustrated the method's sensitivity to algorithm parameters and hot spot features.This new hybrid method for MR thermometry in moving organs combines the strengths of both multi-baseline subtraction and referenceless thermometry and overcomes their fundamental weaknesses.

  View details for DOI 10.1118/1.3475943

  View details for Web of Science ID 000281906000053

  View details for PubMedID 20964221

  View details for PubMedCentralID PMC2945742

• Quantitative Tissue Characterization of Infarct Core and Border Zone in Patients With Ischemic Cardiomyopathy by Magnetic Resonance Is Associated With Future Cardiovascular Events JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Heidary, S., Patel, H., Chung, J., Yokota, H., Gupta, S. N., Bennett, M. V., Katikireddy, C., Nguyen, P., Pauly, J. M., Terashima, M., McConnell, M. V., Yang, P. C. 2010; 55 (24): 2762-2768

  Abstract

  This study evaluates how characterization of tissue heterogeneity of myocardial infarction by cardiovascular magnetic resonance (CMR) is associated with cardiovascular events (CVE) in patients with ischemic cardiomyopathy (ICM).Prior studies demonstrated that the quantification of myocardial scar volume by CMR is superior to left ventricular end-diastolic volume, left ventricular end-systolic volume, and left ventricular ejection fraction (LVEF) in predicting future CVE in ICM patients. Evaluation of infarct heterogeneity by measuring infarct core and border zones through CMR might have a higher association with CVE.Seventy patients (mean LVEF: 25 +/- 11%) considered for revascularization or medical management +/- implantable cardiac defibrillator were enrolled. A 1.5-T GE MRI (Signa, GE Healthcare, Milwaukee, Wisconsin) was used to acquire cine and delayed enhancement images. The patients' core and border zones of infarcted myocardium were analyzed and followed for CVE.Larger infarct border zone and its percentage of myocardium were found in the 29 patients (41%) who had CVE (median 13.3 g [interquartile range (IQR) 8.4 to 25.1 g] vs. 8.0 g [IQR 3.0 to 14.5 g], p = 0.02 and 7.8% [IQR 4.9% to 17.0%] vs. 4.1% [IQR 1.9% to 9.3%], p = 0.02, respectively). The core infarct zone and its percentage of myocardium, left ventricular end-diastolic volume, left ventricular end-systolic volume, and LVEF were not statistically significant. Sub-analysis of the medical management and revascularization patients with CVE demonstrated that the medically managed patients had a larger border zone, whereas there was no difference between border and core zones in the revascularization group (p < 0.05).Quantification of core and border zones and their percentages of myocardium through CMR is associated with future CVE and might assist in the management of patients with ICM.

  View details for DOI 10.1016/j.jacc.2010.01.052

  View details for Web of Science ID 000278565200012

  View details for PubMedID 20538171

• Embolization of a Symptomatic Systemic to Pulmonary (Right-to-left) Venous Shunt Caused by Fibrosing Mediastinitis and Superior Vena Caval Occlusion JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY Sze, D. Y., Fleischmann, D., Ma, A. O., Price, E. A., McConnell, M. V. 2010; 21 (1): 140-143

  Abstract

  Paradoxical embolization can occur when a right-to-left shunt allows a venous thromboembolus to escape filtration by the lungs. Venous collateral pathways draining into the left heart incited by superior vena cava obstruction are a rare acquired right-to-left shunt. Herein, the authors report on a case of transient ischemic attack in a patient with vena caval occlusion secondary to histoplasmosis-related fibrosing mediastinitis, with subclavian vein thrombosis and a right-to-left extracardiac shunt diagnosed with echocardiography. Despite the complexity of the collateral network, this shunt was successfully eradicated with coil embolization.

  View details for DOI 10.1016/j.jvir.2009.09.022

  View details for Web of Science ID 000277367500017

  View details for PubMedID 20123198

• IN VITRO VALIDATION OF FINITE ELEMENT MODEL OF AAA HEMODYNAMICS INCORPORATING REALISTIC OUTFLOW BOUNDARY CONDITIONS 12th ASME Summer Bioengineering Conference Kung, E. O., Les, A. S., Medina, F. R., Wicker, R. B., McConnell, M. V., Taylor, C. A. AMER SOC MECHANICAL ENGINEERS. 2010: 419–420

  View details for Web of Science ID 000290705300210

• High-Contrast In Vivo Visualization of Microvessels Using Novel FeCo/GC Magnetic Nanocrystals MAGNETIC RESONANCE IN MEDICINE Lee, J. H., Sherlock, S. P., Terashima, M., Kosuge, H., Suzuki, Y., Goodwin, A., Robinson, J., Seo, W. S., Liu, Z., Luong, R., McConnell, M. V., Nishimura, D. G., Dai, H. 2009; 62 (6): 1497-1509

  Abstract

  FeCo-graphitic carbon shell nanocrystals are a novel MRI contrast agent with unprecedented high per-metal-atom-basis relaxivity (r(1) = 97 mM(-1) sec(-1), r(2) = 400 mM(-1) sec(-1)) and multifunctional capabilities. While the conventional gadolinium-based contrast-enhanced angiographic magnetic MRI has proven useful for diagnosis of vascular diseases, its short circulation time and relatively low sensitivity render high-resolution MRI of morphologically small vascular structures such as those involved in collateral, arteriogenic, and angiogenic vessel formation challenging. Here, by combining FeCo-graphitic carbon shell nanocrystals with high-resolution MRI technique, we demonstrate that such microvessels down to approximately 100 mum can be monitored in high contrast and noninvasively using a conventional 1.5-T clinical MRI system, achieving a diagnostic imaging standard approximating that of the more invasive X-ray angiography. Preliminary in vitro and in vivo toxicity study results also show no sign of toxicity.

  View details for DOI 10.1002/mrm.22132

  View details for Web of Science ID 000272067600017

  View details for PubMedID 19859938

  View details for PubMedCentralID PMC2824553

• Images in clinical medicine. A swinging heart. New England journal of medicine Kapoor, J. R., McConnell, M. V. 2009; 361 (18)

  View details for DOI 10.1056/NEJMicm0802946

  View details for PubMedID 19864670

• Analysis of In Situ and Ex Vivo Vascular Endothelial Growth Factor Receptor Expression During Experimental Aortic Aneurysm Progression ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY Tedesco, M. M., Terashima, M., Blankenberg, F. G., Levashova, Z., Spin, J. M., Backer, M. V., Backer, J. M., Sho, M., Sho, E., McConnell, M. V., Dalman, R. L. 2009; 29 (10): 1452-?

  Abstract

  Mural inflammation and neovascularization are characteristic pathological features of abdominal aortic aneurysm (AAA) disease. Vascular endothelial growth factor receptor (VEGFR) expression may also mediate AAA growth and rupture. We examined VEGFR expression as a function of AAA disease progression in the Apolipoprotein E-deficient (Apo E(-/-)) murine AAA model.Apo E(-/-) mice maintained on a high-fat diet underwent continuous infusion with angiotensin II at 1000 ng/kg/min (Ang II) or vehicle (Control) via subcutaneous osmotic pump. Serial transabdominal ultrasound measurements of abdominal aortic diameter were recorded (n=16 mice, 3 to 4 time points per mouse) for up to 28 days. Near-infrared receptor fluorescent (NIRF) imaging was performed on Ang II mice (n=9) and Controls (n=5) with scVEGF/Cy, a single-chain VEGF homo-dimer labeled with Cy 5.5 fluorescent tracer (7 to 18 microg/mouse IV). NIRF with inactivated single chain VEGF/Cy tracer (scVEGF/In, 18 microg/mouse IV) was performed on 2 additional Ang II mice to control for nonreceptor-mediated tracer binding and uptake. After image acquisition and sacrifice, aortae were harvested for analysis. An additional AAA mouse cohort received either an oral angiogenesis inhibitor or suitable negative or positive controls to clarify the significance of angiogenesis in experimental aneurysm progression. Aneurysms developed in the suprarenal aortic segment of all Ang II mice. Significantly greater fluorescent signal was obtained from aneurysmal aorta as compared to remote, uninvolved aortic segments in Ang II scVEGF/Cy mice or AAA in scVEGF/In mice or suprarenal aortic segments in Control mice. Signal intensity increased in a diameter-dependent fashion in aneurysmal segments. Immunostaining confirmed mural VEGFR-2 expression in medial smooth muscle cells. Treatment with an angiogenesis inhibitor attenuated AAA formation while decreasing mural macrophage infiltration and CD-31(+) cell density.Mural VEGFR expression, as determined by scVEGF/Cy fluorescent imaging and VEGFR-2 immunostaining, increases in experimental AAAs in a diameter-dependent fashion. Angiogenesis inhibition limits AAA progression. Clinical VEGFR expression imaging strategies, if feasible, may improve real-time monitoring of AAA disease progression and response to suppressive strategies.

  View details for DOI 10.1161/ATVBAHA.109.187757

  View details for Web of Science ID 000269848600010

  View details for PubMedID 19574559

  View details for PubMedCentralID PMC2752726

• An unusual case of partial anomalous pulmonary venous drainage: Utility of the cardiac MRI INTERNATIONAL JOURNAL OF CARDIOLOGY Kapoor, J. R., Katikireddy, C., Rubin, G., Schnittger, I., McConnell, M. V. 2009; 133 (1): E35-E36

  View details for DOI 10.1016/j.ijcard.2007.08.113

  View details for Web of Science ID 000263950100046

  View details for PubMedID 18164082

• Society for Cardiovascular Magnetic Resonance guidelines for reporting cardiovascular magnetic resonance examinations JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE Hundley, W. G., Bluemke, D., Bogaert, J. G., Friedrich, M. G., Higgins, C. B., Lawson, M. A., McConnell, M. V., Raman, S. V., van Rossum, A. C., Flamm, S., Kramer, C. M., Nagel, E., Neubauer, S. 2009; 11

  Abstract

  These reporting guidelines are recommended by the Society for Cardiovascular Magnetic Resonance (SCMR) to provide a framework for healthcare delivery systems to disseminate cardiac and vascular imaging findings related to the performance of cardiovascular magnetic resonance (CMR) examinations.

  View details for DOI 10.1186/1532-429X-11-5

  View details for Web of Science ID 000266105700001

  View details for PubMedID 19257889

  View details for PubMedCentralID PMC2662831

• A Human Ferritin Iron Oxide Nano-composite Magnetic Resonance Contrast Agent MAGNETIC RESONANCE IN MEDICINE Uchida, M., Terashima, M., Cunningham, C. H., Suzuki, Y., Willits, D. A., Willis, A. F., Yang, P. C., Tsao, P. S., McConnell, M. V., Young, M. J., Douglas, T. 2008; 60 (5): 1073-1081

  Abstract

  Macrophages play important roles in the immunological defense system, but at the same time they are involved in inflammatory diseases such as atherosclerosis. Therefore, imaging macrophages is critical to assessing the status of these diseases. Toward this goal, a recombinant human H chain ferritin (rHFn)-iron oxide nano composite has been investigated as an MRI contrast agent for labeling macrophages. Iron oxide nanoparticles in the form of magnetite (or maghemite) with narrow size distribution were synthesized in the interior cavity of rHFn. The composite material exhibited the R(2) relaxivity comparable to known iron oxide MRI contrast agents. Furthermore, the mineralized protein cages are readily taken up by macrophages in vitro and provide significant T2* signal loss of the labeled cells. These results encourage further investigation into the development of the rHFn-iron oxide contrast agent to assess inflammatory disease status such as macrophage-rich atherosclerotic plaques in vivo.

  View details for DOI 10.1002/mrm.21761

  View details for Web of Science ID 000260341700008

  View details for PubMedID 18956458

• Multimodal evaluation of in vivo magnetic resonance imaging of myocardial restoration by mouse embryonic stem cells JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Hendry, S. L., van der Bogt, K. E., Sheikh, A. Y., Arai, T., Dylla, S. J., Drukker, M., McConnell, M. V., Kutschka, I., Hoyt, G., Cao, F., Weissman, I. L., Connolly, A. J., Pelletier, M. P., Wu, J. C., Robbins, R. C., Yang, P. C. 2008; 136 (4): 1028-U14

  Abstract

  Mouse embryonic stem cells have demonstrated potential to restore infarcted myocardium after acute myocardial infarction. Although the underlying mechanism remains controversial, magnetic resonance imaging has provided reliable in vivo assessment of functional recovery after cellular transplants. Multimodal comparison of the restorative effects of mouse embryonic stem cells and mouse embryonic fibroblasts was performed to validate magnetic resonance imaging data and provide mechanistic insight.SCID-beige mice (n = 55) underwent coronary artery ligation followed by injection of 2.5 x 10(5) mouse embryonic stem cells, 2.5 x 10(5) mouse embryonic fibroblasts, or normal saline solution. In vivo magnetic resonance imaging of myocardial restoration by mouse embryonic stem cells was evaluated by (1) in vivo pressure-volume loops, (2) in vivo bioluminescence imaging, and (3) ex vivo TaqMan (Roche Molecular Diagnostics, Pleasanton, Calif) polymerase chain reaction and immunohistologic examination.In vivo magnetic resonance imaging demonstrated significant improvement in left ventricular ejection fraction at 1 week in the mouse embryonic stem cell group. This finding was validated with (1) pressure-volume loop analysis demonstrating significantly improved systolic and diastolic functions, (2) bioluminescence imaging and polymerase chain reaction showing superior posttransplant survival of mouse embryonic stem cells, (3) immunohistologic identification of cardiac phenotype within engrafted mouse embryonic stem cells, and (4) polymerase chain reaction measuring increased expressions of angiogenic and antiapoptotic genes and decreased expressions of antifibrotic genes.This study validates in vivo magnetic resonance imaging as an effective means of evaluating the restorative potential of mouse embryonic stem cells.

  View details for DOI 10.1016/j.jtcvs.2007.12.053

  View details for Web of Science ID 000260314800033

  View details for PubMedID 18954646

• Noninvasive assessment of coronary vasodilation using cardiovascular magnetic resonance in patients at high risk for coronary artery disease JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE Nguyen, P. K., Meyer, C., Engvall, J., Yang, P., McConnell, M. V. 2008; 10

  Abstract

  Impaired coronary vasodilation to both endothelial-dependent and endothelial-independent stimuli have been associated with atherosclerosis. Direct measurement of coronary vasodilation using x-ray angiography or intravascular ultrasound is invasive and, thus, not appropriate for asymptomatic patients or for serial follow-up. In this study, high-resolution coronary cardiovascular magnetic resonance (CMR) was used to investigate the vasodilatory response to nitroglycerine (NTG) of asymptomatic patients at high risk for CAD.A total of 46 asymptomatic subjects were studied: 13 high-risk patients [8 with diabetes mellitus (DM), 5 with end stage renal disease (ESRD)] and 33 age-matched controls. Long-axis and cross-sectional coronary artery images were acquired pre- and 5 minutes post-sublingual NTG using a sub-mm-resolution multi-slice spiral coronary CMR sequence. Coronary cross sectional area (CSA) was measured on pre- and post-NTG images and % coronary vasodilation was calculated.Patients with DM and ESRD had impaired coronary vasodilation to NTG compared to age-matched controls (17.8 +/- 7.3% vs. 25.6 +/- 7.1%, p = 0.002). This remained significant for ESRD patients alone (14.8 +/- 7.7% vs. 25.6 +/- 7.1%; p = 0.003) and for DM patients alone (19.8 +/- 6.3% vs. 25.6 +/- 7.1%; p = 0.049), with a non-significant trend toward greater impairment in the ESRD vs. DM patients (14.8 +/- 7.7% vs. 19.8 +/- 6.3%; p = 0.23).Noninvasive coronary CMR demonstrates impairment of coronary vasodilation to NTG in high-risk patients with DM and ESRD. This may provide a functional indicator of subclinical atherosclerosis and warrants clinical follow up to determine prognostic significance.

  View details for DOI 10.1186/1532-429X-10-28

  View details for Web of Science ID 000258405900001

  View details for PubMedID 18513419

• Quantitative characterization of myocardial infarction by cardiovascular magnetic resonance predicts future cardiovascular events in patients with ischemic cardiomyopathy JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE Yokota, H., Heidary, S., Katikireddy, C. K., Nguyen, P., Pauly, J. M., McConnell, M. V., Yang, P. C. 2008; 10

  Abstract

  Cardiovascular magnetic resonance (CMR) can provide quantitative data of the myocardial tissue utilizing high spatial and temporal resolution along with exquisite tissue contrast. Previous studies have correlated myocardial scar tissue with the occurrence of ventricular arrhythmia. This study was conducted to evaluate whether characterization of myocardial infarction by CMR can predict cardiovascular events in patients with ischemic cardiomyopathy (ICM).We consecutively studied 86 patients with ICM (LVEF < 50%, mean LVEF: 26 +/- 12%) with CMR before revascularization or medication therapy +/- implantable cardiac defibrillator, determined the amount of myocardial scar, and followed for development of cardiovascular events. Thirty-three patients (38%) had cardiovascular events (mean follow-up: 20 +/- 16 months). Patients who developed cardiovascular events had larger scar volume and scar percentage of the myocardium than those who did not develop cardiovascular events (16.8 +/- 12.4 cm3 vs. 11.7 +/- 12.6 cm3, p = 0.023 and 10.2 +/- 6.9% vs. 7.2 +/- 6.7%, p = 0.037, respectively). There were no significant differences in LVEDV, LVESV and LVEF between the patients with and without cardiovascular events (231 +/- 76 ml vs. 230 +/- 88 ml; 180 +/- 73 ml vs. 175 +/- 90 ml; and 25 +/- 10% vs. 27 +/- 13%, respectively).Quantification of the scar volume and scar percentage by CMR is superior to LVEDV, LVESV, and LVEF in prognosticating the future likelihood of the development of cardiovascular events in patients with ICM.

  View details for DOI 10.1186/1532-429X-10-17

  View details for Web of Science ID 000257207000002

  View details for PubMedID 18400089

  View details for PubMedCentralID PMC2322993

• Impaired Coronary Vasodilation by Magnetic Resonance Angiography Is Associated With Advanced Coronary Artery Calcification JACC-CARDIOVASCULAR IMAGING Terashima, M., Nguyen, P. K., Rubin, G. D., Iribarren, C., Courtney, B. K., Go, A. S., Fortmann, S. P., McConnell, M. V. 2008; 1 (2): 167-173

  Abstract

  This study evaluated the hypothesis that impaired nitroglycerin (NTG)-induced coronary vasodilation is associated with advanced coronary atherosclerosis in asymptomatic older patients.Atherosclerosis is associated with both structural and functional abnormalities of the vessel wall. Noninvasive functional measures of subclinical coronary atherosclerosis may help characterize high-risk subjects and guide preventive therapy.A total of 236 older patients (age 60 to 72 years, 33% female) without a history of cardiovascular disease were studied. Nitroglycerin-induced coronary vasodilation was measured by magnetic resonance angiography (MRA). Cross-sectional images of the right coronary artery were acquired before and 5 min after 0.4-mg sublingual NTG using a gated, breath-held spiral coronary MRA sequence (0.7-mm resolution). Quantitative analysis of the increase in cross-sectional area was performed in the 90% of patients (n = 212) with adequate image quality. Quantitation of coronary artery calcification (CAC) was performed by multidetector computed tomography using the Agatston method.Forty patients (19%) had advanced CAC (> or =400). Coronary vasodilation to NTG was significantly impaired (p = 0.02) in patients with advanced CAC (median [interquartile range] = 15.9% [4.2% to 28.0%] vs. 21.5% [9.6% to 36.6%] for CAC <400). Importantly, NTG-induced coronary vasodilation remained independently associated with advanced CAC after multivariate analysis incorporating risk factors (p = 0.02) and other potential confounders (p = 0.04). There was no significant difference in coronary vasodilation between men and women, but few women (n = 3) had advanced CAC.Impaired NTG-induced coronary vasodilation by MRA is associated with advanced coronary atherosclerosis in a community-based cohort of older asymptomatic subjects. Coronary MRA may provide a noninvasive functional assessment of subclinical coronary atherosclerosis.

  View details for DOI 10.1016/j.jcmg.2007.12.001

  View details for Web of Science ID 000207649700007

  View details for PubMedID 19356424

• FeCo/graphitic-shell nanocrystals as advanced magnetic-resonance-imaging and near-infrared agents NATURE MATERIALS Seo, W. S., Lee, J. H., Sun, X., Suzuki, Y., Mann, D., Liu, Z., Terashima, M., Yang, P. C., McConnell, M. V., Nishimura, D. G., Dai, H. 2006; 5 (12): 971-976

  Abstract

  Nanocrystals with advanced magnetic or optical properties have been actively pursued for potential biological applications, including integrated imaging, diagnosis and therapy. Among various magnetic nanocrystals, FeCo has superior magnetic properties, but it has yet to be explored owing to the problems of easy oxidation and potential toxicity. Previously, FeCo nanocrystals with multilayered graphitic carbon, pyrolytic carbon or inert metals have been obtained, but not in the single-shelled, discrete, chemically functionalized and water-soluble forms desired for biological applications. Here, we present a scalable chemical vapour deposition method to synthesize FeCo/single-graphitic-shell nanocrystals that are soluble and stable in water solutions. We explore the multiple functionalities of these core-shell materials by characterizing the magnetic properties of the FeCo core and near-infrared optical absorbance of the single-layered graphitic shell. The nanocrystals exhibit ultra-high saturation magnetization, r1 and r2 relaxivities and high optical absorbance in the near-infrared region. Mesenchymal stem cells are able to internalize these nanoparticles, showing high negative-contrast enhancement in magnetic-resonance imaging (MRI). Preliminary in vivo experiments achieve long-lasting positive-contrast enhancement for vascular MRI in rabbits. These results point to the potential of using these nanocrystals for integrated diagnosis and therapeutic (photothermal-ablation) applications.

  View details for DOI 10.1038/nmat1775

  View details for Web of Science ID 000242478600021

  View details for PubMedID 17115025

• Images in cardiovascular medicine. Cardiac magnetic resonance imaging for myocarditis: effective use in medical decision making. Circulation Fenster, B. E., Chan, F. P., Valentine, H. A., Yang, E., McConnell, M. V., Berry, G. J., Yang, P. C. 2006; 113 (22): e842-3

  View details for PubMedID 16754807

• Multicontrast black-blood MRI of carotid arteries: Comparison between 1.5 and 3 Tesla magnetic field strengths JOURNAL OF MAGNETIC RESONANCE IMAGING Yarnykh, V. L., Terashima, M., Hayes, C. E., Shimakawa, A., Takaya, N., Nguyen, P. K., Brittain, J. H., McConnell, M. V., Yuan, C. 2006; 23 (5): 691-698

  Abstract

  To compare black-blood multicontrast carotid imaging at 3T and 1.5T and assess compatibility between morphological measurements of carotid arteries at 1.5T and 3T.Five healthy subjects and two atherosclerosis patients were scanned in 1.5T and 3T scanners with a similar protocol providing transverse T1-, T2-, and proton density (PD)-weighted black-blood images using a fast spin-echo sequence with single- (T1-weighted) or multislice (PD-/T2-weighted) double inversion recovery (DIR) preparation. Wall and lumen signal-to-noise ratio (SNR) and wall/lumen contrast-to-noise ratio (CNR) were compared in 44 artery cross-sections by paired t-test. Interscanner variability of the lumen area (LA), wall area (WA), and mean wall thickness (MWT) was assessed using Bland-Altman analysis.Wall SNR and lumen/wall CNR significantly increased (P < 0.0001) at 3T with a 1.5-fold gain for T1-weighted images and a 1.7/1.8-fold gain for PD-/T2-weighted images. Lumen SNR did not differ for single-slice DIR T1-weighted images (P = 0.2), but was larger at 3T for multislice DIR PD-/T2-weighted images (P = 0.01/0.03). The LA, WA, and MWT demonstrated good agreement with no significant bias (P 0.5), a coefficient of variation (CV) of < 10%, and intraclass correlation coefficient (ICC) of > 0.95.This study demonstrated significant improvement in SNR, CNR, and image quality for high- resolution black-blood imaging of carotid arteries at 3T. Morphologic measurements are compatible between 1.5T and 3T.

  View details for DOI 10.1002/jmri.20562

  View details for Web of Science ID 000237124800011

  View details for PubMedID 16555259

• Dual in vivo magnetic resonance evaluation of magnetically labeled mouse embryonic stem cells and cardiac function at 1.5 T MAGNETIC RESONANCE IN MEDICINE Arai, T., Kofidis, T., Bulte, J. W., de Bruin, J., Venook, R. D., Berry, G. J., McConnell, M. V., Quertermous, T., Robbins, R. C., Yang, P. C. 2006; 55 (1): 203-209

  Abstract

  Cell therapy has demonstrated the potential to restore injured myocardium. A reliable in vivo imaging method to localize transplanted cells and monitor their restorative effects will enable a systematic investigation of this therapeutic modality. The dual MRI capability of imaging both magnetically labeled mouse embryonic stem cells (mESC) and their restorative effects on cardiac function in a murine model of acute myocardial infarction is demonstrated. Serial in vivo MR detection of transplanted mESC and monitoring of the mESC-treated myocardium was conducted over a 4-week period using a 1.5 T clinical scanner. During the 4-week duration, the mESC-treated myocardium demonstrated sustained improvement of the left ventricular (LV) ejection fraction and conservation of LV mass. Furthermore, no significant difference of their restorative effects on the cardiac function was created by the magnetic labeling of mESC. Thus, in vivo MRI enables simultaneous detection of transplanted mESC and their therapeutic effect on the injured myocardium.

  View details for DOI 10.1002/mrm.20702

  View details for Web of Science ID 000234342800025

  View details for PubMedID 16315206

• Primary Meningococcal Pericarditis: Case Report and Review of the Literature Infectious Diseases in Clinical Practice Tsai, V., Vagelos, R., Rosso, F., Boggs, J., McConnell, M. V., Montoya, J. G. 2006; 14 (3): 137-143

  View details for DOI 10.1097/01.idc.0000202256.96798.d6

• Real-time color-flow CMR in adults with congenital heart disease JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE de la Pena, E., Nguyen, P. K., Nayak, K. S., Yang, P. C., Rosenthal, D. N., Hu, B. S., Pauly, J. M., McConnell, M. V. 2006; 8 (6): 809-815

  Abstract

  CMR is valuable in the evaluation of congenital heart disease (CHD). Traditional flow imaging sequences involve cardiac and respiratory gating, increasing scan time and susceptibility to arrhythmias. We studied a real-time color-flow CMR system for the detection of flow abnormalities in 13 adults with CHD. All 16 congenital flow abnormalities previously detected by echocardiography were visualized using color-flow CMR, including atrial septal defects (n = 4), ventricular septal defects (n = 9), aortic coarctation (n = 1), Blalock-Taussig shunt (n = 1) and Fontan shunt (n = 1). Real-time color-flow CMR can identify intra- and extra-cardiac flow abnormalities in adults with congenital heart disease.

  View details for DOI 10.1080/10976640600777728

  View details for Web of Science ID 000241485600007

  View details for PubMedID 17060103

• Peri-infarct ischemia determined by cardiovascular magnetic resonance evaluation of myocardial viability and stress perfusion predicts future cardiovascular events in patients with severe ischemic cardiomyopathy JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE Tsukiji, M., Nguyen, P., Narayan, G., Hellinger, J., Chan, F., Herfkens, R., Pauly, J. M., McConnell, M. V., Yang, P. C. 2006; 8 (6): 773-779

  Abstract

  We assessed whether cardiovascular magnetic resonance imaging (CMR) of peri-infarct ischemia provides prognostic information in severe ischemic cardiomyopathy (ICM) patients referred for revascularization.Twenty-one patients with severe ICM were recruited prospectively for combined stress adenosine perfusion, late gadolinium enhancement, and rest perfusion studies. The patients were followed for in-hospital and post-discharge cardiovascular events.During 12+/- 9.8 months follow-up, 67% of the patients with peri-infarct ischemia and 13% of the patients without peri-infarct ischemia had cardiovascular events (p = 0.03). CONCLUSION. In severe ICM patients, the presence of peri-infarct ischemia was associated with a higher incidence of cardiovascular events.

  View details for DOI 10.1080/10976640600737615

  View details for Web of Science ID 000241485600002

  View details for PubMedID 17060098

• High-resolution real-time spiral MRI for guiding vascular interventions in a rabbit model at 1.5 T. Journal of magnetic resonance imaging : JMRI Terashima, M., Hyon, M., de la Pena-Almaguer, E., Yang, P. C., Hu, B. S., Nayak, K. S., Pauly, J. M., McConnell, M. V. 2005; 22 (5): 687-690

  Abstract

  To study the feasibility of a combined high spatial and temporal resolution real-time spiral MRI sequence for guiding coronary-sized vascular interventions.Eight New Zealand White rabbits (four normal and four with a surgically-created stenosis in the abdominal aorta) were studied. A real-time interactive spiral MRI sequence combining 1.1 x 1.1 mm(2) in-plane resolution and 189-msec total image acquisition time was used to image all phases of an interventional procedure (i.e., guidewire placement, balloon angioplasty, and stenting) in the rabbit aorta using coronary-sized devices on a 1.5 T MRI system.Real-time spiral MRI identified all rabbit aortic stenoses and provided high-temporal-resolution visualization of guide-wires crossing the stenoses in all animals. Angioplasty balloon dilatation and deployment of coronary-sized copper stents in the rabbit aorta were also successfully imaged by real-time spiral MRI.Combining high spatial and temporal resolution with spiral MRI allows real-time MR-guided vascular intervention using coronary-sized devices in a rabbit model. This is a promising approach for guiding coronary interventions.

  View details for PubMedID 16217745

• POsitive contrast magnetic resonance imaging of cells labeled with magnetic nanoparticles MAGNETIC RESONANCE IN MEDICINE Cunningham, C. H., Arai, T., Yang, P. C., McConnell, M. V., Pauly, J. M., Conolly, S. M. 2005; 53 (5): 999-1005

  Abstract

  Contrast agents incorporating superparamagnetic iron-oxide nanoparticles have shown promise as a means to visualize labeled cells using MRI. Labeled cells cause significant signal dephasing due to the magnetic field inhomogeneity induced in water molecules near the cell. With the resulting signal void as the means for detection, the particles behave as a negative contrast agent, which can suffer from partial-volume effects. In this paper, a new method is described for imaging labeled cells with positive contrast. Spectrally selective RF pulses are used to excite and refocus the off-resonance water surrounding the labeled cells so that only the fluid and tissue immediately adjacent to the labeled cells are visible in the image. Phantom, in vitro, and in vivo experiments show the feasibility of the new method. A significant linear correlation (r = 0.87, P < 0.005) between the estimated number of cells and the signal was observed.

  View details for DOI 10.1002/mrm.20477

  View details for Web of Science ID 000228796900002

  View details for PubMedID 15844142

• Noninvasive assessment of coronary vasodilation using magnetic resonance angiography JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Terashima, M., Meyer, C. H., Keeffe, B. G., Putz, E. J., De La Pena-Almaguer, E., Yang, P. C., Hu, B. S., Nishimura, D. G., McConnell, M. V. 2005; 45 (1): 104-110

  Abstract

  The purpose of this study was to investigate the use of coronary magnetic resonance angiography (MRA) for assessing human epicardial coronary artery vasodilation.Coronary vasodilation plays a vital role in the human coronary circulation. Previous studies of epicardial coronary vasodilation have used invasive coronary angiography. Coronary MRA may provide an alternative noninvasive method to directly assess changes in coronary size.Thirty-two subjects were studied: 12 patients (age 55 +/- 18 years) and 20 healthy subjects (age 34 +/- 4 years). High-resolution multi-slice spiral coronary MRA (in-plane resolution of 0.52 to 0.75 mm) was performed before and after sublingual nitroglycerin (NTG). Quantitative analysis of coronary vasodilation was performed on cross-sectional images of the right coronary artery (RCA). A time-course analysis of coronary vasodilation was performed in a subset of eight subjects for 30 min after NTG. Signal-to-noise ratio was also measured on the in-plane RCA images.Coronary MRA demonstrated a 23% increase in cross-sectional area after NTG (16.9 +/- 7.8 mm2 to 20.8 +/- 8.9 mm2, p <0.0001), with significant vasodilation between 3 and 15 min after NTG on time-course analysis. The MRA measurements had low interobserver variability (< or =5%) and good correlation with X-ray angiography (r=0.98). The magnitude of vasodilation correlated with baseline cross-sectional area (r=0.52, p=0.03) and age (r=0.40, p=0.019). Post-NTG images also demonstrated a 31% improvement in coronary signal-to-noise ratio (p = 0.002).Nitroglycerin-enhanced coronary MRA can noninvasively measure coronary artery vasodilation and is a promising noninvasive technique to study coronary vasomotor function.

  View details for DOI 10.1016/j.jacc.2004.09.057

  View details for Web of Science ID 000226012600020

  View details for PubMedID 15629383

• Dynamic real-time architecture in magnetic resonance coronary angiography-a prospective clinical trial JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE Yang, P. C., Santos, J. M., Nguyen, P. K., Scott, G. C., Engvall, J., McConnell, M. V., Wright, G. A., Nishimura, D. G., Pauly, J. M., Hu, B. S. 2004; 6 (4): 885-894

  Abstract

  A dynamic real-time (dRT) architecture has been developed to address limitations in magnetic resonance coronary angiography (MRCA). A prospective clinical trial of 45 patients suspected of coronary artery disease was conducted to determine clinical utility of this integrated real-time system.Clinical implementation of MRCA is not performed routinely today. However, improved anatomic coverage, image quality, and scan flexibility may enhance its clinical utility. A novel real-time architecture addresses these challenges through instantaneous reconfiguration between real-time (RT) and high-resolution (HR) imaging sequences with dynamic selection of the desired element on a custom-designed receiver coil.A total of 45 subjects were recruited consecutively to evaluate scan time, anatomic coverage, image quality, and detection of coronary lesions. Using a modern PC, the dRT switches from RT to gated HR imaging sequence in one repetition time (39 ms). Magnetic resonance imaging (MRI) scanning was performed using a custom-designed coronary coil consisting of two four-inch phase-array circular elements enabled with real-time selection of the desired coil element.All studies were completed in less than 45 minutes and required a mean of 12 breath holds (16 heartbeats). Of the total number of coronary segments, 91% (357/394) were visualized. Excellent or good image quality was achieved in 86% of the segments. Blinded analysis of the coronary arteries revealed sensitivity of 93% and specificity of 88% in the detection of coronary stenoses.The integrated environment of dRT provides a rapid and flexible scan protocol for MRCA while achieving wide anatomical coverage, high image quality, and reliable detection of coronary stenosis in short scan time.

  View details for DOI 10.1016/j.JCMR.20036192

  View details for Web of Science ID 000226039200015

  View details for PubMedID 15646892

• Spiral magnetic resonance coronary angiography - Direct comparison of 1.5 tesla vs. 3 tesla JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE Yang, P. C., Nguyen, P., Shimakawa, A., Brittain, J., Pauly, J., Nishimura, D., Hu, B., McConnell, M. 2004; 6 (4): 877-884

  Abstract

  MR coronary angiography (MRCA) has been demonstrated successfully at 3 Tesla (T). However, the advantages remain unclear. No systematic comparison of MRCA between 1.5 T and 3 T has been performed. Therefore, anatomic coverage, image quality, signal-to-noise ratio (SNR), contrast-to-noise ration (CNR), and susceptibility artifacts were compared in 23 subjects.Identical real-time (RT) and high-resolution (HR) sequences were implemented on the GE 1.5 T (Signa Twinspeed) and 3.0 T (Signa VH/i) whole body systems (GE, Milwaukee, WI). Both scanners were equipped with high-performance gradient systems capable of 40 mT/m peak amplitude and 150 mT/m/ms slew rate. Real-time localization of the coronary arteries was followed by a cardiac-gated, breath-hold HR sequence. Twenty-three subjects were recruited consecutively and underwent both 3 T and 1.5 T MRCA within one week. Coronary coverage based on the number of coronary segments visualized, image quality using a grading scale, SNR, CNR, and presence of susceptibility artifacts were analyzed. A significant improvement in SNR (47%), CNR (30%), and image quality were seen in 3 T. However, a significant increase in susceptibility artifacts was also noted.MRCA at 3 T significantly improves SNR, CNR, and image quality at the expense of susceptibility artifacts. Further optimization of the imaging parameters at 3 T may facilitate clinical implementation of MRCA.

  View details for DOI 10.1081/JCMR.20036180

  View details for Web of Science ID 000226039200014

  View details for PubMedID 15646891

• A visual approach for the accurate determination of echocardiographic left ventricular ejection fraction by medical students JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Hope, M. D., de la Pena, E., Yang, P. C., Liang, D. H., McConnell, M. V., Rosenthal, D. N. 2003; 16 (8): 824-831

  Abstract

  Previously published reports show that there is significant intraobserver, interobserver, and interinstitutional variability in the determination of left ventricular (LV) ejection fraction (EF) by echocardiography. With the increased deployment of echocardiography (eg, handheld devices), there exists a need for developing a simple, intuitive approach for evaluating LVEF that allows a wider range of physicians to accurately and rapidly determine LVEF.We sought to create a system for assessing LVEF that relies on recognition and matching of patterns, rather than on mathematic calculations and geometric assumptions.A library of videoclips of cardiac function was compiled from 54 patients who spanned the spectrum of LVEF. LVEFs were calculated for these patients using standard echocardiographic methods, with further validation of a subsample using cardiac magnetic resonance imaging measurement of LVEF. The library of images was used to create a software tool for assessing LVEF on the basis of a "template-matching" approach. The software tool was then tested on medical students (N=13) to determine whether it enabled relatively untrained individuals to make accurate LVEF estimates.Using a template-matching approach for interpretation of echocardiograms, medical students were able to accurately estimate LVEF after only a limited introduction to echocardiography. Their LVEF estimates showed good correlation and agreement with gold standard (r = 0.88, standard square of the estimate = 6.0, limits of agreement = +12.0%, -15.6%).A new visual approach for assessing cardiac function using template matching can accurately estimate LVEF. With minimal training, medical students can make LVEF estimates that correlate well with gold standard. The application of this new approach includes allowing for the interpretation of LVEF from echocardiograms to be performed by a broader spectrum of physicians.

  View details for DOI 10.1067/S0894-7317(03)00400-0

  View details for Web of Science ID 000184604400007

  View details for PubMedID 12878991

• Spiral magnetic resonance coronary angiography with rapid real-time localization JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Yang, P. C., Meyer, C. H., Terashima, M., Kaji, S., McConnell, M. V., Macovski, A., Pauly, J. M., Nishimura, D. G., Hu, B. S. 2003; 41 (7): 1134-1141

  Abstract

  A spiral high-resolution coronary artery imaging sequence (SH) interfaced with real-time localization system (RT) has been developed. A clinical study of 40 patients suspected of coronary artery disease (CAD) was conducted. Segmented k-space acquisition techniques have dominated magnetic resonance coronary angiography (MRCA) over the last decade. Although a recent multicenter trial using this technique demonstrated encouraging results, the technique was hampered by low specificity. Spiral k-space acquisition had demonstrated several advantages for MRCA. Therefore, a first clinical trial implementing spiral high-resolution coronary imaging sequence with real-time localization (SH-RT) was performed.A clinical study of 40 patients suspected of CAD undergoing X-ray angiography was conducted to analyze the clinical reliability of this novel imaging system. The SH-RT had been designed to exploit the unique capability of two imaging sequences. The RT allowed a rapid localization of the coronary arteries. Then SH achieved multislice acquisition during a short breath-hold with submillimeter resolution. The MRCA data were analyzed for scan time, anatomic coverage, image quality, and accuracy in detecting CAD. In 40 subjects, SH achieved 0.7 to 0.9 mm resolution with 14-heartbeat breath-holds. Excellent or good image quality was achieved in 78% (263/337) of the coronary segments. Blinded consensus reading among three observers generated sensitivity of 76% and specificity of 91% in the detection of CAD compared with X-ray angiography. The MRCA imaging sequence implementing a novel spiral k-space acquisition technique enabled rapid and reliable imaging of the CAD in submillimeter resolution with short breath-holds.

  View details for DOI 10.1016/S0735-1097(03)00079-2

  View details for Web of Science ID 000181968900011

  View details for PubMedID 12679213

• Magnetic resonance coronary angiography. Current cardiology reports Yang, P. C., McConnell, M. V., Nishimura, D. G., Hu, B. S. 2003; 5 (1): 55-62

  Abstract

  Magnetic resonance coronary angiography (MRCA) has witnessed tremendous technical advances over the past decade. Although high-quality images of the coronary arteries have been demonstrated, this imaging modality is not performed routinely today. The fundamental properties of the coronary arteries deterring noninvasive imaging are well known. This article provides an overview of the developmental efforts to overcome these challenges, and highlights key technical and clinical advances. The future prospect of MRCA depends on clinical implementation of the technique. In order to meet this challenge, the following issues must be addressed: contrast- and signal-to-noise ratio, temporal and spatial resolution, and scan protocol.

  View details for PubMedID 12493161

• Echocardiographic and magnetic resonance methods for diagnosing hibernating myocardium NUCLEAR MEDICINE COMMUNICATIONS Cho, S., McConnell, M. V. 2002; 23 (4): 331-339

  Abstract

  Hibernating myocardium refers to regions of impaired left ventricular function at rest due to coronary artery disease that is reversible with revascularization. The accurate identification and assessment of myocardial viability is a critical aspect of the management of the patient with coronary artery disease and left ventricular dysfunction. Several non-invasive methods exist to assist the clinician in distinguishing those patients with significant regions of hibernating myocardium from those who have non-viable scar. This is important not only to identify those patients who would most benefit from percutaneous intervention or surgery, but also to spare the latter group from the morbidity and mortality associated with a revascularization procedure that would provide little benefit. While nuclear medicine imaging is the most widely used means for evaluating myocardial viability, alternative modalities have emerged and have gained increasing acceptance in recent years. This article will review the echocardiographic and magnetic resonance imaging (MRI) methods that are currently available or under investigation to assess myocardial viability. These techniques include rest and stress echocardiography, myocardial contrast echocardiography, stress MRI, contrast-enhanced MRI and magnetic resonance spectroscopy (MRS).

  View details for Web of Science ID 000175245600006

  View details for PubMedID 11930186

• In vivo real-time intravascular MRI JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE Rivas, P. A., Nayak, K. S., Scott, G. C., McConnell, M. V., Kerr, A. B., Nishimura, D. G., Pauly, J. M., Hu, B. S. 2002; 4 (2): 223-232

  Abstract

  The Magnetic resonance imaging (MRI) is an emerging technology for catheter-based imaging and interventions. Real-time MRI is a promising methodfor overcoming catheter and physiologic motion for intravascular imaging.All imaging was performed on a 1.5 T Signa MRI scanner with high-speed gradients. Multiple catheter coils were designed and constructed, including low-profile, stub-matched coils. Coil sensitivity patterns and SNR measurements were compared. Real-time imaging was performed with an interleaved spiral sequence using a dedicated workstation, providing real-time data acquisition, image reconstruction and interactive control and display. Real-time "black-blood" imaging was achieved through incorporation of off-slice saturation pulses. The imaging sequence was tested in a continuous flow phantom and then in vivo in the rabbit aorta using a 2 mm catheter coil.The real-time intravascular imaging sequence achieved 120-440 micron resolution at up to 16 frames per second. Low-profile stub-tuned catheter coils achieved similar SNR to larger traditional coil designs. In the phantom experiments, addition of real-time black-blood saturation pulses effectively suppressed the flow signal and allowed visualization of the phantom wall. In vivo experiments clearly showed real-time intravascular imaging of the rabbit aortic wall with minimal motion artifacts and effective blood signal suppression.Real-time imaging with low-profile coil designs provides significant enhancements to intravascular MRI.

  View details for Web of Science ID 000176057200005

  View details for PubMedID 12074137

• The diagnosis of congenital coronary anomalies with magnetic resonance imaging CORONARY ARTERY DISEASE Danias, P. G., Stuber, M., McConnell, M. V., Manning, W. J. 2001; 12 (8): 621-626

  View details for Web of Science ID 000173023400005

  View details for PubMedID 11811327

• Imaging techniques to predict cardiovascular risk. Current cardiology reports McConnell, M. V. 2000; 2 (4): 300-307

  Abstract

  Conventional cardiovascular imaging, with a focus on identifying flow-limiting stenoses, does not directly image the atherosclerotic lesion. Recent clinical and pathobiologic data indicate that stenosis severity does not dictate cardiovascular risk and that there are functional, structural, and biologic features of atherosclerosis that are associated with cardiovascular events. Imaging technologies, such as ultrasound, light, x-ray, magnetic resonance, and targeted contrast agents, have been developed to characterize directly the atherosclerotic vessel wall. They provide promising approaches to predict cardiovascular risk and facilitate further study of the mechanisms of atherosclerosis progression and its response to therapy.

  View details for PubMedID 10953263

• Clinical role of coronary magnetic resonance angiography in the diagnosis of anomalous coronary arteries JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE McConnell, M. V., Stuber, M., Manning, W. J. 2000; 2 (3): 217-224

  Abstract

  Though rare, anomalous coronary artery disease is a well-known cause of myocardial ischemia and sudden death among children and young adults. The projectional nature of conventional x-ray angiography often leads to difficulty in the definition of anomalous vessels. Studies have now documented the high accuracy of coronary magnetic resonance angiography (MRA) for the noninvasive detection and definition of anomalous coronary arteries among patients with suspected anomalous coronary arteries of congenital conditions associated with anomalous coronary arteries. With increasing clinical experience, coronary MRA will likely emerge as the gold standard for the diagnosis of this condition.

  View details for Web of Science ID 000165077200009

  View details for PubMedID 11545120

• Contrast agent-enhanced, free-breathing, three-dimensional coronary magnetic resonance angiography JOURNAL OF MAGNETIC RESONANCE IMAGING Stuber, M., Botnar, R. M., Danias, P. G., McConnell, M. V., Kissinger, K. V., Yucel, E. K., Manning, W. J. 1999; 10 (5): 790-799

  Abstract

  For free-breathing, high-resolution, three-dimensional coronary magnetic resonance angiography (MRA), the use of intravascular contrast agents may be helpful for contrast enhancement between coronary blood and myocardium. In six patients, 0.1 mmol/kg of the intravascular contrast agent MS-325/AngioMARK was given intravenously followed by double-oblique, free-breathing, three-dimensional inversion-recovery coronary MRA with real-time navigator gating and motion correction. Contrast-enhanced, three-dimensional coronary MRA images were compared with images obtained with a T2 prepulse (T2Prep) without exogenous contrast. The contrast-enhanced images demonstrated a 69% improvement in the contrast-to-noise ratio (6.6 +/- 1.1 vs. 11.1 +/- 2.5; P < 0.01) compared with the T2Prep approach. By using the intravascular agent, extensive portions (> 80 mm) of the native left and right coronary system could be displayed consistently with sub-millimeter in-plane resolution. The intravascular contrast agent, MS-325/AngioMARK, leads to a considerable enhancement of the blood/muscle contrast for coronary MRA compared with T2Prep techniques. The clinical value of the agent remains to be defined in a larger patient series. J. Magn. Reson. Imaging 1999;10:790-799.

  View details for Web of Science ID 000087572100025

  View details for PubMedID 10548790

• MRI of rabbit atherosclerosis in response to dietary cholesterol lowering ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY McConnell, M. V., Aikawa, M., Maier, S. E., Ganz, P., Libby, P., Lee, R. T. 1999; 19 (8): 1956-1959

  Abstract

  Direct imaging of the atherosclerotic plaque, rather than the angiographic lumen, may provide greater insight into the response of atherosclerosis to cholesterol-lowering therapy. Aortic plaque was studied in vivo by MRI in rabbits undergoing dietary cholesterol intervention. Thirty-one rabbits underwent aortic balloon injury and high-cholesterol diet for 4 months and then were assigned to low-cholesterol versus continued high-cholesterol diet for up to an additional 16 months. High-resolution (310 micrometer) fast spin-echo MRI of the abdominal aorta was performed at 4, 12, and 20 months and compared with histology. MRI demonstrated a significant reduction in % area stenosis in rabbits placed on low-cholesterol diet (44.6+/-2. 1% at 20 months versus 55.8+/-1.5% at 4 months, P=0.0002). In contrast, % area stenosis increased in rabbits maintained on high-cholesterol diet (69.8+/-3.8% at 20 months versus 55.8+/-1.5% at 4 months, P=0.001). Similarly, plaque thickness decreased significantly in the low-cholesterol group (0.60+/-0.05 mm at 20 months versus 0.85+/-0.06 mm at 4 months, P=0.006), with a trend toward increase in the high-cholesterol group (1.02+/-0.08 mm at 20 months versus 0.85+/-0.06 mm at 4 months, P=0.1). Thus, in rabbits undergoing dietary cholesterol lowering, MRI detected regression of aortic atherosclerotic plaque in vivo. Plaque progression was seen with maintenance of high-cholesterol diet. MRI is a promising noninvasive technology for directly imaging atherosclerosis and its response to therapeutic interventions.

  View details for Web of Science ID 000082104500019

  View details for PubMedID 10446077

• Recovery of regional right ventricular function after thrombolysis for pulmonary embolism AMERICAN JOURNAL OF CARDIOLOGY Nass, N., McConnell, M. V., Goldhaber, S. Z., Chyu, S., Solomon, S. D. 1999; 83 (5): 804-806

  Abstract

  Abnormalities in right ventricular regional and global function can occur in the setting of acute pulmonary embolism. Treatment of acute pulmonary embolism with thrombolysis is associated with significant improvement in regional and global right ventricular function.

  View details for Web of Science ID 000078930900036

  View details for PubMedID 10080447

• Effects of a single, daily alcoholic beverage on lipid and hemostatic markers of cardiovascular risk AMERICAN JOURNAL OF CARDIOLOGY McConnell, M. V., Vavouranakis, I., Wu, L. L., Vaughan, D. E., Ridker, P. M. 1997; 80 (9): 1226-?

  Abstract

  There is substantial epidemiologic data, but limited experimental data, supporting the mortality benefit of low-dose alcohol consumption. A regimen of a single, daily alcoholic beverage was sufficient to increase both high-density lipoprotein (HDL) (4.4%, p = 0.03) and HDL2 (7.7%, p = 0.04) in men and women, but did not significantly affect hemostatic markers of cardiovascular risk.

  View details for Web of Science ID A1997YD11600024

  View details for PubMedID 9359559

• Prospective navigator correction of image position for coronary MR angiography RADIOLOGY Danias, P. G., McConnell, M. V., Khasgiwala, V. C., Chuang, M. L., Edelman, R. R., Manning, W. J. 1997; 203 (3): 733-736

  Abstract

  To determine the potential benefit of prospective navigator correction of image position for coronary magnetic resonance (MR) angiography.Two-dimensional MR angiograms were obtained with free breathing in 12 adult subjects. Navigator gating was used with and without prospective correction and with gating windows set at 3, 5, and 7 mm. MR angiograms were compared with those obtained with conventional, end-expiratory breath holding.Navigator gating with correction resulted in image quality equivalent to that obtained with breath holding, even with the 7-mm gating window. In contrast, navigator gating without correction allowed only maintenance of image quality similar to that obtained with breath holding for the 3- and 5-mm windows and resulted in decreased image quality with the 7-mm window (P < .05). Use of navigator gating with correction and the 7-mm window resulted in a 28% decrease in imaging time compared with breath holding and a 33% decrease compared with the 3-mm gating window (P < .05 for both comparisons).Prospective, adaptive navigator correction of image position for free-breathing coronary MR angiography is a promising, novel approach to compensate for respiratory motion.

  View details for Web of Science ID A1997XA57800026

  View details for PubMedID 9169696

• Comparison of respiratory suppression methods and navigator locations for MR coronary angiography AMERICAN JOURNAL OF ROENTGENOLOGY McConnell, M. V., Khasgiwala, V. C., Savord, B. J., Chen, M. H., Chuang, M. L., Edelman, R. R., Manning, W. J. 1997; 168 (5): 1369-1375

  Abstract

  Currently, breath-holding during MR coronary angiography is used to minimize respiratory motion. This technique requires patient cooperation and is associated with slice registration errors. The goal of this study was to evaluate alternative non-breath-hold techniques for MR coronary angiography during free breathing.Subjects underwent MR coronary angiography using an ECG-gated, fat-suppressed, segmented K-space, gradient-echo sequence. Images were obtained during free breathing using both real-time navigator gating and respiratory bellows gating. These were compared with images obtained during conventional breath-holding. The optimal navigator location (diaphragmatic or cardiac) was also studied. Image quality, registration error, and scan time were measured for all scans.Navigator gating for MR coronary angiography during free breathing resulted in image quality equivalent to that obtained during breath-holding and was superior to that obtained with respiratory bellows gating (p < .04). Also, navigator gating reduced registration errors by 75% compared with breath-holding (p < .01) and did not increase scan time. No significant differences in the parameters measured were observed among the different navigator locations.Real-time navigator gating for MR coronary angiography during free breathing achieved image quality and scan time equivalent to breath-holding. Navigator gating also significantly reduced registration error. Compared with breath-holding and respiratory bellows gating, navigator gating during free breathing is a more optimal approach for suppression of respiratory motion during MR coronary angiography.

  View details for Web of Science ID A1997WV56800051

  View details for PubMedID 9129447

• Prospective adaptive navigator correction for breath-hold MR coronary angiography MAGNETIC RESONANCE IN MEDICINE McConnell, M. V., Khasgiwala, V. C., Savord, B. J., Chen, M. H., Chuang, M. L., Edelman, R. R., Manning, W. J. 1997; 37 (1): 148-152

  Abstract

  Current MR coronary angiography (MRCA) methods use breath-holding to minimize respiratory motion. A major limitation to this technique is misregistration between imaging slices due to breath-hold variability. Prospective adaptive correction of image location using real-time navigator measurement of diaphragm position is a potential method for improving slice registration in breath-hold MRCA. Ten subjects underwent MRCA using an ECG-gated, fat-suppressed, segmented k-space, gradient-echo sequence. Transverse and coronal images were acquired using standard breath-holding with and without prospective navigator correction. Breath-hold MRCA with prospective navigator correction resulted in a 47% reduction in craniocaudal slice registration error compared to standard breath-holding (0.9 +/- 0.2 mm versus 1.7 +/- 0.4 mm, P = 0.04). Prospective adaptive navigator correction of image location significantly improves slice registration for breath-hold MRCA and is a promising motion correction technique for cardiac MR.

  View details for Web of Science ID A1997VZ62900020

  View details for PubMedID 8978644

• Adaptive correction of imaging plane position in segmented k-space cine cardiac MRI J Magn Reson Imaging Chuang, M. L., Chen, M. H., Khasgiwala, V. C., McConnell, M. V., Edelman, R. R., Manning, W. J. 1997; 7 (5): 811-4
• Pathogenic mechanisms of atherosclerosis: effect of lipid lowering on the biology of atherosclerosis. American journal of medicine Ganz, P., Creager, M. A., Fang, J. C., McConnell, M. V., Lee, R. T., Libby, P., SELWYN, A. P. 1996; 101 (4A): 4A10S-16S

  Abstract

  Numerous trials have demonstrated that cholesterol-lowering therapy leads to marked reductions in cardiovascular and overall mortality and in the need for coronary revascularization. Angiographic regression trials have shown that cholesterol lowering can reduce progression and, in some instances, achieve regression of coronary atherosclerotic lesions. However, recent studies have contradicted the traditional view that the clinical course of coronary artery disease is closely linked to the severity of coronary artery stenosis. It is now apparent that stenoses responsible for myocardial infarction or unstable angina are typically mild rather than severe. These observations suggest that regression may not be the principal mechanism by which cholesterol lowering affects cardiovascular risk. Two mechanisms---plaque stabilization and improved endothelial function-have been examined in this regard. Basic studies suggest that cholesterol lowering favorably alters those features of atherosclerosis that promote plaque stability. Recent clinical studies have clearly established that aggressive lipid-lowering therapy improves endothelial function and reduces myocardial ischemia in patients with hypercholesterolemia.

  View details for PubMedID 8900332

• Regional right ventricular dysfunction detected by echocadiography in acute pulmonary embolism AMERICAN JOURNAL OF CARDIOLOGY McConnell, M. V., Solomon, S. D., Rayan, M. E., Come, P. C., Goldhaber, S. Z., Lee, R. T. 1996; 78 (4): 469-473

  Abstract

  This study analyzed the regional pattern of right ventricular (RV) dysfunction on transthoracic echocardiograms in patients with and without acute pulmonary embolism. Quantitative (centerline) and qualitative (wall motion score) analyses of segmental RV free wall motion were performed on a "training" cohort of 41 patients (group 1), including 14 patients with acute pulmonary embolism, 9 patients with primary pulmonary hypertension, and 18 normal subjects. Patients with acute pulmonary embolism had a distinct regional pattern of RV dysfunction, with akinesia of the mid-free wall (centerline excursion: -0.2 +/- 0.8 mm, p = 0.0001 vs normal) but normal motion at the apex (centerline excursion: 5.7 +/- 0.8 mm, p = NS vs normal). In contrast, patients with primary pulmonary hypertension had abnormal wall motion in all regions (p <0.03 vs normal). This echocardiographic finding of normal wall motion at the apex and abnormal wall motion in the mid-free wall in acute pulmonary embolism was then tested in a "validation" cohort of 85 patients (group 2), consisting of hospitalized patients with RV dysfunction from any cause, including 13 patients with acute pulmonary embolism. The finding had a 77% sensitivity and a 94% specificity for the diagnosis of acute pulmonary embolism, with a positive predictive value of 71% and a negative predictive value of 96%. Thus, a distinct echocardiographic pattern of regional RV dysfunction, in which the apex is spared occurs in acute pulmonary embolism. This finding should raise the level of clinical suspicion for the diagnosis of acute pulmonary embolism.

  View details for Web of Science ID A1996VD82700016

  View details for PubMedID 8752195

• IDENTIFICATION OF ANOMALOUS CORONARY-ARTERIES AND THEIR ANATOMIC COURSE BY MAGNETIC-RESONANCE CORONARY ANGIOGRAPHY CIRCULATION McConnell, M. V., Ganz, P., SELWYN, A. P., Li, W., Edelman, R. R., Manning, W. J. 1995; 92 (11): 3158-3162

  Abstract

  Anomalous coronary arteries are a rare but recognized cause of myocardial ischemia and sudden death. Identification currently requires x-ray angiography, which may have difficulty defining the three-dimensional course of the anomalous vessel. Magnetic resonance coronary angiography (MRCA) has been shown to image coronary artery anatomy noninvasively. We hypothesize that MRCA may be useful in the identification of anomalous coronary arteries and their anatomic course.Sixteen patients (9 men, 7 women, age 44 to 81 years) with anomalous aortic origins of the coronary arteries by conventional x-ray angiography underwent MRCA. Multiple images of the major epicardial coronary arteries were obtained by use of a breathhold, fat-suppressed, segmented-k space, gradient-echo technique by investigators blinded to all patient data. Anomalous coronary artery pathology, by x-ray angiography, included right-sided left main coronary artery (n = 3), right-sided left circumflex artery (n = 6), separate left-sided left anterior descending and left circumflex arteries (n = 2), left-sided right coronary artery (n = 4), and an anteriorly displaced right coronary artery (n = 1). MRCA correctly identified the anomalous coronary vessel(s) in 14 of 15 patients. In 1 patient, the anomalous vessel was incorrectly identified, and in 2 patients the course of the anomalous vessel was not clearly seen; one of these was a nondominant, anomalous right coronary artery.MRCA is a useful technique for the noninvasive identification of anomalous coronary arteries and their anatomic course.

  View details for Web of Science ID A1995TG29200004

  View details for PubMedID 7586298

• CELLULAR BASIS OF ALLOGRAFT-REJECTION INVIVO .5. EXAMINATION OF THE MECHANISMS RESPONSIBLE FOR THE DIFFERING EFFICACY OF MONOCLONAL-ANTIBODY TO CD4+ T-CELL SUBSETS IN LOW-RESPONDER AND HIGH-RESPONDER RAT STRAINS JOURNAL OF IMMUNOLOGY ILANO, A. L., McConnell, M. V., Gurley, K. E., Spinelli, A., Pearce, N. W., Hall, B. M. 1989; 143 (9): 2828-2836

  Abstract

  MRC OX35, an anti-CD4 mAb, was used to treat high responder Wistar Furth (W/F) (RT1u) and low responder DA (RT1a) rats which had been grafted with directly vascularized hearts from PVG (RT1c) rats across a full MHC plus non-MHC incompatibility. Four doses of mAb at 7 mg/kg given in the first 2 wk postgrafting induced indefinite graft survival (greater than 150 days) in DA hosts, but only delayed rejection to 18 to 42 days in W/F as compared to rejection times of 6 to 8 days in untreated rats. The extension of MRC OX35 treatment to 6 wk in W/F rats induced indefinite graft survival in three of six rats. During treatment MRC OX35 therapy only partially depleted CD4+ cells, and all circulating CD4+ cells were coated with MRC OX35. The capacity of naive CD4+ and CD8+ cells from W/F and DA to be activated to PVG alloantigen was compared both in vitro in an MLC assay and in vivo by an adoptive transfer assay of their capacity to restore rejection of PVG heart grafts in irradiated syngeneic hosts. CD4+ cells from both W/F and DA proliferated in MLC and restored graft rejection. W/F CD8+ cells both proliferated in MLC and restored rejection, but DA CD8+ cells neither proliferated nor reconstituted rejection. Examination of lymphocytes from MRC OX35 treated hosts with long-surviving grafts showed that they were neither depleted of CD4+ T cells nor did they lack the capacity to proliferate to PVG Ag in MLC, this response being similar to that to third-party Ag or by naive lymphocytes. Compared to first-set rejection, PVG skin graft rejection was delayed 2 to 3 days in W/F and 10 to 12 days in DA rats with long-surviving grafts after MRC OX35 therapy, whereas they rejected third-party skin grafts in first-set tempo. These studies show that differences in graft survival in anti-CD4 treated low and high responder strains may be due to the inherent capacity of CD8+ cells to be activated to effect rejection independent of CD4+ cells in W/F but not in DA. In those hosts that accept grafts, there is no evidence of clonal deletion, but there appears to be a form of unresponsiveness akin to that induced in adult rats by other immunosuppressive therapies that protects the graft from rejection.

  View details for Web of Science ID A1989AW84000008

  View details for PubMedID 2572644

• COMPARISON OF CD4 AND CD8 T-CELL REACTIVITY IN HIGH-RESPONDER AND LOW-RESPONDER STRAIN COMBINATIONS IN THE RAT TRANSPLANTATION PROCEEDINGS McConnell, M. V., Hall, B. M. 1989; 21 (2): 3294-3295

  View details for Web of Science ID A1989U239800025

  View details for PubMedID 2496503

• PACEMAKER DIAGNOSTIC DIAGRAMS PACE-PACING AND CLINICAL ELECTROPHYSIOLOGY Olson, W. H., McConnell, M. V., Sah, R. L., Beck, R. C., Sutton, R. 1985; 8 (5): 691-700

  Abstract

  Dual-chamber pacemakers interact with cardiac rhythms in complex ways. The resultant surface electrocardiograms (ECGs) are often very difficult to interpret. A simple and automatic diagnostic diagram is described that graphically illustrates pacemaker-heart interactions. Pacemaker operation is explained by a continuous series of lines and symbols that interconnect any sequence of paced and sensed events in both chambers. Fixed, programmable, and adaptive pacemaker timing intervals are all shown in a simple format. The pacemaker diagnostic diagram is plotted directly below the ECG to help users interpret the paced cardiac rhythm. The pacemaker diagnostic diagram is generated by software in a pacemaker programmer from: (1) telemetered real-time event markers; (2) fixed and programmable timing parameters (lower rate, AV interval, etc.); (3) pacemaker conditional logic. If this computer analysis of the telemetered event markers is not consistent with normal pacemaker operation, a specific error-message is printed. The pacemaker diagnostic diagram should be useful for instruction, pacemaker follow-up, and troubleshooting.

  View details for Web of Science ID A1985AQP1600010

  View details for PubMedID 2414751