Bio

Clinical Focus


  • Cardiology (Heart)
  • Cardiovascular Disease

Academic Appointments


Administrative Appointments


  • Associate Professor, Stanford Division of Cardiovascular Medicine (2012 - Present)
  • Director, Cardiothoracic MRI Program, Stanford Division of Cardiovascular Medicine (2012 - Present)
  • Director, Cardiovascular Stem Cell Laboratory, Stanford Division of Cardiovascular Medicine (2005 - Present)
  • Assistant Professor, Stanford Division of Cardiovascular Medicine (2005 - 2012)
  • Clinical Instructor & Staff Physician, Stanford Division of Cardiovascular Medicine (1999 - 2005)
  • Cardiology Fellow, Stanford Division of Cardiovascular Medicine (1994 - 1999)

Honors & Awards


  • Cardiovascular Cell Therapy Research Network Principal Investigator, National Institutes of Health (2012)
  • Melvin Judkins Young Investigator Award, 1st Place, senior author, American Heart Association (2011)
  • Melvin Judkins Young Investigator Award, 1st Place, senior author, American Heart Association (2010)
  • Melvin Judkins Young Investigator Award, 1st Place, senior author, American Heart Association (2009)
  • Judge, Young Investigator Awards Competition: Physiology, Pharmacology, and Pathology, American College of Cardiology (2008)
  • K18 Career Enhancement Award in Stem Cell Research, National Institutes of Health (2007)
  • Young Investigator Award, Finalist, American College of Cardiology (2007)
  • Vivien Thomas Young Investigator Award, American Heart Association (2005)
  • Young Investigator Award, Finalist, American College of Cardiology (Senior Author) (2005)
  • Young Investigator Award, Finalist, American College of Cardiology (Senior Author) (2004)
  • Teaching Award, Stanford University School of Medicine (2004)
  • Glaxo Smith Kline Scholar, American Federation of Medical Research (2003)
  • Career Development Award, National Institute of Health (2000)
  • Edwin L Alderman Award for Excellence in Research, Stanford Cardiovascular Medicine (1999)
  • Young Investigator Award, American College of Cardiology (1998)
  • Physiology & Pharmacology Research Award, Stanford Cardiovascular Medicine (1997)
  • Soloman's Scholarship, UCLA Dept of Medicine (1993)
  • Cum Laude, Yale University School of Medicine (1989)

Professional Education


  • Medical Education:Yale University School of Medicine (1989) CT
  • Fellowship:Stanford University School of Medicine (1998) CA
  • Board Certification: Echocardiography, National Board of Echocardiography (2008)
  • Board Certification: Cardiovascular Disease, American Board of Internal Medicine (1999)
  • Residency:UCLA Medical Center (1993) CA
  • Internship:UCLA - School of Medicine (1990) CA
  • Resident, UCLA Department of Medicine, Internal Medicine (1993)
  • MD, Yale University, MD, Cum Laude (1989)
  • MA, Stanford University, East Asian Studies (1984)
  • BAS, Stanford University, Biology and East Asian Studies (1984)

Community and International Work


  • Editor, Journal of Cardiovascular Magnetic Resonance

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

  • Member, American Heart Association, National Grant Study Committee

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

  • Member, American Heart Association, Western Regional Grant Study Committee

    Ongoing Project

    No

    Opportunities for Student Involvement

    No

  • Board Member, National Center for Space Biological Technologies (NASA)

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

  • Language Background

    Ongoing Project

    Yes

    Opportunities for Student Involvement

    No

Research & Scholarship

Current Research and Scholarly Interests


Dr. Yang's research focuses on comprehensive evaluation of myocardial injury and restoration using novel molecular and cellular MRI techniques. By combining the chemical sensitivity of nuclear magnetic resonance with high spatial and temporal resolution, integrated imaging of a wide range of regenerative processes in the cardiovascular system is possible. This innovative approach enables in vivo imaging of stem cell biology and their effects on the myocardium. The novel MRI techniques are employed to investigate a broad spectrum of cardiovascular stem cells derived from human pluripotent and adult stem cells. Dr. Yang's research has been supported by the National Institutes of Health, American Heart Association, California Institute of Regenerative Medicine, Stanford Cardiovascular Institute, and private organizations.

Clinical Trials


  • Patients With Intermittent Claudication Injected With ALDH Bright Cells Recruiting

    The purpose of this study is to find out if aldehyde dehydrogenase bright (ALDHbr) cells taken from a patient's bone marrow can be placed safely, via intramuscular injections, into their affected calf and lower thigh muscles and improve blood flow and/or peak walking time in patients experiencing pain associated with blocked blood vessels in the leg.

    View full details

  • An Evaluation of a Developmentally-Based Parent Training Program for Children With Autism Recruiting

    The purpose of this study is to assess the efficacy of a parent training program in the treatment of social and communication deficits in children with autism. Specifically, this study will evaluate a developmentally based parent delivered intervention in the community developed by Pacific Autism Center for Education (PACE).

    View full details

Teaching

2014-15 Courses


Postdoctoral Advisees


Publications

Journal Articles


  • 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-?

    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 Web of Science ID 000351834500001

    View details for PubMedID 25654979

  • Structural Insight into Tetrameric hTRPV1 from Homology Modeling, Molecular Docking, Molecular Dynamics Simulation, Virtual Screening, and Bioassay Validations JOURNAL OF CHEMICAL INFORMATION AND MODELING Feng, Z., Pearce, L. V., Xu, X., Yang, X., Yang, P., Blumberg, P. M., Xie, X. 2015; 55 (3): 572-588

    Abstract

    The transient receptor potential vanilloid type 1 (TRPV1) is a heat-activated cation channel protein, which contributes to inflammation, acute and persistent pain. Antagonists of human TRPV1 (hTRPV1) represent a novel therapeutic approach for the treatment of pain. Developing various antagonists of hTRPV1, however, has been hindered by the unavailability of a 3D structure of hTRPV1. Recently, the 3D structures of rat TRPV1 (rTRPV1) in the presence and absence of ligand have been reported as determined by cryo-EM. rTRPV1 shares 85.7% sequence identity with hTRPV1. In the present work, we constructed and reported the 3D homology tetramer model of hTRPV1 based on the cryo-EM structures of rTRPV1. Molecular dynamics (MD) simulations, energy minimizations, and prescreen were applied to select and validate the best model of hTRPV1. The predicted binding pocket of hTRPV1 consists of two adjacent monomers subunits, which were congruent with the experimental rTRPV1 data and the cyro-EM structures of rTRPV1. The detailed interactions between hTRPV1 and its antagonists or agonists were characterized by molecular docking, which helped us to identify the important residues. Conformational changes of hTRPV1 upon antagonist/agonist binding were also explored by MD simulation. The different movements of compounds led to the different conformational changes of monomers in hTRPV1, indicating that TRPV1 works in a concerted way, resembling some other channel proteins such as aquaporins. We observed that the selective filter was open when hTRPV1 bound with an agonist during MD simulation. For the lower gate of hTRPV1, we observed large similarities between hTRPV1 bound with antagonist and with agonist. A five-point pharmacophore model based on several antagonists was established, and the structural model was used to screen in silico for new antagonists for hTRPV1. By using the 3D TRPV1 structural model above, the pilot in silico screening has begun to yield promising hits with activity as hTRPV1 antagonists, several of which showed substantial potency.

    View details for DOI 10.1021/ci5007189

    View details for Web of Science ID 000351652900010

    View details for PubMedID 25642729

  • Small-molecule inhibitors targeting INK4 protein p18(INK4C) enhance ex vivo expansion of haematopoietic stem cells NATURE COMMUNICATIONS Gao, Y., Yang, P., Shen, H., Yu, H., Song, X., Zhang, L., Zhang, P., Cheng, H., Xie, Z., Hao, S., Dong, F., Ma, S., Ji, Q., Bartlow, P., Ding, Y., Wang, L., Liu, H., Li, Y., Cheng, H., Miao, W., Yuan, W., Yuan, Y., Cheng, T., Xie, X. 2015; 6

    Abstract

    Among cyclin-dependent kinase inhibitors that control the G1 phase in cell cycle, only p18 and p27 can negatively regulate haematopoietic stem cell (HSC) self-renewal. In this manuscript, we demonstrate that p18 protein is a more potent inhibitor of HSC self-renewal than p27 in mouse models and its deficiency promoted HSC expansion in long-term culture. Single-cell analysis indicated that deleting p18 gene favoured self-renewing division of HSC in vitro. Based on the structure of p18 protein and in-silico screening, we further identified novel smallmolecule inhibitors that can specifically block the activity of p18 protein. Our selected lead compounds were able to expand functional HSCs in a short-term culture. Thus, these putative small-molecule inhibitors for p18 protein are valuable for further dissecting the signalling pathways of stem cell self-renewal and may help develop more effective chemical agents for therapeutic expansion of HSC.

    View details for DOI 10.1038/ncomms7328

    View details for Web of Science ID 000350291300004

    View details for PubMedID 25692908

  • Cardiovascular remodeling relates to elevated childhood blood pressure: Beijing Blood Pressure Cohort Study INTERNATIONAL JOURNAL OF CARDIOLOGY Liang, Y., Hou, D., Shan, X., Zhao, X., Hu, Y., Jiang, B., Wang, L., Liu, J., Cheng, H., Yang, P., Shan, X., Yan, Y., Chowienczyk, P. J., Mi, J. 2014; 177 (3): 836-839

    Abstract

    There are few studies investigating the long-term association between childhood blood pressure (BP) and adult cardiovascular remodeling. We seek to examine the effect of elevated childhood BP on cardiovascular remodeling in early or middle adulthood.We used the "Beijing BP Cohort Study", where 1259 subjects aged 6-18 years old were followed over 24 years from childhood (1987) to early or middle adulthood (2011). Anthropometric measures and BP were obtained at baseline and follow-up examinations. Carotid-femoral pulse wave velocity (cfPWV), carotid intima-media thickness (cIMT), and left ventricular mass index (LVMI) were measured to assess cardiovascular remodeling in early or middle adulthood. Multiple logistic regression models were used to assess the odds ratio (OR) and 95% confidence interval (CI) for cardiovascular remodeling.82 out of 384 children with elevated BP (21.4%) had adult hypertension. Compared to those with normal BP, children with elevated BP were at 2.1 times (95% CI: 1.4-3.1) likely to develop hypertension in early or middle adulthood. Compared to those with normal BP, children with elevated BP were at higher OR of developing high cfPWV (OR=1.8, 95% CI=1.3-2.4), high cIMT (1.4, 1.0-1.9), or high LVMI (1.4, 1.0-1.9) in early or middle adulthood. The ORs for remodeling (for any measures) were 1.4 (0.9-2.0) in early adulthood for children age 6-11 years, and 1.6 (1.1-2.4) in middle adulthood for those aged 12-18 years.Children with elevated BP from 6 years old have accelerated remodeling on both cardiac and arterial system in early or middle adulthood.

    View details for DOI 10.1016/j.ijcard.2014.11.013

    View details for Web of Science ID 000345697200055

    View details for PubMedID 25465829

  • Nonrigid autofocus motion correction for coronary MR angiography with a 3D cones trajectory. Magnetic resonance in medicine Ingle, R. R., Wu, H. H., Addy, N. O., Cheng, J. Y., Yang, P. C., Hu, B. S., Nishimura, D. G. 2014; 72 (2): 347-361

    Abstract

    To implement a nonrigid autofocus motion correction technique to improve respiratory motion correction of free-breathing whole-heart coronary magnetic resonance angiography acquisitions using an image-navigated 3D cones sequence.2D image navigators acquired every heartbeat are used to measure superior-inferior, anterior-posterior, and right-left translation of the heart during a free-breathing coronary magnetic resonance angiography scan using a 3D cones readout trajectory. Various tidal respiratory motion patterns are modeled by independently scaling the three measured displacement trajectories. These scaled motion trajectories are used for 3D translational compensation of the acquired data, and a bank of motion-compensated images is reconstructed. From this bank, a gradient entropy focusing metric is used to generate a nonrigid motion-corrected image on a pixel-by-pixel basis. The performance of the autofocus motion correction technique is compared with rigid-body translational correction and no correction in phantom, volunteer, and patient studies.Nonrigid autofocus motion correction yields improved image quality compared to rigid-body-corrected images and uncorrected images. Quantitative vessel sharpness measurements indicate superiority of the proposed technique in 14 out of 15 coronary segments from three patient and two volunteer studies.The proposed technique corrects nonrigid motion artifacts in free-breathing 3D cones acquisitions, improving image quality compared to rigid-body motion correction. Magn Reson Med, 2013. © 2013 Wiley Periodicals, Inc.

    View details for DOI 10.1002/mrm.24924

    View details for PubMedID 24006292

  • Graphite Oxide Nanoparticles with Diameter Greater than 20 nm Are Biocompatible with Mouse Embryonic Stem Cells and Can Be Used in a Tissue Engineering System. Small Wang, I. E., Robinson, J. T., Do, G., Hong, G., Gould, D. R., Dai, H., Yang, P. C. 2014; 10 (8): 1479-1484

    Abstract

    Graphite oxide sheets demonstrate size-dependent uptake and toxicity towards embryonic stem cells. Graphite oxide sheets larger than 20 nm are biocompatible and can be safely used with mouse embryonic stem cells, while graphite oxide sheets smaller than 20 nm in diameter reduced cell proliferation and increased cell toxicity.

    View details for DOI 10.1002/smll.201303133

    View details for PubMedID 24376186

  • 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 Web of Science ID 000334315700006

    View details for PubMedID 24444659

  • Multi-cellular interactions sustain long-term contractility of human pluripotent stem cell-derived cardiomyocytes. Am J Transl Res PW, B., SA, M., KH, N., OJ, A., CS, S., MA, B., Y, M., PJ, K., JC, W., NF, H., PC, Y. 2014; 6 (6)
  • Effects of Frequent Hemodialysis on Ventricular Volumes and Left Ventricular Remodeling CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Chan, C. T., Greene, T., Chertow, G. M., Kliger, A. S., Stokes, J. B., Beck, G. J., Daugirdas, J. T., Kotanko, P., Larive, B., Levin, N. W., Mehta, R. L., Rocco, M., Sanz, J., Yang, P. C., Rajagopalan, S. 2013; 8 (12): 2106-2116

    Abstract

    Higher left ventricular volume is associated with death in patients with ESRD. This work investigated the effects of frequent hemodialysis on ventricular volumes and left ventricular remodeling.The Frequent Hemodialysis Network daily trial randomized 245 patients to 12 months of six times per week versus three times per week in-center hemodialysis; the Frequent Hemodialysis Network nocturnal trial randomized 87 patients to 12 months of six times per week nocturnal hemodialysis versus three times per week predominantly home-based hemodialysis. Left and right ventricular end systolic and diastolic volumes, left ventricular mass, and ejection fraction at baseline and end of the study were ascertained by cardiac magnetic resonance imaging. The ratio of left ventricular mass/left ventricular end diastolic volume was used as a surrogate marker of left ventricular remodeling. In each trial, the effect of frequent dialysis on left or right ventricular end diastolic volume was tested between predefined subgroups.In the daily trial, frequent hemodialysis resulted in significant reductions in left ventricular end diastolic volume (-11.0% [95% confidence interval, -16.1% to -5.5%]), left ventricular end systolic volume (-14.8% [-22.7% to -6.2%]), right ventricular end diastolic volume (-11.6% [-19.0% to -3.6%]), and a trend for right ventricular end systolic volume (-11.3% [-21.4% to 0.1%]) compared with conventional therapy. The magnitude of reduction in left and right ventricular end diastolic volumes with frequent hemodialysis was accentuated among patients with residual urine output<100 ml/d (P value [interaction]=0.02). In the nocturnal trial, there were no significant changes in left or right ventricular volumes. The frequent dialysis interventions had no substantial effect on the ratio of left ventricular mass/left ventricular end diastolic volume in either trial.Frequent in-center hemodialysis reduces left and right ventricular end systolic and diastolic ventricular volumes as well as left ventricular mass, but it does not affect left ventricular remodeling.

    View details for DOI 10.2215/CJN.03280313

    View details for Web of Science ID 000327951100012

  • Expert Consensus for Multi-Modality Imaging Evaluation of Cardiovascular Complications of Radiotherapy in Adults: A Report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Lancellotti, P., Nkomo, V. T., Badano, L. P., Bergler, J., Bogaert, J., Davin, L., Cosyns, B., Coucke, P., Dulgheru, R., Edvardsen, T., Gaemperli, O., Galderisi, M., Griffin, B., Heidenreich, P. A., Nieman, K., Plana, J. C., Port, S. C., Scherrer-Crosbie, M., Schwartz, R. G., Sebag, I. A., Voigt, J., Wann, S., Yang, P. C. 2013; 26 (9): 1013-1032

    Abstract

    Cardiac toxicity is one of the most concerning side effects of anti-cancer therapy. The gain in life expectancy obtained with anti-cancer therapy can be compromised by increased morbidity and mortality associated with its cardiac complications. While radiosensitivity of the heart was initially recognized only in the early 1970s, the heart is regarded in the current era as one of the most critical dose-limiting organs in radiotherapy. Several clinical studies have identified adverse clinical consequences of radiation-induced heart disease (RIHD) on the outcome of long-term cancer survivors. A comprehensive review of potential cardiac complications related to radiotherapy is warranted. An evidence-based review of several imaging approaches used to detect, evaluate, and monitor RIHD is discussed. Recommendations for the early identification and monitoring of cardiovascular complications of radiotherapy by cardiac imaging are also proposed.

    View details for DOI 10.1016/j.echo.2013.07.005

    View details for Web of Science ID 000324028300003

    View details for PubMedID 23998694

  • Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING Lancellotti, P., Nkomo, V. T., Badano, L. P., Bergler, J., Bogaert, J., Davin, L., Cosyns, B., Coucke, P., Dulgheru, R., Edvardsen, T., Gaemperli, O., Galderisi, M., Griffin, B., Heidenreich, P. A., Nieman, K., Plana, J. C., Port, S. C., Scherrer-Crosbie, M., Schwartz, R. G., Sebag, I. A., Voigt, J., Wann, S., Yang, P. C. 2013; 14 (8): 721-740
  • Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. European heart journal cardiovascular Imaging Lancellotti, P., Nkomo, V. T., Badano, L. P., Bergler-Klein, J., Bogaert, J., Davin, L., Cosyns, B., Coucke, P., Dulgheru, R., Edvardsen, T., Gaemperli, O., Galderisi, M., Griffin, B., Heidenreich, P. A., Nieman, K., Plana, J. C., Port, S. C., Scherrer-Crosbie, M., Schwartz, R. G., Sebag, I. A., Voigt, J., Wann, S., Yang, P. C. 2013; 14 (8): 721-740

    Abstract

    Cardiac toxicity is one of the most concerning side effects of anti-cancer therapy. The gain in life expectancy obtained with anti-cancer therapy can be compromised by increased morbidity and mortality associated with its cardiac complications. While radiosensitivity of the heart was initially recognized only in the early 1970s, the heart is regarded in the current era as one of the most critical dose-limiting organs in radiotherapy. Several clinical studies have identified adverse clinical consequences of radiation-induced heart disease (RIHD) on the outcome of long-term cancer survivors. A comprehensive review of potential cardiac complications related to radiotherapy is warranted. An evidence-based review of several imaging approaches used to detect, evaluate, and monitor RIHD is discussed. Recommendations for the early identification and monitoring of cardiovascular complications of radiotherapy by cardiac imaging are also proposed.

    View details for DOI 10.1093/ehjci/jet123

    View details for PubMedID 23847385

  • Phase II Clinical Research Design in Cardiology Learning the Right Lessons Too Well: Observations and Recommendations From the Cardiovascular Cell Therapy Research Network (CCTRN) CIRCULATION Hare, J. M., Bolli, R., Cooke, J. P., Gordon, D. J., Henry, T. D., Perin, E. C., March, K. L., Murphy, M. P., Pepine, C. J., Simari, R. D., Skarlatos, S. I., Traverse, J. H., Willerson, J. T., Szady, A. D., Taylor, D. A., Vojvodic, R. W., Yang, P. C., Moye, L. A. 2013; 127 (15): 1630-1635
  • Human amniotic mesenchymal stem cell-derived induced pluripotent stem cells may generate a universal source of cardiac cells. Stem cells and development Ge, X., Wang, I. E., Toma, I., Sebastiano, V., Liu, J., Butte, M. J., Reijo Pera, R. A., Yang, P. C. 2012; 21 (15): 2798-2808

    Abstract

    Human amniotic mesenchymal stem cells (hAMSCs) demonstrated partially pluripotent characteristics with a strong expression of Oct4 and Nanog genes and immunomodulatory properties characterized by the absence of HLA-DR and the presence of HLA-G and CD59. The hAMSCs were reprogrammed into induced pluripotent stem cells (iPSCs) that generate a promising source of universal cardiac cells. The hAMSC-derived iPSCs (MiPSCs) successfully underwent robust cardiac differentiation to generate cardiomyocytes. This study investigated 3 key properties of the hAMSCs and MiPSCs: (1) the reprogramming efficiency of the partially pluripotent hAMSCs to generate MiPSCs; (2) immunomodulatory properties of the hAMSCs and MiPSCs; and (3) the cardiac differentiation potential of the MiPSCs. The characteristic iPSC colony formation was observed within 10 days after the transduction of the hAMSCs with a single integration polycistronic vector containing 4 Yamanaka factors. Immunohistology and reverse transcription-polymerase chain reaction assays revealed that the MiPSCs expressed stem cell surface markers and pluripotency-specific genes. Furthermore, the hAMSCs and MiPSCs demonstrated immunomodulatory properties enabling successful engraftment in the SVJ mice. Finally, the cardiac differentiation of MiPSCs exhibited robust spontaneous contractility, characteristic calcium transience across the membrane, a high expression of cardiac genes and mature cardiac phenotypes, and a contractile force comparable to cardiomyocytes. Our results demonstrated that the hAMSCs are reprogrammed with a high efficiency into MiPSCs, which possess pluripotent, immunomodulatory, and precardiac properties. The MiPSC-derived cardiac cells express a c-kit cell surface marker, which may be employed to purify the cardiac cell population and enable allogeneic cardiac stem cell therapy.

    View details for DOI 10.1089/scd.2011.0435

    View details for PubMedID 22530853

  • Bone marrow cell therapy in clinical trials: a review of the literature. Reviews on recent clinical trials Kim, P. J., Yang, P. C. 2012; 7 (3): 204-213

    Abstract

    Spurred by remarkable findings in animal studies, there has been strong interest in evaluating the potential of adult stem cells to improve left ventricular function in the past decade. Driven by the need to treat the increasing number of patients with coronary artery disease, numerous studies have attempted to define a role for bone marrow cell therapy in clinical use. However, the conflicting results of these studies can be confusing. This article will review the landmark trials evaluating bone marrow cell therapy in the past decade and describe the current state of adult stem cell therapy and its future direction herein.

    View details for PubMedID 22540909

  • Theranostic effect of serial manganese-enhanced magnetic resonance imaging of human embryonic stem cell derived teratoma MAGNETIC RESONANCE IN MEDICINE Chung, J., Dash, R., Kee, K., Barral, J. K., Kosuge, H., Robbins, R. C., Nishimura, D., Reijo-Pera, R. A., Yang, P. C. 2012; 68 (2): 595-599

    Abstract

    Although human embryonic stem cell (hESC) hold therapeutic potential, teratoma formation has deterred clinical translation. Manganese (Mn(2+)) enters metabolically active cells through voltage-gated calcium channels and subsequently, induces T(1) shortening. We hypothesized that serial manganese-enhanced MRI would have theranostic effect to assess hESC survival, teratoma formation, and hESC-derived teratoma reduction through intracellular accumulation of Mn(2+). Firefly luciferase transduced hESCs (hESC-Lucs) were transplanted into severe combined immunodeficient mouse hindlimbs to form teratoma. The chemotherapy group was injected with MnCl(2) intraperitoneally three times a week. The control group was given MnCl(2) only prior to manganese-enhanced MRI. Longitudinal evaluation by manganese-enhanced MRI and bioluminescence imaging was performed. The chemotherapy group showed significant reduction in the teratoma volume and luciferase activity at weeks 6 and 8. Histology revealed increased proportion of dead cells and caspase 3 positive cells in the chemotherapy group. Systemic administration of MnCl(2) enabled simultaneous monitoring and elimination of hESC-derived teratoma cells by higher intracellular accumulation of Mn(2+).

    View details for DOI 10.1002/mrm.23262

    View details for Web of Science ID 000306318900032

    View details for PubMedID 22190225

  • Is Reliable In Vivo Detection of Stem Cell Viability Possible in a Large Animal Model of Myocardial Injury? CIRCULATION Yang, P. C. 2012; 126 (4): 388-390
  • Apelin Enhances Directed Cardiac Differentiation of Mouse and Human Embryonic Stem Cells PLOS ONE Wang, I. E., Wang, X., Ge, X., Anderson, J., Ho, M., Ashley, E., Liu, J., Butte, M. J., Yazawa, M., Dolmetsch, R. E., Quertermous, T., Yang, P. C. 2012; 7 (6)

    Abstract

    Apelin is a peptide ligand for an orphan G-protein coupled receptor (APJ receptor) and serves as a critical gradient for migration of mesodermal cells fated to contribute to the myocardial lineage. The present study was designed to establish a robust cardiac differentiation protocol, specifically, to evaluate the effect of apelin on directed differentiation of mouse and human embryonic stem cells (mESCs and hESCs) into cardiac lineage. Different concentrations of apelin (50, 100, 500 nM) were evaluated to determine its differentiation potential. The optimized dose of apelin was then combined with mesodermal differentiation factors, including BMP-4, activin-A, and bFGF, in a developmentally specific temporal sequence to examine the synergistic effects on cardiac differentiation. Cellular, molecular, and physiologic characteristics of the apelin-induced contractile embryoid bodies (EBs) were analyzed. It was found that 100 nM apelin resulted in highest percentage of contractile EB for mESCs while 500 nM had the highest effects on hESCs. Functionally, the contractile frequency of mESCs-derived EBs (mEBs) responded appropriately to increasing concentration of isoprenaline and diltiazem. Positive phenotype of cardiac specific markers was confirmed in the apelin-treated groups. The protocol, consisting of apelin and mesodermal differentiation factors, induced contractility in significantly higher percentage of hESC-derived EBs (hEBs), up-regulated cardiac-specific genes and cell surface markers, and increased the contractile force. In conclusion, we have demonstrated that the treatment of apelin enhanced cardiac differentiation of mouse and human ESCs and exhibited synergistic effects with mesodermal differentiation factors.

    View details for DOI 10.1371/journal.pone.0038328

    View details for Web of Science ID 000305339900024

    View details for PubMedID 22675543

  • Determinants of Left Ventricular Mass in Patients on Hemodialysis Frequent Hemodialysis Network (FHN) Trials CIRCULATION-CARDIOVASCULAR IMAGING Chan, C. T., Greene, T., Chertow, G. M., Kliger, A. S., Stokes, J. B., Beck, G. J., Daugirdas, J. T., Kotanko, P., Larive, B., Levin, N. W., Mehta, R. L., Rocco, M., Sanz, J., Schiller, B. M., Yang, P. C., Rajagopalan, S. 2012; 5 (2): 251-261

    Abstract

    An increase in left ventricular mass (LVM) is associated with mortality and cardiovascular morbidity in patients with end-stage renal disease.The Frequent Hemodialysis Network (FHN) Daily Trial randomized 245 patients to 12 months of 6 times per week daily in-center hemodialysis or conventional hemodialysis; the FHN Nocturnal Trial randomized 87 patients to 12 months of 6 times per week nocturnal hemodialysis or conventional hemodialysis. The main cardiac secondary outcome was change in LVM. In each trial, we examined whether several predefined baseline demographic or clinical factors as well as change in volume removal, blood pressure, or solute clearance influenced the effect of frequent hemodialysis on LVM. In the Daily Trial, frequent hemodialysis resulted in a significant reduction in LVM (13.1 g; 95% CI, 5.0-21.3 g; P=0.002), LVM index (6.9 g/m(2); 95% CI, 2.4-11.3 g/m(2); P=0.003), and percent change in geometric mean of LVM (7.0%; 95% CI, 1.0%-12.6; P=0.02). Similar trends were noted in the Nocturnal Trial but did not reach statistical significance. In the Daily Trial, a more pronounced effect of frequent hemodialysis on LVM was evident among patients with left ventricular hypertrophy at baseline. Changes in LVM were associated with changes in blood pressure (conventional hemodialysis: R=0.28, P=0.01, daily hemodialysis: R=0.54, P<0.001) and were not significantly associated with changes in other parameters.Frequent in-center hemodialysis reduces LVM. The benefit of frequent hemodialysis on LVM may be mediated by salutary effects on blood pressure. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00264758.

    View details for DOI 10.1161/CIRCIMAGING.111.969923

    View details for Web of Science ID 000302122700014

    View details for PubMedID 22360996

  • Synthesis of an in vivo MRI-detectable apoptosis probe. Journal of visualized experiments : JoVE Lam, J., Simpson, P. C., Yang, P. C., Dash, R. 2012

    Abstract

    Cellular apoptosis is a prominent feature of many diseases, and this programmed cell death typically occurs before clinical manifestations of disease are evident. A means to detect apoptosis in its earliest, reversible stages would afford a pre-clinical 'window' during which preventive or therapeutic measures could be taken to protect the heart from permanent damage. We present herein a simple and robust method to conjugate human Annexin V (ANX), which avidly binds to cells in the earliest, reversible stages of apoptosis, to superparamagnetic iron oxide (SPIO) nanoparticles, which serve as an MRI-detectable contrast agent. The conjugation method begins with an oxidation of the SPIO nanoparticles, which oxidizes carboxyl groups on the polysaccharide shell of SPIO. Purified ANX protein is then added in the setting of a sodium borate solution to facilitate covalent interaction of ANX with SPIO in a reducing buffer. A final reduction step with sodium borohydride is performed to complete the reduction, and then the reaction is quenched. Unconjugated ANX is removed from the mix by microcentrifuge filtration. The size and purity of the ANX-SPIO product is verified by dynamic light scattering (DLS). This method does not require addition to, or modification of, the polysaccharide SPIO shell, as opposed to cross-linked iron oxide particle conjugation methods or biotin-labeled nanoparticles. As a result, this method represents a simple, robust approach that may be extended to conjugation of other proteins of interest.

    View details for DOI 10.3791/3775

    View details for PubMedID 22871963

  • In vivo Molecular MRI of Cell Survival and Teratoma Formation Following Embryonic Stem Cell Transplantation Into the Injured Murine Myocardium MAGNETIC RESONANCE IN MEDICINE Chung, J., Kee, K., Barral, J. K., Dash, R., Kosuge, H., Wang, X., Weissman, I., Robbins, R. C., Nishimura, D., Quertermous, T., Reijo-Pera, R. A., Yang, P. C. 2011; 66 (5): 1374-1381

    Abstract

    Embryonic stem cells (ESCs) have shown the potential to restore cardiac function after myocardial injury. Superparamagnetic iron oxide nanoparticles (SPIO) have been widely employed to label ESCs for cellular MRI. However, nonspecific intracellular accumulation of SPIO limits long-term in vivo assessment of the transplanted cells. To overcome this limitation, a novel reporter gene (RG) has been developed to express antigens on the ESC surface. By employing SPIO-conjugated monoclonal antibody against these antigens (SPIO-MAb), the viability of transplanted ESCs can be detected in vivo. This study aims to develop a new molecular MRI method to assess in vivo ESC viability, proliferation, and teratoma formation. The RG is designed to express 2 antigens (hemagglutinin A and myc) and luciferase on the ESC surface. The two antigens serve as the molecular targets for SPIO-MAb. The human and mouse ESCs were transduced with the RG (ESC-RGs) and transplanted into the peri-infarct area using the murine myocardial injury model. In vivo MRI was performed following serial intravenous administration of SPIO-MAb. Significant hypointense signal was generated from the viable and proliferating ESCs and subsequent teratoma. This novel molecular MRI technique enabled in vivo detection of early ESC-derived teratoma formation in the injured murine myocardium.

    View details for DOI 10.1002/mrm.22929

    View details for Web of Science ID 000296389800019

    View details for PubMedID 21604295

  • A Molecular MRI Probe to Detect Treatment of Cardiac Apoptosis In Vivo MAGNETIC RESONANCE IN MEDICINE Dash, R., Chung, J., Chan, T., Yamada, M., Barral, J., Nishimura, D., Yang, P. C., Simpson, P. C. 2011; 66 (4): 1152-1162

    Abstract

    Cell death by apoptosis is critical in myocardial diseases, and noninvasive detection of early, reversible apoptosis might be useful clinically. Exogenous Annexin-V (ANX) protein binds membrane phosphatidylserine, which is externalized in early apoptosis. A molecular MRI probe was constructed with superparamagnetic iron oxide (SPIO) conjugated to recombinant human ANX (ANX-SPIO). Apoptosis was induced with doxorubicin, a cardiotoxic cancer drug, in culture in neonatal rat ventricular myocytes, cardiac fibroblasts, and mesenchymal stem cells, and in vivo in the mouse heart. ANX-SPIO was validated using T2*-weighted 3T MRI. ANX-SPIO produced T2* signal loss, reflecting iron content, that correlated highly with independent apoptosis markers; bound with high affinity to apoptotic myocytes by competition assay (Ki 69 nM); detected apoptosis in culture much earlier than did TUNEL stain; and revealed fibroblast resistance to apoptosis. With apoptosis in vivo, ANX-SPIO produced diffuse myocardial T2* signal loss that correlated with increased iron stain and caspase activity. Treatment with an alpha-1-adrenergic agonist in vivo reversed apoptosis and eliminated the ANX-SPIO MRI signal. It is concluded that cardiac MRI of ANX-SPIO detects early, nonischemic cardiac apoptosis in culture and in vivo, and can identify reversibly injured cardiac cells in diseased hearts, when treatment is still possible.

    View details for DOI 10.1002/mrm.22876

    View details for Web of Science ID 000295356500027

    View details for PubMedID 21360750

  • Contrast echocardiography: finding its place in stem cell therapy MINERVA CARDIOANGIOLOGICA Kim, P. J., Yang, P. C. 2011; 59 (5): 491-497

    Abstract

    To date, the underlying mechanism responsible for the restoration of the injured myocardium following transplantation of stem cells has not been clearly identified. Molecular imaging is essential to the continued progress of stem cell therapy by elucidating the biology of transplanted stem cells in vivo. Currently, several imaging modalities are in development in the rapidly evolving field of molecular imaging. Contrast echocardiography has the potential to define its role in shaping the future development of stem cell therapy. We describe the current state of contrast echocardiography and its future direction herein.

    View details for Web of Science ID 000208662500009

  • 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

  • alpha B-Crystallin Improves Murine Cardiac Function and Attenuates Apoptosis in Human Endothelial Cells Exposed to Ischemia-Reperfusion ANNALS OF THORACIC SURGERY Velotta, J. B., Kimura, N., Chang, S. H., Chung, J., Itoh, S., Rothbard, J., Yang, P. C., Steinman, L., Robbins, R. C., Fischbein, M. P. 2011; 91 (6): 1907-1913

    Abstract

    This study investigates the protective effect of exogenous ?B-crystallin (CryAB) on myocardial function after ischemia-reperfusion injury.Mice underwent temporary left anterior descending artery occlusion for 30 minutes. Either CryAB (50 ?g) or phosphate-buffered saline (100 ?L [n=6, each group]) were injected in the intramyocardial medial and lateral perinfarct zone 15 minutes before reperfusion. Intraperitoneal injections were administered every other day. Left ventricular ejection fraction was evaluated on postoperative day 40 with magnetic resonance imaging. To investigate the effect of CryAB on apoptosis after hypoxia/reoxygenation in vitro, murine atrial cardiomyocytes (HL-1 cells) or human microvascular endothelial cells (HMEC-1) were incubated with either 50 ?g CryAB (500 ?g /10 mL) or phosphate-buffered saline in a hypoxia chamber for 6, 12, and 24 hours, followed by 30 minutes of reoxygenation at room air. Apoptosis was then assessed by western blot (Bcl-2, free bax, cleaved caspases-3, 9, PARP) and enzyme-linked immunosorbent assay analyses (cytoplasmic histone-associated DNA fragments and caspase-3 activity).On postoperative day 40, CryAB-treated mice had a 1.8-fold increase in left ventricular ejection fraction versus control mice (27%±6% versus 15%±4% SD, p<0.005). In vitro, (1) the HL-1 cells showed no significant difference in apoptotic protein expression, cytoplasmic histone-associated DNA fragments, or caspase-3 activity; (2) the HMEC-1 cells had increased but not significant apoptotic protein expression with, however, a significant decrease in cytoplasmic histone-associated DNA fragments (1.5-fold, p<0.01) and caspase-3 activity (2.7-fold, p<0.005).Exogenous CryAB administration significantly improves cardiac function after ischemia-reperfusion injury, in vivo. The protective anti-apoptotic affects of CryAB may target the endothelial cell.

    View details for DOI 10.1016/j.athoracsur.2011.02.072

    View details for Web of Science ID 000291019400043

    View details for PubMedID 21619989

  • 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

  • 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

  • Positive Contrast with Alternating Repetition Time SSFP (PARTS): A Fast Imaging Technique for SPIO-Labeled Cells MAGNETIC RESONANCE IN MEDICINE Cukur, T., Yamada, M., Overall, W. R., Yang, P., Nishimura, D. G. 2010; 63 (2): 427-437

    Abstract

    There has been recent interest in positive-contrast MRI methods for noninvasive tracking of cells labeled with superparamagnetic iron-oxide nanoparticles. Low-tip-angle balanced steady-state free precession sequences have been used for fast, high-resolution, and flow-insensitive positive-contrast imaging; however, the contrast can be compromised by the limited suppression of the on-resonant and fat signals. In this work, a new technique that produces positive contrast with alternating repetition time steady-state free precession is proposed to achieve robust background suppression for a broad range of tissue parameters. In vitro and in vivo experiments demonstrate the reliability of the generated positive contrast. The results indicate that the proposed method can enhance the suppression level by up to 18 dB compared with conventional balanced steady-state free precession.

    View details for DOI 10.1002/mrm.22241

    View details for Web of Science ID 000273995200019

    View details for PubMedID 20099331

  • Molecular Imaging of Stem Cell Transplantation in Myocardial Disease. Current cardiovascular imaging reports Chung, J., Yang, P. C. 2010; 3 (2): 106-112

    Abstract

    Stem cell therapy has been heralded as a novel therapeutic option for cardiovascular disease. In vivo molecular imaging has emerged as an indispensible tool in investigating stem cell biology post-transplantation into the myocardium and in evaluating the therapeutic efficacy. This review highlights the features of each molecular imaging modality and discusses how these modalities have been applied to evaluate stem cell therapy.

    View details for PubMedID 20396619

  • Manganese-Guided Cellular MRI of Human Embryonic Stem Cell and Human Bone Marrow Stromal Cell Viability MAGNETIC RESONANCE IN MEDICINE Yamada, M., Gurney, P. T., Chung, J., Kundu, P., Drukker, M., Smith, A. K., Weissman, I. L., Nishimura, D., Robbins, R. C., Yang, P. C. 2009; 62 (4): 1047-1054

    Abstract

    This study investigated the ability of MnCl(2) as a cellular MRI contrast agent to determine the in vitro viability of human embryonic stem cells (hESC) and human bone marrow stromal cells (hBMSC). Basic MRI parameters including T(1) and T(2) values of MnCl(2)-labeled hESC and hBMSC were measured and viability signal of manganese (Mn(2+))-labeled cells was validated. Furthermore, the biological activity of Ca(2+)-channels was modulated utilizing both Ca(2+)-channel agonist and antagonist to evaluate concomitant signal changes. Metabolic effects of MnCl(2)-labeling were also assessed using assays for cell viability, proliferation, and apoptosis. Finally, in vivo Mn(2+)-guided MRI of the transplanted hESC was successfully achieved and validated by bioluminescence imaging.

    View details for DOI 10.1002/mrm.22071

    View details for Web of Science ID 000270558700025

    View details for PubMedID 19526508

  • Magnetic resonance imaging of human embryonic stem cells. Current protocols in stem cell biology Chung, J., Yamada, M., Yang, P. C. 2009; Chapter 5: Unit 5A 3-?

    Abstract

    Magnetic resonance imaging (MRI) may emerge as an ideal non-invasive imaging modality to monitor stem cell therapy in the failing heart. This imaging modality generates any arbitrary tomographic view at high spatial and temporal resolution with exquisite intrinsic tissue contrast. This capability enables robust evaluation of both the cardiac anatomy and function. Traditionally, superparamagnetic iron oxide nanoparticle (SPIO) has been widely used for cellular MRI due to SPIO's ability to enhance sensitivity of MRI by inducing remarkable hypointense, negative signal, "blooming effect" on T2*-weighted MRI acquisition. Recently, manganese chloride (MnCl(2)) has been reported by our laboratory for its ability as a contrast agent to track biological activity of viable cells. Hyperintense, positive signals can be achieved from the Mn(2+)-labeled stem cells on T1-weighted MRI acquisition. Cytotoxicity is a potential drawback of Mn(2+) labeling of the cells. However, in our laboratory the labeling method has been optimized to minimize cytotoxic effects. This article describes two different magnetic labeling methods of human embryonic stem cells (hESC) using SPIO and MnCl(2).

    View details for DOI 10.1002/9780470151808.sc05a03s10

    View details for PubMedID 19653198

  • Self-Refocused Spatial-Spectral Pulse for Positive Contrast Imaging of Cells Labeled with SPIO Nanoparticles MAGNETIC RESONANCE IN MEDICINE Balchandani, P., Yamada, M., Pauly, J., Yang, P., Spielman, D. 2009; 62 (1): 183-192

    Abstract

    MRI has been used extensively to noninvasively track the location of cells labeled with superparamagnetic iron-oxide nanoparticles (SPIOs) in vivo. Typically, SPIOs are employed as a negative contrast agent which makes it difficult to differentiate labeled cells from extraneous sources of inhomogeneity and actual voids in the image. As a result, several novel approaches have been put forth to obtain positive contrast from SPIOs. One technique proposed by Cunningham et al. utilizes spectrally selective pulses to excite and refocus spins in the vicinity of the SPIOs. Although the frequency selectivity of this technique provides effective positive contrast, the lack of slice selectivity results in interfering signal from sources of off-resonance outside the slice of interest. We have developed a self-refocused spatial-spectral (SR-SPSP) pulse to achieve slice-selective spin-echo imaging of off-resonant spins. Using a self-refocused pulse affords flexibility in echo-time selection since the spin echo may be placed at any time after the end of the pulse. The spatial selectivity achieved by the SR-SPSP RF pulse eliminates background signal from out-of-slice regions and reduces the on-resonant water suppression requirements. Phantom and in vivo data demonstrate that positive contrast and slice-selectivity are achieved using this novel RF pulse.

    View details for DOI 10.1002/mrm.21973

    View details for Web of Science ID 000267404300020

    View details for PubMedID 19449385

  • Comparison of Optical Bioluminescence Reporter Gene and Superparamagnetic Iron Oxide MR Contrast Agent as Cell Markers for Noninvasive Imaging of Cardiac Cell Transplantation MOLECULAR IMAGING AND BIOLOGY Chen, I. Y., Greve, J. M., Gheysens, O., Willmann, J. K., Rodriguez-Porcel, M., Chu, P., Sheikh, A. Y., Faranesh, A. Z., Paulmurugan, R., Yang, P. C., Wu, J. C., Gambhir, S. S. 2009; 11 (3): 178-187

    Abstract

    In this study, we compared firefly luciferase (Fluc) reporter gene and superparamagnetic iron oxide (Feridex) as cell markers for longitudinal monitoring of cardiomyoblast graft survival using optical bioluminescence imaging (BLI) and magnetic resonance imaging (MRI), respectively.Rats (n = 31) underwent an intramyocardial injection of cardiomyoblasts (2 x 10(6)) labeled with Fluc, Feridex, or no marker (control) or an injection of Feridex alone (75 microg). Afterward, rats were serially imaged with BLI or MRI and killed at different time points for histological analysis.BLI revealed a drastically different cell survival kinetics (half-life = 2.65 days over 6 days) than that revealed by MRI (half-life = 16.8 days over 80 days). Injection of Feridex alone led to prolonged tissue retention of Feridex (> or =16 days) and persistent MR signal (> or =42 days).Fluc BLI reporter gene imaging is a more accurate gauge of transplanted cell survival as compared to MRI of Feridex-labeled cells.

    View details for DOI 10.1007/s11307-008-0182-z

    View details for Web of Science ID 000265686900005

    View details for PubMedID 19034584

  • Imaging Survival and Function of Transplanted Cardiac Resident Stem Cells JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Li, Z., Lee, A., Huang, M., Chun, H., Chung, J., Chu, P., Hoyt, G., Yang, P., Rosenberg, J., Robbins, R. C., Wu, J. C. 2009; 53 (14): 1229-1240

    Abstract

    The goal of this study is to characterize resident cardiac stem cells (CSCs) and investigate their therapeutic efficacy in myocardial infarction by molecular imaging methods.CSCs have been isolated and characterized in vitro. These cells offer a provocative method to regenerate the damaged myocardium. However, the survival kinetics and function of transplanted CSCs have not been fully elucidated.CSCs were isolated from L2G85 transgenic mice (FVB strain background) that constitutively express both firefly luciferase and enhanced green fluorescence protein reporter gene. CSCs were characterized in vitro and transplanted in vivo into murine infarction models. Multimodality noninvasive imaging techniques were used to assess CSC survival and therapeutic efficacy for restoration of cardiac function.CSCs can be isolated from L2G85 mice, and fluorescence-activated cell sorting analysis showed expression of resident CSC markers (Sca-1, c-Kit) and mesenchymal stem cell markers (CD90, CD106). Afterwards, 5 x 10(5) CSCs (n = 30) or phosphate-buffered saline control (n = 15) was injected into the hearts of syngeneic FVB mice undergoing left anterior descending artery ligation. Bioluminescence imaging showed poor donor cell survival by week 8. Echocardiogram, invasive hemodynamic pressure-volume analysis, positron emission tomography imaging with fluorine-18-fluorodeoxyglucose, and cardiac magnetic resonance imaging demonstrated no significant difference in cardiac contractility and viability between the CSC and control group. Finally, postmortem analysis confirmed transplanted CSCs integrated with host cardiomyocytes by immunohistology.In a mouse myocardial infarction model, Sca-1-positive CSCs provide no long-term engraftment and benefit to cardiac function as determined by multimodality imaging.

    View details for DOI 10.1016/j.jacc.2008.12.036

    View details for Web of Science ID 000264724500011

    View details for PubMedID 19341866

  • In Vivo Serial Evaluation of Superparamagnetic Iron-Oxide Labeled Stem Cells by Off-Resonance Positive Contrast MAGNETIC RESONANCE IN MEDICINE Suzuki, Y., Cunningham, C. H., Noguchi, K., Chen, I. Y., Weissman, I. L., Yeung, A. C., Robbins, R. C., Yang, P. C. 2008; 60 (6): 1269-1275

    Abstract

    MRI is emerging as a diagnostic modality to track iron-oxide-labeled stem cells. This study investigates whether an off-resonance (OR) pulse sequence designed to generate positive contrast at 1.5T can assess the location, quantity, and viability of delivered stem cells in vivo. Using mouse embryonic stem cell transfected with luciferase reporter gene (luc-mESC), multimodality validation of OR signal was conducted to determine whether engraftment parameters of superparamagnetic iron-oxide labeled luc-mESC (SPIO-luc-mESC) could be determined after cell transplantation into the mouse hindlimb. A significant increase in signal- and contrast-to-noise of the SPIO-luc-mESC was achieved with the OR technique when compared to a gradient recalled echo (GRE) sequence. A significant correlation between the quantity of SPIO-luc-mESC and OR signal was observed immediately after transplantation (R(2) = 0.74, P < 0.05). The assessment of transplanted cell viability by bioluminescence imaging (BLI) showed a significant increase of luciferase activities by day 16, while the MRI signal showed no difference. No significant correlation between BLI and MRI signals of cell viability was observed. In conclusion, using an OR sequence the precise localization and quantitation of SPIO-labeled stem cells in both space and time were possible. However, the OR sequence did not allow evaluation of cell viability.

    View details for DOI 10.1002/mrm.21816

    View details for Web of Science ID 000261225100001

    View details for PubMedID 19030159

  • 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

  • Multimodality Evaluation of the Viability of Stem Cells Delivered Into Different Zones of Myocardial Infarction CIRCULATION-CARDIOVASCULAR IMAGING Hung, T., Suzuki, Y., Urashima, T., Caffarelli, A., Hoyt, G., Sheikh, A. Y., Yeung, A. C., Weissman, I., Robbins, R. C., Bulte, J. W., Yang, P. C. 2008; 1 (1): 6-13

    Abstract

    We tested the hypothesis that multimodality imaging of mouse embryonic stem cells (mESCs) provides accurate assessment of cellular location, viability, and restorative potential after transplantation into different zones of myocardial infarction.Mice underwent left anterior descending artery ligation followed by transplantation of dual-labeled mESCs with superparamagnetic iron oxide and luciferase via direct injection into 3 different zones of myocardial infarction: intra-infarction, peri-infarction, and normal (remote). One day after transplantation, magnetic resonance imaging enabled assessment of the precise anatomic locations of mESCs. Bioluminescence imaging allowed longitudinal analysis of cell viability through detection of luciferase activity. Subsequent evaluation of myocardial regeneration and functional restoration was performed by echocardiography and pressure-volume loop analysis. Using 16-segment analysis, we demonstrated precise localization of dual-labeled mESCs. A strong correlation between histology and magnetic resonance imaging was established (r=0.962, P=0.002). Bioluminescent imaging data demonstrated that cell viability in the remote group was significantly higher than in other groups. Echocardiography and pressure-volume loop analysis revealed improved functional restoration in animals treated with mESCs, although myocardial regeneration was not observed.Multimodality evaluation of mESC engraftment in the heterogeneous tissue of myocardial infarction is possible. Magnetic resonance imaging demonstrated accurate anatomic localization of dual-labeled mESCs. Bioluminescent imaging enabled assessment of variable viability of mESCs transplanted into the infarcted myocardium. Echocardiography and pressure-volume loop analysis validated the restorative potential of mESCs. Although mESCs transplanted into the remote zone demonstrated the highest viability, precise delivery of mESCs into the peri-infarction region might be equally critical in restoring the injured myocardium.

    View details for DOI 10.1161/CIRCIMAGING.108.767343

    View details for Web of Science ID 000266039600003

    View details for PubMedID 19808509

  • Human ESC vs. iPSC-Pros and Cons JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH Pappas, J. J., Yang, P. C. 2008; 1 (2): 96-99

    View details for DOI 10.1007/s12265-008-9032-2

    View details for Web of Science ID 000207734800003

    View details for PubMedID 20559900

  • 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

  • Comparison of reporter gene and iron particle labeling for tracking fate of human embryonic stem cells and differentiated endothelial cells in living subjects STEM CELLS Li, Z., Suzuki, Y., Huang, M., Cao, F., Xie, X., Connolly, A. J., Yang, P. C., Wu, J. C. 2008; 26 (4): 864-873

    Abstract

    Human embryonic stem (hES) cells are pluripotent stem cells capable of self-renewal and differentiation into virtually all cell types. Thus, they hold tremendous potential as cell sources for regenerative therapies. The concurrent development of accurate, sensitive, and noninvasive technologies capable of monitoring hES cells engraftment in vivo can greatly expedite basic research prior to future clinical translation. In this study, hES cells were stably transduced with a lentiviral vector carrying a novel double-fusion reporter gene that consists of firefly luciferase and enhanced green fluorescence protein. Reporter gene expression had no adverse effects on cell viability, proliferation, or differentiation to endothelial cells (human embryonic stem cell-derived endothelial cells [hESC-ECs]). To compare the two popular imaging modalities, hES cells and hESC-ECs were then colabeled with superparamagnetic iron oxide particles before transplantation into murine hind limbs. Longitudinal magnetic resonance (MR) imaging showed persistent MR signals in both cell populations that lasted up to 4 weeks. By contrast, bioluminescence imaging indicated divergent signal patterns for hES cells and hESC-ECs. In particular, hESC-ECs showed significant bioluminescence signals at day 2, which decreased progressively over the following 4 weeks, whereas bioluminescence signals from undifferentiated hES cells increased dramatically during the same period. Post-mortem histology and immunohistochemistry confirmed teratoma formation after injection of undifferentiated hES cells but not hESC-ECs. From these data taken together, we concluded that reporter gene is a better marker for monitoring cell viability, whereas iron particle labeling is a better marker for high-resolution detection of cell location by MR. Furthermore, transplantation of predifferentiated rather than undifferentiated hES cells would be more suited for avoiding teratoma formation.

    View details for DOI 10.1634/stemcells.2007-0843

    View details for Web of Science ID 000255000000003

    View details for PubMedID 18218820

  • In vitro comparison of the biological effects of three transfection methods for magnetically labeling mouse embryonic stem cells with ferumoxides MAGNETIC RESONANCE IN MEDICINE Suzuki, Y., Zhang, S., Kundu, P., Yeung, A. C., Robbins, R. C., Yang, P. C. 2007; 57 (6): 1173-1179

    Abstract

    In vivo MRI of stem cells (SCs) is an emerging application to evaluate the role of cell therapy in restoring the injured myocardium. The high spatial and temporal resolution combined with iron-oxide-based intracellular labeling techniques will provide a sensitive, noninvasive, dual imaging modality for both cells and myocardium. In order to facilitate this novel imaging approach, much effort has been directed towards developing efficient transfection methods. While techniques utilizing poly-L-lysine (PLL), protamine sulfate (PS), and electroporation (ELP) have been proposed, the fundamental biological effects of these methods on mouse embryonic SCs (mESC) have not been investigated systematically. In this study a longitudinal in vitro evaluation of cellular viability, apoptosis, proliferation, and cardiac differentiation of magnetically labeled mESC was conducted. No significant difference was seen in these biological parameters among the three transfection methods. However, cardiac differentiation was most attenuated by ELP, and iron uptake was most effective by PS.

    View details for DOI 10.1002/mrm.21219

    View details for Web of Science ID 000246979900022

    View details for PubMedID 17534917

  • Magnetic resonance imaging of progressive cardiomyopathic changes in the db/db mouse AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Yue, P., Arai, T., Terashima, M., Sheikh, A. Y., Cao, F., Charo, D., Hoyt, G., Robbins, R. C., Ashley, E. A., Wu, J., Yang, P. C., Tsao, P. S. 2007; 292 (5): H2106-H2118

    Abstract

    The db/db mouse is a well-established model of diabetes. Previous reports have documented contractile dysfunction (i.e., cardiomyopathy) in these animals, although the extant literature provides limited insights into cardiac structure and function as they change over time. To better elucidate the natural history of cardiomyopathy in db/db mice, we performed cardiac magnetic resonance (CMR) scans on these animals. CMR imaging was conducted with a 4.7-T magnet on female db/db mice and control db/+ littermates at 5, 9, 13, 17, and 22 wk of age. Gated gradient echo sequences were used to obtain cineographic short-axis slices from apex to base. From these images left ventricular (LV) mass (LVM), wall thickness, end-diastolic volume (LVEDV), and ejection fraction (LVEF) were determined. Additionally, cardiac [(18)F]fluorodeoxyglucose ([(18)F]FDG) PET scanning, pressure-volume loops, and real-time quantitative PCR on db/db myocardium were performed. Relative to control, db/db mice developed significant increases in LVM and wall thickness as early as 9 wk of age. LVEDV diverged slightly later, at 13 wk. Interestingly, compared with the baseline level, LVEF in the db/db group did not decrease significantly until 22 wk. Additionally, [(18)F]FDG metabolic imaging showed a 40% decrease in glucose uptake in db/db mice. Furthermore, contractile dysfunction was observed in 15-wk db/db mice undergoing pressure-volume loops. Finally, real-time quantitative PCR revealed an age-dependent recapitulation of the fetal gene program, consistent with a myopathic process. In summary, as assessed by CMR, db/db mice develop characteristic structural and functional changes consistent with cardiomyopathy.

    View details for DOI 10.1152/ajpheart.00856.2006

    View details for Web of Science ID 000247777200012

    View details for PubMedID 17122193

  • Cardiovascular MRI for stem cell therapy. Current cardiology reports Suzuki, Y., Yeung, A. C., Yang, P. C. 2007; 9 (1): 45-50

    Abstract

    Stem cell therapy may provide an alternative therapeutic option for severe congestive heart failure (CHF). Despite the promise generated by this novel approach, precise in vivo monitoring of the transplanted cells and of subsequent myocardial restoration remains a challenge. The development of a sensitive, noninvasive imaging technology to track stem cells while assessing cardiac function is critical to monitor therapeutic efficacy. In vivo cardiovascular MRI of stem cells is an emerging application to identify, localize, and monitor stem cells while simultaneously evaluating the restoration of the injured myocardium following stem cell therapy. Furthermore, advances in scanner technology, pulse sequence design, and associated hardware have resulted in real-time guidance of catheter-based intervention to deliver cells accurately to the regions of myocardial injury. These capabilities have positioned MRI as the primary comprehensive imaging modality to monitor cell therapy.

    View details for PubMedID 17362684

  • 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

  • Collagen matrices enhance survival of transplanted cardiomyoblasts and contribute to functional improvement of ischemic rat hearts CIRCULATION Kutschka, I., Chen, I. Y., Kofidis, T., Arai, T., von Degenfeld, G., Sheikh, A. Y., Hendry, S. L., Pearl, J., Hoyt, G., Sista, R., Yang, P. C., Blau, H. M., Gambhir, S. S., Robbins, R. C. 2006; 114: I167-I173

    Abstract

    Cardiac cell transplantation is limited by poor graft viability. We aimed to enhance the survival of transplanted cardiomyoblasts using growth factor-supplemented collagen matrices.H9c2 cardiomyoblasts were lentivirally transduced to express firefly luciferase and green fluorescent protein (GFP). Lewis rats underwent ligation of the left anterior descending artery (LAD) ligation to induce an anterior wall myocardial infarction. Hearts (n=9/group) were harvested and restored ex vivo with 1 x 10(6) genetically labeled H9c2 cells either in (1) saline-suspension, or seeded onto (2) collagen-matrix (Gelfoam [GF];), (3) GF/Matrigel (GF/MG), (4) GF/MG/VEGF (10 microg/mL), or (5) GF/MG/FGF (10 microg/mL). Hearts were then abdominally transplanted into syngeneic recipients (working heart model). Controls (n=6/group) underwent infarction followed by GF implantation or saline injection. Cell survival was evaluated using optical bioluminescence on days 1, 5, 8, 14, and 28 postoperatively. At 4 weeks, fractional shortening and ejection fraction were determined using echocardiography and magnetic resonance imaging, respectively. Graft characteristics were assessed by immunohistology. Bioluminescence signals on days 5, 8, and 14 were higher for GF-based grafts compared with plain H9c2 injections (P<0.03). Signals were higher for GF/MG grafts compared with GF alone (P<0.02). GFP-positive, spindle-shaped H9c2 cells were found integrated in the infarct border zones at day 28. Left ventricular (LV) function of hearts implanted with collagen-based grafts was better compared with controls (P<0.05). Vascular endothelial growth factor or fibroblast growth factor did not further improve graft survival or heart function.Collagen matrices enhance early survival of H9c2 cardiomyoblasts after transplantation into ischemic hearts and lead to improved LV function. Further optimization of the graft design should make restoration of large myocardial infarctions by tissue engineering approaches effective.

    View details for DOI 10.1161/CIRCULATIONAHA.105.001297

    View details for Web of Science ID 000238688200028

    View details for PubMedID 16820568

  • 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

  • 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

  • Indirect magnetic resonance lymphangiography to assess lymphatic function in experimental murine lymphedema. Lymphatic research and biology Pan, D., Suzuki, Y., Yang, P. C., Rockson, S. G. 2006; 4 (4): 211-216

    Abstract

    Recently, indirect magnetic resonance lymphangiography with gadolinium (Gd) has been demonstrated to offer the potential for safe, high-resolution visualization of the lymphatic vessels, in addition to the lymph nodes. In this study, the potential utility of indirect Gd contrast magnetic resonance imaging of lymphatic vascular function was investigated in the murine tail. Functional imaging of healthy mice is contrasted with the findings in experimentally-induced lymphatic vascular insufficiency.Postsurgical lymphedema was experimentally created in the murine tail. Normal and lymphedematous mouse tails were imaged following direct subcutaneous administration of Gadolinium-DTPA, 0.1 mmol/kg. Images were obtained in axial and coronal planes with a T1-weighted spin echo inversion-recovery sequence.In the normal tail, both of the bilateral major collecting lymphatics were clearly visualized as the Gd tracer was cleared from the interstitial compartment. In contrast, the Gd tracer accumulated at the prior surgical site in the lymphedematous tail. Quantitative assessment of Gd clearance demonstrates that accumulation of Gd correlates with the impedance to lymph flow proximal to the site of surgical lymphatic ablation.Magnetic resonance is a feasible and reliable method to be applied to quantitative functional imaging of the lymphatic vasculature in experimental models of lymphedema.

    View details for PubMedID 17394404

  • 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

  • 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

  • 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

  • Early diagnosis of hemochromatosis-related cardiomyopathy with magnetic resonance imaging JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE Ptaszek, L. M., Price, E. T., Hu, M. Y., Yang, P. C. 2005; 7 (4): 689-692

    Abstract

    The hallmark of hemochromatosis is the deposition of iron in multiple tissue types, most notably the skin, liver, pancreas, thyroid, and heart. Definitive diagnosis of iron deposition generally requires invasive methods, such as direct tissue biopsy. We describe a 40 year-old woman with end-stage liver disease secondary to hereditary hemochromatosis and alcohol abuse, who was referred to the cardiology service as part of an evaluation for orthotopic liver transplant. The patient had no cardiac history but a dobutamine stress echocardiogram, performed as a portion of the pre-operative cardiac evaluation, could not be completed due to intermittent, supraventricular tachycardia. Additional cardiac testing, including electrocardiography and resting echocardiography, raised suspicion for cardiomyopathy related to hemochromatosis but was non-diagnostic. Cardiac magnetic resonance (MR) of this patient revealed deposition of iron in the myocardium and established the diagnosis of hemachromatosis-related cardiomyopathy. These findings suggest that cardiac MR may be more sensitive than other non-invasive, diagnostic tools in the initial evaluation of hemochromatosis-related cardiomyopathy and may be used as an alternative to myocardial biopsy. We propose that conventional T1- and T2-weighted spin echo MR sequences can be used routinely as non-invasive modalities to assess the presence of iron deposition in the tissues of patients with hemochromatosis.

    View details for DOI 10.1081/JCMR-200065632

    View details for Web of Science ID 000231431000012

    View details for PubMedID 16136860

  • 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

  • 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

  • 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

  • Real-time interactive coronary MRA MAGNETIC RESONANCE IN MEDICINE Nayak, K. S., Pauly, J. M., Yang, P. C., Hu, B. S., Meyer, C. H., Nishimura, D. G. 2001; 46 (3): 430-435

    Abstract

    An interactive real-time imaging system capable of rapid coronary artery imaging is described. High-resolution spiral and circular echo planar trajectories were used to achieve 0.8 x 1.6 mm2 resolution in 135 ms (CEPI) or 1.13 x 1.13 mm2 resolution in 189 ms (spirals), over a 20-cm FOV. Using a sliding window reconstruction, display rates of up to 37 images/sec were achieved. Initial results indicate this technique can perform as a high-quality 2D coronary localizer and with SNR improvement may enable rapid screening of the coronary tree.

    View details for Web of Science ID 000170740300004

    View details for PubMedID 11550232

  • Rapid evaluation of left ventricular volume and mass without breath-holding using real-time interactive cardiac magnetic resonance imaging system JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Kaji, S., Yang, P. C., Kerr, A. B., Tang, W. H., Meyer, C. H., Macovski, A., Pauly, J. M., Nishimura, D. G., Hu, B. S. 2001; 38 (2): 527-533

    Abstract

    The purpose of this study was to validate cardiac measurements derived from real-time cardiac magnetic resonance imaging (MRI) as compared with well-validated conventional cine MRI.Although cardiac MRI provides accurate assessment of left ventricular (LV) volume and mass, most techniques have been relatively slow and required electrocardiogram (ECG) gating over many heart beats. A newly developed real-time MRI system allows continuous real-time dynamic acquisition and display without cardiac gating or breath-holding.Fourteen healthy volunteers and nine patients with heart failure underwent real-time and cine MRI in the standard short-axis orientation with a 1.5T MRI scanner. Nonbreath-holding cine MRI was performed with ECG gating and respiratory compensation. Left ventricular end-diastolic volume (LVEDV), left ventricular endsystolic volume (LVESV), ejection fraction (EF) and LV mass calculated from the images obtained by real-time MRI were compared to those obtained by cine MRI.The total study time including localization for real-time MRI was significantly shorter than cine MRI (8.6 +/- 2.3 vs. 24.7 +/- 3.5 min, p < 0.001). Both imaging techniques yielded good quality images allowing cardiac measurements. The measurements of LVEDV, LVESV, EF and LV mass obtained with real-time MRI showed close correlation with those obtained with cine MRI (LVEDV: r = 0.985, p < 0.001; LVESV: r = 0.994, p < 0.001; EF: r = 0.975, p < 0.001; LV mass: r = 0.977, p < 0.001).Real-time MRI provides accurate measurements of LV volume and mass in a time-efficient manner with respect to image acquisition.

    View details for Web of Science ID 000170205800033

    View details for PubMedID 11499748

  • New real-time interactive cardiac magnetic resonance imaging system complements echocardiography JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Yang, P. C., Kerr, A. B., Liu, A. C., Liang, D. H., Hardy, C., Meyer, C. H., Macovski, A., Pauly, J. M., Hu, B. S. 1998; 32 (7): 2049-2056

    Abstract

    We conducted an initial clinical trial of a newly developed cardiac magnetic resonance imaging (CMRI) system. We evaluated left ventricular (LV) function in 85 patients to compare the clinical utility of the CMRI system with echocardiography, the current noninvasive gold standard.Conventional CMRI systems require cardiac-gating and respiratory compensation to synthesize a single image from data acquired over multiple cardiac cycles. In contrast, the new CMRI system allows continuous real-time dynamic acquisition and display of any scan plane at 16 images/s without the need for cardiac gating or breath-holding.A conventional 1.5T Signa MRI Scanner (GE, Milwaukee, Wisconsin) was modified by the addition of an interactive workstation and a bus adapter. The new CMRI system underwent clinical trial by testing its ability to evaluate global and regional LV function. The first group (A) consisted of 31 patients with acceptable echocardiography image quality. The second group (B) consisted of 31 patients with suboptimal echocardiography image quality. The third group (C) consisted of 29 patients with severe lung disease or congenital cardiac malformation who frequently have suboptimal echo study. Two independent observers scored wall motion and image quality using the standard 16-segment model and rank-order analysis.CMRI evaluation was complete in less than 15 min. In group A, no significant difference was found between ECHO and CMRI studies (p = NS). In group B, adequate visualization of wall segments was obtained 38% of the time using ECHO and 97% of the time using CMRI (p < 0.0001). When grouped into coronary segments, adequate visualization of at least one segment occurred in 18 of 30 patients (60%) with ECHO and in all 30 patients (100%) with CMRI (p < 0.0001). In group C, adequate visualization of the wall segments was obtained in 58% (CI 0.53-0.62) of the time using echocardiography and 99.7% (CI 0.99-1.0) of the time using CMRI (p < 0.0001).The new CMRI system provides clinically reliable evaluation of LV function and complements suboptimal echocardiography. In comparison with the conventional CMRI, the new CMRI system significantly reduces scan time, patient discomfort and associated cost.

    View details for Web of Science ID 000077396200039

    View details for PubMedID 9857892

Conference Proceedings


  • In vivo magnetic resonance evaluation of the effects of mouse embryonic stem cells on cardiac function Arai, T., de Bruin, J., Kofidis, T., Venook, R., McConnell, M. V., Quertermous, T., Robbins, R., Yang, P. C. ELSEVIER SCIENCE INC. 2004: 532A-532A
  • Contrast-enhanced MRI demonstrates acute response to vascular injury Terashima, M., De La Pena-Almaguer, E., Yang, P. C., Hu, B. S., McConnell, M. V. ELSEVIER SCIENCE INC. 2002: 389A-389A
  • NTG-enhanced coronary MRA: Improved SNR and vasodilation time course Terashima, M., Keeffe, B. G., Putz, E. J., Yang, P. C., De La Pena-Almaguer, E., Hu, B. S., Nishimura, D. G., Meyer, C. H., McConnell, M. V. ELSEVIER SCIENCE INC. 2002: 218A-218A
  • High-resolution real-time magnetic resonance imaging for vascular interventions. Terashima, M., De La Pena-Almaguer, E., Nayak, K., Pauly, J. M., Yang, P. C., Hu, B. S., McConnell, M. V. EXCERPTA MEDICA INC. 2001: 89G-89G

Stanford Medicine Resources: