Associate Professor of Medicine (Cardiovascular Medicine) at the Stanford University Medical Center


  • 3D image-based navigators for coronary MR angiography MAGNETIC RESONANCE IN MEDICINE Addy, N. O., Ingle, R. R., Luo, J., Baron, C. A., Yang, P. C., Hu, B. S., Nishimura, D. G. 2017; 77 (5): 1874-1883

    View details for DOI 10.1002/mrm.26269

    View details for Web of Science ID 000399666400014

  • Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease: The CCTRN Patients with Intermittent Claudication Injected with ALDH Bright Cells (PACE) Trial. Circulation Perin, E. C., Murphy, M. P., March, K. L., Bolli, R., Loughran, J., Yang, P. C., Leeper, N. J., Dalman, R. L., Alexander, J. Q., Henry, T. D., Traverse, J. H., Pepine, C. J., Anderson, R. D., Berceli, S., Willerson, J. T., Muthupillai, R., Gahremanpour, A. A., Raveendran, G., Velazquez, O. C., Hare, J. M., Schulman, I. H., Kasi, V. S., Hiatt, W. R., Ambale-Venkatesh, B., Lima, J. A., Taylor, D. A., Resende, M. M., Gee, A. P., Durett, A. G., Bloom, J., Richman, S., G'Sell, P., Williams, S., Khan, F., Ross, E. G., Santoso, M. R., Goldman, J., Leach, D., Handberg, E., Cheong, B. Y., Piece, N. A., Difede, D., Bruhn-Ding, B., Caldwell, E., Bettencourt, J., Lai, D., Piller, L. B., Simpson, L. M., Cohen, M., Sayre, S. L., Vojvodic, R. W., Moyé, L., Ebert, R. F., Simari, R. D., Hirsch, A. T. 2017


    Atherosclerotic peripheral artery disease affects 8% to 12% of Americans >65 years of age and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE (Patients With Intermittent Claudication Injected With ALDH Bright Cells) is a National Heart, Lung, and Blood Institute-sponsored, randomized, double-blind, placebo-controlled, phase 2 exploratory clinical trial designed to assess the safety and efficacy of autologous bone marrow-derived aldehyde dehydrogenase bright (ALDHbr) cells in patients with peripheral artery disease and to explore associated claudication physiological mechanisms.All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by 10 injections into the thigh and calf of the index leg. The coprimary end points were change from baseline to 6 months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging, as well as safety.A total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at 9 sites, of whom 78 had analyzable data (57 male, 21 female patients; mean age, 66±9 years). The mean±SEM differences in the change over 6 months between study groups for PWT (0.9±0.8 minutes; 95% confidence interval [CI] -0.6 to 2.5; P=0.238), collateral count (0.9±0.6 arteries; 95% CI, -0.2 to 2.1; P=0.116), peak hyperemic popliteal flow (0.0±0.4 mL/s; 95% CI, -0.8 to 0.8; P=0.978), and capillary perfusion (-0.2±0.6%; 95% CI, -1.3 to 0.9; P=0.752) were not significant. In addition, there were no significant differences for the secondary end points, including quality-of-life measures. There were no adverse safety outcomes. Correlative relationships between magnetic resonance imaging measures and PWT were not significant. A post hoc exploratory analysis suggested that ALDHbr cell administration might be associated with an increase in the number of collateral arteries (1.5±0.7; 95% CI, 0.1-2.9; P=0.047) in participants with completely occluded femoral arteries.ALDHbr cell administration did not improve PWT or magnetic resonance outcomes, and the changes in PWT were not associated with the anatomic or physiological magnetic resonance imaging end points. Future peripheral artery disease cell therapy investigational trial design may be informed by new anatomic and perfusion insights.URL: Unique identifier: NCT01774097.

    View details for DOI 10.1161/CIRCULATIONAHA.116.025707

    View details for PubMedID 28209728

    View details for PubMedCentralID PMC5388585

  • Exosomes Generated From iPSC-Derivatives New Direction for Stem Cell Therapy in Human Heart Diseases CIRCULATION RESEARCH Jung, J., Fu, X., Yang, P. C. 2017; 120 (2): 407-417


    Cardiovascular disease (CVD) is the leading cause of death in modern society. The adult heart innately lacks the capacity to repair and regenerate the damaged myocardium from ischemic injury. Limited understanding of cardiac tissue repair process hampers the development of effective therapeutic solutions to treat CVD such as ischemic cardiomyopathy. In recent years, rapid emergence of induced pluripotent stem cells (iPSC) and iPSC-derived cardiomyocytes presents a valuable opportunity to replenish the functional cells to the heart. The therapeutic effects of iPSC-derived cells have been investigated in many preclinical studies. However, the underlying mechanisms of iPSC-derived cell therapy are still unclear, and limited engraftment of iPSC-derived cardiomyocytes is well known. One facet of their mechanism is the paracrine effect of the transplanted cells. Microvesicles such as exosomes secreted from the iPSC-derived cardiomyocytes exert protective effects by transferring the endogenous molecules to salvage the injured neighboring cells by regulating apoptosis, inflammation, fibrosis, and angiogenesis. In this review, we will focus on the current advances in the exosomes from iPSC derivatives and discuss their therapeutic potential in the treatment of CVD.

    View details for DOI 10.1161/CIRCRESAHA.116.309307

    View details for Web of Science ID 000392226200022

    View details for PubMedID 28104773

  • Identification of cardiovascular risk factors associated with bone marrow cell subsets in patients with STEMI: a biorepository evaluation from the CCTRN TIME and LateTIME clinical trials BASIC RESEARCH IN CARDIOLOGY Contreras, A., Orozco, A. F., Resende, M., Schutt, R. C., Traverse, J. H., Henry, T. D., Lai, D., Cooke, J. P., Bolli, R., Cohen, M. L., Moye, L., Pepine, C. J., Yang, P. C., Perin, E. C., Willerson, J. T., Taylor, D. A. 2017; 112 (1)


    Autologous bone marrow mononuclear cell (BM-MNC) therapy for patients with ST-segment elevation myocardial infarction (STEMI) has produced inconsistent results, possibly due to BM-MNC product heterogeneity. Patient-specific cardiovascular risk factors (CRFs) may contribute to variations in BM-MNC composition. We sought to identify associations between BM-MNC subset frequencies and specific CRFs in STEMI patients. Bone marrow was collected from 191 STEMI patients enrolled in the CCTRN TIME and LateTIME trials. Relationships between BM-MNC subsets and CRFs were determined with multivariate analyses. An assessment of CRFs showed that hyperlipidemia and hypertension were associated with a higher frequency of CD11b(+) cells (P = 0.045 and P = 0.016, respectively). In addition, we found that females had lower frequencies of CD11b(+) (P = 0.018) and CD45(+)CD14(+) (P = 0.028) cells than males, age was inversely associated with the frequency of CD45(+)CD31(+) cells (P = 0.001), smoking was associated with a decreased frequency of CD45(+)CD31(+) cells (P = 0.013), glucose level was positively associated with the frequency of CD45(+)CD3(+) cells, and creatinine level (an indicator of renal function) was inversely associated with the frequency of CD45(+)CD3(+) cells (P = 0.015). In conclusion, the frequencies of monocytic, lymphocytic, and angiogenic BM-MNCs varied in relation to patients' CRFs. These phenotypic variations may affect cell therapy outcomes and might be an important consideration when selecting patients for and reviewing results from autologous cell therapy trials.

    View details for DOI 10.1007/s00395-016-0592-z

    View details for Web of Science ID 000392310300003

    View details for PubMedID 27882430

  • Baseline assessment and comparison of arterial anatomy, hyperemic flow, and skeletal muscle perfusion in peripheral artery disease: The Cardiovascular Cell Therapy Research Network "Patients with Intermittent Claudication Injected with ALDH Bright Cells" (CCTRN PACE) study AMERICAN HEART JOURNAL Venkatesh, B. A., Nauffal, V., Noda, C., Fujii, T., Yang, P. C., Bettencourt, J., Ricketts, E. P., Murphy, M., Leeper, N. J., Moye, L., Ebert, R. F., Muthupillai, R., Bluemke, D. A., Perin, E. C., Hirsch, A. T., Lima, J. A. 2017; 183: 24-34


    Peripheral artery disease (PAD) is important to public health as a major contributor to cardiovascular morbidity and mortality. Recent developments in magnetic resonance imaging (MRI) techniques permit improved assessment of PAD anatomy and physiology, and may serve as surrogate end points after proangiogenic therapies.The PACE study is a randomized, double-blind, placebo-controlled clinical trial designed to assess the physiologic impact and potential clinical efficacy of autologous bone marrow-derived ALDH(br) stem cells. The primary MRI end points of the study are as follows: (1) total collateral count, (2) calf muscle plasma volume (a measure of capillary perfusion) by dynamic contrast-enhanced MRI, and (3) peak hyperemic popliteal flow by phase-contrast MRI (PC-MRI).The interreader and intrareader and test-retest results demonstrated good-to-excellent reproducibility (interclass correlation coefficient range 0.61-0.98) for all magnetic resonance measures. The PAD participants (n=82) had lower capillary perfusion measured by calf muscle plasma volume (3.8% vs 5.6%) and peak hyperemic popliteal flow (4.1 vs 13.5mL/s) as compared with the healthy participants (n=16), with a significant level of collateralization.Reproducibility of the MRI primary end points in PACE was very good to excellent. The PAD participants exhibited decreased calf muscle capillary perfusion as well as arterial flow reserve when compared with healthy participants. The MRI tools used in PACE may advance PAD science by enabling accurate measurement of PAD microvascular anatomy and perfusion before and after stem cell or other PAD therapies.

    View details for DOI 10.1016/j.ahj.2016.09.013

    View details for Web of Science ID 000390259600004

    View details for PubMedID 27979038

    View details for PubMedCentralID PMC5172389

  • Apelin-13 infusion salvages the peri-infarct region to preserve cardiac function after severe myocardial injury INTERNATIONAL JOURNAL OF CARDIOLOGY Chung, W., Cho, A., Byun, K., Moon, J., Ge, X., Seo, H., Moon, E., Dash, R., Yang, P. C. 2016; 222: 361-367


    Apelin-13 (A13) regulates cardiac homeostasis. However, the effects and mechanism of A13 infusion after an acute myocardial injury (AMI) have not been elucidated. This study assesses the restorative effects and mechanism of A13 on the peri-infarct region in murine AMI model.51 FVB/N mice (12weeks, 30g) underwent AMI. A week following injury, continuous micro-pump infusion of A13 (0.5μg/g/day) and saline was initiated for 4-week duration. Dual contrast MRI was conducted on weeks 1, 2, 3, and 5, consisting of delayed-enhanced and manganese-enhanced MRI. Four mice in each group were followed for an extended period of 4weeks without further infusion and underwent MRI scans on weeks 7 and 9.A13 infusion demonstrated preserved LVEF compared to saline from weeks 1 to 4 (21.9±3.2% to 23.1±1.7%* vs. 23.5±1.7% to 16.9±2.8%, *p=0.02), which persisted up to 9weeks post-MI (+1.4%* vs. -9.4%, *p=0.03). Mechanistically, dual contrast MRI demonstrated significant decrease in the peri-infarct and scar % volume in A13 group from weeks 1 to 4 (15.1 to 7.4% and 34.3 to 25.1%, p=0.02, respectively). This was corroborated by significant increase in 5-ethynyl-2'-deoxyuridine (EdU(+)) cells by A13 vs. saline groups in the peri-infarct region (16.5±3.1% vs. 8.1±1.6%; p=0.04), suggesting active cell mitosis. Finally, significantly enhanced mobilization of CD34(+) cells in the peripheral blood and up-regulation of APJ, fibrotic, and apoptotic genes in the peri-infarct region were found.A13 preserves cardiac performance by salvaging the peri-infarct region and may contribute to permanent restoration of the severely injured myocardium.

    View details for DOI 10.1016/j.ijcard.2016.07.263

    View details for Web of Science ID 000384698300066

    View details for PubMedID 27500765

  • Magnetic Resonance Imaging of Cardiac Strain Pattern Following Transplantation of Human Tissue Engineered Heart Muscles CIRCULATION-CARDIOVASCULAR IMAGING Qin, X., Riegler, J., Tiburcy, M., Zhao, X., Chour, T., Ndoye, B., Michael Nguyen, M., Adams, J., Ameen, M., Denney, T. S., Yang, P. C., Patricia Nguyen, P., Zimmermann, W. H., Wu, J. C. 2016; 9 (11)


    The use of tissue engineering approaches in combination with exogenously produced cardiomyocytes offers the potential to restore contractile function after myocardial injury. However, current techniques assessing changes in global cardiac performance after such treatments are plagued by relatively low detection ability. Since the treatment is locally performed, this detection could be improved by myocardial strain imaging that measures regional contractility.Tissue engineered heart muscles (EHMs) were generated by casting human embryonic stem cell-derived cardiomyocytes with collagen in preformed molds. EHMs were transplanted (n=12) to cover infarct and border zones of recipient rat hearts 1 month after ischemia reperfusion injury. A control group (n=10) received only sham placement of sutures without EHMs. To assess the efficacy of EHMs, magnetic resonance imaging and ultrasound-based strain imaging were performed before and 4 weeks after transplantation. In addition to strain imaging, global cardiac performance was estimated from cardiac magnetic resonance imaging. Although no significant differences were found for global changes in left ventricular ejection fraction (control -9.6±1.3% versus EHM -6.2±1.9%; P=0.17), regional myocardial strain from tagged magnetic resonance imaging was able to detect preserved systolic function in EHM-treated animals compared with control (control 4.4±1.0% versus EHM 1.0±0.6%; P=0.04). However, ultrasound-based strain failed to detect any significant change (control 2.1±3.0% versus EHM 6.3±2.9%; P=0.46).This study highlights the feasibility of using cardiac strain from tagged magnetic resonance imaging to assess functional changes in rat models following localized regenerative therapies, which may not be detected by conventional measures of global systolic performance.

    View details for DOI 10.1161/CIRCIMAGING.116.004731

    View details for Web of Science ID 000388482500003

    View details for PubMedID 27903535

    View details for PubMedCentralID PMC5378466

  • Aligned nanofibrillar collagen scaffolds - Guiding lymphangiogenesis for treatment of acquired lymphedema. Biomaterials Hadamitzky, C., Zaitseva, T. S., Bazalova-Carter, M., Paukshto, M. V., Hou, L., Strassberg, Z., Ferguson, J., Matsuura, Y., Dash, R., Yang, P. C., Kretchetov, S., Vogt, P. M., Rockson, S. G., Cooke, J. P., Huang, N. F. 2016; 102: 259-267


    Secondary lymphedema is a common disorder associated with acquired functional impairment of the lymphatic system. The goal of this study was to evaluate the therapeutic efficacy of aligned nanofibrillar collagen scaffolds (BioBridge) positioned across the area of lymphatic obstruction in guiding lymphatic regeneration. In a porcine model of acquired lymphedema, animals were treated with BioBridge scaffolds, alone or in conjunction with autologous lymph node transfer as a source of endogenous lymphatic growth factor. They were compared with a surgical control group and a second control group in which the implanted BioBridge was supplemented with exogenous vascular endothelial growth factor-C (VEGF-C). Three months after implantation, immunofluorescence staining of lymphatic vessels demonstrated a significant increase in lymphatic collectors within close proximity to the scaffolds. To quantify the functional impact of scaffold implantation, bioimpedance was used as an early indicator of extracellular fluid accumulation. In comparison to the levels prior to implantation, the bioimpedance ratio was significantly improved only in the experimental BioBridge recipients with or without lymph node transfer, suggesting restoration of functional lymphatic drainage. These results further correlated with quantifiable lymphatic collectors, as visualized by contrast-enhanced computed tomography. They demonstrate the therapeutic potential of BioBridge scaffolds in secondary lymphedema.

    View details for DOI 10.1016/j.biomaterials.2016.05.040

    View details for PubMedID 27348849

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


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

    View details for DOI 10.1148/radiol.2016140049

    View details for PubMedID 27308957

    View details for PubMedCentralID PMC5006716

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


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

    View details for DOI 10.1148/radiol.2016151150

    View details for PubMedID 27332865

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  • Bone marrow cell characteristics associated with patient profile and cardiac performance outcomes in the LateTIME-Cardiovascular Cell Therapy Research Network (CCTRN) trial. American heart journal Bhatnagar, A., Bolli, R., Johnstone, B. H., Traverse, J. H., Henry, T. D., Pepine, C. J., Willerson, J. T., Perin, E. C., Ellis, S. G., Zhao, D. X., Yang, P. C., Cooke, J. P., Schutt, R. C., Trachtenberg, B. H., Orozco, A., Resende, M., Ebert, R. F., Sayre, S. L., Simari, R. D., Moyé, L., Cogle, C. R., Taylor, D. A. 2016; 179: 142-150


    Although several preclinical studies have shown that bone marrow cell (BMC) transplantation promotes cardiac recovery after myocardial infarction, clinical trials with unfractionated bone marrow have shown variable improvements in cardiac function.To determine whether in a population of post-myocardial infarction patients, functional recovery after BM transplant is associated with specific BMC subpopulation, we examined the association between BMCs with left ventricular (LV) function in the LateTIME-CCTRN trial.In this population, we found that older individuals had higher numbers of BM CD133(+) and CD3(+) cells. Bone marrow from individuals with high body mass index had lower CD45(dim)/CD11b(dim) levels, whereas those with hypertension and higher C-reactive protein levels had higher numbers of CD133(+) cells. Smoking was associated with higher levels of CD133(+)/CD34(+)/VEGFR2(+) cells and lower levels of CD3(+) cells. Adjusted multivariate analysis indicated that CD11b(dim) cells were negatively associated with changes in LV ejection fraction and wall motion in both the infarct and border zones. Change in LV ejection fraction was positively associated with CD133(+), CD34(+), and CD45(+)/CXCR4(dim) cells as well as faster BMC growth rates in endothelial colony forming assays.In the LateTIME population, BM composition varied with patient characteristics and treatment. Irrespective of cell therapy, recovery of LV function was greater in patients with greater BM abundance of CD133(+) and CD34(+) cells and worse in those with higher levels of CD11b(dim) cells. Bone marrow phenotype might predict clinical response before BMC therapy and administration of selected BM constituents could potentially improve outcomes of other future clinical trials.

    View details for DOI 10.1016/j.ahj.2016.06.018

    View details for PubMedID 27595689

  • Novel MRI Contrast Agent from Magnetotactic Bacteria Enables In Vivo Tracking of iPSC-derived Cardiomyocytes SCIENTIFIC REPORTS Mahmoudi, M., Tachibana, A., Goldstone, A. B., Woo, Y. J., Chakraborty, P., Lee, K. R., Foote, C. S., Piecewicz, S., Barrozo, J. C., Wakeel, A., Rice, B. W., Bell, C. B., Yang, P. C. 2016; 6

    View details for DOI 10.1038/srep26960

    View details for Web of Science ID 000377072000001

  • Concise Review: Review and Perspective of Cell Dosage and Routes of Administration From Preclinical and Clinical Studies of Stem Cell Therapy for Heart Disease STEM CELLS TRANSLATIONAL MEDICINE Golpanian, S., Schulman, I. H., Ebert, R. F., Heldman, A. W., Difede, D. L., Yang, P. C., Wu, J. C., Bolli, R., Perin, E. C., Moye, L., Simari, R. D., Wolf, A., Hare, J. M. 2016; 5 (2): 186-191


    : An important stage in the development of any new therapeutic agent is establishment of the optimal dosage and route of administration. This can be particularly challenging when the treatment is a biologic agent that might exert its therapeutic effects via complex or poorly understood mechanisms. Multiple preclinical and clinical studies have shown paradoxical results, with inconsistent findings regarding the relationship between the cell dose and clinical benefit. Such phenomena can, at least in part, be attributed to variations in cell dosing or concentration and the route of administration (ROA). Although clinical trials of cell-based therapy for cardiovascular disease began more than a decade ago, specification of the optimal dosage and ROA has not been established. The present review summarizes what has been learned regarding the optimal cell dosage and ROA from preclinical and clinical studies of stem cell therapy for heart disease and offers a perspective on future directions.Preclinical and clinical studies on cell-based therapy for cardiovascular disease have shown inconsistent results, in part because of variations in study-specific dosages and/or routes of administration (ROA). Future preclinical studies and smaller clinical trials implementing cell-dose and ROA comparisons are warranted before proceeding to pivotal trials.

    View details for DOI 10.5966/sctm.2015-0101

    View details for Web of Science ID 000370914400007

    View details for PubMedID 26683870

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


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

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

    View details for PubMedID 26846539

  • Novel MRI Contrast Agent from Magnetotactic Bacteria Enables In Vivo Tracking of iPSC-derived Cardiomyocytes. Scientific reports Mahmoudi, M., Tachibana, A., Goldstone, A. B., Woo, Y. J., Chakraborty, P., Lee, K. R., Foote, C. S., Piecewicz, S., Barrozo, J. C., Wakeel, A., Rice, B. W., Bell Iii, C. B., Yang, P. C. 2016; 6: 26960-?


    Therapeutic delivery of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) represents a novel clinical approach to regenerate the injured myocardium. However, methods for robust and accurate in vivo monitoring of the iCMs are still lacking. Although superparamagnetic iron oxide nanoparticles (SPIOs) are recognized as a promising tool for in vivo tracking of stem cells using magnetic resonance imaging (MRI), their signal persists in the heart even weeks after the disappearance of the injected cells. This limitation highlights the inability of SPIOs to distinguish stem cell viability. In order to overcome this shortcoming, we demonstrate the use of a living contrast agent, magneto-endosymbionts (MEs) derived from magnetotactic bacteria for the labeling of iCMs. The ME-labeled iCMs were injected into the infarcted area of murine heart and probed by MRI and bioluminescence imaging (BLI). Our findings demonstrate that the MEs are robust and effective biological contrast agents to track iCMs in an in vivo murine model. We show that the MEs clear within one week of cell death whereas the SPIOs remain over 2 weeks after cell death. These findings will accelerate the clinical translation of in vivo MRI monitoring of transplanted stem cell at high spatial resolution and sensitivity.

    View details for DOI 10.1038/srep26960

    View details for PubMedID 27264636

    View details for PubMedCentralID PMC4893600