Professor of Medicine (Cardiovascular Medicine)

Publications

  • Recommendations for Nomenclature and Definition Of Cell Products Intended for Human Cardiovascular Use. Cardiovascular research Taylor, D. A., Chacon-Alberty, L., Sampaio, L. C., Del Hierro, M. G., Perin, E. C., Mesquita, F. C., Henry, T. D., Traverse, J. H., Pepine, C. J., Hare, J. M., Murphy, M. P., Yang, P. C., March, K. L., Vojvodic, R. W., Ebert, R. F., Bolli, R., Cardiovascular Cell Therapy Research Network (CCTRN) 2021

    Abstract

    Exogenous cell-based therapy has emerged as a promising new strategy to facilitate repair of hearts damaged by acute or chronic injury. However, the field of cell-based therapy is handicapped by the lack of standardized definitions and terminology, making comparisons across studies challenging. Even the term "stem cell therapy" is misleading because only a small percentage of cells derived from adult bone marrow, peripheral blood, or adipose tissue meets the accepted hematopoietic or developmental definition of stem cells. Furthermore, cells (stem or otherwise) are dynamic biological products, meaning that their surface marker expression, phenotypic and functional characteristics, and the products they secrete in response to their microenvironment can change. It is also important to point out that most surface markers are seldom specific for a cell type. In this article, we discuss the lack of consistency in the descriptive terminology used in cell-based therapies and offer guidelines aimed at standardizing nomenclature and definitions to improve communication among investigators and the general public.

    View details for DOI 10.1093/cvr/cvab270

    View details for PubMedID 34387303

  • Dual Contrast Manganese-Enhanced MRI and Gadolinium Delayed-Enhanced MRI Detect Heterogenous Myocardial Viability in Ischemic Cardiomyopathy JACC-CARDIOVASCULAR IMAGING Tada, Y., Santoso, M. R., Heidary, S., Sano, H., Tachibana, A., Matsuura, Y., Harnish, P., Yang, P. C. 2021; 14 (7): 1474-1476

    View details for DOI 10.1016/j.jcmg.2020.12.025

    View details for Web of Science ID 000697114900022

    View details for PubMedID 33744127

  • EXOSOMES FROM HUMAN INDUCED PLURIPOTENT STEM CELL-DERIVED CARDIOMYOCYTES (ICMS) AND MESENCHYMAL STEM CELLS (MSCS) RECOVER HEART FUNCTION IN PORCINE ACUTE MYOCARDIAL INFARCTION (MI) MODEL Bayardo, N., O'Brien, C., Vaskova, E., Lyons, J., Tada, Y., Yang, P. ELSEVIER SCIENCE INC. 2021: 19
  • MIR-20B AND-92A ENHANCES CARDIOMYOCYTE CELL CYCLE RE-ENTRY AND PROLIFERATION IN THE ISCHEMIC MYOCARDIUM Jung, J., Ikeda, G., Tada, Y., Yang, P. ELSEVIER SCIENCE INC. 2021: 175
  • A Phase II Study of Autologous Mesenchymal Stromal Cells and c-kit Positive Cardiac Cells, Alone or in Combination, in Patients with Ischemic Heart Failure: The CCTRN CONCERT-HF Trial. European journal of heart failure Bolli, R., Mitrani, R. D., Hare, J. M., Pepine, C. J., Perin, E. C., Willerson, J. T., Traverse, J. H., Henry, T. D., Yang, P. C., Murphy, M. P., March, K. L., Schulman, I. H., Ikram, S., Lee, D. P., O'Brien, C., Lima, J. A., Ostovaneh, M. R., Ambale-Venkatesh, B., Lewis, G., Khan, A., Bacallao, K., Valasaki, K., Longsomboon, B., Gee, A. P., Richman, S., Taylor, D. A., Lai, D., Sayre, S. L., Bettencourt, J., Vojvodic, R. W., Cohen, M. L., Simpson, L., Aguilar, D., Loghin, C., Moye, L., Ebert, R. F., Davis, B. R., Simari, R. D., Cardiovascular Cell Therapy Research Network (CCTRN) 2021

    Abstract

    AIMS: CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischemic cardiomyopathy.METHODS AND RESULTS: Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12months. Seven centers enrolled 125 participants with left ventricular ejection fraction (LVEF) of 28.6±6.1% and scar size 19.4±5.8%, in NYHA class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (-22% vs. placebo, P=0.043). Quality of life (MLHFQ score) was significantly improved by MSCs alone (P=0.050) and MSCs+CPCs (P=0.023) vs. placebo. LVEF, LV volumes, scar size, 6-min walking distance, and peak VO2 did not differ significantly among groups.CONCLUSIONS: This is the first multicenter trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischemic HF without affecting LV function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.

    View details for DOI 10.1002/ejhf.2178

    View details for PubMedID 33811444

  • Comparative analysis on the anti-inflammatory/immune effect of mesenchymal stem cell therapy for the treatment of pulmonary arterial hypertension. Scientific reports Oh, S. n., Jang, A. Y., Chae, S. n., Choi, S. n., Moon, J. n., Kim, M. n., Spiekerkoetter, E. n., Zamanian, R. T., Yang, P. C., Hwang, D. n., Byun, K. n., Chung, W. J. 2021; 11 (1): 2012

    Abstract

    Despite the advancement of targeted therapy for pulmonary arterial hypertension (PAH), poor prognosis remains a reality. Mesenchymal stem cells (MSCs) are one of the most clinically feasible alternative treatment options. We compared the treatment effects of adipose tissue (AD)-, bone marrow (BD)-, and umbilical cord blood (UCB)-derived MSCs in the rat monocrotaline-induced pulmonary hypertension (PH) model. The greatest improvement in the right ventricular function was observed in the UCB-MSCs treated group. The UCB-MSCs treated group also exhibited the greatest improvement in terms of the largest decrease in the medial wall thickness, perivascular fibrosis, and vascular cell proliferation, as well as the lowest levels of recruitment of innate and adaptive immune cells and associated inflammatory cytokines. Gene expression profiling of lung tissue confirmed that the UCB-MSCs treated group had the most notably attenuated immune and inflammatory profiles. Network analysis further revealed that the UCB-MSCs group had the greatest therapeutic effect in terms of the normalization of all three classical PAH pathways. The intravenous injection of the UCB-MSCs, compared with those of other MSCs, showed superior therapeutic effects in the PH model for the (1) right ventricular function, (2) vascular remodeling, (3) immune/inflammatory profiles, and (4) classical PAH pathways.

    View details for DOI 10.1038/s41598-021-81244-1

    View details for PubMedID 33479312

    View details for PubMedCentralID PMC7820276

  • Mitochondria-Rich Extracellular Vesicles Rescue Patient-Specific Cardiomyocytes From Doxorubicin Injury: Insights Into the SENECA Trial. JACC. CardioOncology O'Brien, C. G., Ozen, M. O., Ikeda, G., Vaskova, E., Jung, J. H., Bayardo, N., Santoso, M. R., Shi, L., Wahlquist, C., Jiang, Z., Jung, Y., Zeng, Y., Egan, E., Sinclair, R., Gee, A., Witteles, R., Mercola, M., Svensson, K. J., Demirci, U., Yang, P. C. 2021; 3 (3): 428-440

    Abstract

    Anthracycline-induced cardiomyopathy (AIC) is a significant source of morbidity and mortality in cancer survivors. The role of mesenchymal stem cells (MSCs) in treating AIC was evaluated in the SENECA trial, a Phase 1 National Heart, Lung, and Blood Institute-sponsored study, but the mechanisms underpinning efficacy in human tissue need clarification.The purpose of this study was to perform an in vitro clinical trial evaluating the efficacy and putative mechanisms of SENECA trial-specific MSCs in treating doxorubicin (DOX) injury, using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iCMs) generated from SENECA patients.Patient-specific iCMs were injured with 1 μmol/L DOX for 24 hours, treated with extracellular vesicles (EVs) from MSCs by either coculture or direct incubation and then assessed for viability and markers of improved cellular physiology. MSC-derived EVs were separated into large extracellular vesicles (L-EVs) (>200 nm) and small EVs (<220nm) using a novel filtration system.iCMs cocultured with MSCs in a transwell system demonstrated improved iCM viability and attenuated apoptosis. L-EVs but not small EVs recapitulated this therapeutic effect. L-EVs were found to be enriched in mitochondria, which were shown to be taken up by iCMs. iCMs treated with L-EVs demonstrated improved contractility, reactive oxygen species production, ATP production, and mitochondrial biogenesis. Inhibiting L-EV mitochondrial function with 1-methyl-4-phenylpyridinium attenuated efficacy.L-EV-mediated mitochondrial transfer mitigates DOX injury in patient-specific iCMs. Although SENECA was not designed to test MSC efficacy, consistent tendencies toward a positive effect were observed across endpoints. Our results suggest a mechanism by which MSCs may improve cardiovascular performance in AIC independent of regeneration, which could inform future trial design evaluating the therapeutic potential of MSCs.

    View details for DOI 10.1016/j.jaccao.2021.05.006

    View details for PubMedID 34604804

    View details for PubMedCentralID PMC8463733

  • Peripheral Blood Biomarkers Associated With Improved Functional Outcome in Patients With Chronic Left Ventricular Dysfunction: A Biorepository Evaluation of the FOCUS-CCTRN Trial. Frontiers in cardiovascular medicine Chacon Alberty, L., Perin, E. C., Willerson, J. T., Gahremanpour, A., Bolli, R., Yang, P. C., Traverse, J. H., Lai, D., Pepine, C. J., Taylor, D. A. 2021; 8: 698088

    Abstract

    Cell therapy trials for heart failure (HF) have shown modest improvement; however, the mechanisms underlying improvement in some patients but not others are not well understood. Although immune cells are important in the course of HF, our understanding of the immune processes in HF is limited. The objective of this study was to evaluate associations between temporal changes in peripheral blood (PB) cell subpopulations and improved outcome in patients with chronic ischemic cardiomyopathy after bone marrow-derived mononuclear cell therapy or placebo in the FOCUS-CCTRN trial. Peripheral blood was collected at days 0, 1, 30, 90, and 180 from consented participants. We used flow cytometry to compare PB populations in patients with the best (cohort 1) or worst functional outcome (cohort 2) in three primary endpoints: left ventricular (LV) ejection fraction, LV end-systolic volume, and maximal oxygen consumption (VO2 max). A linear mixed model was used to assess changes over time in 32 cell populations. The difference between each time point and baseline was calculated as linear contrast. Compared with cohort 2, patients who improved (cohort 1) had a higher frequency of CD45+CD19+ B cells at days 0, 1, 90, and 180. CD11B+ cells increased over baseline at day 1 in both cohorts and remained higher in cohort 2 until day 30. CD45+CD133+ progenitor cells decreased over baseline at day 30 in cohort 1. We identified specific cell subpopulations associated with improved cardiac function in patients with chronic LV dysfunction. These findings may improve patient selection and prediction of outcomes in cell therapy trials.

    View details for DOI 10.3389/fcvm.2021.698088

    View details for PubMedID 34540912

  • miR-106a-363 cluster in extracellular vesicles promotes endogenous myocardial repair via Notch3 pathway in ischemic heart injury. Basic research in cardiology Jung, J. H., Ikeda, G. n., Tada, Y. n., von Bornstädt, D. n., Santoso, M. R., Wahlquist, C. n., Rhee, S. n., Jeon, Y. J., Yu, A. C., O'brien, C. G., Red-Horse, K. n., Appel, E. A., Mercola, M. n., Woo, J. n., Yang, P. C. 2021; 116 (1): 19

    Abstract

    Endogenous capability of the post-mitotic human heart holds great promise to restore the injured myocardium. Recent evidence indicates that the extracellular vesicles (EVs) regulate cardiac homeostasis and regeneration. Here, we investigated the molecular mechanism of EVs for self-repair. We isolated EVs from human iPSC-derived cardiomyocytes (iCMs), which were exposed to hypoxic (hEVs) and normoxic conditions (nEVs), and examined their roles in in vitro and in vivo models of cardiac injury. hEV treatment significantly improved the viability of hypoxic iCMs in vitro and cardiac function of severely injured murine myocardium in vivo. Microarray analysis of the EVs revealed significantly enriched expression of the miR-106a-363 cluster (miR cluster) in hEVs vs. nEVs. This miR cluster preserved survival and contractility of hypoxia-injured iCMs and maintained murine left-ventricular (LV) chamber size, improved LV ejection fraction, and reduced myocardial fibrosis of the injured myocardium. RNA-Seq analysis identified Jag1-Notch3-Hes1 as a target intracellular pathway of the miR cluster. Moreover, the study found that the cell cycle activator and cytokinesis genes were significantly up-regulated in the iCMs treated with miR cluster and Notch3 siRNA. Together, these results suggested that the miR cluster in the EVs stimulated cardiomyocyte cell cycle re-entry by repressing Notch3 to induce cell proliferation and augment myocardial self-repair. The miR cluster may represent an effective therapeutic approach for ischemic cardiomyopathy.

    View details for DOI 10.1007/s00395-021-00858-8

    View details for PubMedID 33742276

  • Mitochondria-Rich Extracellular Vesicles From Autologous Stem Cell-Derived Cardiomyocytes Restore Energetics of Ischemic Myocardium. Journal of the American College of Cardiology Ikeda, G. n., Santoso, M. R., Tada, Y. n., Li, A. M., Vaskova, E. n., Jung, J. H., O'Brien, C. n., Egan, E. n., Ye, J. n., Yang, P. C. 2021; 77 (8): 1073–88

    Abstract

    Mitochondrial dysfunction results in an imbalance between energy supply and demand in a failing heart. An innovative therapy that targets the intracellular bioenergetics directly through mitochondria transfer may be necessary.The purpose of this study was to establish a preclinical proof-of-concept that extracellular vesicle (EV)-mediated transfer of autologous mitochondria and their related energy source enhance cardiac function through restoration of myocardial bioenergetics.Human-induced pluripotent stem cell-derived cardiomyocytes (iCMs) were employed. iCM-conditioned medium was ultracentrifuged to collect mitochondria-rich EVs (M-EVs). Therapeutic effects of M-EVs were investigated using in vivo murine myocardial infarction (MI) model.Electron microscopy revealed healthy-shaped mitochondria inside M-EVs. Confocal microscopy showed that M-EV-derived mitochondria were transferred into the recipient iCMs and fused with their endogenous mitochondrial networks. Treatment with 1.0 × 108/ml M-EVs significantly restored the intracellular adenosine triphosphate production and improved contractile profiles of hypoxia-injured iCMs as early as 3 h after treatment. In contrast, isolated mitochondria that contained 300× more mitochondrial proteins than 1.0 × 108/ml M-EVs showed no effect after 24 h. M-EVs contained mitochondrial biogenesis-related messenger ribonucleic acids, including proliferator-activated receptor γ coactivator-1α, which on transfer activated mitochondrial biogenesis in the recipient iCMs at 24 h after treatment. Finally, intramyocardial injection of 1.0 × 108 M-EVs demonstrated significantly improved post-MI cardiac function through restoration of bioenergetics and mitochondrial biogenesis.M-EVs facilitated immediate transfer of their mitochondrial and nonmitochondrial cargos, contributing to improved intracellular energetics in vitro. Intramyocardial injection of M-EVs enhanced post-MI cardiac function in vivo. This therapy can be developed as a novel, precision therapeutic for mitochondria-related diseases including heart failure.

    View details for DOI 10.1016/j.jacc.2020.12.060

    View details for PubMedID 33632482

  • Precise Measurement of Physical Activities and High-Impact Motion: Feasibility of Smart Activity Sensor System IEEE SENSORS JOURNAL Liu, H., Chuang, Y., Liu, C., Yang, P. C., Fuh, C. 2021; 21 (1): 568–80
  • Allogeneic Mesenchymal Cell Therapy in Anthracycline-Induced Cardiomyopathy Heart Failure Patients: The CCTRN SENECA Trial. JACC. CardioOncology Bolli, R., Perin, E. C., Willerson, J. T., Yang, P. C., Traverse, J. H., Henry, T. D., Pepine, C. J., Mitrani, R. D., Hare, J. M., Murphy, M. P., March, K. L., Ikram, S., Lee, D. P., O'Brien, C., Durand, J., Miller, K., Lima, J. A., Ostovaneh, M. R., Ambale-Venkatesh, B., Gee, A. P., Richman, S., Taylor, D. A., Sayre, S. L., Bettencourt, J., Vojvodic, R. W., Cohen, M. L., Simpson, L. M., Lai, D., Aguilar, D., Loghin, C., Moye, L., Ebert, R. F., Davis, B. R., Simari, R. D., Cardiovascular Cell Therapy Research Network (CCTRN) 2020; 2 (4): 581–95

    Abstract

    BACKGROUND: Anthracycline-induced cardiomyopathy (AIC) may be irreversible with a poor prognosis, disproportionately affecting women and young adults. Administration of allogeneic bone marrow-derived mesenchymal stromal cells (allo-MSCs) is a promising approach to heart failure (HF) treatment.OBJECTIVES: SENECA (Stem Cell Injection in Cancer Survivors) was a phase 1 study of allo-MSCs in AIC.METHODS: Cancer survivors with chronic AIC (mean age 56.6 years; 68% women; NT-proBNP 1,426 pg/ml; 6 enrolled in an open-label, lead-in phase and 31 subjects randomized 1:1) received 1 * 108 allo-MSCs or vehicle transendocardially. Primary objectives were safety and feasibility. Secondary efficacy measures included cardiac function and structure measured by cardiac magnetic resonance imaging (CMR), functional capacity, quality of life (Minnesota Living with Heart Failure Questionnaire), and biomarkers.RESULTS: A total of 97% of subjects underwent successful study product injections; all allo-MSC-assigned subjects received the target dose of cells. Follow-up visits were well-attended (92%) with successful collection of endpoints in 94% at the 1-year visit. Although 58% of subjects had non-CMR compatible devices, CMR endpoints were successfully collected in 84% of subjects imaged at 1 year. No new tumors were reported. There were no significant differences between allo-MSC and vehicle groups with regard to clinical outcomes. Secondary measures included 6-min walk test (p = 0.056) and Minnesota Living with Heart Failure Questionnaire score (p = 0.048), which tended to favor the allo-MSC group.CONCLUSIONS: In this first-in-human study of cell therapy in patients with AIC, transendocardial administration of allo-MSCs appears safe and feasible, and CMR was successfully performed in the majority of the HF patients with devices. This study lays the groundwork for phase 2 trials aimed at assessing efficacy of cell therapy in patients with AIC.

    View details for DOI 10.1016/j.jaccao.2020.09.001

    View details for PubMedID 33403362

  • A Phase I Study of Allogeneic Mesenchymal Stem Cell Therapy in Patients with Heart Failure Secondary to Anthracycline-induced Cardiomyopathy: The Cctrn Stem Cell Injection in Cancer Survivors (Seneca) Trial Bolli, R., Perin, E. C., Willerson, J. T., Yang, P. C., Traverse, J. H., Henry, T. D., Pepine, C. J., Mitrani, R. D., Hare, J. M., Murphy, M. P., Lima, J. A., Gee, A. P., Taylor, D. A., Lai, D., Ebert, R. F., Davis, B. R., Simari, R. D. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2020: S97
  • SULFATED DEXTRAN-COATED IRON OXIDE NANOPARTICLES DETECT INFLAMMATION IN THE PERI-INFARCT REGION POST-ACUTE MYOCARDIAL INFARCTION Tada, Y., Ikeda, G., Louie, A., Yang, P. ELSEVIER SCIENCE INC. 2020: 1792
  • MITOCHONDRIA CONTAINING EXTRACELLULAR VESICLES FROM AUTOLOGOUS INDUCED PLURIPOTENT STEM CELL DERIVED CARDIOMYOCYTES RESTORE BIOENERGETICS IN ISCHEMIC MYOCARDIUM Ikeda, G., Santoso, M., Tada, Y., Vaskova, E., O'Brien, C. G., Jung, J., Yang, P. C. ELSEVIER SCIENCE INC. 2020: 3659