Professor of Medicine (Cardiovascular Medicine)

Publications

  • 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

  • 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
  • Exosomes From Induced Pluripotent Stem Cell-Derived Cardiomyocytes Promote Autophagy for Myocardial Repair. Journal of the American Heart Association Santoso, M. R., Ikeda, G., Tada, Y., Jung, J., Vaskova, E., Sierra, R. G., Gati, C., Goldstone, A. B., von Bornstaedt, D., Shukla, P., Wu, J. C., Wakatsuki, S., Woo, Y. J., Yang, P. C. 2020; 9 (6): e014345

    Abstract

    Background Induced pluripotent stem cells and their differentiated cardiomyocytes (iCMs) have tremendous potential as patient-specific therapy for ischemic cardiomyopathy following myocardial infarctions, but difficulties in viable transplantation limit clinical translation. Exosomes secreted from iCMs (iCM-Ex) can be robustly collected in vitro and injected in lieu of live iCMs as a cell-free therapy for myocardial infarction. Methods and Results iCM-Ex were precipitated from iCM supernatant and characterized by protein marker expression, nanoparticle tracking analysis, and functionalized nanogold transmission electron microscopy. iCM-Ex were then used in in vitro and in vivo models of ischemic injuries. Cardiac function in vivo was evaluated by left ventricular ejection fraction and myocardial viability measurements by magnetic resonance imaging. Cardioprotective mechanisms were studied by JC-1 (tetraethylbenzimidazolylcarbocyanine iodide) assay, immunohistochemistry, quantitative real-time polymerase chain reaction, transmission electron microscopy, and immunoblotting. iCM-Ex measured 140nm and expressed CD63 and CD9. iCM and iCM-Ex microRNA profiles had significant overlap, indicating that exosomal content was reflective of the parent cell. Mice treated with iCM-Ex demonstrated significant cardiac improvement post-myocardial infarction, with significantly reduced apoptosis and fibrosis. In vitro iCM apoptosis was significantly reduced by hypoxia and exosome biogenesis inhibition and restored by treatment with iCM-Ex or rapamycin. Autophagosome production and autophagy flux was upregulated in iCM-Ex groups in vivo and in vitro. Conclusions iCM-Ex improve post-myocardial infarction cardiac function by regulating autophagy in hypoxic cardiomyoytes, enabling a cell-free, patient-specific therapy for ischemic cardiomyopathy.

    View details for DOI 10.1161/JAHA.119.014345

    View details for PubMedID 32131688

  • Manganese-enhanced T1 mapping to quantify myocardial viability: validation with 18F-fluorodeoxyglucose positron emission tomography. Scientific reports Spath, N. n., Tavares, A. n., Gray, G. A., Baker, A. H., Lennen, R. J., Alcaide-Corral, C. J., Dweck, M. R., Newby, D. E., Yang, P. C., Jansen, M. A., Semple, S. I. 2020; 10 (1): 2018

    Abstract

    Gadolinium chelates are widely used in cardiovascular magnetic resonance imaging (MRI) as passive intravascular and extracellular space markers. Manganese, a biologically active paramagnetic calcium analogue, provides novel intracellular myocardial tissue characterisation. We previously showed manganese-enhanced MRI (MEMRI) more accurately quantifies myocardial infarction than gadolinium delayed-enhancement MRI (DEMRI). Here, we evaluated the potential of MEMRI to assess myocardial viability compared to gold-standard 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) viability. Coronary artery ligation surgery was performed in male Sprague-Dawley rats (n = 13) followed by dual MEMRI and 18F-FDG PET imaging at 10-12 weeks. MEMRI was achieved with unchelated (EVP1001-1) or chelated (mangafodipir) manganese. T1 mapping MRI was followed by 18F-FDG micro-PET, with tissue taken for histological correlation. MEMRI and PET demonstrated good agreement with histology but native T1 underestimated infarct size. Quantification of viability by MEMRI, PET and MTC were similar, irrespective of manganese agent. MEMRI showed superior agreement with PET than native T1. MEMRI showed excellent agreement with PET and MTC viability. Myocardial MEMRI T1 correlated with 18F-FDG standard uptake values and influx constant but not native T1. Our findings indicate that MEMRI identifies and quantifies myocardial viability and has major potential for clinical application in myocardial disease and regenerative therapies.

    View details for DOI 10.1038/s41598-020-58716-x

    View details for PubMedID 32029765

  • Sacubitril/Valsartan Improves Cardiac Function and Decreases Myocardial Fibrosis Via Downregulation of Exosomal miR-181a in a Rodent Chronic Myocardial Infarction Model. Journal of the American Heart Association Vaskova, E. n., Ikeda, G. n., Tada, Y. n., Wahlquist, C. n., Mercola, M. n., Yang, P. C. 2020: e015640

    Abstract

    Background Exosomes are small extracellular vesicles that function as intercellular messengers and effectors. Exosomal cargo contains regulatory small molecules, including miRNAs, mRNAs, lncRNAs, and small peptides that can be modulated by different pathological stimuli to the cells. One of the main mechanisms of action of drug therapy may be the altered production and/or content of the exosomes. Methods and Results We studied the effects on exosome production and content by neprilysin inhibitor/angiotensin receptor blockers, sacubitril/valsartan and valsartan alone, using human-induced pluripotent stem cell-derived cardiomyocytes under normoxic and hypoxic injury model in vitro, and assessed for physiologic correlation using an ischemic myocardial injury rodent model in vivo. We demonstrated that the treatment with sacubitril/valsartan and valsartan alone resulted in the increased production of exosomes by induced pluripotent stem cell-derived cardiomyocytes in vitro in both conditions as well as in the rat plasma in vivo. Next-generation sequencing of these exosomes exhibited downregulation of the expression of rno-miR-181a in the sacubitril/valsartan treatment group. In vivo studies employing chronic rodent myocardial injury model demonstrated that miR-181a antagomir has a beneficial effect on cardiac function. Subsequently, immunohistochemical and molecular studies suggested that the downregulation of miR-181a resulted in the attenuation of myocardial fibrosis and hypertrophy, restoring the injured rodent heart after myocardial infarction. Conclusions We demonstrate that an additional mechanism of action of the pleiotropic effects of sacubitril/valsartan may be mediated by the modulation of the miRNA expression level in the exosome payload.

    View details for DOI 10.1161/JAHA.119.015640

    View details for PubMedID 32538237

  • Ferumoxytol-enhanced cardiovascular magnetic resonance detection of early stage acute myocarditis. Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance Tada, Y., Tachibana, A., Heidary, S., Yang, P. C., McConnell, M. V., Dash, R. 2019; 21 (1): 77

    Abstract

    BACKGROUND: The diagnostic utility of cardiovascular magnetic resonance (CMR) is limited during the early stages of myocarditis. This study examined whether ferumoxytol-enhanced CMR (FE-CMR) could detect an earlier stage of acute myocarditis compared to gadolinium-enhanced CMR.METHODS: Lewis rats were induced to develop autoimmune myocarditis. CMR (3T, GE Signa) was performed at the early- (day 14, n=7) and the peak-phase (day 21, n=8) of myocardial inflammation. FE-CMR was evaluated as % myocardial dephasing signal loss on gradient echo images at 6 and 24h (6h- & 24h-FE-CMR) following the administration of ferumoxytol (300mumolFe/kg). Pre- and post-contrast T2* mapping was also performed. Early (EGE) and late (LGE) gadolinium enhancement was obtained after the administration of gadolinium-DTPA (0.5mmol/kg) on day 14 and 21. Healthy rats were used as control (n=6).RESULTS: Left ventricular ejection fraction (LVEF) was preserved at day 14 with inflammatory cells but no fibrosis seen on histology. EGE and LGE at day 14 both showed limited myocardial enhancement (EGE: 11.7±15.5%; LGE: 8.7±8.7%; both p=ns vs. controls). In contrast, 6h-FE-CMR detected extensive myocardial signal loss (33.2±15.0%, p=0.02 vs. EGE and p<0.01 vs. LGE). At day 21, LVEF became significantly decreased (47.4±16.4% vs control: 66.2±6.1%, p<0.01) with now extensive myocardial involvement detected on EGE, LGE, and 6h-FE-CMR (41.6±18.2% of LV). T2* mapping also detected myocardial uptake of ferumoxytol both at day 14 (6h R2*=299±112s-1vs control: 125±26s-1, p<0.01) and day 21 (564±562s-1, p<0.01 vs control). Notably, the myocardium at peak-phase myocarditis also showed significantly higher pre-contrast T2* (27±5ms vs control: 16±1ms, p<0.001), and the extent of myocardial necrosis had a strong positive correlation with T2* (r=0.86, p<0.001).CONCLUSIONS: FE-CMR acquired at 6h enhance detection of early stages of myocarditis before development of necrosis or fibrosis, which could potentially enable appropriate therapeutic intervention.

    View details for DOI 10.1186/s12968-019-0587-7

    View details for PubMedID 31842900

  • Iron Oxide Labeling and Tracking of Extracellular Vesicles MAGNETOCHEMISTRY Tada, Y., Yang, P. C. 2019; 5 (4)
  • Meta-analysis of short- and long-term efficacy of mononuclear cell transplantation in patients with myocardial infarction. American heart journal Yang, D., O'Brien, C. G., Ikeda, G., Traverse, J. H., Taylor, D. A., Henry, T. D., Bolli, R., Yang, P. C. 2019; 220: 155–75

    Abstract

    BACKGROUND: Mononuclear cells (MNCs) have been tested in clinical trials across multiple cardiovascular pathologies with mixed results. Major adverse cardiac events (MACE) and markers of cardiovascular capacity have been particularly challenging to interpret because of small size. This meta-analysis is aimed to assess the efficacy of MNC therapy in randomized clinical trials to identify the markers of efficiency that could influence future trial design.METHODS: PubMed, Embase, Cochrane library, and ClinicalTrials.gov were searched from inception through November 8, 2018. Changes in left ventricular ejection fraction (LVEF) and infarct size from baseline to follow-up were selected as primary outcomes. Changes in the left ventricular end-systolic volume, left ventricular end-diastolic volume, brain natriuretic peptide/N-terminal pro-B-type natriuretic peptide, 6-minute walk test, New York Heart Association class, and MACE incidences were considered secondary outcomes.RESULTS: In short-term follow-up, patients treated with MNCs demonstrated a significant increase in absolute LVEF of 2.21% (95% CI 1.59-2.83; P < .001; I2 = 32%) and 6.01% (95% CI 4.45-7.57; P < .001; I2 = 0%) in acute myocardial infarction (AMI) and ischemic cardiomyopathy studies, respectively. This effect was sustained in long-term follow-up. MNC therapy significantly reduced left ventricular end-systolic volume; however, infarct size, 6-minute walk test, New York Heart Association class, and MACE rates were comparable.CONCLUSIONS: MNC therapy may convey a modest but sustained increase in LVEF in ischemic cardiomyopathy patients, supporting further investigation. AMI trials, however, demonstrated minimal improvement in LVEF of unclear clinical significance, suggesting a limited role for MNC therapy in AMI.

    View details for DOI 10.1016/j.ahj.2019.09.005

    View details for PubMedID 31821904