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

Publications

  • MICROVESICLES LARGER THAN 200NM RESCUE CARDIOMYOCYTES FROM DOXORUBICIN INJURY IN A PATIENT-SPECIFIC MODEL OF ANTHRACYCLINE INDUCED CARDIOMYOPATHY O'Brien, C., Shi, L., Ozgun, M., Vaskova, E., Santoso, M., Jung, J., Ikeda, G., Demirci, U., Yang, P. ELSEVIER SCIENCE INC. 2019: 688
  • Myocardial viability of the peri-infarct region measured by T1 mapping post manganese-enhanced MRI correlates with LV dysfunction. International journal of cardiology Tada, Y., Heidary, S., Tachibana, A., Zaman, J., Neofytou, E., Dash, R., Wu, J. C., Yang, P. C. 2019

    Abstract

    BACKGROUND: Manganese-enhanced MRI (MEMRI) detects viable cardiomyocytes based on the intracellular manganese uptake via L-type calcium-channels. This study aimed to quantify myocardial viability based on manganese uptake by viable myocardium in the infarct core (IC), peri-infarct region (PIR) and remote myocardium (RM) using T1 mapping before and after MEMRI and assess their association with cardiac function and arrhythmogenesis.METHODS: Fifteen female swine had a 60-minute balloon ischemia-reperfusion injury in the LAD. MRI (Signa 3T, GE Healthcare) and electrophysiological study (EPS) were performed 4 weeks later. MEMRI and delayed gadolinium-enhanced MRI (DEMRI) were acquired on LV short axis. The DEMRI positive total infarct area was subdivided into the regions of MEMRI-negative non-viable IC and MEMRI-positive viable PIR. T1 mapping was performed to evaluate native T1, post-MEMRI T1, and delta R1 (R1post-R1pre, where R1 equals 1/T1) of each territory. Their correlation with LV function and EPS data was assessed.RESULTS: PIR was characterized by intermediate native T1 (1530.5 ± 75.2 ms) compared to IC (1634.7 ± 88.4 ms, p = 0.001) and RM (1406.4 ± 37.9 ms, p < 0.0001). Lower post-MEMRI T1 of PIR (1136.3 ± 99.6 ms) than IC (1262.6 ± 126.8 ms, p = 0.005) and higher delta R1 (0.23 ± 0.08 s-1) of PIR than IC (0.18 ± 0.09 s-1, p = 0.04) indicated higher myocardial manganese uptake of PIR compared to IC. Post-MEMRI T1 (r = -0.57, p = 0.02) and delta R1 (r = 0.51, p = 0.04) of PIR correlated significantly with LVEF.CONCLUSIONS: PIR is characterized by higher manganese uptake compared to the infarct core. In the subacute phase post-IR, PIR viability measured by post-MEMRI T1 correlates with cardiac function.

    View details for DOI 10.1016/j.ijcard.2019.01.101

    View details for PubMedID 30739802

  • Whole-heart coronary MR angiography using a 3D cones phyllotaxis trajectory. Magnetic resonance in medicine Malave, M. O., Baron, C. A., Addy, N. O., Cheng, J. Y., Yang, P. C., Hu, B. S., Nishimura, D. G. 2018

    Abstract

    PURPOSE: To develop a 3D cones steady-state free precession sequence with improved robustness to respiratory motion while mitigating eddy current artifacts for free-breathing whole-heart coronary magnetic resonance angiography.METHOD: The proposed sequence collects cone interleaves using a phyllotaxis pattern, which allows for more distributed k-space sampling for each heartbeat compared to a typical sequential collection pattern. A Fibonacci number of segments is chosen to minimize eddy current effects with the trade-off of an increased number of acquisition heartbeats. For verification, phyllotaxis-cones is compared to sequential-cones through simulations, phantom studies, and in vivo coronary scans with 8 subjects using 2D image-based navigators for retrospective motion correction.RESULTS: Simulated point spread functions and moving phantom results show less coherent motion artifacts for phyllotaxis-cones compared to sequential-cones. Assessment of the right and left coronary arteries using reader scores and the image edge profile acutance vessel sharpness metric indicate superior image quality and sharpness for phyllotaxis-cones.CONCLUSION: Phyllotaxis 3D cones results in improved qualitative image scores and coronary vessel sharpness for free-breathing whole-heart coronary magnetic resonance angiography compared to standard sequential ordering when using a steady-state free precession sequence.

    View details for DOI 10.1002/mrm.27475

    View details for PubMedID 30370941

  • Rationale and Design of the SENECA (StEm cell iNjECtion in cAncer survivors) Trial AMERICAN HEART JOURNAL Bolli, R., Hare, J. M., Henry, T. D., Lenneman, C. G., March, K. L., Miller, K., Pepine, C. J., Perin, E. C., Traverse, J. H., Willerson, J. T., Yang, P. C., Gee, A. P., Lima, J. A., Moye, L., Vojvodic, R. W., Sayre, S. L., Bettencourt, J., Cohen, M., Ebert, R. F., Simari, R. D., Cardiovasc Cell Therapy Res 2018; 201: 54–62

    Abstract

    SENECA (StEm cell iNjECtion in cAncer survivors) is a phase I, randomized, double-blind, placebo-controlled study to evaluate the safety and feasibility of delivering allogeneic mesenchymal stromal cells (allo-MSCs) transendocardially in subjects with anthracycline-induced cardiomyopathy (AIC).AIC is an incurable and often fatal syndrome, with a prognosis worse than that of ischemic or nonischemic cardiomyopathy. Recently, cell therapy with MSCs has emerged as a promising new approach to repair damaged myocardium.The study population is 36 cancer survivors with a diagnosis of AIC, left ventricular (LV) ejection fraction ≤40%, and symptoms of heart failure (NYHA class II-III) on optimally-tolerated medical therapy. Subjects must be clinically free of cancer for at least two years with a ≤ 30% estimated five-year risk of recurrence. The first six subjects participated in an open-label, lead-in phase and received 100 million allo-MSCs; the remaining 30 will be randomized 1:1 to receive allo-MSCs or vehicle via 20 transendocardial injections. Efficacy measures (obtained at baseline, 6 months, and 12 months) include MRI evaluation of LV function, LV volumes, fibrosis, and scar burden; assessment of exercise tolerance (six-minute walk test) and quality of life (Minnesota Living with Heart Failure Questionnaire); clinical outcomes (MACE and cumulative days alive and out of hospital); and biomarkers of heart failure (NT-proBNP).This is the first clinical trial using direct cardiac injection of cells for the treatment of AIC. If administration of allo-MSCs is found feasible and safe, SENECA will pave the way for larger phase II/III studies with therapeutic efficacy as the primary outcome.

    View details for DOI 10.1016/j.ahj.2018.02.009

    View details for Web of Science ID 000436562100008

    View details for PubMedID 29910056

  • Rationale and Design of the CONCERT-HF Trial (Combination of Mesenchymal and c-kit(+) Cardiac Stem Cells As Regenerative Therapy for Heart Failure) CIRCULATION RESEARCH Bolli, R., Hare, J. M., March, K. L., Pepine, C. J., Willerson, J. T., Perin, E. C., Yang, P. C., Henry, T. D., Traverse, J. H., Mitrani, R. D., Khan, A., Hernandez-Schulman, I., Taylor, D. A., DiFede, D. L., Lima, J. C., Chugh, A., Loughran, J., Vojvodic, R. W., Sayre, S. L., Bettencourt, J., Cohen, M., Moye, L., Ebert, R. F., Simari, R. D., Cardiovasc Cell Therapy Res 2018; 122 (12): 1703–15

    Abstract

    Autologous bone marrow mesenchymal stem cells (MSCs) and c-kit+ cardiac progenitor cells (CPCs) are 2 promising cell types being evaluated for patients with heart failure (HF) secondary to ischemic cardiomyopathy. No information is available in humans about the relative efficacy of MSCs and CPCs and whether their combination is more efficacious than either cell type alone.CONCERT-HF (Combination of Mesenchymal and c-kit+ Cardiac Stem Cells As Regenerative Therapy for Heart Failure) is a phase II trial aimed at elucidating these issues by assessing the feasibility, safety, and efficacy of transendocardial administration of autologous MSCs and CPCs, alone and in combination, in patients with HF caused by chronic ischemic cardiomyopathy (coronary artery disease and old myocardial infarction).Using a randomized, double-blinded, placebo-controlled, multicenter, multitreatment, and adaptive design, CONCERT-HF examines whether administration of MSCs alone, CPCs alone, or MSCs+CPCs in this population alleviates left ventricular remodeling and dysfunction, reduces scar size, improves quality of life, or augments functional capacity. The 4-arm design enables comparisons of MSCs alone with CPCs alone and with their combination. CONCERT-HF consists of 162 patients, 18 in a safety lead-in phase (stage 1) and 144 in the main trial (stage 2). Stage 1 is complete, and stage 2 is currently randomizing patients from 7 centers across the United States.CONCERT-HF will provide important insights into the potential therapeutic utility of MSCs and CPCs, given alone and in combination, for patients with HF secondary to ischemic cardiomyopathy.URL: http://www.clinicaltrials.gov. Unique identifier: NCT02501811.

    View details for DOI 10.1161/CIRCRESAHA.118.312978

    View details for Web of Science ID 000434652500012

    View details for PubMedID 29703749

    View details for PubMedCentralID PMC5993622

  • MANGANESE-ENHANCED T1 MAPPING IN MYOCARDIAL INFARCTION: VALIDATION WITH F-18-FDG PET/MR Spath, N. B., Tavares, A., Gray, G. A., Dweck, M. R., Newby, D. E., Yang, P. C., Jansen, M. A., Semple, S. I. BMJ PUBLISHING GROUP. 2018: A9
  • EXOSOMES PRODUCED BY HUMAN AMNIOTIC MESENCHYMAL STEM CELL-DERIVED INDUCED PLURIPOTENT STEM CELLS MODULATE IMMUNE RESPONSE IN MURINE MYOCARDIAL INJURY MODEL Jang, A., Seo, H., Bornstaedt, D., Jung, J., Vaskova, E., Yang, P. ELSEVIER SCIENCE INC. 2018: 82
  • EXOSOMAL MIR-106A-363 CLUSTER FROM THE HYPOXIC HUMAN IPSC-DERIVED CARDIOMYOCYTES RESTORE THE ISCHEMIC MYOCARDIUM Jung, J., Tada, Y., Bornstaedt, D., Wahlquist, C., Mercola, M., Woo, Y., Yang, P. ELSEVIER SCIENCE INC. 2018: 14
  • PLEIOTROPIC EFFECTS OF THE EXOSOMES FROM IPSC-DERIVATIVES IN RESTORING INJURED MYOCARDIUM Vaskova, E., Tada, Y., von Bornstaedt, D., Woo, Y., Yang, P. ELSEVIER SCIENCE INC. 2018: 80
  • Circulating Biomarkers to Identify Responders in Cardiac Cell therapy (vol 7, 4419, 2017) SCIENTIFIC REPORTS Jokerst, J. V., Cauwenberghs, N., Kuznetsova, T., Haddad, F., Sweeney, T., Hou, J., Rosenberg-Hasson, Y., Zhao, E., Schutt, R., Bolli, R., Traverse, J. H., Pepine, C. J., Henry, T. D., Schulman, I. H., Moye, L., Taylor, D. A., Yang, P. C. 2018; 8: 4257

    Abstract

    A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

    View details for DOI 10.1038/s41598-018-22121-2

    View details for Web of Science ID 000426650500003

    View details for PubMedID 29511207

    View details for PubMedCentralID PMC5840173

  • Induced Pluripotent Stem Cell (iPSC)-Derived Exosomes for Precision Medicine in Heart Failure CIRCULATION RESEARCH Yang, P. C. 2018; 122 (5): 661–63

    View details for DOI 10.1161/CIRCRESAHA.118.312657

    View details for Web of Science ID 000426550100007

    View details for PubMedID 29496797

    View details for PubMedCentralID PMC5836744

  • Effect of Cell Sex on Uptake of Nanoparticles: The Overlooked Factor at the Nanobio Interface ACS NANO Serpooshan, V., Sheibani, S., Pushparaj, P., Wojcik, M., Jang, A. Y., Santoso, M. R., Jang, J. H., Huang, H., Safavi-Sohi, R., Haghjoo, N., Nejadnik, H., Aghaverdi, H., Vali, H., Kinsella, J., Presley, J., Xu, K., Yang, P., Mahmoudi, M. 2018; 12 (3): 2253–66

    Abstract

    Cellular uptake of nanoparticles (NPs) depends on the nature of the nanobio system including the solid nanocomponents ( e. g., physicochemical properties of NPs), nanobio interfaces ( e. g., protein corona composition), and the cellular characteristics ( e. g., cell type). In this study, we document the role of sex in cellular uptake of NPs as an "overlooked" factor in nanobio interface investigations. We demonstrate that cell sex leads to differences in NP uptake between male and female human amniotic stem cells (hAMSCs), with greater uptake by female cells. hAMSCs are one of the earliest sources of somatic stem cells. The experiments were replicated with primary fibroblasts isolated from the salivary gland of adult male and female donors of similar ages, and again the extent of NP uptake was altered by cell sex. However, in contrast to hAMSCs, uptake was greater in male cells. We also found out that female versus male amniotic stem cells exhibited different responses to reprogramming into induced pluripotent stem cells (iPSCs) by the Yamanaka factors. Thus, future studies should consider the effect of sex on the nanobio interactions to optimize clinical translation of NPs and iPSC biology and to help researchers to better design and produce safe and efficient therapeutic sex-specific NPs.

    View details for DOI 10.1021/acsnano.7b06212

    View details for Web of Science ID 000428972600018

    View details for PubMedID 29536733

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

    Abstract

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

    View details for DOI 10.1371/journal.pone.0192662

    View details for Web of Science ID 000425554200021

    View details for PubMedID 29462173

    View details for PubMedCentralID PMC5819797

  • TIME Trial: Effect of Timing of Stem Cell Delivery Following ST-Elevation Myocardial Infarction on the Recovery of Global and Regional Left Ventricular Function: Final 2-Year Analysis CIRCULATION RESEARCH Traverse, J. H., Henry, T. D., Pepine, C. J., Willerson, J. T., Chugh, A., Yang, P. C., Zhao, D. M., Ellis, S. G., Forder, J. R., Perin, E. C., Penn, M. S., Hatzopoulos, A. K., Chambers, J. C., Baran, K. W., Raveendran, G., Gee, A. P., Taylor, D. A., Moye, L., Ebert, R. F., Simari, R. D. 2018; 122 (3): 479–88

    Abstract

    The TIME trial (Timing in Myocardial Infarction Evaluation) was the first cell therapy trial sufficiently powered to determine if timing of cell delivery after ST-segment-elevation myocardial infarction affects recovery of left ventricular (LV) function.To report the 2-year clinical and cardiac magnetic resonance imaging results and their modification by microvascular obstruction.TIME was a randomized, double-blind, placebo-controlled trial comparing 150 million bone marrow mononuclear cells versus placebo in 120 patients with anterior ST-segment-elevation myocardial infarctions resulting in LV dysfunction. Primary end points included changes in global (LV ejection fraction) and regional (infarct and border zone) function. Secondary end points included changes in LV volumes, infarct size, and major adverse cardiac events. Here, we analyzed the continued trajectory of these measures out to 2 years and the influence of microvascular obstruction present at baseline on these long-term outcomes. At 2 years (n=85), LV ejection fraction was similar in the bone marrow mononuclear cells (48.7%) and placebo groups (51.6%) with no difference in regional LV function. Infarct size and LV mass decreased ≥30% in each group at 6 months and declined gradually to 2 years. LV volumes increased ≈10% at 6 months and remained stable to 2 years. Microvascular obstruction was present in 48 patients at baseline and was associated with significantly larger infarct size (56.5 versus 36.2 g), greater adverse LV remodeling, and marked reduction in LV ejection fraction recovery (0.2% versus 6.2%).In one of the longest serial cardiac magnetic resonance imaging analyses of patients with large anterior ST-segment-elevation myocardial infarctions, bone marrow mononuclear cells administration did not improve recovery of LV function over 2 years. Microvascular obstruction was associated with reduced recovery of LV function, greater adverse LV remodeling, and more device implantations. The use of cardiac magnetic resonance imaging leads to greater dropout of patients over time because of device implantation in patients with more severe LV dysfunction resulting in overestimation of clinical stability of the cohort.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00684021.

    View details for DOI 10.1161/CIRCRESAHA.117.311466

    View details for Web of Science ID 000423876100017

    View details for PubMedID 29208679

    View details for PubMedCentralID PMC5805626

  • Molecular Imaging of Stem Cells and Exosomes for Myocardial Regeneration CURRENT CARDIOVASCULAR IMAGING REPORTS Santoso, M. R., Yang, P. C. 2017; 10 (11)