Professor of Medicine (Cardiovascular Medicine)


  • Microvascular Obstruction Identifies a Subgroup of Patients Who Benefit from Stem Cell Therapy Following ST-Elevation Myocardial Infarction. American heart journal Davidson, S. J., Roncalli, J., Surder, D., Corti, R., Chugh, A. R., Yang, P. C., Henry, T. D., Stanberry, L., Lemarchand, P., Beregi, J. P., Traverse, J. H. 2023


    Microvascular obstruction (MVO) is associated with greater infarct size, adverse left-ventricular (LV) remodeling and reduced ejection fraction following ST-elevation myocardial infarction (STEMI). We hypothesized that patients with MVO may constitute a subgroup of patients that would benefit from intracoronary stem cell delivery with bone marrow mononuclear cells (BMCs) given previous findings that BMCs tended to improve LV function only in patients with significant LV dysfunction.We analyzed the cardiac MRIs of 356 patients (303 M, 53 F) with anterior STEMIs who received autologous BMCs or placebo / control as part of 4 randomized clinical trials that included the Cardiovascular Cell Therapy Research Network (CCTRN) TIME trial and its pilot, the multi-center French BONAMI trial and SWISS-AMI trials. A total of 327g patients had paired imaging data at one year. All patients received 100 - 150 million intracoronary autologous BMCs or placebo / control 3 - 7 days following primary PCI and stenting. LV function, volumes, infarct size and MVO were assessed prior to infusion of BMCs and 1 year later. Patients with MVO (n=210) had reduced LVEF and much greater infarct size and LV volumes compared to patients without MVO (n=146) (p < 0.01). At 12 months, patients with MVO who received BMCs had significantly greater recovery of LVEF compared to those patients with MVO who received placebo (absolute difference = 2.7%; p < 0.05). Similarly, left-ventricular end-diastolic (LVEDVI) and end-systolic volume indices (LVESVI) demonstrated significantly less adverse remodeling in patients with MVO who received BMCs compared to placebo. In contrast, no improvement in LVEF or LV volumes was observed in those patients without MVO who received BMCs compared to placebo.The presence of MVO on cardiac MRI following STEMI identifies a subgroup of patients who benefit from intracoronary stem cell therapy.

    View details for DOI 10.1016/j.ahj.2023.02.004

    View details for PubMedID 36796572

  • Current challenges and future directions for engineering extracellular vesicles for heart, lung, blood and sleep diseases. Journal of extracellular vesicles Li, G., Chen, T., Dahlman, J., Eniola-Adefeso, L., Ghiran, I. C., Kurre, P., Lam, W. A., Lang, J. K., Marbán, E., Martín, P., Momma, S., Moos, M., Nelson, D. J., Raffai, R. L., Ren, X., Sluijter, J. P., Stott, S. L., Vunjak-Novakovic, G., Walker, N. D., Wang, Z., Witwer, K. W., Yang, P. C., Lundberg, M. S., Ochocinska, M. J., Wong, R., Zhou, G., Chan, S. Y., Das, S., Sundd, P. 2023; 12 (2): e12305


    Extracellular vesicles (EVs) carry diverse bioactive components including nucleic acids, proteins, lipids and metabolites that play versatile roles in intercellular and interorgan communication. The capability to modulate their stability, tissue-specific targeting and cargo render EVs as promising nanotherapeutics for treating heart, lung, blood and sleep (HLBS) diseases. However, current limitations in large-scale manufacturing of therapeutic-grade EVs, and knowledge gaps in EV biogenesis and heterogeneity pose significant challenges in their clinical application as diagnostics or therapeutics for HLBS diseases. To address these challenges, a strategic workshop with multidisciplinary experts in EV biology and U.S. Food and Drug Administration (USFDA) officials was convened by the National Heart, Lung and Blood Institute. The presentations and discussions were focused on summarizing the current state of science and technology for engineering therapeutic EVs for HLBS diseases, identifying critical knowledge gaps and regulatory challenges and suggesting potential solutions to promulgate translation of therapeutic EVs to the clinic. Benchmarks to meet the critical quality attributes set by the USFDA for other cell-based therapeutics were discussed. Development of novel strategies and approaches for scaling-up EV production and the quality control/quality analysis (QC/QA) of EV-based therapeutics were recognized as the necessary milestones for future investigations.

    View details for DOI 10.1002/jev2.12305

    View details for PubMedID 36775986

  • Extracellular vesicle-derived circCEBPZOS attenuates postmyocardial infarction remodeling by promoting angiogenesis via the miR-1178-3p/PDPK1 axis. Communications biology Yu, L., Liang, Y., Zhang, M., Yang, P. C., Hinek, A., Mao, S. 2023; 6 (1): 133


    Emerging studies indicate that extracellular vesicles (EVs) and their inner circular RNAs (circRNAs), play key roles in the gene regulatory network and cardiovascular repair. However, our understanding of EV-derived circRNAs in cardiac remodeling after myocardial infarction (MI) remains limited. Here we show that the level of circCEBPZOS is downregulated in serum EVs of patients with the adverse cardiac remodeling compared with those without post-MI remodeling or normal subjects. Loss-of-function approaches in vitro establish that circCEBPZOS robustly promote angiogenesis. Overexpression of circCEBPZOS in mice attenuates MI-induced left ventricular dysfunction, accompanied by a larger functional capillary network at the border zone. Further exploration of the downstream target gene indicates that circCEBPZOS acts as a competing endogenous RNA by directly binding to miR-1178-3p and thereby inducing transcription of its target gene phosphoinositide-dependent kinase-1 (PDPK1). Together, our results reveal that circCEBPZOS attenuates detrimental post-MI remodeling via the miR-1178-3p/PDPK1 axis, which facilitates revascularization, ultimately improving the cardiac function.

    View details for DOI 10.1038/s42003-023-04505-x

    View details for PubMedID 36726025

  • High-resolution, respiratory-resolved coronary MRA using a Phyllotaxis-reordered variable-density 3D cones trajectory. Magnetic resonance imaging Koundinyan, S. P., Baron, C. A., Malavé, M. O., Ong, F., Addy, N. O., Cheng, J. Y., Yang, P. C., Hu, B. S., Nishimura, D. G. 2023


    To develop a respiratory-resolved motion-compensation method for free-breathing, high-resolution coronary magnetic resonance angiography (CMRA) using a 3D cones trajectory.To achieve respiratory-resolved 0.98 mm resolution images in a clinically relevant scan time, we undersample the imaging data with a variable-density 3D cones trajectory. For retrospective motion compensation, translational estimates from 3D image-based navigators (3D iNAVs) are used to bin the imaging data into four phases from end-expiration to end-inspiration. To ensure pseudo-random undersampling within each respiratory phase, we devise a phyllotaxis readout ordering scheme mindful of eddy current artifacts in steady state free precession imaging. Following binning, residual 3D translational motion within each phase is computed using the 3D iNAVs and corrected for in the imaging data. The noise-like aliasing characteristic of the combined phyllotaxis and cones sampling pattern is leveraged in a compressed sensing reconstruction with spatial and temporal regularization to reduce aliasing in each of the respiratory phases.In initial studies of six subjects, respiratory motion compensation using the proposed method yields improved image quality compared to non-respiratory-resolved approaches with no motion correction and with 3D translational correction. Qualitative assessment by two cardiologists and quantitative evaluation with the image edge profile acutance metric indicate the superior sharpness of coronary segments reconstructed with the proposed method (P < 0.01).We have demonstrated a new method for free-breathing, high-resolution CMRA based on a variable-density 3D cones trajectory with modified phyllotaxis ordering and respiratory-resolved motion compensation with 3D iNAVs.

    View details for DOI 10.1016/j.mri.2023.01.008

    View details for PubMedID 36646397

  • Angiogenic stem cell delivery platform to augment post-infarction neovasculature and reverse ventricular remodeling. Scientific reports Shin, H. S., Thakore, A., Tada, Y., Pedroza, A. J., Ikeda, G., Chen, I. Y., Chan, D., Jaatinen, K. J., Yajima, S., Pfrender, E. M., Kawamura, M., Yang, P. C., Wu, J. C., Appel, E. A., Fischbein, M. P., Woo, Y., Shudo, Y. 2022; 12 (1): 17605


    Many cell-based therapies are challenged by the poor localization of introduced cells and the use of biomaterial scaffolds with questionable biocompatibility or bio-functionality. Endothelial progenitor cells (EPCs), a popular cell type used in cell-based therapies due to their robust angiogenic potential, are limited in their therapeutic capacity to develop into mature vasculature. Here, we demonstrate a joint delivery of human-derived endothelial progenitor cells (EPC) and smooth muscle cells (SMC) as a scaffold-free, bi-level cell sheet platform to improve ventricular remodeling and function in an athymic rat model of myocardial infarction. The transplanted bi-level cell sheet on the ischemic heart provides a biomimetic microenvironment and improved cell-cell communication, enhancing cell engraftment and angiogenesis, thereby improving ventricular remodeling. Notably, the increased density of vessel-like structures and upregulation of biological adhesion and vasculature developmental genes, such as Cxcl12 and Notch3, particularly in the ischemic border zone myocardium, were observed following cell sheet transplantation. We provide compelling evidence that this SMC-EPC bi-level cell sheet construct can be a promising therapy to repair ischemic cardiomyopathy.

    View details for DOI 10.1038/s41598-022-21510-y

    View details for PubMedID 36266453

    View details for PubMedCentralID PMC9584918

  • Spinning-enabled wireless amphibious origami millirobot. Nature communications Ze, Q., Wu, S., Dai, J., Leanza, S., Ikeda, G., Yang, P. C., Iaccarino, G., Zhao, R. R. 2022; 13 (1): 3118


    Wireless millimeter-scale origami robots have recently been explored with great potential for biomedical applications. Existing millimeter-scale origami devices usually require separate geometrical components for locomotion and functions. Additionally, none of them can achieve both on-ground and in-water locomotion. Here we report a magnetically actuated amphibious origami millirobot that integrates capabilities of spinning-enabled multimodal locomotion, delivery of liquid medicine, and cargo transportation with wireless operation. This millirobot takes full advantage of the geometrical features and folding/unfolding capability of Kresling origami, a triangulated hollow cylinder, to fulfill multifunction: its geometrical features are exploited for generating omnidirectional locomotion in various working environments through rolling, flipping, and spinning-induced propulsion; the folding/unfolding is utilized as a pumping mechanism for controlled delivery of liquid medicine; furthermore, the spinning motion provides a sucking mechanism for targeted solid cargo transportation. We anticipate the amphibious origami millirobots can potentially serve as minimally invasive devices for biomedical diagnoses and treatments.

    View details for DOI 10.1038/s41467-022-30802-w

    View details for PubMedID 35701405

  • Regenerating Endothelium and Restoring Microvascular Endothelial Function. JACC. Cardiovascular imaging Hare, J. M., Yang, P. 2022; 15 (5): 825-827

    View details for DOI 10.1016/j.jcmg.2022.02.014

    View details for PubMedID 35512955

  • Stem Cell and Exosome Therapy in Pulmonary Hypertension. Korean circulation journal Oh, S., Jung, J., Ahn, K., Jang, A. Y., Byun, K., Yang, P. C., Chung, W. 2022; 52 (2): 110-122


    Pulmonary hypertension is a rare and progressive illness with a devastating prognosis. Promising research efforts have advanced the understanding and recognition of the pathobiology of pulmonary hypertension. Despite remarkable achievements in terms of improving the survival rate, reducing disease progression, and enhancing quality of life, pulmonary arterial hypertension (PAH) is not completely curable. Therefore, an effective treatment strategy is still needed. Recently, many studies of the underlying molecular mechanisms and technological developments have led to new approaches and paradigms for PAH treatment. Management based on stem cells and related paracrine effects, epigenetic drugs and gene therapies has yielded prospective results for PAH treatment in preclinical research. Further trials are ongoing to optimize these important insights into clinical circumstances.

    View details for DOI 10.4070/kcj.2021.0191

    View details for PubMedID 35128849

  • 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


    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

  • 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


    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


    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


    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