Dr. Rhee is a general cardiologist with specialized clinical and research training in cardiovascular drug toxicity and pharmacogenomics. She completed clinical cardiology fellowship and internal medicine residency training at Stanford University School of Medicine. During her post-doctoral training, Dr. Rhee's research focused on elucidating cardiotoxic effects of iron overload and of multiple chemotherapeutic agents using patient-specific induced pluripotent stem cells (iPSCs) derived models. Her current research employs clinical data, population genomics, and patient-derived iPSCs models to study genetic determinants and mechanisms of drug-induced cardiovascular toxicities. Dr. Rhee's clinic sees cardio-oncology patients and focuses on devising new methods for minimizing cardiovascular complications in that population.

Academic Appointments

Honors & Awards

  • K08 Mentored Clinical Scientist Research Career Development Awards, National Institutes of Health (08/2020-07/2025)
  • Career Development Award, American Heart Association (07/2019-06/2022)
  • Ruth L. Kirschtein NRSA NIH Postdoctoral Fellowship, National Institutes of Health (01/2016-06/2019)
  • Excellence in Cardiology Fellowship Award, American College of Cardiology (05/2017)
  • Women in Cardiology Award for Trainee Excellence, American Heart Association (11/2015)
  • Timothy F. Beckett, JR award for Best Clinical Teaching by a Medicine Fellow, Stanford University (06/2015)
  • HHMI Research Training Fellowships for Medical Students, Howard Hughes Medical Institute (07/2009-06/2010)
  • Gold medal, 33rd International Chemistry Olympiad committee (2001)

Professional Education

  • BS, MIT, Biology, Chemical Engineering (2006)
  • MD, Harvard Medical School (2011)
  • Board Certification, American Board of Internal Medicine, Internal Medicine (2014)
  • Board Certification, American Board of Internal Medicine, Cardiovascular Medicine (2017)

All Publications

  • Author Correction: Large-scale generation of functional mRNA-encapsulating exosomes via cellular nanoporation. Nature biomedical engineering Yang, Z., Shi, J., Xie, J., Wang, Y., Sun, J., Liu, T., Zhao, Y., Zhao, X., Wang, X., Ma, Y., Malkoc, V., Chiang, C., Deng, W., Chen, Y., Fu, Y., Kwak, K. J., Fan, Y., Kang, C., Yin, C., Rhee, J., Bertani, P., Otero, J., Lu, W., Yun, K., Lee, A. S., Jiang, W., Teng, L., Kim, B. Y., Lee, L. J. 2021


    A Correction to this paper has been published:

    View details for DOI 10.1038/s41551-021-00725-w

    View details for PubMedID 34131325

  • Racial and Ethnic Disparities in Cardio-Oncology A Call to Action JACC: CARDIOONCOLOGY Fazal, M., Malisa, J., Rhee, J., Witteles, R. M., Rodriguez, F. 2021; 3 (2): 201-204
  • Impact of Hormonal Therapies for Treatment of Hormone-Dependent Cancers (Breast and Prostate) on the Cardiovascular System: Effects and Modifications: A Scientific Statement From the American Heart Association CIRCULATION-GENOMIC AND PRECISION MEDICINE Okwuosa, T. M., Morgans, A., Rhee, J., Reding, K. W., Maliski, S., Plana, J., Volgman, A., Moseley, K. F., Porter, C. B., Ismail-Khan, R., Amer Heart Assoc Cardiooncology, Council Arteriosclerosis Thrombos, Council Cardiovasc Radiology 2021; 14 (3): 390-407


    Cardiovascular disease and cancer are the leading causes of death in the United States, and hormone-dependent cancers (breast and prostate cancer) are the most common noncutaneous malignancies in women and men, respectively. The hormonal (endocrine-related) therapies that serve as a backbone for treatment of both cancers improve survival but also increase cardiovascular morbidity and mortality among survivors. This consensus statement describes the risks associated with specific hormonal therapies used to treat breast and prostate cancer and provides an evidence-based approach to prevent and detect adverse cardiovascular outcomes. Areas of uncertainty are highlighted, including the cardiovascular effects of different durations of hormonal therapy, the cardiovascular risks associated with combinations of newer generations of more intensive hormonal treatments, and the specific cardiovascular risks that affect individuals of various races/ethnicities. Finally, there is an emphasis on the use of a multidisciplinary approach to the implementation of lifestyle and pharmacological strategies for management and risk reduction both during and after active treatment.

    View details for DOI 10.1161/HCG.0000000000000082

    View details for Web of Science ID 000661620500001

    View details for PubMedID 33896190

  • Race and Genetics in Congenital Heart Disease: Application of iPSCs, Omics, and Machine Learning Technologies. Frontiers in cardiovascular medicine Mullen, M. n., Zhang, A. n., Lui, G. K., Romfh, A. W., Rhee, J. W., Wu, J. C. 2021; 8: 635280


    Congenital heart disease (CHD) is a multifaceted cardiovascular anomaly that occurs when there are structural abnormalities in the heart before birth. Although various risk factors are known to influence the development of this disease, a full comprehension of the etiology and treatment for different patient populations remains elusive. For instance, racial minorities are disproportionally affected by this disease and typically have worse prognosis, possibly due to environmental and genetic disparities. Although research into CHD has highlighted a wide range of causal factors, the reasons for these differences seen in different patient populations are not fully known. Cardiovascular disease modeling using induced pluripotent stem cells (iPSCs) is a novel approach for investigating possible genetic variants in CHD that may be race specific, making it a valuable tool to help solve the mystery of higher incidence and mortality rates among minorities. Herein, we first review the prevalence, risk factors, and genetics of CHD and then discuss the use of iPSCs, omics, and machine learning technologies to investigate the etiology of CHD and its connection to racial disparities. We also explore the translational potential of iPSC-based disease modeling combined with genome editing and high throughput drug screening platforms.

    View details for DOI 10.3389/fcvm.2021.635280

    View details for PubMedID 33681306

    View details for PubMedCentralID PMC7925393

  • Atlas of Exosomal microRNAs Secreted From Human iPSC-Derived Cardiac Cell Types. Circulation Chandy, M., Rhee, J., Ozen, M. O., Williams, D. R., Pepic, L., Liu, C., Zhang, H., Malisa, J., Lau, E., Demirci, U., Wu, J. C. 2020; 142 (18): 1794–96

    View details for DOI 10.1161/CIRCULATIONAHA.120.048364

    View details for PubMedID 33136510

  • Primer on Biomarker Discovery in Cardio-Oncology: Application of Omics Technologies. JACC. CardioOncology Rhee, J., Ky, B., Armenian, S. H., Yancy, C. W., Wu, J. C. 2020; 2 (3): 379–84

    View details for DOI 10.1016/j.jaccao.2020.07.006

    View details for PubMedID 33073248

  • IMPROVE-IT A Final Closure to Carcinogenicity of Ezetimibe? JACC: CARDIOONCOLOGY Lewis, E. F., Rhee, J. 2020; 2 (3): 397–99
  • The Regulation of Endothelial Function Through Hmgcr/mevalonate Pathway Mediated Yap Activity Liu, C., Liu, Y., Chen, C., Ameen, M., Yang, H., Shen, M., Rhee, J., Chen, I. Y., Sayed, N., Wu, J. C. LIPPINCOTT WILLIAMS & WILKINS. 2020
  • Clinical trial in a dish using iPSCs shows lovastatin improves endothelial dysfunction and cellular cross-talk in LMNA cardiomyopathy. Science translational medicine Sayed, N., Liu, C., Ameen, M., Himmati, F., Zhang, J. Z., Khanamiri, S., Moonen, J., Wnorowski, A., Cheng, L., Rhee, J., Gaddam, S., Wang, K. C., Sallam, K., Boyd, J. H., Woo, Y. J., Rabinovitch, M., Wu, J. C. 2020; 12 (554)


    Mutations in LMNA, the gene that encodes lamin A and C, causes LMNA-related dilated cardiomyopathy (DCM) or cardiolaminopathy. LMNA is expressed in endothelial cells (ECs); however, little is known about the EC-specific phenotype of LMNA-related DCM. Here, we studied a family affected by DCM due to a frameshift variant in LMNA Human induced pluripotent stem cell (iPSC)-derived ECs were generated from patients with LMNA-related DCM and phenotypically characterized. Patients with LMNA-related DCM exhibited clinical endothelial dysfunction, and their iPSC-ECs showed decreased functionality as seen by impaired angiogenesis and nitric oxide (NO) production. Moreover, genome-edited isogenic iPSC lines recapitulated the EC disease phenotype in which LMNA-corrected iPSC-ECs showed restoration of EC function. Simultaneous profiling of chromatin accessibility and gene expression dynamics by combining assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing (RNA-seq) as well as loss-of-function studies identified Kruppel-like factor 2 (KLF2) as a potential transcription factor responsible for the EC dysfunction. Gain-of-function studies showed that treatment of LMNA iPSC-ECs with KLF2 agonists, including lovastatin, rescued the EC dysfunction. Patients with LMNA-related DCM treated with lovastatin showed improvements in clinical endothelial dysfunction as indicated by increased reactive hyperemia index. Furthermore, iPSC-derived cardiomyocytes (iPSC-CMs) from patients exhibiting the DCM phenotype showed improvement in CM function when cocultured with iPSC-ECs and lovastatin. These results suggest that impaired cross-talk between ECs and CMs can contribute to the pathogenesis of LMNA-related DCM, and statin may be an effective therapy for vascular dysfunction in patients with cardiolaminopathy.

    View details for DOI 10.1126/scitranslmed.aax9276

    View details for PubMedID 32727917

  • Correction to: Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response. Current cardiology reports Zhu, H., Rhee, J., Cheng, P., Waliany, S., Chang, A., Witteles, R. M., Maecker, H., Davis, M. M., Nguyen, P. K., Wu, S. M. 2020; 22 (5): 36


    It has been pointed out that the second paragraph of the section "Treatments for SARS-CoV-2 Infection" contains an error. The original article has been corrected.

    View details for DOI 10.1007/s11886-020-01302-4

    View details for PubMedID 32405913

  • Multimodality Imaging for Risk Assessment of Inherited Cardiomyopathies CURRENT CARDIOVASCULAR RISK REPORTS O'Sullivan, J. W., Rhee, J., Hsu, D., Wheeler, M. T., Nieman, K. 2020; 14 (5)
  • RNA Sequencing Analysis of Induced Pluripotent Stem Cell-Derived Cardiomyocytes from Congenital Heart Disease Patients. Circulation research Kitani, T. n., Tian, L. n., Zhang, T. n., Itzhaki, I. n., Zhang, J. Z., Ma, N. n., Liu, C. n., Rhee, J. W., Romfh, A. n., Lui, G. K., Wu, J. C. 2020

    View details for DOI 10.1161/CIRCRESAHA.119.315653

    View details for PubMedID 32070195

  • Cardiovascular Complications in Patients with COVID-19: Consequences of Viral Toxicities and Host Immune Response Curr Cardiol Rep Zhu, H., Rhee, J., Cheng, P., Waliany, S., Chang, A., Witteles, R. M., Maecker, H., Davis, M. M., Nguyen, P. K., Wu, S. M. 2020; 22 (5)
  • Modeling Secondary Iron Overload Cardiomyopathy with Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes. Cell reports Rhee, J. W., Yi, H. n., Thomas, D. n., Lam, C. K., Belbachir, N. n., Tian, L. n., Qin, X. n., Malisa, J. n., Lau, E. n., Paik, D. T., Kim, Y. n., Choi, B. S., Sayed, N. n., Sallam, K. n., Liao, R. n., Wu, J. C. 2020; 32 (2): 107886


    Excessive iron accumulation in the heart causes iron overload cardiomyopathy (IOC), which initially presents as diastolic dysfunction and arrhythmia but progresses to systolic dysfunction and end-stage heart failure when left untreated. However, the mechanisms of iron-related cardiac injury and how iron accumulates in human cardiomyocytes are not well understood. Herein, using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), we model IOC and screen for drugs to rescue the iron overload phenotypes. Human iPSC-CMs under excess iron exposure recapitulate early-stage IOC, including oxidative stress, arrhythmia, and contractile dysfunction. We find that iron-induced changes in calcium kinetics play a critical role in dysregulation of CM functions. We identify that ebselen, a selective divalent metal transporter 1 (DMT1) inhibitor and antioxidant, could prevent the observed iron overload phenotypes, supporting the role of DMT1 in iron uptake into the human myocardium. These results suggest that ebselen may be a potential preventive and therapeutic agent for treating patients with secondary iron overload.

    View details for DOI 10.1016/j.celrep.2020.107886

    View details for PubMedID 32668256

  • Innovation in Precision Cardio-Oncology During the Coronavirus Pandemic and Into a Post-pandemic World. Frontiers in cardiovascular medicine Brown, S., Rhee, J., Guha, A., Rao, V. U. 2020; 7: 145

    View details for DOI 10.3389/fcvm.2020.00145

    View details for PubMedID 32923460

  • Cardiovascular Risks in Patients with COVID-19: Potential Mechanisms and Areas of Uncertainty. Current cardiology reports Cheng, P. n., Zhu, H. n., Witteles, R. M., Wu, J. C., Quertermous, T. n., Wu, S. M., Rhee, J. W. 2020; 22 (5): 34


    COronaVirus Disease 2019 (COVID-19) has spread at unprecedented speed and scale into a global pandemic with cardiovascular risk factors and complications emerging as important disease modifiers. We aim to review available clinical and biomedical literature on cardiovascular risks of COVID-19.SARS-CoV2, the virus responsible for COVID-19, enters the cell via ACE2 expressed in select organs. Emerging epidemiological evidence suggest cardiovascular risk factors are associated with increased disease severity and mortality in COVID-19 patients. Patients with a more severe form of COVID-19 are also more likely to develop cardiac complications such as myocardial injury and arrhythmia. The true incidence of and mechanism underlying these events remain elusive. Cardiovascular diseases appear intricately linked with COVID-19, with cardiac complications contributing to the elevated morbidity/mortality of COVID-19. Robust epidemiologic and biologic studies are urgently needed to better understand the mechanism underlying these associations to develop better therapies.

    View details for DOI 10.1007/s11886-020-01293-2

    View details for PubMedID 32350632

  • Large-scale generation of functional mRNA-encapsulating exosomes via cellular nanoporation. Nature biomedical engineering Yang, Z., Shi, J., Xie, J., Wang, Y., Sun, J., Liu, T., Zhao, Y., Zhao, X., Wang, X., Ma, Y., Malkoc, V., Chiang, C., Deng, W., Chen, Y., Fu, Y., Kwak, K. J., Fan, Y., Kang, C., Yin, C., Rhee, J., Bertani, P., Otero, J., Lu, W., Yun, K., Lee, A. S., Jiang, W., Teng, L., Kim, B. Y., Lee, L. J. 2019


    Exosomes are attractive as nucleic-acid carriers because of their favourable pharmacokinetic and immunological properties and their ability to penetrate physiological barriers that are impermeable to synthetic drug-delivery vehicles. However, inserting exogenous nucleic acids, especially large messenger RNAs, into cell-secreted exosomes leads to low yields. Here we report a cellular-nanoporation method for the production of large quantities of exosomes containing therapeutic mRNAs and targeting peptides. We transfected various source cells with plasmid DNAs and stimulated the cells with a focal and transient electrical stimulus that promotes the release of exosomes carrying transcribed mRNAs and targeting peptides. Compared with bulk electroporation and other exosome-production strategies, cellular nanoporation produced up to 50-fold more exosomes and a more than 103-fold increase in exosomal mRNA transcripts, even from cells with low basal levels of exosome secretion. In orthotopic phosphatase and tensin homologue (PTEN)-deficient glioma mouse models, mRNA-containing exosomes restored tumour-suppressor function, enhanced inhibition of tumour growth and increased survival. Cellular nanoporation may enable the use of exosomes as a universal nucleic-acid carrier for applications requiring transcriptional manipulation.

    View details for DOI 10.1038/s41551-019-0485-1

    View details for PubMedID 31844155

  • Human-induced Pluripotent Stem Cell-derived Cardiomyocytes as a Model for Trastuzumab-Induced Cardiac Dysfunction Kitani, T., Ong, S., Lam, C. K., Rhee, J., Zhang, J. Z., Oikonomopoulos, A., Ma, N., Tian, L., Lee, J., Telli, M. L., Witteles, R. M., Sharma, A., Sayed, N., Wu, J. C. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • Identifying the Transcriptome Signature of Calcium Channel Blocker in Human iPSC-Derived Cardiomyocytes Lam, C., Tian Lei, Belbachir, N., Wnorowski, A., Shrestha, R., Ma Ning, Kitani, T., Rhee, J. W., Wu, J. C. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • Adiponectin Receptor 3 is Associated With Endothelial Nitric Oxide Synthase Dysfunction and Predicts Insulin Resistance in South Asians Chandy, M., Sayed, N., Lau, E., Liu, C., Wei Tzu-Tang, Chen, I. Y., Thomas, D., Rhee, J., Oh, B., Pepic, L., Husain, M., Quertermous, T., Nallamshetty, S., Wu, J. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • Studying Cardiovascular Effects of Marijuana on Healthy Individuals Using Human Derived Induced Pluripotent Stem Cells Wei, T., Chandy, M., Chen, I. Y., Wo, H., Khanamiri, S., Nishiga, M., Seidl, F., Sayed, N., Liu, C., Rhee, J., Obal, D., Chour, T., Wu, J. C. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • Multi-Omics Investigation of Cardiomyocyte-to-Fibroblast Crosstalk in Human iPSC Models Lau, E., Chandy, M. J., Williams, D. R., Shrestha, R., Rhee, J., Wu, J. C. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • Identifying the Transcriptome Signatures of Calcium Channel Blockers in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes CIRCULATION RESEARCH Lam, C., Tian, L., Belbachir, N., Wnorowski, A., Shrestha, R., Ma, N., Kitani, T., Rhee, J., Wu, J. C. 2019; 125 (2): 212–22
  • Targeted and Selective Treatment of Pluripotent Stem Cell-derived Teratomas Using External Beam Radiation in a Small-animal Model. Journal of visualized experiments : JoVE Sallam, K., Rhee, J., Chour, T., D'addabbo, J., Lee, A. S., Graves, E., Nguyen, P. K. 2019


    The growing number of victims of "stem cell tourism," the unregulated transplantation of stem cells worldwide, has raised concerns about the safety of stem cell transplantation. Although the transplantation of differentiated rather than undifferentiated cells is common practice, teratomas can still arise from the presence of residual undifferentiated stem cells at the time of transplant or from spontaneous mutations in differentiated cells. Because stem cell therapies are often delivered into anatomically sensitive sites, even small tumors can be clinically devastating, resulting in blindness, paralysis, cognitive abnormalities, and cardiovascular dysfunction. Surgical access to these sites may also be limited, leaving patients with few therapeutic options. Controlling stem cell misbehavior is, therefore, critical for the clinical translation of stem cell therapy. External beam radiation offers an effective means of delivering targeted therapy to decrease the teratoma burden while minimizing injury to surrounding organs. Additionally, this method avoids genetic manipulation or viral transduction of stem cells-which are associated with additional clinical safety and efficacy concerns. Here, we describe a protocol to create pluripotent stem cell-derived teratomas in mice and to apply external beam radiation therapy to selectively ablate these tumors in vivo.

    View details for PubMedID 30829317

  • Electronic Cigarettes: Where There Is Smoke There Is Disease. Journal of the American College of Cardiology Wu, J. C., Rhee, J. W., Sallam, K. n. 2019; 74 (25): 3121–23

    View details for DOI 10.1016/j.jacc.2019.10.029

    View details for PubMedID 31856968

  • Human Induced Pluripotent Stem Cell Model of Trastuzumab-Induced Cardiac Dysfunction in Breast Cancer Patients. Circulation Kitani, T. n., Ong, S. G., Lam, C. K., Rhee, J. W., Zhang, J. Z., Oikonomopoulos, A. n., Ma, N. n., Tian, L. n., Lee, J. n., Telli, M. L., Witteles, R. M., Sharma, A. n., Sayed, N. n., Wu, J. C. 2019


    Molecular targeted chemotherapies have been shown to significantly improve cancer patient outcomes, but often cause cardiovascular side effects that limit their use and impair patients' quality of life. Cardiac dysfunction induced by these therapies, especially trastuzumab, shows a distinct cardiotoxic clinical phenotype compared to cardiotoxicity induced by conventional chemotherapies.We employed the human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM) platform to determine the underlying cellular mechanisms in trastuzumab-induced cardiac dysfunction. We assessed the effects of trastuzumab on structural and functional properties in iPSC-CMs from healthy individuals and performed RNA-sequencing (RNA-seq) to further examine the effect of trastuzumab on iPSC-CMs. We also generated iPSCs from patients receiving trastuzumab and examined whether patients' phenotype could be recapitulated in vitro using patient-specific iPSC-CMs.We found that clinically relevant doses of trastuzumab significantly impaired the contractile and calcium handling properties of iPSC-CMs without inducing cardiomyocyte death or sarcomeric disorganization. RNA-seq and subsequent functional analysis revealed mitochondrial dysfunction and altered cardiac energy metabolism pathway as primary causes of trastuzumab-induced cardiotoxic phenotype. Human iPSC-CMs generated from patients who received trastuzumab and experienced severe cardiac dysfunction were more vulnerable to trastuzumab treatment, compared to iPSC-CMs generated from patients who did not experience cardiac dysfunction following trastuzumab therapy. Importantly, metabolic modulation with AMPK activators could avert the adverse effects induced by trastuzumab.Our results indicate that alterations in cellular metabolic pathways in cardiomyocytes could be a key mechanism underlying the development of cardiac dysfunction following trastuzumab therapy; therefore, targeting the altered metabolism may be a promising therapeutic approach for trastuzumab-induced cardiac dysfunction.

    View details for PubMedID 30866650

  • Modelling diastolic dysfunction in induced pluripotent stem cell-derived cardiomyocytes from hypertrophic cardiomyopathy patients. European heart journal Wu, H. n., Yang, H. n., Rhee, J. W., Zhang, J. Z., Lam, C. K., Sallam, K. n., Chang, A. C., Ma, N. n., Lee, J. n., Zhang, H. n., Blau, H. M., Bers, D. M., Wu, J. C. 2019


    Diastolic dysfunction (DD) is common among hypertrophic cardiomyopathy (HCM) patients, causing major morbidity and mortality. However, its cellular mechanisms are not fully understood, and presently there is no effective treatment. Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) hold great potential for investigating the mechanisms underlying DD in HCM and as a platform for drug discovery.In the present study, beating iPSC-CMs were generated from healthy controls and HCM patients with DD. Micropatterned iPSC-CMs from HCM patients showed impaired diastolic function, as evidenced by prolonged relaxation time, decreased relaxation rate, and shortened diastolic sarcomere length. Ratiometric Ca2+ imaging indicated elevated diastolic [Ca2+]i and abnormal Ca2+ handling in HCM iPSC-CMs, which were exacerbated by β-adrenergic challenge. Combining Ca2+ imaging and traction force microscopy, we observed enhanced myofilament Ca2+ sensitivity (measured as dF/Δ[Ca2+]i) in HCM iPSC-CMs. These results were confirmed with genome-edited isogenic iPSC lines that carry HCM mutations, indicating that cytosolic diastolic Ca2+ overload, slowed [Ca2+]i recycling, and increased myofilament Ca2+ sensitivity, collectively impairing the relaxation of HCM iPSC-CMs. Treatment with partial blockade of Ca2+ or late Na+ current reset diastolic Ca2+ homeostasis, restored diastolic function, and improved long-term survival, suggesting that disturbed Ca2+ signalling is an important cellular pathological mechanism of DD. Further investigation showed increased expression of L-type Ca2+channel (LTCC) and transient receptor potential cation channels (TRPC) in HCM iPSC-CMs compared with control iPSC-CMs, which likely contributed to diastolic [Ca2+]i overload.In summary, this study recapitulated DD in HCM at the single-cell level, and revealed novel cellular mechanisms and potential therapeutic targets of DD using iPSC-CMs.

    View details for DOI 10.1093/eurheartj/ehz326

    View details for PubMedID 31219556

  • Marked Vascular Dysfunction in a Case of Peripartum Cardiomyopathy. Journal of vascular research Khanamiri, S. n., Rhee, J. W., Paik, D. T., Chen, I. Y., Liu, C. n., Sayed, N. n. 2019; 56 (1): 11–15


    Peripartum cardiomyopathy (PPCM) is a rare form of congestive heart failure characterized by left ventricular dysfunction that develops towards the end of pregnancy or during the early postpartum phase. Even though the majority of PPCM patients show partial or complete recovery of their heart functions, the mortality rate of PPCM remains high. Previous research has suggested that vascular dysfunction triggered by late-gestational hormones and potent anti-angiogenic factors play key roles in the pathogenesis of PPCM; however, the exact mechanisms remain elusive due to limited patient tissues for characterization. Here, we report a case of PPCM where the coronary vessels from the patient's explanted heart showed marked vascular dysfunction with impaired nitric oxide response. Importantly, these vessels exhibited deficient adenosine-mediated vasorelaxation when subjected to myograph studies, suggesting impaired Kv7 ion channels. Results from this work may lead to new therapeutic strategies for improving Kv7 function in PPCM patients.

    View details for PubMedID 30763932

  • Activation of PDGF pathway links LMNA mutation to dilated cardiomyopathy. Nature Lee, J. n., Termglinchan, V. n., Diecke, S. n., Itzhaki, I. n., Lam, C. K., Garg, P. n., Lau, E. n., Greenhaw, M. n., Seeger, T. n., Wu, H. n., Zhang, J. Z., Chen, X. n., Gil, I. P., Ameen, M. n., Sallam, K. n., Rhee, J. W., Churko, J. M., Chaudhary, R. n., Chour, T. n., Wang, P. J., Snyder, M. P., Chang, H. Y., Karakikes, I. n., Wu, J. C. 2019


    Lamin A/C (LMNA) is one of the most frequently mutated genes associated with dilated cardiomyopathy (DCM). DCM related to mutations in LMNA is a common inherited cardiomyopathy that is associated with systolic dysfunction and cardiac arrhythmias. Here we modelled the LMNA-related DCM in vitro using patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Electrophysiological studies showed that the mutant iPSC-CMs displayed aberrant calcium homeostasis that led to arrhythmias at the single-cell level. Mechanistically, we show that the platelet-derived growth factor (PDGF) signalling pathway is activated in mutant iPSC-CMs compared to isogenic control iPSC-CMs. Conversely, pharmacological and molecular inhibition of the PDGF signalling pathway ameliorated the arrhythmic phenotypes of mutant iPSC-CMs in vitro. Taken together, our findings suggest that the activation of the PDGF pathway contributes to the pathogenesis of LMNA-related DCM and point to PDGF receptor-β (PDGFRB) as a potential therapeutic target.

    View details for DOI 10.1038/s41586-019-1406-x

    View details for PubMedID 31316208

  • Large-Scale Single-Cell RNA-Seq Reveals Molecular Signatures of Heterogeneous Populations of Human Induced Pluripotent Stem Cell-Derived Endothelial Cells CIRCULATION RESEARCH Paik, D. T., Tian, L., Lee, J., Sayed, N., Chen, I. Y., Rhee, S., Rhee, J., Kim, Y., Wirka, R. C., Buikema, J. W., Wu, S. M., Red-Horse, K., Quertermous, T., Wu, J. C. 2018; 123 (4): 443–50
  • Dyslipidaemia: In vivo genome editing of ANGPTL3: a therapy for atherosclerosis? Nature reviews. Cardiology Rhee, J., Wu, J. C. 2018; 15 (5): 259–60

    View details for PubMedID 29618844

  • In vivo genome editing of ANGPTL3: a therapy for atherosclerosis? NATURE REVIEWS CARDIOLOGY Rhee, J., Wu, J. C. 2018; 15 (5): 259–60
  • Cardiac Cell Cycle Activation as a Strategy to Improve iPSC-Derived Cardiomyocyte Therapy. Circulation research Rhee, J. W., Wu, J. C. 2018; 122 (1): 14–16

    View details for PubMedID 29301838

  • Human iPSC-Derived Endothelial Cells Predict Predilection to Atherogenesis by Endothelial Proinflammatory Activation Paik, D. T., Kim, Y., Rhee, J., Yi, H., Mishra, R., Wu, J. C. LIPPINCOTT WILLIAMS & WILKINS. 2017: E98
  • Navigating Genetic and Phenotypic Uncertainty in Left Ventricular Noncompaction CIRCULATION-CARDIOVASCULAR GENETICS Rhee, J., Grove, M. E., Ashley, E. A. 2017; 10 (4)
  • Navigating Genetic and Phenotypic Uncertainty in Left Ventricular Noncompaction. Circulation. Cardiovascular genetics Rhee, J. W., Grove, M. E., Ashley, E. A. 2017; 10 (4)

    View details for DOI 10.1161/CIRCGENETICS.117.001857

    View details for PubMedID 28798026

  • Restoration of Impaired Diastolic Function in Hypertrophic Cardiomyopathy Induced Pluripotent Stem Cell-derived Cardiomyocytes by Re-balancing the Calcium Homeostasis Wu, H., Yang, H., Zhang, J., Lam, C., Rhee, J., Seeger, T., Sallam, K., Ma, N., Wu, J. LIPPINCOTT WILLIAMS & WILKINS. 2017
  • Incremental Value of Deformation Imaging and Hemodynamics Following Heart Transplantation: Insights From Graft Function Profiling. JACC. Heart failure Kobayashi, Y. n., Sudini, N. L., Rhee, J. W., Aymami, M. n., Moneghetti, K. J., Bouajila, S. n., Kobayashi, Y. n., Kim, J. B., Schnittger, I. n., Teuteberg, J. J., Khush, K. K., Fearon, W. F., Haddad, F. n. 2017; 5 (12): 930–39


    This study investigated to define graft dysfunction and to determine its incremental association with long-term outcome after heart transplantation (HT).Although graft failure is an established cause of late mortality after HT, few studies have analyzed the prognostic value of graft dysfunction at 1- and 5-year follow-up of HT.Patients who underwent HT and completed their first annual evaluation with right heart catheterization and echocardiography at Stanford University between January 1999 and December 2011 were included in the study. Hierarchical clustering was used to identify modules to capture independent features of graft dysfunction at 1 year. The primary endpoint for analysis consisted of the composite of cardiovascular mortality, re-transplantation, or heart failure hospitalization within 5 years of HT. The study further explored whether changes in graft dysfunction between 1 and 5 years were associated with 10-year all-cause mortality.A total of 215 HT recipients were included in the study. Using hierarchical clustering, 3 functional modules were identified; among them, left ventricular global longitudinal strain (LVGLS), stroke volume index, and right atrial pressure (RAP) or pulmonary capillary wedge pressure (PCWP) captured key features of graft function. Graft dysfunction based on pre defined LVGLS in absolute value <14%, stroke volume index <35 ml/m2, RAP >10 mm Hg, or PCWP >15 mm Hg were present in 41%, 36%, and 27%, respectively. The primary endpoint at 5 years occurred in 52 patients (24%), whereas 10-year all-cause mortality occurred in 30 (27%) of 110 patients alive at 5 years. On multivariate analysis, RAP (standardized hazard ratio: 1.63), LVGLS (standardized hazard ratio: 1.39), and a history of hemodynamically compromising rejection within 1 year (hazard ratio: 2.18) were independent predictors of 5-year outcome. RAP at 5 years, as well as change in RAP from 1 to 5 years, was predictive of 10-year all-cause mortality.RAP and LVGLS at the first annual evaluation provide complementary prognostic information in predicting 5-year outcome after HT.

    View details for PubMedID 29191301

  • Potential Strategies to Address the Major Clinical Barriers Facing Stem Cell Regenerative Therapy for Cardiovascular Disease: A Review. JAMA cardiology Nguyen, P. K., Neofytou, E., Rhee, J., Wu, J. C. 2016; 1 (8): 953-962


    Although progress continues to be made in the field of stem cell regenerative medicine for the treatment of cardiovascular disease, significant barriers to clinical implementation still exist.To summarize the current barriers to the clinical implementation of stem cell therapy in patients with cardiovascular disease and to discuss potential strategies to overcome them.Information for this review was obtained through a search of PubMed and the Cochrane database for English-language studies published between January 1, 2000, and July 25, 2016. Ten randomized clinical trials and 8 systematic reviews were included.One of the major clinical barriers facing the routine implementation of stem cell therapy in patients with cardiovascular disease is the limited and inconsistent benefit observed thus far. Reasons for this finding are unclear but may be owing to poor cell retention and survival, as suggested by numerous preclinical studies and a small number of human studies incorporating imaging to determine cell fate. Additional studies in humans using imaging to determine cell fate are needed to understand how these factors contribute to the limited efficacy of stem cell therapy. Treatment strategies to address poor cell retention and survival are under investigation and include the following: coadministration of immunosuppressive and prosurvival agents, delivery of cardioprotective factors packaged in exosomes rather than the cells themselves, and use of tissue-engineering strategies to provide structural support for cells. If larger grafts are achieved using these strategies, it will be imperative to carefully monitor for the potential risks of tumorigenicity, immunogenicity, and arrhythmogenicity.Despite important achievements to date, stem cell therapy is not yet ready for routine clinical implementation. Significant research is still needed to address the clinical barriers outlined herein before the next wave of large clinical trials is under way.

    View details for DOI 10.1001/jamacardio.2016.2750

    View details for PubMedID 27579998

  • Adult Stem Cell Therapy and Heart Failure, 2000 to 2016: A Systematic Review. JAMA cardiology Nguyen, P. K., Rhee, J., Wu, J. C. 2016; 1 (7): 831-841


    Stem cell therapy is a promising treatment strategy for patients with heart failure, which accounts for more than 10% of deaths in the United States annually. Despite more than a decade of research, further investigation is still needed to determine whether stem cell regenerative therapy is an effective treatment strategy and can be routinely implemented in clinical practice.To describe the progress in cardiac stem cell regenerative therapy using adult stem cells and to highlight the merits and limitations of clinical trials performed to date.Information for this review was obtained through a search of PubMed and the Cochrane database for English-language studies published between January 1, 2000, and July 26, 2016. Twenty-nine randomized clinical trials and 7 systematic reviews and meta-analyses were included in this review.Although adult stem cells were once believed to have the ability to create new heart tissue, preclinical studies suggest that these cells release cardioprotective paracrine factors that activate endogenous pathways, leading to myocardial repair. Subsequent randomized clinical trials, most of which used autologous bone marrow mononuclear cells, have found only a modest benefit in patients receiving stem cell therapy. The lack of a significant benefit may result from variations in trial methods, discrepancies in reporting, and an overreliance on surrogate end points.Although stem cell therapy for cardiovascular disease is not yet ready for routine clinical application, significant progress continues to be made. Physicians should be aware of the current status of this treatment so that they can better inform their patients who may be in search of alternative therapies.

    View details for DOI 10.1001/jamacardio.2016.2225

    View details for PubMedID 27557438

  • Human-induced pluripotent stem cell approaches to model inborn and acquired metabolic heart diseases. Current opinion in cardiology Chanana, A. M., Rhee, J., Wu, J. C. 2016; 31 (3): 266-274


    The article provides an overview of advances in the induced pluripotent stem cell field to model cardiomyopathies of inherited inborn errors of metabolism and acquired metabolic syndromes in vitro.Several inborn errors of metabolism have been studied using 'disease in a dish' models, including Pompe disease, Danon disease, Fabry disease, and Barth syndrome. Disease phenotypes of complex metabolic syndromes, such as diabetes mellitus and aldehyde dehydrogenase 2 deficiency, have also been observed.Differentiation of patient and disease-specific induced pluripotent stem cell-derived cardiomyocytes has provided the capacity to model deleterious cardiometabolic diseases to understand molecular mechanisms, perform drug screens, and identify novel drug targets.

    View details for DOI 10.1097/HCO.0000000000000277

    View details for PubMedID 27022891

  • Continuous flow left ventricular assist device placement complicated by aortic valve thrombus and myocardial infarction INTERNATIONAL JOURNAL OF CARDIOLOGY Kim, J. B., Rhee, J., Brenner, D. A., Ha, R., Banerjee, D., Yeung, A. C., Tremmel, J. A. 2014; 176 (3): E102-E103
  • Continuous flow left ventricular assist device placement complicated by aortic valve thrombus and myocardial infarction. International journal of cardiology Kim, J. B., Rhee, J. W., Brenner, D. A., Ha, R., Banerjee, D., Yeung, A. C., Tremmel, J. A. 2014; 176 (3): e102-3

    View details for DOI 10.1016/j.ijcard.2014.07.248

    View details for PubMedID 25183539

  • Clinical Features, Use of Evidence-Based Therapies, and Cardiovascular Outcomes Among Patients With Chronic Kidney Disease Following Non-ST-Elevation Acute Coronary Syndrome CLINICAL CARDIOLOGY Rhee, J., Wiviott, S. D., Scirica, B. M., Gibson, C. M., Murphy, S. A., Bonaca, M. P., Morrow, D. A., Mega, J. L. 2014; 37 (6): 350-356


    Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular events following acute coronary syndrome (ACS). The underlying pathobiology and optimal treatments for this population continue to be evaluated.Patients with CKD will receive fewer evidence-based therapies and experience high rates of adverse cardiovascular events in both the short- and long term.The MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes-Thrombolysis in Myocardial Infarction 36) trial randomized non-ST-elevation ACS patients to ranolazine or placebo, with no exclusion for renal dysfunction (except dialysis). We conducted a prespecified analysis among 6543 patients based on the degree of CKD.Patients with worse renal function were older with more comorbidities (P < 0.0001 for each). They were less likely to receive evidence-based cardiovascular medicines (P < 0.04 for each). Rates of an early invasive management strategy varied based on renal function; however, among patients with the highest TIMI risk scores, the rates of an early invasive management strategy were similar regardless of glomerular filtration rate (GFR) (Pinteraction = 0.005). Lower GFR was associated with increased rates of cardiovascular disease or myocardial infarction in the short and long term, even after adjustment (GFR <30 vs ≥90 mL/min/1.73 m(2) ; hazard ratio [HR]: 3.24 [95% confidence interval {CI}: 1.26-8.38] through 7 days and HR: 2.12 [95% CI: 1.33-3.39] through 1 year). The effect of ranolazine vs placebo on clinical outcomes was similar among those with and without CKD (Pinteraction = not significant).Following ACS, patients with renal dysfunction had more cardiovascular risk factors but were less likely to receive evidence-based medical therapies. A strong graded, independent relationship between the degree of CKD and poor clinical outcomes was observed over time. Continued efforts to optimize ACS treatment strategies in patients with CKD are warranted.

    View details for DOI 10.1002/clc.22253

    View details for PubMedID 24481910

  • Elevated Right Ventricular Operant Diastolic Elastance Strongly Predicts Increased Risk of Mortality Following Heart Transplantation Rhee, J., Sudini, N. L., Pham, M., Fearon, W., Lee, D., Beygui, R. E., Montoya, J. G., Wu, J. C., Vrtovec, B., Hunt, S. A., Haddad, F. LIPPINCOTT WILLIAMS & WILKINS. 2013
  • Advances in nanotechnology for the management of coronary artery disease TRENDS IN CARDIOVASCULAR MEDICINE Rhee, J., Wu, J. C. 2013; 23 (2): 39-45


    Nanotechnology holds tremendous potential to advance the current treatment of coronary artery disease. Nanotechnology may assist medical therapies by providing a safe and efficacious delivery platform for a variety of drugs aimed at modulating lipid disorders, decreasing inflammation and angiogenesis within atherosclerotic plaques, and preventing plaque thrombosis. Nanotechnology may improve coronary stent applications by promoting endothelial recovery on a stent surface utilizing bio-mimetic nanofibrous scaffolds, and also by preventing in-stent restenosis using nanoparticle-based delivery of drugs that are decoupled from stents. Additionally, nanotechnology may enhance tissue-engineered graft materials for application in coronary artery bypass grafting by facilitating cellular infiltration and remodeling of a graft matrix.

    View details for DOI 10.1016/j.tcm.2012.08.009

    View details for PubMedID 23245913

  • The Effect of Age on Outcomes of Coronary Artery Bypass Surgery Compared With Balloon Angioplasty or Bare-Metal Stent Implantation Among Patients With Multivessel Coronary Disease JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Flather, M., Rhee, J., Boothroyd, D. B., Boersma, E., Brooks, M. M., Carrie, D., Clayton, T. C., Danchin, N., Hamm, C. W., Hueb, W. A., King, S. B., Pocock, S. J., Rodriguez, A. E., Serruys, P., Sigwart, U., Stables, R. H., Hlatky, M. A. 2012; 60 (21): 2150-2157


    This study sought to assess whether patient age modifies the comparative effectiveness of coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI).Increasingly, CABG and PCI are performed in older patients to treat multivessel disease, but their comparative effectiveness is uncertain.Individual data from 7,812 patients randomized in 1 of 10 clinical trials of CABG or PCI were pooled. Age was analyzed as a continuous variable in the primary analysis and was divided into tertiles for descriptive purposes (≤56.2 years, 56.3 to 65.1 years, ≥65.2 years). The outcomes assessed were death, myocardial infarction and repeat revascularization over complete follow-up, and angina at 1 year.Older patients were more likely to have hypertension, diabetes, and 3-vessel disease compared with younger patients (p < 0.001 for trend). Over a median follow-up of 5.9 years, the effect of CABG versus PCI on mortality varied according to age (interaction p < 0.01), with adjusted CABG-to-PCI hazard ratios and 95% confidence intervals (CI) of 1.23 (95% CI: 0.95 to 1.59) in the youngest tertile; 0.89 (95% CI: 0.73 to 1.10) in the middle tertile; and 0.79 (95% CI: 0.67 to 0.94) in the oldest tertile. The CABG-to-PCI hazard ratio of less than 1 for patients 59 years of age and older. A similar interaction of age with treatment was present for the composite outcome of death or myocardial infarction. In contrast, patient age did not alter the comparative effectiveness of CABG and PCI on the outcomes of repeat revascularization or angina.Patient age modifies the comparative effectiveness of CABG and PCI on hard cardiac events, with CABG favored at older ages and PCI favored at younger ages.

    View details for DOI 10.1016/j.jacc.2012.08.982

    View details for Web of Science ID 000311077600004

  • In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid-polymeric nanoparticles PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Chan, J. M., Rhee, J., Drum, C. L., Bronson, R. T., Golomb, G., Langer, R., Farokhzad, O. C. 2011; 108 (48): 19347-19352


    Following recent successes with percutaneous coronary intervention (PCI) for treating coronary artery disease (CAD), many challenges remain. In particular, mechanical injury from the procedure results in extensive endothelial denudation, exposing the underlying collagen IV-rich basal lamina, which promotes both intravascular thrombosis and smooth muscle proliferation. Previously, we reported the engineering of collagen IV-targeting nanoparticles (NPs) and demonstrated their preferential localization to sites of arterial injury. Here, we develop a systemically administered, targeted NP system to deliver an antiproliferative agent to injured vasculature. Approximately 60-nm lipid-polymeric NPs were surface functionalized with collagen IV-targeting peptides and loaded with paclitaxel. In safety studies, the targeted NPs showed no signs of toxicity and a ≥3.5-fold improved maximum tolerated dose versus paclitaxel. In efficacy studies using a rat carotid injury model, paclitaxel (0.3 mg/kg or 1 mg/kg) was i.v. administered postprocedure on days 0 and 5. The targeted NP group resulted in lower neointima-to-media (N/M) scores at 2 wk versus control groups of saline, paclitaxel, or nontargeted NPs. Compared with sham-injury groups, an ∼50% reduction in arterial stenosis was observed with targeted NP treatment. The combination of improved tolerability, sustained release, and vascular targeting could potentially provide a safe and efficacious option in the management of CAD.

    View details for DOI 10.1073/pnas.1115945108

    View details for Web of Science ID 000297463100052

    View details for PubMedID 22087004

  • Spatiotemporal controlled delivery of nanoparticles to injured vasculature PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Chan, J. M., Zhang, L., Tong, R., Ghosh, D., Gao, W., Liao, G., Yuet, K. P., Gray, D., Rhee, J., Cheng, J., Golomb, G., Libby, P., Langer, R., Farokhzad, O. C. 2010; 107 (5): 2213-2218


    There are a number of challenges associated with designing nanoparticles for medical applications. We define two challenges here: (i) conventional targeting against up-regulated cell surface antigens is limited by heterogeneity in expression, and (ii) previous studies suggest that the optimal size of nanoparticles designed for systemic delivery is approximately 50-150 nm, yet this size range confers a high surface area-to-volume ratio, which results in fast diffusive drug release. Here, we achieve spatial control by biopanning a phage library to discover materials that target abundant vascular antigens exposed in disease. Next, we achieve temporal control by designing 60-nm hybrid nanoparticles with a lipid shell interface surrounding a polymer core, which is loaded with slow-eluting conjugates of paclitaxel for controlled ester hydrolysis and drug release over approximately 12 days. The nanoparticles inhibited human aortic smooth muscle cell proliferation in vitro and showed greater in vivo vascular retention during percutaneous angioplasty over nontargeted controls. This nanoparticle technology may potentially be used toward the treatment of injured vasculature, a clinical problem of primary importance.

    View details for DOI 10.1073/pnas.0914585107

    View details for Web of Science ID 000274296300074

    View details for PubMedID 20133865