Patricia Nguyen

All Publications

• Immunotherapy-Associated Atherosclerosis: A Comprehensive Review of Recent Findings and Implications for Future Research Current Treatment Options in Cardiovascular Medicine Chan, A., Torelli, S., Cheng, E., Batchelder, R., Waliany, S., Neal, J., Witteles, R., Nguyen, P., Cheng, P., Zhu, H. 2023

  View details for DOI 10.1007/s11936-023-01024-0

• The Role of Single-Cell Profiling and Deep Immunophenotyping in Understanding Immune Therapy Cardiotoxicity JACC: CardioOncology Huang, Y. V., Waliany, S., Lee, D., Galdos, F. X., Witteles, R. M., Neal, J. W., Fan, A. C., Maecker, H. T., Nguyen, P. K., Wu, S. M., Zhu, H. 2022; 4 (5): 629–634

  View details for DOI 10.1016/j.jaccao.2022.08.012

• 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)

  View details for DOI 10.1007/s11886-020-01292-3

• Molecular Imaging of Inflammation in Ischemic Heart Disease CURRENT CARDIOVASCULAR IMAGING REPORTS Bakerman, I., Wardak, M., Nguyen, P. K. 2018; 11 (6)

  View details for DOI 10.1007/s12410-018-9452-6

  View details for Web of Science ID 000433197200002

• Molecular Imaging of Inflammation in Ischemic Heart Disease (vol 11, 2018) CURRENT CARDIOVASCULAR IMAGING REPORTS Bakerman, I., Wardak, M., Nguyen, P. K. 2018; 11 (6)

  View details for DOI 10.1007/s12410-018-9454-4

  View details for Web of Science ID 000433197200003

• Prolonged survival of transplanted stem cells after ischaemic injury via the slow release of pro-survival peptides from a collagen matrix Nature Biomedical Engineering Lee, A. S., Inayathullah, ., Lijkwan, . A., Zhao, X., Sun, W., Park, S., Hong, W. X., Parekh, M. B., Malkovskiy, A. V., Lau, E., Qin, X., Pothineni,, . R., Sanchez-Freire, ., Kooreman, N. G., Ebert, A. D., Chan, C. K., Nguyen, P. K., Rajadas, J., Wu, J. C. 2018; 2 (2): 104–13

  Abstract

  Stem-cell-based therapies hold considerable promise for regenerative medicine. However, acute donor-cell death within several weeks after cell delivery remains a critical hurdle for clinical translation. Co-transplantation of stem cells with pro-survival factors can improve cell engraftment, but this strategy has been hampered by the typically short half-lives of the factors and by the use of Matrigel and other scaffolds that are not chemically defined. Here, we report a collagen-dendrimer biomaterial crosslinked with pro-survival peptide analogues that adheres to the extracellular matrix and slowly releases the peptides, significantly prolonging stem cell survival in mouse models of ischaemic injury. The biomaterial can serve as a generic delivery system to improve functional outcomes in cell-replacement therapy.

  View details for DOI 10.1038/s41551-018-0191-4

  View details for PubMedCentralID PMC5927627

• The Gift of Light: Using Multiplexed Optical Imaging to Probe Cardiac Metabolism in Health and Disease. Circulation. Cardiovascular imaging Wardak, M. n., Nguyen, P. K. 2018; 11 (3): e007597

  View details for PubMedID 29555838

• Multimodality molecular imaging in cardiac regenerative therapy. Journal of nuclear cardiology Vo, D., Nguyen, P. K. 2017

  Abstract

  Stem cell therapy holds great promise for the repair and regeneration of damaged myocardium. Disappointing results from recent large-scale randomized trials using adult stem cells, however, have led some to question the efficacy of this new therapeutic. Because most clinical stem cell trials have not incorporated molecular imaging to track cell fate, it may be premature to abandon this approach. Herein, we will review how multimodality imaging can be incorporated into cardiac regenerative therapy to facilitate the translation of stem cell therapy.

  View details for DOI 10.1007/s12350-017-0785-3

  View details for PubMedID 28185234

• 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

  Abstract

  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

• DNA damage-associated biomarkers in studying individual sensitivity to low-dose radiation from cardiovascular imaging. European heart journal Lee, W. H., Nguyen, P. K., Fleischmann, D., Wu, J. C. 2016; 37 (40): 3075-3080

  View details for PubMedID 27272147

• 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

  Abstract

  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

• Molecular probes for cardiovascular imaging. Journal of nuclear cardiology Liang, G., Nguyen, P. K. 2016; 23 (4): 783-789

  Abstract

  Molecular probes provide imaging signal and contrast for the visualization, characterization, and measurement of biological processes at the molecular level. These probes can be designed to target the cell or tissue of interest and must be retained at the imaging site until they can be detected by the appropriate imaging modality. In this article, we will discuss the basic design of molecular probes, differences among the various types of probes, and general strategies for their evaluation of cardiovascular disease.

  View details for DOI 10.1007/s12350-016-0501-8

  View details for PubMedID 27189171

• Microfluidic Single-Cell Analysis of Transplanted Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes After Acute Myocardial Infarction. Circulation Ong, S., Huber, B. C., Lee, W. H., Kodo, K., Ebert, A. D., Ma, Y., Nguyen, P. K., Diecke, S., Chen, W., Wu, J. C. 2015; 132 (8): 762-771

  Abstract

  Human induced pluripotent stem cells (iPSCs) are attractive candidates for therapeutic use, with the potential to replace deficient cells and to improve functional recovery in injury or disease settings. Here, we test the hypothesis that human iPSC-derived cardiomyocytes (iPSC-CMs) can secrete cytokines as a molecular basis to attenuate adverse cardiac remodeling after myocardial infarction.Human iPSCs were generated from skin fibroblasts and differentiated in vitro with a small molecule-based protocol. Troponin(+) iPSC-CMs were confirmed by immunohistochemistry, quantitative polymerase chain reaction, fluorescence-activated cell sorting, and electrophysiological measurements. Afterward, 2×10(6) iPSC-CMs derived from a cell line transduced with a vector expressing firefly luciferase and green fluorescent protein were transplanted into adult NOD/SCID mice with acute left anterior descending artery ligation. Control animals received PBS injection. Bioluminescence imaging showed limited engraftment on transplantation into ischemic myocardium. However, magnetic resonance imaging of animals transplanted with iPSC-CMs showed significant functional improvement and attenuated cardiac remodeling compared with PBS-treated control animals. To understand the underlying molecular mechanism, microfluidic single-cell profiling of harvested iPSC-CMs, laser capture microdissection of host myocardium, and in vitro ischemia stimulation were used to demonstrate that the iPSC-CMs could release significant levels of proangiogenic and antiapoptotic factors in the ischemic microenvironment.Transplantation of human iPSC-CMs into an acute mouse myocardial infarction model can improve left ventricular function and attenuate cardiac remodeling. Because of limited engraftment, most of the effects are possibly explained by paracrine activity of these cells.

  View details for DOI 10.1161/CIRCULATIONAHA.114.015231

  View details for PubMedID 26304668

• Microfluidic Single-Cell Analysis of Transplanted Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes After Acute Myocardial Infarction CIRCULATION Ong, S., Huber, B. C., Hee Lee, W., Kodo, K., Ebert, A. D., Ma, Y., Nguyen, P. K., Diecke, S., Chen, W., Wu, J. C. 2015; 132 (8): 762-771

  Abstract

  Human induced pluripotent stem cells (iPSCs) are attractive candidates for therapeutic use, with the potential to replace deficient cells and to improve functional recovery in injury or disease settings. Here, we test the hypothesis that human iPSC-derived cardiomyocytes (iPSC-CMs) can secrete cytokines as a molecular basis to attenuate adverse cardiac remodeling after myocardial infarction.Human iPSCs were generated from skin fibroblasts and differentiated in vitro with a small molecule-based protocol. Troponin(+) iPSC-CMs were confirmed by immunohistochemistry, quantitative polymerase chain reaction, fluorescence-activated cell sorting, and electrophysiological measurements. Afterward, 2×10(6) iPSC-CMs derived from a cell line transduced with a vector expressing firefly luciferase and green fluorescent protein were transplanted into adult NOD/SCID mice with acute left anterior descending artery ligation. Control animals received PBS injection. Bioluminescence imaging showed limited engraftment on transplantation into ischemic myocardium. However, magnetic resonance imaging of animals transplanted with iPSC-CMs showed significant functional improvement and attenuated cardiac remodeling compared with PBS-treated control animals. To understand the underlying molecular mechanism, microfluidic single-cell profiling of harvested iPSC-CMs, laser capture microdissection of host myocardium, and in vitro ischemia stimulation were used to demonstrate that the iPSC-CMs could release significant levels of proangiogenic and antiapoptotic factors in the ischemic microenvironment.Transplantation of human iPSC-CMs into an acute mouse myocardial infarction model can improve left ventricular function and attenuate cardiac remodeling. Because of limited engraftment, most of the effects are possibly explained by paracrine activity of these cells.

  View details for DOI 10.1161/CIRCULATIONAHA.114.015231

  View details for Web of Science ID 000360204800014

• Assessment of the Radiation Effects of Cardiac CT Angiography Using Protein and Genetic Biomarkers JACC-CARDIOVASCULAR IMAGING Nguyen, P. K., Lee, W. H., Li, Y. F., Hong, W. X., Hu, S., Chan, C., Liang, G., Nguyen, I., Ong, S., Churko, J., Wang, J., Altman, R. B., Fleischmann, D., Wu, J. C. 2015; 8 (8): 873-884

  View details for DOI 10.1016/j.jcmg.2015.04.016

  View details for Web of Science ID 000359895400001

  View details for PubMedID 26210695

• Large Animal Models of Ischemic Cardiomyopathy: Are They Enough to Bridge the Translational Gap? Journal of nuclear cardiology Nguyen, P. K., Wu, J. C. 2015; 22 (4): 666-672

  View details for DOI 10.1007/s12350-015-0078-7

  View details for PubMedID 25777782

• Assessment of the Radiation Effects of Cardiac CT Angiography Using Protein and Genetic Biomarkers. JACC. Cardiovascular imaging Nguyen, P. K., Lee, W. H., Li, Y. F., Hong, W. X., Hu, S., Chan, C., Liang, G., Nguyen, I., Ong, S., Churko, J., Wang, J., Altman, R. B., Fleischmann, D., Wu, J. C. 2015; 8 (8): 873-884

  Abstract

  The purpose of this study was to evaluate whether radiation exposure from cardiac computed tomographic angiography (CTA) is associated with deoxyribonucleic acid (DNA) damage and whether damage leads to programmed cell death and activation of genes involved in apoptosis and DNA repair.Exposure to radiation from medical imaging has become a public health concern, but whether it causes significant cell damage remains unclear.We conducted a prospective cohort study in 67 patients undergoing cardiac CTA between January 2012 and December 2013 in 2 U.S. medical centers. Median blood radiation exposure was estimated using phantom dosimetry. Biomarkers of DNA damage and apoptosis were measured by flow cytometry, whole genome sequencing, and single cell polymerase chain reaction.The median dose length product was 1,535.3 mGy•cm (969.7 to 2,674.0 mGy•cm). The median radiation dose to the blood was 29.8 mSv (18.8 to 48.8 mSv). Median DNA damage increased 3.39% (1.29% to 8.04%, p < 0.0001) and median apoptosis increased 3.1-fold (1.4- to 5.1-fold, p < 0.0001) post-radiation. Whole genome sequencing revealed changes in the expression of 39 transcription factors involved in the regulation of apoptosis, cell cycle, and DNA repair. Genes involved in mediating apoptosis and DNA repair were significantly changed post-radiation, including DDB2 (1.9-fold [1.5- to 3.0-fold], p < 0.001), XRCC4 (3.0-fold [1.1- to 5.4-fold], p = 0.005), and BAX (1.6-fold [0.9- to 2.6-fold], p < 0.001). Exposure to radiation was associated with DNA damage (odds ratio [OR]: 1.8 [1.2 to 2.6], p = 0.003). DNA damage was associated with apoptosis (OR: 1.9 [1.2 to 5.1], p < 0.0001) and gene activation (OR: 2.8 [1.2 to 6.2], p = 0.002).Patients exposed to >7.5 mSv of radiation from cardiac CTA had evidence of DNA damage, which was associated with programmed cell death and activation of genes involved in apoptosis and DNA repair.

  View details for DOI 10.1016/j.jcmg.2015.04.016

  View details for PubMedID 26210695

• Manganese-Enhanced Magnetic Resonance Imaging Enables In Vivo Confirmation of Peri-Infarct Restoration Following Stem Cell Therapy in a Porcine Ischemia-Reperfusion Model. Journal of the American Heart Association Dash, R., Kim, P. J., Matsuura, Y., Ikeno, F., Metzler, S., Huang, N. F., Lyons, J. K., Nguyen, P. K., Ge, X., Foo, C. W., McConnell, M. V., Wu, J. C., Yeung, A. C., Harnish, P., Yang, P. C. 2015; 4 (7)

  Abstract

  The exact mechanism of stem cell therapy in augmenting the function of ischemic cardiomyopathy is unclear. In this study, we hypothesized that increased viability of the peri-infarct region (PIR) produces restorative benefits after stem cell engraftment. A novel multimodality imaging approach simultaneously assessed myocardial viability (manganese-enhanced magnetic resonance imaging [MEMRI]), myocardial scar (delayed gadolinium enhancement MRI), and transplanted stem cell engraftment (positron emission tomography reporter gene) in the injured porcine hearts.Twelve adult swine underwent ischemia-reperfusion injury. Digital subtraction of MEMRI-negative myocardium (intrainfarct region) from delayed gadolinium enhancement MRI-positive myocardium (PIR and intrainfarct region) clearly delineated the PIR in which the MEMRI-positive signal reflected PIR viability. Human amniotic mesenchymal stem cells (hAMSCs) represent a unique population of immunomodulatory mesodermal stem cells that restored the murine PIR. Immediately following hAMSC delivery, MEMRI demonstrated an increased PIR viability signal compared with control. Direct PIR viability remained higher in hAMSC-treated hearts for >6 weeks. Increased PIR viability correlated with improved regional contractility, left ventricular ejection fraction, infarct size, and hAMSC engraftment, as confirmed by immunocytochemistry. Increased MEMRI and positron emission tomography reporter gene signal in the intrainfarct region and the PIR correlated with sustained functional augmentation (global and regional) within the hAMSC group (mean change, left ventricular ejection fraction: hAMSC 85±60%, control 8±10%; P<0.05) and reduced chamber dilatation (left ventricular end-diastole volume increase: hAMSC 24±8%, control 110±30%; P<0.05).The positron emission tomography reporter gene signal of hAMSC engraftment correlates with the improved MEMRI signal in the PIR. The increased MEMRI signal represents PIR viability and the restorative potential of the injured heart. This in vivo multimodality imaging platform represents a novel, real-time method of tracking PIR viability and stem cell engraftment while providing a mechanistic explanation of the therapeutic efficacy of cardiovascular stem cells.

  View details for DOI 10.1161/JAHA.115.002044

  View details for PubMedID 26215972

• Variable activation of the DNA damage response pathways in patients undergoing single-photon emission computed tomography myocardial perfusion imaging. Circulation. Cardiovascular imaging Lee, W. H., Nguyen, P., Hu, S., Liang, G., Ong, S., Han, L., Sanchez-Freire, V., Lee, A. S., Vasanawala, M., Segall, G., Wu, J. C. 2015; 8 (2)

  Abstract

  Although single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI) has improved the diagnosis and risk stratification of patients with suspected coronary artery disease, it remains a primary source of low-dose radiation exposure for cardiac patients. To determine the biological effects of low-dose radiation from SPECT MPI, we measured the activation of the DNA damage response pathways using quantitative flow cytometry and single-cell gene expression profiling.Blood samples were collected from patients before and after SPECT MPI (n=63). Overall, analysis of all recruited patients showed no marked differences in the phosphorylation of proteins (H2AX, protein 53, and ataxia telangiectasia mutated) after SPECT. The majority of patients also had either downregulated or unchanged expression in DNA damage response genes at both 24 and 48 hours post-SPECT. Interestingly, a small subset of patients with increased phosphorylation had significant upregulation of genes associated with DNA damage, whereas those with no changes in phosphorylation had significant downregulation or no difference, suggesting that some patients may potentially be more sensitive to low-dose radiation exposure.Our findings showed that SPECT MPI resulted in a variable activation of the DNA damage response pathways. Although only a small subset of patients had increased protein phosphorylation and elevated gene expression postimaging, continued care should be taken to reduce radiation exposure to both the patients and operators.

  View details for DOI 10.1161/CIRCIMAGING.114.002851

  View details for PubMedID 25609688

• Variable activation of the DNA damage response pathways in patients undergoing single-photon emission computed tomography myocardial perfusion imaging. Circulation. Cardiovascular imaging Hee Lee, W., Nguyen, P., Hu, S., Liang, G., Ong, S., Han, L., Sanchez-Freire, V., Lee, A. S., Vasanawala, M., Segall, G., Wu, J. C. 2015; 8 (2): e002851

  Abstract

  Although single-photon emission computed tomography myocardial perfusion imaging (SPECT MPI) has improved the diagnosis and risk stratification of patients with suspected coronary artery disease, it remains a primary source of low-dose radiation exposure for cardiac patients. To determine the biological effects of low-dose radiation from SPECT MPI, we measured the activation of the DNA damage response pathways using quantitative flow cytometry and single-cell gene expression profiling.Blood samples were collected from patients before and after SPECT MPI (n=63). Overall, analysis of all recruited patients showed no marked differences in the phosphorylation of proteins (H2AX, protein 53, and ataxia telangiectasia mutated) after SPECT. The majority of patients also had either downregulated or unchanged expression in DNA damage response genes at both 24 and 48 hours post-SPECT. Interestingly, a small subset of patients with increased phosphorylation had significant upregulation of genes associated with DNA damage, whereas those with no changes in phosphorylation had significant downregulation or no difference, suggesting that some patients may potentially be more sensitive to low-dose radiation exposure.Our findings showed that SPECT MPI resulted in a variable activation of the DNA damage response pathways. Although only a small subset of patients had increased protein phosphorylation and elevated gene expression postimaging, continued care should be taken to reduce radiation exposure to both the patients and operators.

  View details for DOI 10.1161/CIRCIMAGING.114.002851

  View details for PubMedID 25609688

  View details for PubMedCentralID PMC4354894

• Manganese-Enhanced Magnetic Resonance Imaging Enables In Vivo Confirmation of Peri-Infarct Restoration Following Stem Cell Therapy in a Porcine Ischemia-Reperfusion Model. Journal of the American Heart Association Dash, R., Kim, P. J., Matsuura, Y., Ikeno, F., Metzler, S., Huang, N. F., Lyons, J. K., Nguyen, P. K., Ge, X., Wong Po Foo, C., McConnell, M. V., Wu, J. C., Yeung, A. C., Harnish, P., Yang, P. C. 2015; 4 (7)

  View details for DOI 10.1161/JAHA.115.002044

  View details for PubMedID 26215972

• Stem Cell Imaging: From Bench to Bedside CELL STEM CELL Nguyen, P. K., Riegler, J., Wu, J. C. 2014; 14 (4): 431-444

  Abstract

  Although cellular therapies hold great promise for the treatment of human disease, results from several initial clinical trials have not shown a level of efficacy required for their use as a first line therapy. Here we discuss how in vivo molecular imaging has helped identify barriers to clinical translation and potential strategies that may contribute to successful transplantation and improved outcomes, with a focus on cardiovascular and neurological diseases. We conclude with a perspective on the future role of molecular imaging in defining safety and efficacy for clinical implementation of stem cell therapies.

  View details for DOI 10.1016/j.stem.2014.03.009

  View details for Web of Science ID 000334766400008

  View details for PubMedID 24702995

• Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity. Circulation Liang, P., Lan, F., Lee, A. S., Gong, T., Sanchez-Freire, V., Wang, Y., Diecke, S., Sallam, K., Knowles, J. W., Wang, P. J., Nguyen, P. K., Bers, D. M., Robbins, R. C., Wu, J. C. 2013; 127 (16): 1677-1691

  Abstract

  Cardiotoxicity is a leading cause for drug attrition during pharmaceutical development and has resulted in numerous preventable patient deaths. Incidents of adverse cardiac drug reactions are more common in patients with preexisting heart disease than the general population. Here we generated a library of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with various hereditary cardiac disorders to model differences in cardiac drug toxicity susceptibility for patients of different genetic backgrounds.Action potential duration and drug-induced arrhythmia were measured at the single cell level in hiPSC-CMs derived from healthy subjects and patients with hereditary long QT syndrome, familial hypertrophic cardiomyopathy, and familial dilated cardiomyopathy. Disease phenotypes were verified in long QT syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy hiPSC-CMs by immunostaining and single cell patch clamp. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and the human ether-a-go-go-related gene expressing human embryonic kidney cells were used as controls. Single cell PCR confirmed expression of all cardiac ion channels in patient-specific hiPSC-CMs as well as hESC-CMs, but not in human embryonic kidney cells. Disease-specific hiPSC-CMs demonstrated increased susceptibility to known cardiotoxic drugs as measured by action potential duration and quantification of drug-induced arrhythmias such as early afterdepolarizations and delayed afterdepolarizations.We have recapitulated drug-induced cardiotoxicity profiles for healthy subjects, long QT syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy patients at the single cell level for the first time. Our data indicate that healthy and diseased individuals exhibit different susceptibilities to cardiotoxic drugs and that use of disease-specific hiPSC-CMs may predict adverse drug responses more accurately than the standard human ether-a-go-go-related gene test or healthy control hiPSC-CM/hESC-CM screening assays.

  View details for DOI 10.1161/CIRCULATIONAHA.113.001883

  View details for PubMedID 23519760

  View details for PubMedCentralID PMC3870148

• Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity. Circulation Liang, P., Lan, F., Lee, A. S., Gong, T., Sanchez-Freire, V., Wang, Y., Diecke, S., Sallam, K., Knowles, J. W., Wang, P. J., Nguyen, P. K., Bers, D. M., Robbins, R. C., Wu, J. C. 2013; 127 (16): 1677-1691

  View details for DOI 10.1161/CIRCULATIONAHA.113.001883

  View details for PubMedID 23519760

• Abnormal Calcium Handling Properties Underlie Familial Hypertrophic Cardiomyopathy Pathology in Patient-Specific Induced Pluripotent Stem Cells CELL STEM CELL Lan, F., Lee, A. S., Liang, P., Sanchez-Freire, V., Nguyen, P. K., Wang, L., Han, L., Yen, M., Wang, Y., Sun, N., Abilez, O. J., Hu, S., Ebert, A. D., Navarrete, E. G., Simmons, C. S., Wheeler, M., Pruitt, B., Lewis, R., Yamaguchi, Y., Ashley, E. A., Bers, D. M., Robbins, R. C., Longaker, M. T., Wu, J. C. 2013; 12 (1): 101-113

  Abstract

  Familial hypertrophic cardiomyopathy (HCM) is a prevalent hereditary cardiac disorder linked to arrhythmia and sudden cardiac death. While the causes of HCM have been identified as genetic mutations in the cardiac sarcomere, the pathways by which sarcomeric mutations engender myocyte hypertrophy and electrophysiological abnormalities are not understood. To elucidate the mechanisms underlying HCM development, we generated patient-specific induced pluripotent stem cell cardiomyocytes (iPSC-CMs) from a ten-member family cohort carrying a hereditary HCM missense mutation (Arg663His) in the MYH7 gene. Diseased iPSC-CMs recapitulated numerous aspects of the HCM phenotype including cellular enlargement and contractile arrhythmia at the single-cell level. Calcium (Ca(2+)) imaging indicated dysregulation of Ca(2+) cycling and elevation in intracellular Ca(2+) ([Ca(2+)](i)) are central mechanisms for disease pathogenesis. Pharmacological restoration of Ca(2+) homeostasis prevented development of hypertrophy and electrophysiological irregularities. We anticipate that these findings will help elucidate the mechanisms underlying HCM development and identify novel therapies for the disease.

  View details for DOI 10.1016/j.stem.2012.10.010

  View details for Web of Science ID 000313839500014

  View details for PubMedID 23290139

  View details for PubMedCentralID PMC3638033

• Microfluidic Single-Cell Analysis Shows That Porcine Induced Pluripotent Stem Cell-Derived Endothelial Cells Improve Myocardial Function by Paracrine Activation CIRCULATION RESEARCH Gu, M., Nguyen, P. K., Lee, A. S., Xu, D., Hu, S., Plews, J. R., Han, L., Huber, B. C., Lee, W. H., Gong, Y., de Almeida, P. E., Lyons, J., Ikeno, F., Pacharinsak, C., Connolly, A. J., Gambhir, S. S., Robbins, R. C., Longaker, M. T., Wu, J. C. 2012; 111 (7): 882-893

  Abstract

  Induced pluripotent stem cells (iPSCs) hold great promise for the development of patient-specific therapies for cardiovascular disease. However, clinical translation will require preclinical optimization and validation of large-animal iPSC models.To successfully derive endothelial cells from porcine iPSCs and demonstrate their potential utility for the treatment of myocardial ischemia.Porcine adipose stromal cells were reprogrammed to generate porcine iPSCs (piPSCs). Immunohistochemistry, quantitative PCR, microarray hybridization, and angiogenic assays confirmed that piPSC-derived endothelial cells (piPSC-ECs) shared similar morphological and functional properties as endothelial cells isolated from the autologous pig aorta. To demonstrate their therapeutic potential, piPSC-ECs were transplanted into mice with myocardial infarction. Compared with control, animals transplanted with piPSC-ECs showed significant functional improvement measured by echocardiography (fractional shortening at week 4: 27.2±1.3% versus 22.3±1.1%; P<0.001) and MRI (ejection fraction at week 4: 45.8±1.3% versus 42.3±0.9%; P<0.05). Quantitative protein assays and microfluidic single-cell PCR profiling showed that piPSC-ECs released proangiogenic and antiapoptotic factors in the ischemic microenvironment, which promoted neovascularization and cardiomyocyte survival, respectively. Release of paracrine factors varied significantly among subpopulations of transplanted cells, suggesting that transplantation of specific cell populations may result in greater functional recovery.In summary, this is the first study to successfully differentiate piPSCs-ECs from piPSCs and demonstrate that transplantation of piPSC-ECs improved cardiac function after myocardial infarction via paracrine activation. Further development of these large animal iPSC models will yield significant insights into their therapeutic potential and accelerate the clinical translation of autologous iPSC-based therapy.

  View details for DOI 10.1161/CIRCRESAHA.112.269001

  View details for PubMedID 22821929

• Safe Genetic Modification of Cardiac Stem Cells Using a Site-Specific Integration Technique Meeting of the American-Heart-Association Lan, F., Liu, J., Narsinh, K. H., Hu, S., Han, L., Lee, A. S., Karow, M., Nguyen, P. K., Nag, D., Calos, M. P., Robbins, R. C., Wu, J. C. LIPPINCOTT WILLIAMS & WILKINS. 2012: S20-?

  Abstract

  Human cardiac progenitor cells (hCPCs) are a promising cell source for regenerative repair after myocardial infarction. Exploitation of their full therapeutic potential may require stable genetic modification of the cells ex vivo. Safe genetic engineering of stem cells, using facile methods for site-specific integration of transgenes into known genomic contexts, would significantly enhance the overall safety and efficacy of cellular therapy in a variety of clinical contexts.We used the phiC31 site-specific recombinase to achieve targeted integration of a triple fusion reporter gene into a known chromosomal context in hCPCs and human endothelial cells. Stable expression of the reporter gene from its unique chromosomal integration site resulted in no discernible genomic instability or adverse changes in cell phenotype. Namely, phiC31-modified hCPCs were unchanged in their differentiation propensity, cellular proliferative rate, and global gene expression profile when compared with unaltered control hCPCs. Expression of the triple fusion reporter gene enabled multimodal assessment of cell fate in vitro and in vivo using fluorescence microscopy, bioluminescence imaging, and positron emission tomography. Intramyocardial transplantation of genetically modified hCPCs resulted in significant improvement in myocardial function 2 weeks after cell delivery, as assessed by echocardiography (P=0.002) and MRI (P=0.001). We also demonstrated the feasibility and therapeutic efficacy of genetically modifying differentiated human endothelial cells, which enhanced hind limb perfusion (P<0.05 at day 7 and 14 after transplantation) on laser Doppler imaging.The phiC31 integrase genomic modification system is a safe, efficient tool to enable site-specific integration of reporter transgenes in progenitor and differentiated cell types.

  View details for DOI 10.1161/CIRCULATIONAHA.111.084913

  View details for Web of Science ID 000314150200003

  View details for PubMedID 22965984

  View details for PubMedCentralID PMC3481839

• Early Stem Cell Engraftment Predicts Late Cardiac Functional Recovery Preclinical Insights From Molecular Imaging CIRCULATION-CARDIOVASCULAR IMAGING Liu, J., Narsinh, K. H., Lan, F., Wang, L., Nguyen, P. K., Hu, S., Lee, A., Han, L., Gong, Y., Huang, M., Nag, D., Rosenberg, J., Chouldechova, A., Robbins, R. C., Wu, J. C. 2012; 5 (4): 481-490

  Abstract

  Human cardiac progenitor cells have demonstrated great potential for myocardial repair in small and large animals, but robust methods for longitudinal assessment of their engraftment in humans is not yet readily available. In this study, we sought to optimize and evaluate the use of positron emission tomography (PET) reporter gene imaging for monitoring human cardiac progenitor cell (hCPC) transplantation in a mouse model of myocardial infarction.hCPCs were isolated and expanded from human myocardial samples and stably transduced with herpes simplex virus thymidine kinase (TK) PET reporter gene. Thymidine kinase-expressing hCPCs were characterized in vitro and transplanted into murine myocardial infarction models (n=57). Cardiac echocardiographic, magnetic resonance imaging and pressure-volume loop analyses revealed improvement in left ventricular contractile function 2 weeks after transplant (hCPC versus phosphate-buffered saline, P<0.03). Noninvasive PET imaging was used to track hCPC fate over a 4-week time period, demonstrating a substantial decline in surviving cells. Importantly, early cell engraftment as assessed by PET was found to predict subsequent functional improvement, implying a "dose-effect" relationship. We isolated the transplanted cells from recipient myocardium by laser capture microdissection for in vivo transcriptome analysis. Our results provide direct evidence that hCPCs augment cardiac function after their transplantation into ischemic myocardium through paracrine secretion of growth factors.PET reporter gene imaging can provide important diagnostic and prognostic information regarding the ultimate success of hCPC treatment for myocardial infarction.

  View details for DOI 10.1161/CIRCIMAGING.111.969329

  View details for Web of Science ID 000313573500014

  View details for PubMedID 22565608

  View details for PubMedCentralID PMC3400712

• Imaging Guiding the Clinical Translation of Cardiac Stem Cell Therapy CIRCULATION RESEARCH Nguyen, P. K., Lan, F., Wang, Y., Wu, J. C. 2011; 109 (8): 962-979

  Abstract

  Stem cells have been touted as the holy grail of medical therapy, with promises to regenerate cardiac tissue, but it appears the jury is still out on this novel therapy. Using advanced imaging technology, scientists have discovered that these cells do not survive nor engraft long-term. In addition, only marginal benefit has been observed in large-animal studies and human trials. However, all is not lost. Further application of advanced imaging technology will help scientists unravel the mysteries of stem cell therapy and address the clinical hurdles facing its routine implementation. In this review, we will discuss how advanced imaging technology will help investigators better define the optimal delivery method, improve survival and engraftment, and evaluate efficacy and safety. Insights gained from this review may direct the development of future preclinical investigations and clinical trials.

  View details for DOI 10.1161/CIRCRESAHA.111.242909

  View details for Web of Science ID 000295368300015

  View details for PubMedID 21960727

  View details for PubMedCentralID PMC3206967

• Preclinical Derivation and Imaging of Autologously Transplanted Canine Induced Pluripotent Stem Cells JOURNAL OF BIOLOGICAL CHEMISTRY Lee, A. S., Xu, D., Plews, J. R., Nguyen, P. K., Nag, D., Lyons, J. K., Han, L., Hu, S., Lan, F., Liu, J., Huang, M., Narsinh, K. H., Long, C. T., de Almeida, P. E., Levi, B., Kooreman, N., Bangs, C., Pacharinsak, C., Ikeno, F., Yeung, A. C., Gambhir, S. S., Robbins, R. C., Longaker, M. T., Wu, J. C. 2011; 286 (37): 32697-32704

  Abstract

  Derivation of patient-specific induced pluripotent stem cells (iPSCs) opens a new avenue for future applications of regenerative medicine. However, before iPSCs can be used in a clinical setting, it is critical to validate their in vivo fate following autologous transplantation. Thus far, preclinical studies have been limited to small animals and have yet to be conducted in large animals that are physiologically more similar to humans. In this study, we report the first autologous transplantation of iPSCs in a large animal model through the generation of canine iPSCs (ciPSCs) from the canine adipose stromal cells and canine fibroblasts of adult mongrel dogs. We confirmed pluripotency of ciPSCs using the following techniques: (i) immunostaining and quantitative PCR for the presence of pluripotent and germ layer-specific markers in differentiated ciPSCs; (ii) microarray analysis that demonstrates similar gene expression profiles between ciPSCs and canine embryonic stem cells; (iii) teratoma formation assays; and (iv) karyotyping for genomic stability. Fate of ciPSCs autologously transplanted to the canine heart was tracked in vivo using clinical positron emission tomography, computed tomography, and magnetic resonance imaging. To demonstrate clinical potential of ciPSCs to treat models of injury, we generated endothelial cells (ciPSC-ECs) and used these cells to treat immunodeficient murine models of myocardial infarction and hindlimb ischemia.

  View details for DOI 10.1074/jbc.M111.235739

  View details for Web of Science ID 000294726800078

  View details for PubMedID 21719696

  View details for PubMedCentralID PMC3173214

• Novel MicroRNA Prosurvival Cocktail for Improving Engraftment and Function of Cardiac Progenitor Cell Transplantation Annual Meeting of the American-Heart-Association Hu, S., Huang, M., Nguyen, P. K., Gong, Y., Li, Z., Jia, F., Lan, F., Liu, J., Nag, D., Robbins, R. C., Wu, J. C. LIPPINCOTT WILLIAMS & WILKINS. 2011: S27–S34

  Abstract

  Although stem cell therapy has provided a promising treatment for myocardial infarction, the low survival of the transplanted cells in the infarcted myocardium is possibly a primary reason for failure of long-term improvement. Therefore, the development of novel prosurvival strategies to boost stem cell survival will be of significant benefit to this field.Cardiac progenitor cells (CPCs) were isolated from transgenic mice, which constitutively express firefly luciferase and green fluorescent protein. The CPCs were transduced with individual lentivirus carrying the precursor of miR-21, miR-24, and miR-221, a cocktail of these 3 microRNA precursors, or green fluorescent protein as a control. After challenge in serum free medium, CPCs treated with the 3 microRNA cocktail showed significantly higher viability compared with untreated CPCs. After intramuscular and intramyocardial injections, in vivo bioluminescence imaging showed that microRNA cocktail-treated CPCs survived significantly longer after transplantation. After left anterior descending artery ligation, microRNA cocktail-treated CPCs boost the therapeutic efficacy in terms of functional recovery. Histological analysis confirmed increased myocardial wall thickness and CPC engraftment in the myocardium with the microRNA cocktail. Finally, we used bioinformatics analysis and experimental validation assays to show that Bim, a critical apoptotic activator, is an important target gene of the microRNA cocktail, which collectively can bind to the 3'UTR region of Bim and suppress its expression.We have demonstrated that a microRNA prosurvival cocktail (miR-21, miR-24, and miR-221) can improve the engraftment of transplanted cardiac progenitor cells and therapeutic efficacy for treatment of ischemic heart disease.

  View details for DOI 10.1161/CIRCULATIONAHA.111.017954

  View details for Web of Science ID 000294782800004

  View details for PubMedID 21911815

  View details for PubMedCentralID PMC3181082

• Double Knockdown of Prolyl Hydroxylase and Factor-Inhibiting Hypoxia-Inducible Factor With Nonviral Minicircle Gene Therapy Enhances Stem Cell Mobilization and Angiogenesis After Myocardial Infarction Annual Meeting of the American-Heart-Association Huang, M., Nguyen, P., Jia, F., Hu, S., Gong, Y., de Almeida, P. E., Wang, L., Nag, D., Kay, M. A., Giaccia, A. J., Robbins, R. C., Wu, J. C. LIPPINCOTT WILLIAMS & WILKINS. 2011: S46–S54

  Abstract

  Under normoxic conditions, hypoxia-inducible factor (HIF)-1α is rapidly degraded by 2 hydroxylases: prolyl hydroxylase (PHD) and factor-inhibiting HIF-1 (FIH). Because HIF-1α mediates the cardioprotective response to ischemic injury, its upregulation may be an effective therapeutic option for ischemic heart failure.PHD and FIH were cloned from mouse embryonic stem cells. The best candidate short hairpin (sh) sequences for inhibiting PHD isoenzyme 2 and FIH were inserted into novel, nonviral, minicircle vectors. In vitro studies after cell transfection of mouse C2C12 myoblasts, HL-1 atrial myocytes, and c-kit(+) cardiac progenitor cells demonstrated higher expression of angiogenesis factors in the double-knockdown group compared with the single-knockdown and short hairpin scramble control groups. To confirm in vitro data, shRNA minicircle vectors were injected intramyocardially after left anterior descending coronary artery ligation in adult FVB mice (n=60). Functional studies using MRI, echocardiography, and pressure-volume loops showed greater improvement in cardiac function in the double-knockdown group. To assess mechanisms of this functional recovery, we performed a cell trafficking experiment, which demonstrated significantly greater recruitment of bone marrow cells to the ischemic myocardium in the double-knockdown group. Fluorescence-activated cell sorting showed significantly higher activation of endogenous c-kit(+) cardiac progenitor cells. Immunostaining showed increased neovascularization and decreased apoptosis in areas of injured myocardium. Finally, western blots and laser-capture microdissection analysis confirmed upregulation of HIF-1α protein and angiogenesis genes, respectively.We demonstrated that HIF-1α upregulation by double knockdown of PHD and FIH synergistically increases stem cell mobilization and myocardial angiogenesis, leading to improved cardiac function.

  View details for DOI 10.1161/CIRCULATIONAHA.110.014019

  View details for Web of Science ID 000294782800006

  View details for PubMedID 21911818

  View details for PubMedCentralID PMC3181087

• Imaging Atherosclerosis With F18-Fluorodeoxyglucose Positron Emission Tomography What Are We Actually Seeing? JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Wu, J. C., Nguyen, P. K. 2011; 58 (6): 615-617

  View details for DOI 10.1016/j.jacc.2011.04.021

  View details for Web of Science ID 000293167200010

  View details for PubMedID 21798424

• Physical Activity in Older Subjects Is Associated With Increased Coronary Vasodilation The ADVANCE Study JACC-CARDIOVASCULAR IMAGING Nguyen, P. K., Terashima, M., Fair, J. M., Varady, A., Taylor-Piliae, R. E., Iribarren, C., Go, A. S., Haskell, W. L., Hlatky, M. A., Fortmann, S. P., McConnell, M. V. 2011; 4 (6): 622-629

  Abstract

  We investigated the association between physical activity and coronary vasodilation to nitroglycerin (NTG) in the ADVANCE (Atherosclerotic Disease, Vascular Function, and Genetic Epidemiology) cohort of older healthy subjects.Physical activity may exert its beneficial effects by augmenting coronary responsiveness to nitric oxide. The relationship between physical activity and coronary vasodilatory response to NTG, an exogenous nitric oxide donor, has not been studied in a community-based population with typical activity levels.In 212 older adults (ages 60 to 72 years) without cardiovascular disease, we measured the coronary vasodilatory response to NTG using magnetic resonance angiography and physical activity using the Stanford Seven-Day Physical Activity Recall Questionnaire. The primary predictor measure was total physical activity (kcal/kg/day). The primary outcome measure was coronary vasodilatory response (percent increase of cross-sectional area post-NTG).Coronary vasodilation was 27.6% in more active subjects (>35 kcal/kg/day, e.g., 1 h of walking per day) compared to 18.9% in less active subjects (p=0.03). Regression analysis showed a significant positive correlation between coronary vasodilation and physical activity (p=0.003), with a slope (beta) of 1.2% per kcal/kg/day. This finding remained significant after adjustment for cardiac risk factors, coronary calcium, the use of vasoactive or statin medications, and analysis of physical activity by quintiles (p < 0.05). Coronary vasodilation was also associated with physical activity intensity (p = 0.03).In an asymptomatic, community-based cohort of older adults, increased coronary vasodilatory response was independently associated with greater physical activity, supporting the benefits of exercise on the order of 1 h of walking per day.

  View details for DOI 10.1016/j.jcmg.2011.05.001

  View details for PubMedID 21679897

• A comparison of echocardiographic measures of diastolic function for predicting all-cause mortality in a predominantly male population AMERICAN HEART JOURNAL Nguyen, P. K., Schnittger, I., Heidenreich, P. A. 2011; 161 (3): 530-537

  Abstract

  Prior studies demonstrating the prognostic value of echocardiographic measures of diastolic function have been limited by sample size, have included only select clinical populations, and have not incorporated newer measures of diastolic function nor determined their independent prognostic value. The objective of this study is to determine the independent prognostic value of established and new echocardiographic parameters of diastolic function.We included 3,604 consecutive patients referred to 1 of 3 echocardiography laboratories over a 2-year period. We obtained measurements of mitral inflow velocities, pulmonary vein filling pattern, mitral annulus motion (e'), and propagation velocity (V(p)). The primary end point was 1-year all-cause mortality.The mean age of the patients was 68 years, and 95% were male. There were 277 deaths during a mean follow-up of 248 ± 221 days. For patients with reduced left ventricular ejection fraction (LVEF), all measured parameters except for e' were associated with mortality (P < .05) on univariate analysis. For patients with preserved LVEF, the E-wave velocity was significantly associated with mortality (P < .05) on univariate analysis. The deceleration time/E-wave velocity ratio, V(p), and pulmonary vein filling pattern were borderline significant (P < .10). With multivariate analysis, only V(p) was associated with survival for both reduced (P = .02) and preserved LVEF groups (P = .01).In a large, clinically diverse population, most measures of diastolic function were predictive of all-cause mortality without adjustment for patient characteristics. On multivariate analysis, only V(p) was independently associated with total mortality. This association with mortality may be related to factors other than diastolic function and warrants further investigation.

  View details for DOI 10.1016/j.ahj.2010.12.010

  View details for Web of Science ID 000288156400018

  View details for PubMedID 21392608

• Sex differences in the diagnostic evaluation of coronary artery disease JOURNAL OF NUCLEAR CARDIOLOGY Nguyen, P. K., Nag, D., Wu, J. C. 2011; 18 (1): 144-152

  View details for DOI 10.1007/s12350-010-9315-2

  View details for Web of Science ID 000289166700018

  View details for PubMedID 21136229

  View details for PubMedCentralID PMC3657505

• Radiation exposure from imaging tests: is there an increased cancer risk? Expert review of cardiovascular therapy Nguyen, P. K., Wu, J. C. 2011; 9 (2): 177-183

  Abstract

  The increasing exposure to low-dose radiation from diagnostic testing has prompted renewed interest in evaluating its carcinogenic risk, but quantifying health risk from low-dose radiation exposure remains controversial. The current approach is to adopt the linear non-threshold model, which is commonly applied to high-dose exposure, and apply it to assess risk from low-dose exposure. However, existing data are conflicting and limited to epidemiological studies and/or in vitro analyses. In this article, we will discuss the potential cancer risk from low- and high-dose radiation, their effects on DNA repair response pathways, and the best course of action for patients and providers to minimize risk.

  View details for DOI 10.1586/erc.10.184

  View details for PubMedID 21453214

  View details for PubMedCentralID PMC3102578

• Right coronary wall cmr in the older asymptomatic advance cohort: positive remodeling and associations with type 2 diabetes and coronary calcium JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE Terashima, M., Nguyen, P. K., Rubin, G. D., Meyer, C. H., Shimakawa, A., Nishimura, D. G., Ehara, S., Iribarren, C., Courtney, B. K., Go, A. S., Hlatky, M. A., Fortmann, S. P., McConnell, M. V. 2010; 12

  Abstract

  Coronary wall cardiovascular magnetic resonance (CMR) is a promising noninvasive approach to assess subclinical atherosclerosis, but data are limited in subjects over 60 years old, who are at increased risk. The purpose of the study was to evaluate coronary wall CMR in an asymptomatic older cohort.Cross-sectional images of the proximal right coronary artery (RCA) were acquired using spiral black-blood coronary CMR (0.7 mm resolution) in 223 older, community-based patients without a history of cardiovascular disease (age 60-72 years old, 38% female). Coronary measurements (total vessel area, lumen area, wall area, and wall thickness) had small intra- and inter-observer variabilities (r = 0.93~0.99, all p < 0.0001), though one-third of these older subjects had suboptimal image quality. Increased coronary wall thickness correlated with increased coronary vessel area (p < 0.0001), consistent with positive remodeling. On multivariate analysis, type 2 diabetes was the only risk factor associated with increased coronary wall area and thickness (p = 0.03 and p = 0.007, respectively). Coronary wall CMR measures were also associated with coronary calcification (p = 0.01-0.03).Right coronary wall CMR in asymptomatic older subjects showed increased coronary atherosclerosis in subjects with type 2 diabetes as well as coronary calcification. Coronary wall CMR may contribute to the noninvasive assessment of subclinical coronary atherosclerosis in older, at-risk patient groups.

  View details for DOI 10.1186/1532-429X-12-75

  View details for PubMedID 21192815

• Methods to assess stem cell lineage, fate and function ADVANCED DRUG DELIVERY REVIEWS Nguyen, P. K., Nag, D., Wu, J. C. 2010; 62 (12): 1175-1186

  Abstract

  Stem cell therapy has the potential to regenerate injured tissue. For stem cells to achieve their full therapeutic potential, stem cells must differentiate into the target cell, reach the site of injury, survive, and engraft. To fully characterize these cells, evaluation of cell morphology, lineage specific markers, cell specific function, and gene expression must be performed. To monitor survival and engraftment, cell fate imaging is vital. Only then can organ specific function be evaluated to determine the effectiveness of therapy. In this review, we will discuss methods for evaluating the function of transplanted cells for restoring the heart, nervous system, and pancreas. We will also highlight the specific challenges facing these potential therapeutic areas.

  View details for DOI 10.1016/j.addr.2010.08.008

  View details for Web of Science ID 000285325900006

  View details for PubMedID 20816906

  View details for PubMedCentralID PMC3078641

• Nasal continuous positive airway pressure improves myocardial perfusion reserve and endothelial-dependent vasodilation in patients with obstructive sleep apnea JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE Nguyen, P. K., Katikireddy, C. K., McConnell, M. V., Kushida, C., Yang, P. C. 2010; 12

  Abstract

  Obstructive sleep apnea (OSA) has been associated with cardiovascular disease (CVD), but whether OSA is an independent risk factor for CVD is controversial. The purpose of this study is to determine if patients with OSA have subclinical cardiovascular disease that is detectable by multi-modality cardiovascular imaging and whether these abnormalities improve after nasal continuous positive airway pressure (nCPAP).Of the 35 consecutive subjects with newly diagnosed moderate to severe OSA recruited from the Stanford Sleep Disorders Clinic, 20 patients were randomized to active vs. sham nCPAP. Active nCPAP was titrated to pressures that would prevent sleep disordered breathing based on inpatient polysomnography. OSA patients had baseline vascular function abnormalities including decreased myocardial perfusion reserve (MPR), brachial flow mediated dilation (FMD) and nitroglycerin-induced coronary vasodilation. Patients randomized to active nCPAP had improvement of MPR (1.5 ± 0.5 vs. 3.0 ± 1.3, p = 0.02) and brachial FMD (2.5% ± 5.7% vs. 9.0% ± 6.5%, p = 0.03) after treatment, but those randomized to sham nCPAP showed no significant improvement. There were no significant changes seen in chamber sizes, systolic and diastolic function, valvular function and coronary vasodilation to nitroglycerin.Patients with moderate to severe OSA had decreased MPR and brachial FMD that improved after 3 months of nCPAP. These findings suggest that relief of apnea in OSA may improve microvascular disease and endothelial dysfunction, which may prevent the development of overt cardiovascular disease. Further study in a larger patient population may be warranted.

  View details for DOI 10.1186/1532-429X-12-50

  View details for PubMedID 20815898

• Quantitative Tissue Characterization of Infarct Core and Border Zone in Patients With Ischemic Cardiomyopathy by Magnetic Resonance Is Associated With Future Cardiovascular Events JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Heidary, S., Patel, H., Chung, J., Yokota, H., Gupta, S. N., Bennett, M. V., Katikireddy, C., Nguyen, P., Pauly, J. M., Terashima, M., McConnell, M. V., Yang, P. C. 2010; 55 (24): 2762-2768

  Abstract

  This study evaluates how characterization of tissue heterogeneity of myocardial infarction by cardiovascular magnetic resonance (CMR) is associated with cardiovascular events (CVE) in patients with ischemic cardiomyopathy (ICM).Prior studies demonstrated that the quantification of myocardial scar volume by CMR is superior to left ventricular end-diastolic volume, left ventricular end-systolic volume, and left ventricular ejection fraction (LVEF) in predicting future CVE in ICM patients. Evaluation of infarct heterogeneity by measuring infarct core and border zones through CMR might have a higher association with CVE.Seventy patients (mean LVEF: 25 +/- 11%) considered for revascularization or medical management +/- implantable cardiac defibrillator were enrolled. A 1.5-T GE MRI (Signa, GE Healthcare, Milwaukee, Wisconsin) was used to acquire cine and delayed enhancement images. The patients' core and border zones of infarcted myocardium were analyzed and followed for CVE.Larger infarct border zone and its percentage of myocardium were found in the 29 patients (41%) who had CVE (median 13.3 g [interquartile range (IQR) 8.4 to 25.1 g] vs. 8.0 g [IQR 3.0 to 14.5 g], p = 0.02 and 7.8% [IQR 4.9% to 17.0%] vs. 4.1% [IQR 1.9% to 9.3%], p = 0.02, respectively). The core infarct zone and its percentage of myocardium, left ventricular end-diastolic volume, left ventricular end-systolic volume, and LVEF were not statistically significant. Sub-analysis of the medical management and revascularization patients with CVE demonstrated that the medically managed patients had a larger border zone, whereas there was no difference between border and core zones in the revascularization group (p < 0.05).Quantification of core and border zones and their percentages of myocardium through CMR is associated with future CVE and might assist in the management of patients with ICM.

  View details for DOI 10.1016/j.jacc.2010.01.052

  View details for PubMedID 20538171

• Prevalence and Prognostic Significance of Exercise-Induced Right Bundle Branch Block AMERICAN JOURNAL OF CARDIOLOGY Stein, R., Nguyen, P., Abella, J., Olson, H., Myers, J., Froelicher, V. 2010; 105 (5): 677-680

  Abstract

  Exercise-induced (EI) right bundle branch block (RBBB) is an infrequent electrocardiographic phenomenon, and controversy exists regarding its association with cardiovascular disease. We compared the prevalence and prognostic significance of RBBB, abnormal ST depression, and normal electrocardiographic findings in response to exercise testing in 9,623 consecutive veterans who underwent exercise testing from 1987 to 2007. EI RBBB, EI ST depression, and a normal exercise electrocardiographic response occurred in 0.24%, 15.2%, and 71.9% veterans, respectively. After appropriate exclusions, of the 8,047 patients analyzed, 6 patients in the EI RBBB subgroup died. Of these 6 deaths, 3 were cardiovascular deaths during the 9 years of follow-up. The annual death rate was 7.3% (1.4% cardiac deaths), 2.6% (1.2% cardiac deaths), and 1.8% (0.6% cardiac death) among those with EI RBBB, EI ST depression, and a normal ST response, respectively (p <0.0001). The patients with EI RBBB were significantly older, more overweight, and had a greater prevalence of coronary artery disease, heart failure, and hypertension compared to the 2 other subgroups. Patients with EI RBBB had an age-adjusted Cox proportional hazard ratio of 1.13 (p = 0.75, 95% confidence interval 0.51 to 2.5) for all-cause mortality and 1.57 (p = 0.43, 95% confidence interval 0.51 to 4.8) for cardiovascular mortality, respectively. In conclusion, EI RBBB is a rare occurrence during routine clinical exercise testing that appears to be benign.

  View details for DOI 10.1016/j.amjcard.2009.10.050

  View details for Web of Science ID 000278137100017

  View details for PubMedID 20185016

• Noninvasive assessment of coronary vasodilation using cardiovascular magnetic resonance in patients at high risk for coronary artery disease JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE Nguyen, P. K., Meyer, C., Engvall, J., Yang, P., McConnell, M. V. 2008; 10

  Abstract

  Impaired coronary vasodilation to both endothelial-dependent and endothelial-independent stimuli have been associated with atherosclerosis. Direct measurement of coronary vasodilation using x-ray angiography or intravascular ultrasound is invasive and, thus, not appropriate for asymptomatic patients or for serial follow-up. In this study, high-resolution coronary cardiovascular magnetic resonance (CMR) was used to investigate the vasodilatory response to nitroglycerine (NTG) of asymptomatic patients at high risk for CAD.A total of 46 asymptomatic subjects were studied: 13 high-risk patients [8 with diabetes mellitus (DM), 5 with end stage renal disease (ESRD)] and 33 age-matched controls. Long-axis and cross-sectional coronary artery images were acquired pre- and 5 minutes post-sublingual NTG using a sub-mm-resolution multi-slice spiral coronary CMR sequence. Coronary cross sectional area (CSA) was measured on pre- and post-NTG images and % coronary vasodilation was calculated.Patients with DM and ESRD had impaired coronary vasodilation to NTG compared to age-matched controls (17.8 +/- 7.3% vs. 25.6 +/- 7.1%, p = 0.002). This remained significant for ESRD patients alone (14.8 +/- 7.7% vs. 25.6 +/- 7.1%; p = 0.003) and for DM patients alone (19.8 +/- 6.3% vs. 25.6 +/- 7.1%; p = 0.049), with a non-significant trend toward greater impairment in the ESRD vs. DM patients (14.8 +/- 7.7% vs. 19.8 +/- 6.3%; p = 0.23).Noninvasive coronary CMR demonstrates impairment of coronary vasodilation to NTG in high-risk patients with DM and ESRD. This may provide a functional indicator of subclinical atherosclerosis and warrants clinical follow up to determine prognostic significance.

  View details for DOI 10.1186/1532-429X-10-28

  View details for PubMedID 18513419

• Quantitative characterization of myocardial infarction by cardiovascular magnetic resonance predicts future cardiovascular events in patients with ischemic cardiomyopathy JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE Yokota, H., Heidary, S., Katikireddy, C. K., Nguyen, P., Pauly, J. M., McConnell, M. V., Yang, P. C. 2008; 10

  Abstract

  Cardiovascular magnetic resonance (CMR) can provide quantitative data of the myocardial tissue utilizing high spatial and temporal resolution along with exquisite tissue contrast. Previous studies have correlated myocardial scar tissue with the occurrence of ventricular arrhythmia. This study was conducted to evaluate whether characterization of myocardial infarction by CMR can predict cardiovascular events in patients with ischemic cardiomyopathy (ICM).We consecutively studied 86 patients with ICM (LVEF < 50%, mean LVEF: 26 +/- 12%) with CMR before revascularization or medication therapy +/- implantable cardiac defibrillator, determined the amount of myocardial scar, and followed for development of cardiovascular events. Thirty-three patients (38%) had cardiovascular events (mean follow-up: 20 +/- 16 months). Patients who developed cardiovascular events had larger scar volume and scar percentage of the myocardium than those who did not develop cardiovascular events (16.8 +/- 12.4 cm3 vs. 11.7 +/- 12.6 cm3, p = 0.023 and 10.2 +/- 6.9% vs. 7.2 +/- 6.7%, p = 0.037, respectively). There were no significant differences in LVEDV, LVESV and LVEF between the patients with and without cardiovascular events (231 +/- 76 ml vs. 230 +/- 88 ml; 180 +/- 73 ml vs. 175 +/- 90 ml; and 25 +/- 10% vs. 27 +/- 13%, respectively).Quantification of the scar volume and scar percentage by CMR is superior to LVEDV, LVESV, and LVEF in prognosticating the future likelihood of the development of cardiovascular events in patients with ICM.

  View details for DOI 10.1186/1532-429X-10-17

  View details for PubMedID 18400089

• Successful lysis of an aortic prosthetic valve thrombosis with a dosing regimen for peripheral artery and bypass graft occlusions JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Nguyen, P. K., Wasserman, S. M., Fann, J. I., Giacomini, J. 2008; 135 (3): 691-693

  View details for DOI 10.1016/j.jtcvs.2007.11.012

  View details for PubMedID 18329497

• Impaired Coronary Vasodilation by Magnetic Resonance Angiography Is Associated With Advanced Coronary Artery Calcification JACC-CARDIOVASCULAR IMAGING Terashima, M., Nguyen, P. K., Rubin, G. D., Iribarren, C., Courtney, B. K., Go, A. S., Fortmann, S. P., McConnell, M. V. 2008; 1 (2): 167-173

  Abstract

  This study evaluated the hypothesis that impaired nitroglycerin (NTG)-induced coronary vasodilation is associated with advanced coronary atherosclerosis in asymptomatic older patients.Atherosclerosis is associated with both structural and functional abnormalities of the vessel wall. Noninvasive functional measures of subclinical coronary atherosclerosis may help characterize high-risk subjects and guide preventive therapy.A total of 236 older patients (age 60 to 72 years, 33% female) without a history of cardiovascular disease were studied. Nitroglycerin-induced coronary vasodilation was measured by magnetic resonance angiography (MRA). Cross-sectional images of the right coronary artery were acquired before and 5 min after 0.4-mg sublingual NTG using a gated, breath-held spiral coronary MRA sequence (0.7-mm resolution). Quantitative analysis of the increase in cross-sectional area was performed in the 90% of patients (n = 212) with adequate image quality. Quantitation of coronary artery calcification (CAC) was performed by multidetector computed tomography using the Agatston method.Forty patients (19%) had advanced CAC (> or =400). Coronary vasodilation to NTG was significantly impaired (p = 0.02) in patients with advanced CAC (median [interquartile range] = 15.9% [4.2% to 28.0%] vs. 21.5% [9.6% to 36.6%] for CAC <400). Importantly, NTG-induced coronary vasodilation remained independently associated with advanced CAC after multivariate analysis incorporating risk factors (p = 0.02) and other potential confounders (p = 0.04). There was no significant difference in coronary vasodilation between men and women, but few women (n = 3) had advanced CAC.Impaired NTG-induced coronary vasodilation by MRA is associated with advanced coronary atherosclerosis in a community-based cohort of older asymptomatic subjects. Coronary MRA may provide a noninvasive functional assessment of subclinical coronary atherosclerosis.

  View details for DOI 10.1016/j.jcmg.2007.12.001

  View details for PubMedID 19356424

• Peri-infarct ischemia determined by cardiovascular magnetic resonance evaluation of myocardial viability and stress perfusion predicts future cardiovascular events in patients with severe ischemic cardiomyopathy JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE Tsukiji, M., Nguyen, P., Narayan, G., Hellinger, J., Chan, F., Herfkens, R., Pauly, J. M., McConnell, M. V., Yang, P. C. 2006; 8 (6): 773-779

  Abstract

  We assessed whether cardiovascular magnetic resonance imaging (CMR) of peri-infarct ischemia provides prognostic information in severe ischemic cardiomyopathy (ICM) patients referred for revascularization.Twenty-one patients with severe ICM were recruited prospectively for combined stress adenosine perfusion, late gadolinium enhancement, and rest perfusion studies. The patients were followed for in-hospital and post-discharge cardiovascular events.During 12+/- 9.8 months follow-up, 67% of the patients with peri-infarct ischemia and 13% of the patients without peri-infarct ischemia had cardiovascular events (p = 0.03). CONCLUSION. In severe ICM patients, the presence of peri-infarct ischemia was associated with a higher incidence of cardiovascular events.

  View details for DOI 10.1080/10976640600737615

  View details for PubMedID 17060098

• Real-time color-flow CMR in adults with congenital heart disease JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE de la Pena, E., Nguyen, P. K., Nayak, K. S., Yang, P. C., Rosenthal, D. N., Hu, B. S., Pauly, J. M., McConnell, M. V. 2006; 8 (6): 809-815

  Abstract

  CMR is valuable in the evaluation of congenital heart disease (CHD). Traditional flow imaging sequences involve cardiac and respiratory gating, increasing scan time and susceptibility to arrhythmias. We studied a real-time color-flow CMR system for the detection of flow abnormalities in 13 adults with CHD. All 16 congenital flow abnormalities previously detected by echocardiography were visualized using color-flow CMR, including atrial septal defects (n = 4), ventricular septal defects (n = 9), aortic coarctation (n = 1), Blalock-Taussig shunt (n = 1) and Fontan shunt (n = 1). Real-time color-flow CMR can identify intra- and extra-cardiac flow abnormalities in adults with congenital heart disease.

  View details for DOI 10.1080/10976640600777728

  View details for PubMedID 17060103

• Gastrointestinal bleeding CLINICAL PEDIATRICS Nguyen, P. C., Garcia-Careaga, M., Bass, D. 2005; 44 (7): 641-643

  View details for PubMedID 16151574

• Dynamic real-time architecture in magnetic resonance coronary angiography-a prospective clinical trial JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE Yang, P. C., Santos, J. M., Nguyen, P. K., Scott, G. C., Engvall, J., McConnell, M. V., Wright, G. A., Nishimura, D. G., Pauly, J. M., Hu, B. S. 2004; 6 (4): 885-894

  Abstract

  A dynamic real-time (dRT) architecture has been developed to address limitations in magnetic resonance coronary angiography (MRCA). A prospective clinical trial of 45 patients suspected of coronary artery disease was conducted to determine clinical utility of this integrated real-time system.Clinical implementation of MRCA is not performed routinely today. However, improved anatomic coverage, image quality, and scan flexibility may enhance its clinical utility. A novel real-time architecture addresses these challenges through instantaneous reconfiguration between real-time (RT) and high-resolution (HR) imaging sequences with dynamic selection of the desired element on a custom-designed receiver coil.A total of 45 subjects were recruited consecutively to evaluate scan time, anatomic coverage, image quality, and detection of coronary lesions. Using a modern PC, the dRT switches from RT to gated HR imaging sequence in one repetition time (39 ms). Magnetic resonance imaging (MRI) scanning was performed using a custom-designed coronary coil consisting of two four-inch phase-array circular elements enabled with real-time selection of the desired coil element.All studies were completed in less than 45 minutes and required a mean of 12 breath holds (16 heartbeats). Of the total number of coronary segments, 91% (357/394) were visualized. Excellent or good image quality was achieved in 86% of the segments. Blinded analysis of the coronary arteries revealed sensitivity of 93% and specificity of 88% in the detection of coronary stenoses.The integrated environment of dRT provides a rapid and flexible scan protocol for MRCA while achieving wide anatomical coverage, high image quality, and reliable detection of coronary stenosis in short scan time.

  View details for DOI 10.1016/j.JCMR.20036192

  View details for PubMedID 15646892