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Precise Measurement of Physical Activities and High-Impact Motion: Feasibility of Smart Activity Sensor System IEEE SENSORS JOURNAL Liu, H., Chuang, Y., Liu, C., Yang, P. C., Fuh, C. 2021; 21 (1): 568?80
View details for DOI 10.1109/JSEN.2020.3015392

View details for Web of Science ID 000597216600063
Allogeneic Mesenchymal Cell Therapy in Anthracycline-Induced Cardiomyopathy Heart Failure Patients: The CCTRN SENECA Trial. JACC. CardioOncology Bolli, R., Perin, E. C., Willerson, J. T., Yang, P. C., Traverse, J. H., Henry, T. D., Pepine, C. J., Mitrani, R. D., Hare, J. M., Murphy, M. P., March, K. L., Ikram, S., Lee, D. P., O'Brien, C., Durand, J., Miller, K., Lima, J. A., Ostovaneh, M. R., Ambale-Venkatesh, B., Gee, A. P., Richman, S., Taylor, D. A., Sayre, S. L., Bettencourt, J., Vojvodic, R. W., Cohen, M. L., Simpson, L. M., Lai, D., Aguilar, D., Loghin, C., Moye, L., Ebert, R. F., Davis, B. R., Simari, R. D., Cardiovascular Cell Therapy Research Network (CCTRN) 2020; 2 (4): 581?95
Abstract

BACKGROUND: Anthracycline-induced cardiomyopathy (AIC) may be irreversible with a poor prognosis, disproportionately affecting women and young adults. Administration of allogeneic bone marrow-derived mesenchymal stromal cells (allo-MSCs) is a promising approach to heart failure (HF) treatment.OBJECTIVES: SENECA (Stem Cell Injection in Cancer Survivors) was a phase 1 study of allo-MSCs in AIC.METHODS: Cancer survivors with chronic AIC (mean age 56.6 years; 68% women; NT-proBNP 1,426 pg/ml; 6 enrolled in an open-label, lead-in phase and 31 subjects randomized 1:1) received 1 * 108 allo-MSCs or vehicle transendocardially. Primary objectives were safety and feasibility. Secondary efficacy measures included cardiac function and structure measured by cardiac magnetic resonance imaging (CMR), functional capacity, quality of life (Minnesota Living with Heart Failure Questionnaire), and biomarkers.RESULTS: A total of 97% of subjects underwent successful study product injections; all allo-MSC-assigned subjects received the target dose of cells. Follow-up visits were well-attended (92%) with successful collection of endpoints in 94% at the 1-year visit. Although 58% of subjects had non-CMR compatible devices, CMR endpoints were successfully collected in 84% of subjects imaged at 1 year. No new tumors were reported. There were no significant differences between allo-MSC and vehicle groups with regard to clinical outcomes. Secondary measures included 6-min walk test (p = 0.056) and Minnesota Living with Heart Failure Questionnaire score (p = 0.048), which tended to favor the allo-MSC group.CONCLUSIONS: In this first-in-human study of cell therapy in patients with AIC, transendocardial administration of allo-MSCs appears safe and feasible, and CMR was successfully performed in the majority of the HF patients with devices. This study lays the groundwork for phase 2 trials aimed at assessing efficacy of cell therapy in patients with AIC.

View details for DOI 10.1016/j.jaccao.2020.09.001

View details for PubMedID 33403362
A Phase I Study of Allogeneic Mesenchymal Stem Cell Therapy in Patients with Heart Failure Secondary to Anthracycline-induced Cardiomyopathy: The Cctrn Stem Cell Injection in Cancer Survivors (Seneca) Trial Bolli, R., Perin, E. C., Willerson, J. T., Yang, P. C., Traverse, J. H., Henry, T. D., Pepine, C. J., Mitrani, R. D., Hare, J. M., Murphy, M. P., Lima, J. A., Gee, A. P., Taylor, D. A., Lai, D., Ebert, R. F., Davis, B. R., Simari, R. D. CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2020: S97
View details for Web of Science ID 000579889600259
MITOCHONDRIA CONTAINING EXTRACELLULAR VESICLES FROM AUTOLOGOUS INDUCED PLURIPOTENT STEM CELL DERIVED CARDIOMYOCYTES RESTORE BIOENERGETICS IN ISCHEMIC MYOCARDIUM Ikeda, G., Santoso, M., Tada, Y., Vaskova, E., O'Brien, C. G., Jung, J., Yang, P. C. ELSEVIER SCIENCE INC. 2020: 3659
View details for Web of Science ID 000522979103444
SULFATED DEXTRAN-COATED IRON OXIDE NANOPARTICLES DETECT INFLAMMATION IN THE PERI-INFARCT REGION POST-ACUTE MYOCARDIAL INFARCTION Tada, Y., Ikeda, G., Louie, A., Yang, P. ELSEVIER SCIENCE INC. 2020: 1792
View details for Web of Science ID 000522979101779
Exosomes From Induced Pluripotent Stem Cell-Derived Cardiomyocytes Promote Autophagy for Myocardial Repair. Journal of the American Heart Association Santoso, M. R., Ikeda, G., Tada, Y., Jung, J., Vaskova, E., Sierra, R. G., Gati, C., Goldstone, A. B., von Bornstaedt, D., Shukla, P., Wu, J. C., Wakatsuki, S., Woo, Y. J., Yang, P. C. 2020; 9 (6): e014345
Abstract

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

View details for DOI 10.1161/JAHA.119.014345

View details for PubMedID 32131688
Manganese-enhanced T1 mapping to quantify myocardial viability: validation with 18F-fluorodeoxyglucose positron emission tomography. Scientific reports Spath, N., Tavares, A., Gray, G. A., Baker, A. H., Lennen, R. J., Alcaide-Corral, C. J., Dweck, M. R., Newby, D. E., Yang, P. C., Jansen, M. A., Semple, S. I. 2020; 10 (1): 2018
Abstract

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

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

View details for PubMedID 32029765
Sacubitril/Valsartan Improves Cardiac Function and Decreases Myocardial Fibrosis Via Downregulation of Exosomal miR-181a in a Rodent Chronic Myocardial Infarction Model. Journal of the American Heart Association Vaskova, E., Ikeda, G., Tada, Y., Wahlquist, C., Mercola, M., Yang, P. C. 2020: e015640
Abstract

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

View details for DOI 10.1161/JAHA.119.015640

View details for PubMedID 32538237
Ferumoxytol-enhanced cardiovascular magnetic resonance detection of early stage acute myocarditis. Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance Tada, Y., Tachibana, A., Heidary, S., Yang, P. C., McConnell, M. V., Dash, R. 2019; 21 (1): 77
Abstract

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

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

View details for PubMedID 31842900
Iron Oxide Labeling and Tracking of Extracellular Vesicles MAGNETOCHEMISTRY Tada, Y., Yang, P. C. 2019; 5 (4)
View details for DOI 10.3390/magnetochemistry5040060

View details for Web of Science ID 000512352400007
Meta-analysis of short- and long-term efficacy of mononuclear cell transplantation in patients with myocardial infarction. American heart journal Yang, D., O'Brien, C. G., Ikeda, G., Traverse, J. H., Taylor, D. A., Henry, T. D., Bolli, R., Yang, P. C. 2019; 220: 155?75
Abstract

BACKGROUND: Mononuclear cells (MNCs) have been tested in clinical trials across multiple cardiovascular pathologies with mixed results. Major adverse cardiac events (MACE) and markers of cardiovascular capacity have been particularly challenging to interpret because of small size. This meta-analysis is aimed to assess the efficacy of MNC therapy in randomized clinical trials to identify the markers of efficiency that could influence future trial design.METHODS: PubMed, Embase, Cochrane library, and ClinicalTrials.gov were searched from inception through November 8, 2018. Changes in left ventricular ejection fraction (LVEF) and infarct size from baseline to follow-up were selected as primary outcomes. Changes in the left ventricular end-systolic volume, left ventricular end-diastolic volume, brain natriuretic peptide/N-terminal pro-B-type natriuretic peptide, 6-minute walk test, New York Heart Association class, and MACE incidences were considered secondary outcomes.RESULTS: In short-term follow-up, patients treated with MNCs demonstrated a significant increase in absolute LVEF of 2.21% (95% CI 1.59-2.83; P?
View details for DOI 10.1016/j.ahj.2019.09.005

View details for PubMedID 31821904
Combined T2 -preparation and multidimensional outer volume suppression for coronary artery imaging with 3D cones trajectories. Magnetic resonance in medicine Zeng, D. Y., Baron, C. A., Malave, M. O., Kerr, A. B., Yang, P. C., Hu, B. S., Nishimura, D. G. 2019
Abstract

PURPOSE: To develop a modular magnetization preparation sequence for combined T2 -preparation and multidimensional outer volume suppression (OVS) for coronary artery imaging.METHODS: A combined T2 -prepared 1D OVS sequence with fat saturation was defined to contain a 90�-60 180�60 composite nonselective tip-down pulse, two 180�Y hard pulses for refocusing, and a -90� spectral-spatial sinc tip-up pulse. For 2D OVS, 2 modules were concatenated, selective in X and then Y. Bloch simulations predicted robustness of the sequence to B0 and B1 inhomogeneities. The proposed sequence was compared with a T2 -prepared 2D OVS sequence proposed by Luo et al, which uses a spatially selective 2D spiral tip-up. The 2 sequences were compared in phantom studies and in vivo coronary artery imaging studies with a 3D cones trajectory.RESULTS: Phantom results demonstrated superior OVS for the proposed sequence compared with the Luo sequence. In studies on 15 healthy volunteers, the proposed sequence had superior image edge profile acutance values compared with the Luo sequence for the right (P < .05) and left (P < .05) coronary arteries, suggesting superior vessel sharpness. The proposed sequence also had superior signal-to-noise ratio (P < .05) and passband-to-stopband ratio (P < .05). Reader scores and reader preference indicated superior coronary image quality of the proposed sequence for both the right (P < .05) and left (P < .05) coronary arteries.CONCLUSION: The proposed sequence with concatenated 1D spatially selective tip-ups and integrated fat saturation has superior image quality and suppression compared with the Luo sequence with 2D spatially selective tip-up.

View details for DOI 10.1002/mrm.28057

View details for PubMedID 31691350
Broad Genetic Testing in a Clinical Setting Uncovers a High Prevalence of Titin Loss-of-Function Variants in Very Early-Onset Atrial Fibrillation. Circulation. Genomic and precision medicine Goodyer, W. R., Dunn, K., Caleshu, C., Jackson, M., Wylie, J., Moscarello, T., Platt, J., Reuter, C., Smith, A., Trela, A., Ceresnak, S. R., Motonaga, K. S., Ashley, E., Yang, P., Dubin, A. M., Perez, M. 2019
Abstract

Atrial fibrillation (AF) is the most common sustained arrhythmia, affecting approximately 34 million worldwide. The pathophysiology of AF remains incompletely understood but is clearly complex with multiple underlying genetic, physiologic and environmental factors. Very early-onset AF (vEAF) (defined here as onset <45 years and without significant comorbidities), while rare (only ~0.5-3% of AF cases), is highly heritable, with a greater prevalence of rare variants in genes previously associated with AF. Patients with vEAF, therefore, represent an ideal population for discovering novel genes involved in the underlying genetic basis of AF. Notably, the Framingham study showed that patients with AF without comorbidities have a three-fold higher risk for heart failure. Conversely, several forms of inherited cardiomyopathy have been strongly associated with AF suggestive of a shared etiology.

View details for DOI 10.1161/CIRCGEN.119.002713

View details for PubMedID 31638414
Stem Cell-Derived Exosomes Protect Astrocyte Cultures From in vitro Ischemia and Decrease Injury as Post-stroke Intravenous Therapy FRONTIERS IN CELLULAR NEUROSCIENCE Sun, X., Jung, J., Arvola, O., Santoso, M. R., Giffard, R. G., Yang, P. C., Stary, C. M. 2019; 13
View details for DOI 10.3389/fncel.2019.00394

View details for Web of Science ID 000483577400001
Myocardial viability of the peri-infarct region measured by T1 mapping post manganese-enhanced MRI correlates with LV dysfunction INTERNATIONAL JOURNAL OF CARDIOLOGY Tada, Y., Heidary, S., Tachibana, A., Zaman, J., Neofytou, E., Dash, R., Wu, J. C., Yang, P. C. 2019; 281: 8?14
View details for DOI 10.1016/j.ijcard.2019.01.101

View details for Web of Science ID 000459490500002
MICROVESICLES LARGER THAN 200NM RESCUE CARDIOMYOCYTES FROM DOXORUBICIN INJURY IN A PATIENT-SPECIFIC MODEL OF ANTHRACYCLINE INDUCED CARDIOMYOPATHY O'Brien, C., Shi, L., Ozgun, M., Vaskova, E., Santoso, M., Jung, J., Ikeda, G., Demirci, U., Yang, P. ELSEVIER SCIENCE INC. 2019: 688
View details for Web of Science ID 000460565900688
Whole-heart coronary MR angiography using a 3D cones phyllotaxis trajectory MAGNETIC RESONANCE IN MEDICINE Malave, M. O., Baron, C. A., Addy, N., Cheng, J. Y., Yang, P. C., Hu, B. S., Nishimura, D. G. 2019; 81 (2): 1092?1103
View details for DOI 10.1002/mrm.27475

View details for Web of Science ID 000462086300030
Myocardial viability of the peri-infarct region measured by T1 mapping post manganese-enhanced MRI correlates with LV dysfunction. International journal of cardiology Tada, Y., Heidary, S., Tachibana, A., Zaman, J., Neofytou, E., Dash, R., Wu, J. C., Yang, P. C. 2019
Abstract

BACKGROUND: Manganese-enhanced MRI (MEMRI) detects viable cardiomyocytes based on the intracellular manganese uptake via L-type calcium-channels. This study aimed to quantify myocardial viability based on manganese uptake by viable myocardium in the infarct core (IC), peri-infarct region (PIR) and remote myocardium (RM) using T1 mapping before and after MEMRI and assess their association with cardiac function and arrhythmogenesis.METHODS: Fifteen female swine had a 60-minute balloon ischemia-reperfusion injury in the LAD. MRI (Signa 3T, GE Healthcare) and electrophysiological study (EPS) were performed 4?weeks later. MEMRI and delayed gadolinium-enhanced MRI (DEMRI) were acquired on LV short axis. The DEMRI positive total infarct area was subdivided into the regions of MEMRI-negative non-viable IC and MEMRI-positive viable PIR. T1 mapping was performed to evaluate native T1, post-MEMRI T1, and delta R1 (R1post-R1pre, where R1 equals 1/T1) of each territory. Their correlation with LV function and EPS data was assessed.RESULTS: PIR was characterized by intermediate native T1 (1530.5?�?75.2?ms) compared to IC (1634.7?�?88.4?ms, p?=?0.001) and RM (1406.4?�?37.9?ms, p?
View details for PubMedID 30739802
Defining genotype-phenotype relationships in patients with hypertrophic cardiomyopathy using cardiovascular magnetic resonance imaging. PloS one Miller, R. J., Heidary, S., Pavlovic, A., Schlachter, A., Dash, R., Fleischmann, D., Ashley, E. A., Wheeler, M. T., Yang, P. C. 2019; 14 (6): e0217612
Abstract

HCM is the most common inherited cardiomyopathy. Historically, there has been poor correlation between genotype and phenotype. However, CMR has the potential to more accurately assess disease phenotype. We characterized phenotype with CMR in a cohort of patients with confirmed HCM and high prevalence of genetic testing.Patients with a diagnosis of HCM, who had undergone contrast-enhanced CMR were identified. Left ventricular mass index (LVMI) and volumes were measured from steady-state free precession sequences. Late gadolinium enhancement (LGE) was quantified using the full width, half maximum method. All patients were prospectively followed for the development of septal reduction therapy, arrhythmia or death.We included 273 patients, mean age 51.2 � 15.5, 62.9% male. Of those patients 202 (74.0%) underwent genetic testing with 90 pathogenic, likely pathogenic, or rare variants and 13 variants of uncertain significance identified. Median follow-up was 1138 days. Mean LVMI was 82.7 � 30.6 and 145 patients had late gadolinium enhancement (LGE). Patients with beta-myosin heavy chain (MYH7) mutations had higher LV ejection fraction (68.8 vs 59.1, p<0.001) than those with cardiac myosin binding protein C (MYBPC3) mutations. Patients with MYBPC3 mutations were more likely to have LVEF < 55% (29.7% vs 4.9%, p = 0.005) or receive a defibrillator than those with MYH7 mutations (54.1% vs 26.8%, p = 0.020).We found that patients with MYBPC3 mutations were more likely to have impaired ventricular function and may be more prone to arrhythmic events. Larger studies using CMR phenotyping may be capable of identifying additional characteristics associated with less frequent genetic causes of HCM.

View details for DOI 10.1371/journal.pone.0217612

View details for PubMedID 31199839
Stem Cell-Derived Exosomes Protect Astrocyte Cultures From in vitro Ischemia and Decrease Injury as Post-stroke Intravenous Therapy. Frontiers in cellular neuroscience Sun, X., Jung, J. H., Arvola, O., Santoso, M. R., Giffard, R. G., Yang, P. C., Stary, C. M. 2019; 13: 394
Abstract

In the present study, we assessed efficacy of exosomes harvested from human and mouse stem cell cultures in protection of mouse primary astrocyte and neuronal cell cultures following in vitro ischemia, and against ischemic stroke in vivo. Cell media was collected from primary mouse neural stem cell (NSC) cultures or from human induced pluripotent stem cell-derived cardiomyocyte (iCM) cultures. Exosomes were extracted and purified by polyethylene glycol complexing and centrifugation, and exosome size and concentration were determined with a NanoSiteTM particle analyzer. Exosomes were applied to primary mouse cortical astrocyte or neuronal cultures prior to, and/or during, combined oxygen-glucose deprivation (OGD) injury. Cell death was assessed via lactate dehydrogenase (LHD) and propidium iodide staining 24 h after injury. NSC-derived exosomes afforded marked protection to astrocytes following OGD. A more modest (but significant) level of protection was observed with human iCM-derived exosomes applied to astrocytes, and with NSC-derived exosomes applied to primary neuronal cultures. In subsequent experiments, NSC-derived exosomes were injected intravenously into adult male mice 2 h after transient (1 h) middle cerebral artery occlusion (MCAO). Gross motor function was assessed 1 day after reperfusion and infarct volume was assessed 4 days after reperfusion. Mice treated post-stroke with intravenous NSC-derived exosomes exhibited significantly reduced infarct volumes. Together, these results suggest that exosomes isolated from mouse NSCs provide neuroprotection against experimental stroke possibly via preservation of astrocyte function. Intravenous NSC-derived exosome treatment may therefore provide a novel clinical adjuvant for stroke in the immediate post-injury period.

View details for DOI 10.3389/fncel.2019.00394

View details for PubMedID 31551712

View details for PubMedCentralID PMC6733914
Exosomes From Induced Pluripotent Stem Cell-Derived Cardiomyocytes Salvage the Injured Myocardium by Modulation of Autophagy Santoso, M. R., Tada, Y., Ikeda, G., Jung, J., Vaskova, E., Sierra, R. G., Gati, C., Goldstone, A. B., Bornstaedt, D., Shukla, P., Wu, J. C., Wakatsuki, S., Woo, J., Yang, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2018
View details for Web of Science ID 000528619407290
Microvesicles Rescue Cardiomyocytes From Doxorubicin Injury in a Patient Specific Model of Anthracycline Induced Cardiomyopathy O'Brien, C. G., Shi, L., Santoso, M. R., Jung, J., Vaskova, E., Ikeda, G., Ozen, M. O., Demirci, U., Yang, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2018
View details for Web of Science ID 000528619407146
Mitochondria-Containing Extracellular Vesicles Restore Intracellular ATP Production and Promote Viability in Injured Induced Pluripotent Stem Cell-Derived Cardiomyocytes Ikeda, G., Santoso, M. R., Tada, Y., Vaskova, E., Jung, J., Galen, C. O., Shi, L., Yang, P. LIPPINCOTT WILLIAMS & WILKINS. 2018
View details for Web of Science ID 000528619403434
Exosomal miR-106a-363 Cluster Repairs the Injured Myocardium Jung, J., Tada, Y., Wahlquist, C., Bornstadt, D., Santoso, M., Woo, J., Mercola, M., Yang, P. LIPPINCOTT WILLIAMS & WILKINS. 2018
View details for Web of Science ID 000528619403162
Whole-heart coronary MR angiography using a 3D cones phyllotaxis trajectory. Magnetic resonance in medicine Malave, M. O., Baron, C. A., Addy, N. O., Cheng, J. Y., Yang, P. C., Hu, B. S., Nishimura, D. G. 2018
Abstract

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

View details for PubMedID 30370941
Rationale and Design of the SENECA (StEm cell iNjECtion in cAncer survivors) Trial AMERICAN HEART JOURNAL Bolli, R., Hare, J. M., Henry, T. D., Lenneman, C. G., March, K. L., Miller, K., Pepine, C. J., Perin, E. C., Traverse, J. H., Willerson, J. T., Yang, P. C., Gee, A. P., Lima, J. A., Moye, L., Vojvodic, R. W., Sayre, S. L., Bettencourt, J., Cohen, M., Ebert, R. F., Simari, R. D., Cardiovasc Cell Therapy Res 2018; 201: 54?62
Abstract

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

View details for PubMedID 29910056
Rationale and Design of the CONCERT-HF Trial (Combination of Mesenchymal and c-kit(+) Cardiac Stem Cells As Regenerative Therapy for Heart Failure) CIRCULATION RESEARCH Bolli, R., Hare, J. M., March, K. L., Pepine, C. J., Willerson, J. T., Perin, E. C., Yang, P. C., Henry, T. D., Traverse, J. H., Mitrani, R. D., Khan, A., Hernandez-Schulman, I., Taylor, D. A., DiFede, D. L., Lima, J. C., Chugh, A., Loughran, J., Vojvodic, R. W., Sayre, S. L., Bettencourt, J., Cohen, M., Moye, L., Ebert, R. F., Simari, R. D., Cardiovasc Cell Therapy Res 2018; 122 (12): 1703?15
Abstract

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

View details for PubMedID 29703749
MANGANESE-ENHANCED T1 MAPPING IN MYOCARDIAL INFARCTION: VALIDATION WITH F-18-FDG PET/MR Spath, N. B., Tavares, A., Gray, G. A., Dweck, M. R., Newby, D. E., Yang, P. C., Jansen, M. A., Semple, S. I. BMJ PUBLISHING GROUP. 2018: A9
View details for DOI 10.1136/heartjnl-2018-BCVI.25

View details for Web of Science ID 000432593500026
EXOSOMAL MIR-106A-363 CLUSTER FROM THE HYPOXIC HUMAN IPSC-DERIVED CARDIOMYOCYTES RESTORE THE ISCHEMIC MYOCARDIUM Jung, J., Tada, Y., Bornstaedt, D., Wahlquist, C., Mercola, M., Woo, Y., Yang, P. ELSEVIER SCIENCE INC. 2018: 14
View details for DOI 10.1016/S0735-1097(18)30555-2

View details for Web of Science ID 000429659700015
EXOSOMES PRODUCED BY HUMAN AMNIOTIC MESENCHYMAL STEM CELL-DERIVED INDUCED PLURIPOTENT STEM CELLS MODULATE IMMUNE RESPONSE IN MURINE MYOCARDIAL INJURY MODEL Jang, A., Seo, H., Bornstaedt, D., Jung, J., Vaskova, E., Yang, P. ELSEVIER SCIENCE INC. 2018: 82
View details for DOI 10.1016/S0735-1097(18)30623-5

View details for Web of Science ID 000429659700083
PLEIOTROPIC EFFECTS OF THE EXOSOMES FROM IPSC-DERIVATIVES IN RESTORING INJURED MYOCARDIUM Vaskova, E., Tada, Y., von Bornstaedt, D., Woo, Y., Yang, P. ELSEVIER SCIENCE INC. 2018: 80
View details for DOI 10.1016/S0735-1097(18)30621-1

View details for Web of Science ID 000429659700081
Circulating Biomarkers to Identify Responders in Cardiac Cell therapy (vol 7, 4419, 2017) SCIENTIFIC REPORTS Jokerst, J. V., Cauwenberghs, N., Kuznetsova, T., Haddad, F., Sweeney, T., Hou, J., Rosenberg-Hasson, Y., Zhao, E., Schutt, R., Bolli, R., Traverse, J. H., Pepine, C. J., Henry, T. D., Schulman, I. H., Moye, L., Taylor, D. A., Yang, P. C. 2018; 8: 4257
Abstract

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

View details for PubMedID 29511207
Induced Pluripotent Stem Cell (iPSC)-Derived Exosomes for Precision Medicine in Heart Failure CIRCULATION RESEARCH Yang, P. C. 2018; 122 (5): 661?63
View details for PubMedID 29496797
Effect of Cell Sex on Uptake of Nanoparticles: The Overlooked Factor at the Nanobio Interface ACS NANO Serpooshan, V., Sheibani, S., Pushparaj, P., Wojcik, M., Jang, A. Y., Santoso, M. R., Jang, J. H., Huang, H., Safavi-Sohi, R., Haghjoo, N., Nejadnik, H., Aghaverdi, H., Vali, H., Kinsella, J., Presley, J., Xu, K., Yang, P., Mahmoudi, M. 2018; 12 (3): 2253?66
Abstract

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

View details for PubMedID 29536733
Imaging cellular pharmacokinetics of F-18-FDG and 6-NBDG uptake by inflammatory and stem cells PLOS ONE Zaman, R. T., Tuerkcan, S., Mahmoudi, M., Saito, T., Yang, P. C., Chin, F. T., McConnell, M. V., Xing, L. 2018; 13 (2): e0192662
Abstract

Myocardial infarction (MI) causes significant loss of cardiomyocytes, myocardial tissue damage, and impairment of myocardial function. The inability of cardiomyocytes to proliferate prevents the heart from self-regeneration. The treatment for advanced heart failure following an MI is heart transplantation despite the limited availability of the organs. Thus, stem-cell-based cardiac therapies could ultimately prevent heart failure by repairing injured myocardium that reverses cardiomyocyte loss. However, stem-cell-based therapies lack understanding of the mechanisms behind a successful therapy, including difficulty tracking stem cells to provide information on cell migration, proliferation and differentiation. In this study, we have investigated the interaction between different types of stem and inflammatory cells and cell-targeted imaging molecules, 18F-FDG and 6-NBDG, to identify uptake patterns and pharmacokinetics in vitro.Macrophages (both M1 and M2), human induced pluripotent stem cells (hiPSCs), and human amniotic mesenchymal stem cells (hAMSCs) were incubated with either 18F-FDG or 6-NBDG. Excess radiotracer and fluorescence were removed and a 100 ?m-thin CdWO4 scintillator plate was placed on top of the cells for radioluminescence microscopy imaging of 18F-FDG uptake, while no scintillator was needed for fluorescence imaging of 6-NBDG uptake. Light produced following beta decay was imaged with a highly sensitive inverted microscope (LV200, Olympus) and an Electron Multiplying Charge-Couple Device (EM-CCD) camera. Custom-written software was developed in MATLAB for image processing.The average cellular activity of 18F-FDG in a single cell of hAMSCs (0.670�0.028 fCi/?m2, P = 0.001) was 20% and 36% higher compared to uptake in hiPSCs (0.540�0.026 fCi/?m2, P = 0.003) and macrophages (0.430�0.023 fCi/?m2, P = 0.002), respectively. hAMSCs exhibited the slowest influx (0.210 min-1) but the fastest efflux (0.327 min-1) rate compared to the other tested cell lines for 18F-FDG. This cell line also has the highest phosphorylation but exhibited the lowest rate of de-phosphorylation. The uptake pattern for 6-NBDG was very different in these three cell lines. The average cellular activity of 6-NBDG in a single cell of macrophages (0.570�0.230 fM/?m2, P = 0.004) was 38% and 14% higher compared to hiPSCs (0.350�0.160 fM/?m2, P = 0.001) and hAMSCs (0.490�0.028 fM/?m2, P = 0.006), respectively. The influx (0.276 min-1), efflux (0.612 min-1), phosphorylation (0.269 min-1), and de-phosphorylation (0.049 min-1) rates were also highest for macrophages compared to the other two tested cell lines.hAMSCs were found to be 2-3� more sensitive to 18F-FDG molecule compared to hiPSCs/macrophages. However, macrophages exhibited the most sensitivity towards 6-NBDG. Based on this result, hAMSCs targeted with 18F-FDG could be more suitable for understanding the mechanisms behind successful therapy for treating MI patients by gathering information on cell migration, proliferation and differentiation.

View details for PubMedID 29462173
TIME Trial: Effect of Timing of Stem Cell Delivery Following ST-Elevation Myocardial Infarction on the Recovery of Global and Regional Left Ventricular Function: Final 2-Year Analysis CIRCULATION RESEARCH Traverse, J. H., Henry, T. D., Pepine, C. J., Willerson, J. T., Chugh, A., Yang, P. C., Zhao, D. M., Ellis, S. G., Forder, J. R., Perin, E. C., Penn, M. S., Hatzopoulos, A. K., Chambers, J. C., Baran, K. W., Raveendran, G., Gee, A. P., Taylor, D. A., Moye, L., Ebert, R. F., Simari, R. D. 2018; 122 (3): 479?88
Abstract

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

View details for PubMedID 29208679
Molecular Imaging of Stem Cells and Exosomes for Myocardial Regeneration CURRENT CARDIOVASCULAR IMAGING REPORTS Santoso, M. R., Yang, P. C. 2017; 10 (11)
View details for DOI 10.1007/s12410-017-9433-1

View details for Web of Science ID 000413580500002
Challenging the complementarity of different metrics of left atrial function: insight from a cardiomyopathy-based study EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING Kobayashi, Y., Moneghetti, K. J., Boralkar, K., Amsallem, M., Tuzovic, M., Liang, D., Yang, P. C., Narayan, S., Kuznetsova, T., Wu, J. C., Schnittger, I., Haddad, F. 2017; 18 (10): 1153?62
View details for DOI 10.1093/ehjci/jew121

View details for Web of Science ID 000412163300014
Advanced glycation end-product (AGE)-albumin from activated macrophage is critical in human mesenchymal stem cells survival and post-ischemic reperfusion injury SCIENTIFIC REPORTS Son, M., Kang, W., Oh, S., Bayarsaikhan, D., Ahn, H., Lee, J., Park, H., Lee, S., Choi, J., Lee, H., Yang, P. C., Byun, K., Lee, B. 2017; 7: 11593
Abstract

Post-ischemic reperfusion injury (PIRI) triggers an intense inflammatory response which is essential for repair but is also implicated in pathogenesis of post-ischemic remodeling in several organs in human. Stem cell therapy has recently emerged as a promising method for treatment of PIRI in human. However, satisfactory results have not been reported due to severe loss of injected stem cells in PIRI including critical limb ischemia (CLI). For investigating the advanced glycation end-product-albumin (AGE-albumin) from activated macrophages is critical in both muscle cell and stem cell death, we evaluated the recovery of PIRI-CLI by injection of human bone marrow derived mesenchymal stem cells (hBD-MSCs) with or without soluble receptor for AGEs (sRAGE). Our results showed that activated M1 macrophages synthesize and secrete AGE-albumin, which induced the skeletal muscle cell death and injected hBD-MSCs in PIRI-CLI through RAGE increase. Combined injection of sRAGE and hBD-MSCs resulted in enhanced survival of hBD-MSCs and angiogenesis in PIRI-CLI mice. Taken together, AGE-albumin from activated macrophages is critical for both skeletal muscle cell and hBD-MSCs death in PIRI-CLI. Therefore, the inhibition of AGE-albumin from activated macrophages could be a successful therapeutic strategy for treatment of PIRI including CLI with or without stem cell therapy.

View details for PubMedID 28912521
Paracrine Effects of the Pluripotent Stem Cell-Derived Cardiac Myocytes Salvage the Injured Myocardium CIRCULATION RESEARCH Tachibana, A., Santoso, M. R., Mahmoudi, M., Shukla, P., Wang, L., Bennett, M., Goldstone, A. B., Wang, M., Fukushi, M., Ebert, A. D., Woo, Y., Rulifson, E., Yang, P. C. 2017; 121 (6): E22-+
Abstract

Cardiac myocytes derived from pluripotent stem cells have demonstrated the potential to mitigate damage of the infarcted myocardium and improve left ventricular ejection fraction. However, the mechanism underlying the functional benefit is unclear.To evaluate whether the transplantation of cardiac-lineage differentiated derivatives enhance myocardial viability and restore left ventricular ejection fraction more effectively than undifferentiated pluripotent stem cells after a myocardial injury. Herein, we utilize novel multimodality evaluation of human embryonic stem cells (hESCs), hESC-derived cardiac myocytes (hCMs), human induced pluripotent stem cells (iPSCs), and iPSC-derived cardiac myocytes (iCMs) in a murine myocardial injury model.Permanent ligation of the left anterior descending coronary artery was induced in immunosuppressed mice. Intramyocardial injection was performed with (1) hESCs (n=9), (2) iPSCs (n=8), (3) hCMs (n=9), (4) iCMs (n=14), and (5) PBS control (n=10). Left ventricular ejection fraction and myocardial viability, measured by cardiac magnetic resonance imaging and manganese-enhanced magnetic resonance imaging, respectively, was significantly improved in hCM- and iCM-treated mice compared with pluripotent stem cell- or control-treated mice. Bioluminescence imaging revealed limited cell engraftment in all treated groups, suggesting that the cell secretions may underlie the repair mechanism. To determine the paracrine effects of the transplanted cells, cytokines from supernatants from all groups were assessed in vitro. Gene expression and immunohistochemistry analyses of the murine myocardium demonstrated significant upregulation of the promigratory, proangiogenic, and antiapoptotic targets in groups treated with cardiac lineage cells compared with pluripotent stem cell and control groups.This study demonstrates that the cardiac phenotype of hCMs and iCMs salvages the injured myocardium effectively than undifferentiated stem cells through their differential paracrine effects.

View details for PubMedID 28743804
Myocardial Edema on T2-Weighted MRI New Marker of Ischemia Reperfusion Injury and Adverse Myocardial Remodeling CIRCULATION RESEARCH Tada, Y., Yang, P. C. 2017; 121 (4): 326?28
View details for PubMedID 28775009
T1 Map of Post-Myocardial Infarction for Precise Tissue Characterization. Circulation. Cardiovascular imaging Youssef, A. A., Yang, P. C. 2017; 10 (8)
View details for PubMedID 28790127
T1 Map of Post-Myocardial Infarction for Precise Tissue Characterization CIRCULATION-CARDIOVASCULAR IMAGING Youssef, A. A., Yang, P. C. 2017; 10 (8)
View details for DOI 10.1161/CIRCIMAGING.117.006835

View details for Web of Science ID 000407551300016
Circulating Biomarkers to Identify Responders in Cardiac Cell therapy SCIENTIFIC REPORTS Jokerst, J. V., Cauwenberghs, N., Kuznetsova, T., Haddad, F., Sweeney, T., Hou, J., Rosenberg-Hasson, Y., Zhao, E., Schutt, R., Bolli, R., Traverse, J. H., Pepine, C. J., Henry, T. D., Schulman, I. H., Moye, L., Taylor, D. A., Yang, P. C. 2017; 7: 4419
Abstract

Bone marrow mononuclear cell (BM-MNC) therapy in ST-elevation acute myocardial infarction (STEMI) has no biological inclusion criteria. Here, we analyzed 63 biomarkers and cytokines in baseline plasma samples from 77 STEMI patients treated with BM-MNCs in the TIME and Late-TIME trials as well as 61 STEMI patients treated with placebo. Response to cell therapy was defined by changes in left ventricular ejection fraction, systolic/diastolic volumes, and wall motion indexes. We investigated the clinical value of circulating proteins in outcome prediction using significance testing, partial least squares discriminant analysis, and receiver operating characteristic (ROC) analysis. Responders had higher biomarker levels (76-94% elevated) than non-responders. Several biomarkers had values that differed significantly (P?0.70 including interleukin 15. These biomarkers were not involved in the placebo-treated subjects suggesting that they may have predictive power. We conclude that plasma profiling after STEMI may help identify patients with a greater likelihood of response to cell-based treatment. Prospective trials are needed to assess the predictive value of the circulating biomarkers.

View details for PubMedID 28667255
Peripheral Blood Cytokine Levels After Acute Myocardial Infarction IL-1 beta- and IL-6-Related Impairment of Bone Marrow Function CIRCULATION RESEARCH Shahrivari, M., Wise, E., Resende, M., Shuster, J. J., Zhang, J., Bolli, R., Cooke, J. P., Hare, J. M., Henry, T. D., Khan, A., Taylor, D. A., Traverse, J. H., Yang, P. C., Pepine, C. J., Cogle, C. R., Cardiovascular Cell Therapy Res 2017; 120 (12): 1947?57
Abstract

Intracoronary infusion of bone marrow (BM) mononuclear cells after acute myocardial infarction (AMI) has led to limited improvement in left ventricular function. Although experimental AMI models have implicated cytokine-related impairment of progenitor cell function, this response has not been investigated in humans.To test the hypothesis that peripheral blood (PB) cytokines predict BM endothelial progenitor cell colony outgrowth and cardiac function after AMI.BM and PB samples were collected from 87 participants 14 to 21 days after AMI and BM from healthy donors was used as a reference. Correlations between cytokine concentrations and cell phenotypes, cell functions, and post-AMI cardiac function were determined. PB interleukin-6 (IL-6) negatively correlated with endothelial colony-forming cell colony maximum in the BM of patients with AMI (estimate�SE, -0.13�0.05; P=0.007). BM from healthy individuals showed a dose-dependent decrease in endothelial colony-forming cell colony outgrowth in the presence of exogenous IL-1? or IL-6 (P<0.05). Blocking the IL-1R or IL-6R reversed cytokine impairment. In AMI study participants, the angiogenic cytokine platelet-derived growth factor BB glycoprotein correlated positively with BM-derived colony-forming unit-endothelial colony maximum (estimate�SE, 0.01�0.002; P<0.001), multipotent mesenchymal stromal cell colony maximum (estimate�SE, 0.01�0.002; P=0.002) in BM, and mesenchymal stromal cell colony maximum in PB (estimate�SE, 0.02�0.005; P<0.001).Two weeks after AMI, increased PB platelet-derived growth factor BB glycoprotein was associated with increased BM function, whereas increased IL-6 was associated with BM impairment. Validation studies confirmed inflammatory cytokine impairment of BM that could be reversed by blocking IL-1R or IL-6R. Together, these studies suggest that blocking IL-1 or IL-6 receptors may improve the regenerative capacity of BM cells after AMI.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00684060.

View details for PubMedID 28490433
3D image-based navigators for coronary MR angiography MAGNETIC RESONANCE IN MEDICINE Addy, N. O., Ingle, R. R., Luo, J., Baron, C. A., Yang, P. C., Hu, B. S., Nishimura, D. G. 2017; 77 (5): 1874-1883
Abstract

To develop a method for acquiring whole-heart 3D image-based navigators (iNAVs) with isotropic resolution for tracking and correction of localized motion in coronary magnetic resonance angiography (CMRA).To monitor motion in all regions of the heart during a free-breathing scan, a variable-density cones trajectory was designed to collect a 3D iNAV every heartbeat in 176 ms with 4.4 mm isotropic spatial resolution. The undersampled 3D iNAV data were reconstructed with efficient self-consistent parallel imaging reconstruction (ESPIRiT). 3D translational and nonrigid motion-correction methods using 3D iNAVs were compared to previous translational and nonrigid methods using 2D iNAVs.Five subjects were scanned with a 3D cones CMRA sequence, accompanied by both 2D and 3D iNAVs. The quality of the right and left anterior descending coronary arteries was assessed on 2D and 3D iNAV-based motion-corrected images using a vessel sharpness metric and qualitative reader scoring. This assessment showed that nonrigid motion correction based on 3D iNAVs produced results that were noninferior to correction based on 2D iNAVs.The ability to acquire isotropic-resolution 3D iNAVs every heartbeat during a CMRA scan was demonstrated. Such iNAVs enabled direct measurement of localized motion for nonrigid motion correction in free-breathing whole-heart CMRA. Magn Reson Med, 2016. � 2016 Wiley Periodicals, Inc.

View details for DOI 10.1002/mrm.26269

View details for Web of Science ID 000399666400014
Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease: The CCTRN Patients with Intermittent Claudication Injected with ALDH Bright Cells (PACE) Trial. Circulation Perin, E. C., Murphy, M. P., March, K. L., Bolli, R., Loughran, J., Yang, P. C., Leeper, N. J., Dalman, R. L., Alexander, J. Q., Henry, T. D., Traverse, J. H., Pepine, C. J., Anderson, R. D., Berceli, S., Willerson, J. T., Muthupillai, R., Gahremanpour, A. A., Raveendran, G., Velazquez, O. C., Hare, J. M., Schulman, I. H., Kasi, V. S., Hiatt, W. R., Ambale-Venkatesh, B., Lima, J. A., Taylor, D. A., Resende, M. M., Gee, A. P., Durett, A. G., Bloom, J., Richman, S., G'Sell, P., Williams, S., Khan, F., Ross, E. G., Santoso, M. R., Goldman, J., Leach, D., Handberg, E., Cheong, B. Y., Piece, N. A., Difede, D., Bruhn-Ding, B., Caldwell, E., Bettencourt, J., Lai, D., Piller, L. B., Simpson, L. M., Cohen, M., Sayre, S. L., Vojvodic, R. W., Moy�, L., Ebert, R. F., Simari, R. D., Hirsch, A. T. 2017
Abstract

Atherosclerotic peripheral artery disease affects 8% to 12% of Americans >65 years of age and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE (Patients With Intermittent Claudication Injected With ALDH Bright Cells) is a National Heart, Lung, and Blood Institute-sponsored, randomized, double-blind, placebo-controlled, phase 2 exploratory clinical trial designed to assess the safety and efficacy of autologous bone marrow-derived aldehyde dehydrogenase bright (ALDHbr) cells in patients with peripheral artery disease and to explore associated claudication physiological mechanisms.All participants, randomized 1:1 to receive ALDHbr cells or placebo, underwent bone marrow aspiration and isolation of ALDHbr cells, followed by 10 injections into the thigh and calf of the index leg. The coprimary end points were change from baseline to 6 months in peak walking time (PWT), collateral count, peak hyperemic popliteal flow, and capillary perfusion measured by magnetic resonance imaging, as well as safety.A total of 82 patients with claudication and infrainguinal peripheral artery disease were randomized at 9 sites, of whom 78 had analyzable data (57 male, 21 female patients; mean age, 66�9 years). The mean�SEM differences in the change over 6 months between study groups for PWT (0.9�0.8 minutes; 95% confidence interval [CI] -0.6 to 2.5; P=0.238), collateral count (0.9�0.6 arteries; 95% CI, -0.2 to 2.1; P=0.116), peak hyperemic popliteal flow (0.0�0.4 mL/s; 95% CI, -0.8 to 0.8; P=0.978), and capillary perfusion (-0.2�0.6%; 95% CI, -1.3 to 0.9; P=0.752) were not significant. In addition, there were no significant differences for the secondary end points, including quality-of-life measures. There were no adverse safety outcomes. Correlative relationships between magnetic resonance imaging measures and PWT were not significant. A post hoc exploratory analysis suggested that ALDHbr cell administration might be associated with an increase in the number of collateral arteries (1.5�0.7; 95% CI, 0.1-2.9; P=0.047) in participants with completely occluded femoral arteries.ALDHbr cell administration did not improve PWT or magnetic resonance outcomes, and the changes in PWT were not associated with the anatomic or physiological magnetic resonance imaging end points. Future peripheral artery disease cell therapy investigational trial design may be informed by new anatomic and perfusion insights.URL: http://www.clinicaltrials.gov. Unique identifier: NCT01774097.

View details for DOI 10.1161/CIRCULATIONAHA.116.025707

View details for PubMedID 28209728
Exosomes Generated From iPSC-Derivatives New Direction for Stem Cell Therapy in Human Heart Diseases CIRCULATION RESEARCH Jung, J., Fu, X., Yang, P. C. 2017; 120 (2): 407-417
Abstract

Cardiovascular disease (CVD) is the leading cause of death in modern society. The adult heart innately lacks the capacity to repair and regenerate the damaged myocardium from ischemic injury. Limited understanding of cardiac tissue repair process hampers the development of effective therapeutic solutions to treat CVD such as ischemic cardiomyopathy. In recent years, rapid emergence of induced pluripotent stem cells (iPSC) and iPSC-derived cardiomyocytes presents a valuable opportunity to replenish the functional cells to the heart. The therapeutic effects of iPSC-derived cells have been investigated in many preclinical studies. However, the underlying mechanisms of iPSC-derived cell therapy are still unclear, and limited engraftment of iPSC-derived cardiomyocytes is well known. One facet of their mechanism is the paracrine effect of the transplanted cells. Microvesicles such as exosomes secreted from the iPSC-derived cardiomyocytes exert protective effects by transferring the endogenous molecules to salvage the injured neighboring cells by regulating apoptosis, inflammation, fibrosis, and angiogenesis. In this review, we will focus on the current advances in the exosomes from iPSC derivatives and discuss their therapeutic potential in the treatment of CVD.

View details for DOI 10.1161/CIRCRESAHA.116.309307

View details for PubMedID 28104773
Identification of cardiovascular risk factors associated with bone marrow cell subsets in patients with STEMI: a biorepository evaluation from the CCTRN TIME and LateTIME clinical trials BASIC RESEARCH IN CARDIOLOGY Contreras, A., Orozco, A. F., Resende, M., Schutt, R. C., Traverse, J. H., Henry, T. D., Lai, D., Cooke, J. P., Bolli, R., Cohen, M. L., Moye, L., Pepine, C. J., Yang, P. C., Perin, E. C., Willerson, J. T., Taylor, D. A. 2017; 112 (1)
Abstract

Autologous bone marrow mononuclear cell (BM-MNC) therapy for patients with ST-segment elevation myocardial infarction (STEMI) has produced inconsistent results, possibly due to BM-MNC product heterogeneity. Patient-specific cardiovascular risk factors (CRFs) may contribute to variations in BM-MNC composition. We sought to identify associations between BM-MNC subset frequencies and specific CRFs in STEMI patients. Bone marrow was collected from 191 STEMI patients enrolled in the CCTRN TIME and LateTIME trials. Relationships between BM-MNC subsets and CRFs were determined with multivariate analyses. An assessment of CRFs showed that hyperlipidemia and hypertension were associated with a higher frequency of CD11b(+) cells (P�=�0.045 and P�=�0.016, respectively). In addition, we found that females had lower frequencies of CD11b(+) (P�=�0.018) and CD45(+)CD14(+) (P�=�0.028) cells than males, age was inversely associated with the frequency of CD45(+)CD31(+) cells (P�=�0.001), smoking was associated with a decreased frequency of CD45(+)CD31(+) cells (P�=�0.013), glucose level was positively associated with the frequency of CD45(+)CD3(+) cells, and creatinine level (an indicator of renal function) was inversely associated with the frequency of CD45(+)CD3(+) cells (P�=�0.015). In conclusion, the frequencies of monocytic, lymphocytic, and angiogenic BM-MNCs varied in relation to patients' CRFs. These phenotypic variations may affect cell therapy outcomes and might be an important consideration when selecting patients for and reviewing results from autologous cell therapy trials.

View details for DOI 10.1007/s00395-016-0592-z

View details for PubMedID 27882430
The Protein Corona around Nanoparticles Facilitates Stem Cell Labeling for Clinical MR Imaging. Radiology Nejadnik, H., Taghavi-Garmestani, S. M., Madsen, S. J., Li, K., Zanganeh, S., Yang, P., Mahmoudi, M., Daldrup-Link, H. E. 2017: 170130
Abstract

Purpose To evaluate if the formation of a protein corona around ferumoxytol nanoparticles can facilitate stem cell labeling for in vivo tracking with magnetic resonance (MR) imaging. Materials and Methods Ferumoxytol was incubated in media containing human serum (group 1), fetal bovine serum (group 2), StemPro medium (group 3), protamine (group 4), and protamine plus heparin (group 5). Formation of a protein corona was characterized by means of dynamic light scattering, ? potential, and liquid chromatography-mass spectrometry. Iron uptake was evaluated with 3,3'-diaminobenzidine-Prussian blue staining, lysosomal staining, and inductively coupled plasma spectrometry. To evaluate the effect of a protein corona on stem cell labeling, human mesenchymal stem cells (hMSCs) were labeled with the above formulations, implanted into pig knee specimens, and investigated with T2-weighted fast spin-echo and multiecho spin-echo sequences on a 3.0-T MR imaging unit. Data in different groups were compared by using a Kruskal-Wallis test. Results Compared with bare nanoparticles, all experimental groups showed significantly increased negative ? values (from -37 to less than -10; P = .008). Nanoparticles in groups 1-3 showed an increased size because of the formation of a protein corona. hMSCs labeled with group 1-5 media showed significantly shortened T2 relaxation times compared with unlabeled control cells (P = .0012). hMSCs labeled with group 3 and 5 media had the highest iron uptake after cells labeled with group 1 medium. After implantation into pig knees, hMSCs labeled with group 1 medium showed significantly shorter T2 relaxation times than hMSCs labeled with group 2-5 media (P = .0022). Conclusion The protein corona around ferumoxytol nanoparticles can facilitate stem cell labeling for clinical cell tracking with MR imaging. (�) RSNA, 2017 Online supplemental material is available for this article.

View details for PubMedID 29091749
A PET/MR Imaging Approach for the Integrated Assessment of Chemotherapy-induced Brain, Heart, and Bone Injuries in Pediatric Cancer Survivors: A Pilot Study. Radiology Theruvath, A. J., Ilivitzki, A., Muehe, A., Theruvath, J., Gulaka, P., Kim, C., Luna-Fineman, S., Sakamoto, K. M., Yeom, K. W., Yang, P., Moseley, M., Chan, F., Daldrup-Link, H. E. 2017: 170073
Abstract

Purpose To develop a positron emission tomography (PET)/magnetic resonance (MR) imaging protocol for evaluation of the brain, heart, and joints of pediatric cancer survivors for chemotherapy-induced injuries in one session. Materials and Methods Three teams of experts in neuroimaging, cardiac imaging, and bone imaging were tasked to develop a 20-30-minute PET/MR imaging protocol for detection of chemotherapy-induced tissue injuries of the brain, heart, and bone. In an institutional review board-approved, HIPAA-compliant, prospective study from April to July 2016, 10 pediatric cancer survivors who completed chemotherapy underwent imaging of the brain, heart, and bone with a 3-T PET/MR imager. Cumulative chemotherapy doses and clinical symptoms were correlated with the severity of MR imaging abnormalities by using linear regression analyses. MR imaging measures of brain perfusion and metabolism were compared among eight patients who were treated with methotrexate and eight untreated age-matched control subjects by using Wilcoxon rank-sum tests. Results Combined brain, heart, and bone examinations were completed within 90 minutes. Eight of 10 cancer survivors had abnormal findings on brain, heart, and bone images, including six patients with and two patients without clinical symptoms. Cumulative chemotherapy doses correlated significantly with MR imaging measures of left ventricular ejection fraction and end-systolic volume, but not with the severity of brain or bone abnormalities. Methotrexate-treated cancer survivors had significantly lower cerebral blood flow and metabolic activity in key brain areas compared with control subjects. Conclusion The feasibility of a single examination for assessment of chemotherapy-induced injuries of the brain, heart, and joints was shown. Earlier detection of tissue injuries may enable initiation of timely interventions and help to preserve long-term health of pediatric cancer survivors. (�) RSNA, 2017 Online supplemental material is available for this article.

View details for PubMedID 28777701
Baseline assessment and comparison of arterial anatomy, hyperemic flow, and skeletal muscle perfusion in peripheral artery disease: The Cardiovascular Cell Therapy Research Network "Patients with Intermittent Claudication Injected with ALDH Bright Cells" (CCTRN PACE) study AMERICAN HEART JOURNAL Venkatesh, B. A., Nauffal, V., Noda, C., Fujii, T., Yang, P. C., Bettencourt, J., Ricketts, E. P., Murphy, M., Leeper, N. J., Moye, L., Ebert, R. F., Muthupillai, R., Bluemke, D. A., Perin, E. C., Hirsch, A. T., Lima, J. A. 2017; 183: 24-34
Abstract

Peripheral artery disease (PAD) is important to public health as a major contributor to cardiovascular morbidity and mortality. Recent developments in magnetic resonance imaging (MRI) techniques permit improved assessment of PAD anatomy and physiology, and may serve as surrogate end points after proangiogenic therapies.The PACE study is a randomized, double-blind, placebo-controlled clinical trial designed to assess the physiologic impact and potential clinical efficacy of autologous bone marrow-derived ALDH(br) stem cells. The primary MRI end points of the study are as follows: (1) total collateral count, (2) calf muscle plasma volume (a measure of capillary perfusion) by dynamic contrast-enhanced MRI, and (3) peak hyperemic popliteal flow by phase-contrast MRI (PC-MRI).The interreader and intrareader and test-retest results demonstrated good-to-excellent reproducibility (interclass correlation coefficient range 0.61-0.98) for all magnetic resonance measures. The PAD participants (n=82) had lower capillary perfusion measured by calf muscle plasma volume (3.8% vs 5.6%) and peak hyperemic popliteal flow (4.1 vs 13.5mL/s) as compared with the healthy participants (n=16), with a significant level of collateralization.Reproducibility of the MRI primary end points in PACE was very good to excellent. The PAD participants exhibited decreased calf muscle capillary perfusion as well as arterial flow reserve when compared with healthy participants. The MRI tools used in PACE may advance PAD science by enabling accurate measurement of PAD microvascular anatomy and perfusion before and after stem cell or other PAD therapies.

View details for DOI 10.1016/j.ahj.2016.09.013

View details for PubMedID 27979038
The NHLBI TIME Trial: Role of Microvascular Obstruction in 2-Year Clinical and MRI Follow-up Traverse, J. H., Henry, T. D., Pepine, C. J., Willerson, J. T., Perin, E. C., Taylor, D. A., Chugh, A. R., Yang, P. C., Ellis, S. G., Zhao, D. X., Penn, M. S., Forder, J. R., Ebert, R. F., Moye, L. A., Simari, R. J. LIPPINCOTT WILLIAMS & WILKINS. 2016: E710
View details for Web of Science ID 000390560100022
Administration of ALDH Bright Cells to Patients With Intermittent Claudication: The NHLBI CCTRN PACE Trial Perin, E. C., Murphy, M., March, K., Bolli, R., Leeper, N. J., Yang, P. C., Alexander, J., Henry, T. D., Traverse, J. H., Pepine, C. J., Willerson, J. T., Velasquez, O., Hare, J. M., Kasi, V. S., Lima, J. A., Hiatt, W. R., Taylor, D. A., Gee, A. P., Moye, L., Ebert, R. F., Simari, R. D., Hirsch, A. T. LIPPINCOTT WILLIAMS & WILKINS. 2016: E709
View details for Web of Science ID 000390560100020
Magnetic Resonance Imaging of Cardiac Strain Pattern Following Transplantation of Human Tissue Engineered Heart Muscles CIRCULATION-CARDIOVASCULAR IMAGING Qin, X., Riegler, J., Tiburcy, M., Zhao, X., Chour, T., Ndoye, B., Michael Nguyen, M., Adams, J., Ameen, M., Denney, T. S., Yang, P. C., Patricia Nguyen, P., Zimmermann, W. H., Wu, J. C. 2016; 9 (11)
Abstract

The use of tissue engineering approaches in combination with exogenously produced cardiomyocytes offers the potential to restore contractile function after myocardial injury. However, current techniques assessing changes in global cardiac performance after such treatments are plagued by relatively low detection ability. Since the treatment is locally performed, this detection could be improved by myocardial strain imaging that measures regional contractility.Tissue engineered heart muscles (EHMs) were generated by casting human embryonic stem cell-derived cardiomyocytes with collagen in preformed molds. EHMs were transplanted (n=12) to cover infarct and border zones of recipient rat hearts 1 month after ischemia reperfusion injury. A control group (n=10) received only sham placement of sutures without EHMs. To assess the efficacy of EHMs, magnetic resonance imaging and ultrasound-based strain imaging were performed before and 4 weeks after transplantation. In addition to strain imaging, global cardiac performance was estimated from cardiac magnetic resonance imaging. Although no significant differences were found for global changes in left ventricular ejection fraction (control -9.6�1.3% versus EHM -6.2�1.9%; P=0.17), regional myocardial strain from tagged magnetic resonance imaging was able to detect preserved systolic function in EHM-treated animals compared with control (control 4.4�1.0% versus EHM 1.0�0.6%; P=0.04). However, ultrasound-based strain failed to detect any significant change (control 2.1�3.0% versus EHM 6.3�2.9%; P=0.46).This study highlights the feasibility of using cardiac strain from tagged magnetic resonance imaging to assess functional changes in rat models following localized regenerative therapies, which may not be detected by conventional measures of global systolic performance.

View details for DOI 10.1161/CIRCIMAGING.116.004731

View details for Web of Science ID 000388482500003

View details for PubMedID 27903535

View details for PubMedCentralID PMC5378466
Apelin-13 infusion salvages the peri-infarct region to preserve cardiac function after severe myocardial injury INTERNATIONAL JOURNAL OF CARDIOLOGY Chung, W., Cho, A., Byun, K., Moon, J., Ge, X., Seo, H., Moon, E., Dash, R., Yang, P. C. 2016; 222: 361-367
Abstract

Apelin-13 (A13) regulates cardiac homeostasis. However, the effects and mechanism of A13 infusion after an acute myocardial injury (AMI) have not been elucidated. This study assesses the restorative effects and mechanism of A13 on the peri-infarct region in murine AMI model.51 FVB/N mice (12weeks, 30g) underwent AMI. A week following injury, continuous micro-pump infusion of A13 (0.5?g/g/day) and saline was initiated for 4-week duration. Dual contrast MRI was conducted on weeks 1, 2, 3, and 5, consisting of delayed-enhanced and manganese-enhanced MRI. Four mice in each group were followed for an extended period of 4weeks without further infusion and underwent MRI scans on weeks 7 and 9.A13 infusion demonstrated preserved LVEF compared to saline from weeks 1 to 4 (21.9�3.2% to 23.1�1.7%* vs. 23.5�1.7% to 16.9�2.8%, *p=0.02), which persisted up to 9weeks post-MI (+1.4%* vs. -9.4%, *p=0.03). Mechanistically, dual contrast MRI demonstrated significant decrease in the peri-infarct and scar % volume in A13 group from weeks 1 to 4 (15.1 to 7.4% and 34.3 to 25.1%, p=0.02, respectively). This was corroborated by significant increase in 5-ethynyl-2'-deoxyuridine (EdU(+)) cells by A13 vs. saline groups in the peri-infarct region (16.5�3.1% vs. 8.1�1.6%; p=0.04), suggesting active cell mitosis. Finally, significantly enhanced mobilization of CD34(+) cells in the peripheral blood and up-regulation of APJ, fibrotic, and apoptotic genes in the peri-infarct region were found.A13 preserves cardiac performance by salvaging the peri-infarct region and may contribute to permanent restoration of the severely injured myocardium.

View details for DOI 10.1016/j.ijcard.2016.07.263

View details for PubMedID 27500765
The Promise and Challenge of Induced Pluripotent Stem Cells for Cardiovascular Applications. JACC. Basic to translational science Youssef, A. A., Ross, E. G., Bolli, R., Pepine, C. J., Leeper, N. J., Yang, P. C. 2016; 1 (6): 510-523
Abstract

The recent discovery of human-induced pluripotent stem cells (iPSCs) has revolutionized the field of stem cells. iPSCs have demonstrated that biological development is not an irreversible process and that mature adult somatic cells can be induced to become pluripotent. This breakthrough is projected to advance our current understanding of many disease processes and revolutionize the approach to effective therapeutics. Despite the great promise of iPSCs, many translational challenges still remain. In this article, we review the basic concept of induction of pluripotency as a novel approach to understand cardiac regeneration, cardiovascular disease modeling and drug discovery. We critically reflect on the current results of preclinical and clinical studies using iPSCs for these applications with appropriate emphasis on the challenges facing clinical translation.

View details for DOI 10.1016/j.jacbts.2016.06.010

View details for PubMedID 28580434
Challenging the complementarity of different metrics of left atrial function: insight from a cardiomyopathy-based study. European heart journal cardiovascular Imaging Kobayashi, Y., Moneghetti, K. J., Boralkar, K., Amsallem, M., Tuzovic, M., Liang, D., Yang, P. C., Narayan, S., Kuznetsova, T., Wu, J. C., Schnittger, I., Haddad, F. 2016
Abstract

Left ventricular (LV) strain provides incremental values to LV ejection fraction (LVEF) in predicting outcome. We sought to investigate if similar relationship is observed between left atrial (LA) emptying fraction and LA strain.In this study, we selected 50 healthy subjects, 50 patients with dilated, 50 hypertrophic, and 50 infiltrative (light-chain (AL) amyloidosis) cardiomyopathy (CMP). Echocardiographic measures included LVEF and LA emptying fraction as well as LV and LA longitudinal strain (LVLS and LALS). After regression analysis, comparison of least square means of LA strain among aetiologies was performed. Intraclass correlation coefficient (ICC) and coefficient of variation (COV) were used in the assessment of variability and reproducibility of LV and LA metrics. The mean LVLS and all LA metrics were impaired in patients with all CMP compared with healthy subjects. In contrast to the moderate relationship between LVEF and LVLS (r = -0.51, P < 0.001), there was a strong linear relationship between LA emptying fraction and LA strain (r = 0.87, P < 0.001). In multiple regression analysis, total LA strain was associated with LVLS (? = -0.48, P < 0.001), lateral E/e' (? = -0.24, P < 0.001), age (? = -0.21, P < 0.001), and heart rate (? = -0.14, P = 0.02). The least square mean of LA strain adjusted for the parameters was not different among aetiologies (ANOVA P = 0.82). The ICC (>0.77) and COV (<13) were acceptable.In contrast to LV measures, there is a strong linear relationship between volumetric and longitudinal deformation indices of left atrium irrespective of CMP aetiology. Either LA emptying fraction or LA strain could be used as an important parameter in predictive models.

View details for PubMedID 27638850
Aligned nanofibrillar collagen scaffolds - Guiding lymphangiogenesis for treatment of acquired lymphedema. Biomaterials Hadamitzky, C., Zaitseva, T. S., Bazalova-Carter, M., Paukshto, M. V., Hou, L., Strassberg, Z., Ferguson, J., Matsuura, Y., Dash, R., Yang, P. C., Kretchetov, S., Vogt, P. M., Rockson, S. G., Cooke, J. P., Huang, N. F. 2016; 102: 259-267
Abstract

Secondary lymphedema is a common disorder associated with acquired functional impairment of the lymphatic system. The goal of this study was to evaluate the therapeutic efficacy of aligned nanofibrillar collagen scaffolds (BioBridge) positioned across the area of lymphatic obstruction in guiding lymphatic regeneration. In a porcine model of acquired lymphedema, animals were treated with BioBridge scaffolds, alone or in conjunction with autologous lymph node transfer as a source of endogenous lymphatic growth factor. They were compared with a surgical control group and a second control group in which the implanted BioBridge was supplemented with exogenous vascular endothelial growth factor-C (VEGF-C). Three months after implantation, immunofluorescence staining of lymphatic vessels demonstrated a significant increase in lymphatic collectors within close proximity to the scaffolds. To quantify the functional impact of scaffold implantation, bioimpedance was used as an early indicator of extracellular fluid accumulation. In comparison to the levels prior to implantation, the bioimpedance ratio was significantly improved only in the experimental BioBridge recipients with or without lymph node transfer, suggesting restoration of functional lymphatic drainage. These results further correlated with quantifiable lymphatic collectors, as visualized by contrast-enhanced computed tomography. They demonstrate the therapeutic potential of BioBridge scaffolds in secondary lymphedema.

View details for DOI 10.1016/j.biomaterials.2016.05.040

View details for PubMedID 27348849
Multimodality Molecular Imaging of Cardiac Cell Transplantation: Part I. Reporter Gene Design, Characterization, and Optical in Vivo Imaging of Bone Marrow Stromal Cells after Myocardial Infarction. Radiology Parashurama, N., Ahn, B., Ziv, K., Ito, K., Paulmurugan, R., Willmann, J. K., Chung, J., Ikeno, F., Swanson, J. C., Merk, D. R., Lyons, J. K., Yerushalmi, D., Teramoto, T., Kosuge, H., Dao, C. N., Ray, P., Patel, M., Chang, Y., Mahmoudi, M., Cohen, J. E., Goldstone, A. B., Habte, F., Bhaumik, S., Yaghoubi, S., Robbins, R. C., Dash, R., Yang, P. C., Brinton, T. J., Yock, P. G., McConnell, M. V., Gambhir, S. S. 2016; 280 (3): 815-825
Abstract

Purpose To use multimodality reporter-gene imaging to assess the serial survival of marrow stromal cells (MSC) after therapy for myocardial infarction (MI) and to determine if the requisite preclinical imaging end point was met prior to a follow-up large-animal MSC imaging study. Materials and Methods Animal studies were approved by the Institutional Administrative Panel on Laboratory Animal Care. Mice (n = 19) that had experienced MI were injected with bone marrow-derived MSC that expressed a multimodality triple fusion (TF) reporter gene. The TF reporter gene (fluc2-egfp-sr39ttk) consisted of a human promoter, ubiquitin, driving firefly luciferase 2 (fluc2), enhanced green fluorescent protein (egfp), and the sr39tk positron emission tomography reporter gene. Serial bioluminescence imaging of MSC-TF and ex vivo luciferase assays were performed. Correlations were analyzed with the Pearson product-moment correlation, and serial imaging results were analyzed with a mixed-effects regression model. Results Analysis of the MSC-TF after cardiac cell therapy showed significantly lower signal on days 8 and 14 than on day 2 (P = .011 and P = .001, respectively). MSC-TF with MI demonstrated significantly higher signal than MSC-TF without MI at days 4, 8, and 14 (P = .016). Ex vivo luciferase activity assay confirmed the presence of MSC-TF on days 8 and 14 after MI. Conclusion Multimodality reporter-gene imaging was successfully used to assess serial MSC survival after therapy for MI, and it was determined that the requisite preclinical imaging end point, 14 days of MSC survival, was met prior to a follow-up large-animal MSC study. (�) RSNA, 2016 Online supplemental material is available for this article.

View details for DOI 10.1148/radiol.2016140049

View details for PubMedID 27308957
Multimodality Molecular Imaging of Cardiac Cell Transplantation: Part II. In Vivo Imaging of Bone Marrow Stromal Cells in Swine with PET/CT and MR Imaging. Radiology Parashurama, N., Ahn, B., Ziv, K., Ito, K., Paulmurugan, R., Willmann, J. K., Chung, J., Ikeno, F., Swanson, J. C., Merk, D. R., Lyons, J. K., Yerushalmi, D., Teramoto, T., Kosuge, H., Dao, C. N., Ray, P., Patel, M., Chang, Y., Mahmoudi, M., Cohen, J. E., Goldstone, A. B., Habte, F., Bhaumik, S., Yaghoubi, S., Robbins, R. C., Dash, R., Yang, P. C., Brinton, T. J., Yock, P. G., McConnell, M. V., Gambhir, S. S. 2016; 280 (3): 826-836
Abstract

Purpose To quantitatively determine the limit of detection of marrow stromal cells (MSC) after cardiac cell therapy (CCT) in swine by using clinical positron emission tomography (PET) reporter gene imaging and magnetic resonance (MR) imaging with cell prelabeling. Materials and Methods Animal studies were approved by the institutional administrative panel on laboratory animal care. Seven swine received 23 intracardiac cell injections that contained control MSC and cell mixtures of MSC expressing a multimodality triple fusion (TF) reporter gene (MSC-TF) and bearing superparamagnetic iron oxide nanoparticles (NP) (MSC-TF-NP) or NP alone. Clinical MR imaging and PET reporter gene molecular imaging were performed after intravenous injection of the radiotracer fluorine 18-radiolabeled 9-[4-fluoro-3-(hydroxyl methyl) butyl] guanine ((18)F-FHBG). Linear regression analysis of both MR imaging and PET data and nonlinear regression analysis of PET data were performed, accounting for multiple injections per animal. Results MR imaging showed a positive correlation between MSC-TF-NP cell number and dephasing (dark) signal (R(2) = 0.72, P = .0001) and a lower detection limit of at least approximately 1.5 � 10(7) cells. PET reporter gene imaging demonstrated a significant positive correlation between MSC-TF and target-to-background ratio with the linear model (R(2) = 0.88, P = .0001, root mean square error = 0.523) and the nonlinear model (R(2) = 0.99, P = .0001, root mean square error = 0.273) and a lower detection limit of 2.5 � 10(8) cells. Conclusion The authors quantitatively determined the limit of detection of MSC after CCT in swine by using clinical PET reporter gene imaging and clinical MR imaging with cell prelabeling. (�) RSNA, 2016 Online supplemental material is available for this article.

View details for DOI 10.1148/radiol.2016151150

View details for PubMedID 27332865
Bone marrow cell characteristics associated with patient profile and cardiac performance outcomes in the LateTIME-Cardiovascular Cell Therapy Research Network (CCTRN) trial. American heart journal Bhatnagar, A., Bolli, R., Johnstone, B. H., Traverse, J. H., Henry, T. D., Pepine, C. J., Willerson, J. T., Perin, E. C., Ellis, S. G., Zhao, D. X., Yang, P. C., Cooke, J. P., Schutt, R. C., Trachtenberg, B. H., Orozco, A., Resende, M., Ebert, R. F., Sayre, S. L., Simari, R. D., Moy�, L., Cogle, C. R., Taylor, D. A. 2016; 179: 142-150
Abstract

Although several preclinical studies have shown that bone marrow cell (BMC) transplantation promotes cardiac recovery after myocardial infarction, clinical trials with unfractionated bone marrow have shown variable improvements in cardiac function.To determine whether in a population of post-myocardial infarction patients, functional recovery after BM transplant is associated with specific BMC subpopulation, we examined the association between BMCs with left ventricular (LV) function in the LateTIME-CCTRN trial.In this population, we found that older individuals had higher numbers of BM CD133(+) and CD3(+) cells. Bone marrow from individuals with high body mass index had lower CD45(dim)/CD11b(dim) levels, whereas those with hypertension and higher C-reactive protein levels had higher numbers of CD133(+) cells. Smoking was associated with higher levels of CD133(+)/CD34(+)/VEGFR2(+) cells and lower levels of CD3(+) cells. Adjusted multivariate analysis indicated that CD11b(dim) cells were negatively associated with changes in LV ejection fraction and wall motion in both the infarct and border zones. Change in LV ejection fraction was positively associated with CD133(+), CD34(+), and CD45(+)/CXCR4(dim) cells as well as faster BMC growth rates in endothelial colony forming assays.In the LateTIME population, BM composition varied with patient characteristics and treatment. Irrespective of cell therapy, recovery of LV function was greater in patients with greater BM abundance of CD133(+) and CD34(+) cells and worse in those with higher levels of CD11b(dim) cells. Bone marrow phenotype might predict clinical response before BMC therapy and administration of selected BM constituents could potentially improve outcomes of other future clinical trials.

View details for DOI 10.1016/j.ahj.2016.06.018

View details for PubMedID 27595689
Novel MRI Contrast Agent from Magnetotactic Bacteria Enables In Vivo Tracking of iPSC-derived Cardiomyocytes SCIENTIFIC REPORTS Mahmoudi, M., Tachibana, A., Goldstone, A. B., Woo, Y. J., Chakraborty, P., Lee, K. R., Foote, C. S., Piecewicz, S., Barrozo, J. C., Wakeel, A., Rice, B. W., Bell, C. B., Yang, P. C. 2016; 6
Abstract

Therapeutic delivery of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) represents a novel clinical approach to regenerate the injured myocardium. However, methods for robust and accurate in vivo monitoring of the iCMs are still lacking. Although superparamagnetic iron oxide nanoparticles (SPIOs) are recognized as a promising tool for in vivo tracking of stem cells using magnetic resonance imaging (MRI), their signal persists in the heart even weeks after the disappearance of the injected cells. This limitation highlights the inability of SPIOs to distinguish stem cell viability. In order to overcome this shortcoming, we demonstrate the use of a living contrast agent, magneto-endosymbionts (MEs) derived from magnetotactic bacteria for the labeling of iCMs. The ME-labeled iCMs were injected into the infarcted area of murine heart and probed by MRI and bioluminescence imaging (BLI). Our findings demonstrate that the MEs are robust and effective biological contrast agents to track iCMs in an in vivo murine model. We show that the MEs clear within one week of cell death whereas the SPIOs remain over 2 weeks after cell death. These findings will accelerate the clinical translation of in vivo MRI monitoring of transplanted stem cell at high spatial resolution and sensitivity.

View details for DOI 10.1038/srep26960

View details for Web of Science ID 000377072000001

View details for PubMedCentralID PMC4893600
3D image-based navigators for coronary MR angiography. Magnetic resonance in medicine Addy, N. O., Ingle, R. R., Luo, J., Baron, C. A., Yang, P. C., Hu, B. S., Nishimura, D. G. 2016
Abstract

To develop a method for acquiring whole-heart 3D image-based navigators (iNAVs) with isotropic resolution for tracking and correction of localized motion in coronary magnetic resonance angiography (CMRA).To monitor motion in all regions of the heart during a free-breathing scan, a variable-density cones trajectory was designed to collect a 3D iNAV every heartbeat in 176 ms with 4.4 mm isotropic spatial resolution. The undersampled 3D iNAV data were reconstructed with efficient self-consistent parallel imaging reconstruction (ESPIRiT). 3D translational and nonrigid motion-correction methods using 3D iNAVs were compared to previous translational and nonrigid methods using 2D iNAVs.Five subjects were scanned with a 3D cones CMRA sequence, accompanied by both 2D and 3D iNAVs. The quality of the right and left anterior descending coronary arteries was assessed on 2D and 3D iNAV-based motion-corrected images using a vessel sharpness metric and qualitative reader scoring. This assessment showed that nonrigid motion correction based on 3D iNAVs produced results that were noninferior to correction based on 2D iNAVs.The ability to acquire isotropic-resolution 3D iNAVs every heartbeat during a CMRA scan was demonstrated. Such iNAVs enabled direct measurement of localized motion for nonrigid motion correction in free-breathing whole-heart CMRA. Magn Reson Med, 2016. � 2016 Wiley Periodicals, Inc.

View details for DOI 10.1002/mrm.26269

View details for PubMedID 27174590
TARGETED SUPERPARAMAGNETIC IRON OXIDE NANOPARTICLES FACILITATE ENGRAFTMENT OF THE IPSC-DERIVED CARDIOMYOCYTES INTO THE INJURED MURINE MYOCARDIUM Mahmoudi, M., Tachibana, A., Cohen, J., Goldstone, A., Edwards, B., Rulifson, E., Woo, Y., Yang, P. ELSEVIER SCIENCE INC. 2016: 2126
View details for DOI 10.1016/S0735-1097(16)32127-1

View details for Web of Science ID 000375188702972
EXOSOMES FROM THE HUMAN PLACENTA-DERIVED AMNIOTIC MESENCHYMAL STEM CELLS RESTORE THE INJURED MURINE MYOCARDIUM Santoso, M., Mahmoudi, M., Tachibana, A., Sierra, R. G., Matsui, T., Goldstone, A., Edwards, B., Wakatsuki, S., Woo, J., Yang, P. ELSEVIER SCIENCE INC. 2016: 1393
View details for DOI 10.1016/S0735-1097(16)31394-8

View details for Web of Science ID 000375188702239
Concise Review: Review and Perspective of Cell Dosage and Routes of Administration From Preclinical and Clinical Studies of Stem Cell Therapy for Heart Disease STEM CELLS TRANSLATIONAL MEDICINE Golpanian, S., Schulman, I. H., Ebert, R. F., Heldman, A. W., Difede, D. L., Yang, P. C., Wu, J. C., Bolli, R., Perin, E. C., Moye, L., Simari, R. D., Wolf, A., Hare, J. M. 2016; 5 (2): 186-191
Abstract

: An important stage in the development of any new therapeutic agent is establishment of the optimal dosage and route of administration. This can be particularly challenging when the treatment is a biologic agent that might exert its therapeutic effects via complex or poorly understood mechanisms. Multiple preclinical and clinical studies have shown paradoxical results, with inconsistent findings regarding the relationship between the cell dose and clinical benefit. Such phenomena can, at least in part, be attributed to variations in cell dosing or concentration and the route of administration (ROA). Although clinical trials of cell-based therapy for cardiovascular disease began more than a decade ago, specification of the optimal dosage and ROA has not been established. The present review summarizes what has been learned regarding the optimal cell dosage and ROA from preclinical and clinical studies of stem cell therapy for heart disease and offers a perspective on future directions.Preclinical and clinical studies on cell-based therapy for cardiovascular disease have shown inconsistent results, in part because of variations in study-specific dosages and/or routes of administration (ROA). Future preclinical studies and smaller clinical trials implementing cell-dose and ROA comparisons are warranted before proceeding to pivotal trials.

View details for DOI 10.5966/sctm.2015-0101

View details for PubMedID 26683870
Telmisartan in the diabetic murine model of acute myocardial infarction: dual contrast manganese-enhanced and delayed enhancement MRI evaluation of the peri-infarct region. Cardiovascular diabetology Toma, I., Kim, P. J., Dash, R., McConnell, M. V., Nishimura, D., Harnish, P., Yang, P. C. 2016; 15 (1): 24-?
Abstract

A novel MRI technique, employing dual contrast manganese-enhanced MRI (MEMRI) and delayed enhancement MRI (DEMRI), can evaluate the physiologically unstable peri-infarct region. Dual contrast MEMRI-DEMRI enables comprehensive evaluation of telmisartan to salvage the peri-infarct injury to elucidate the underlying mechanism of restoring the ischemic cardiomyopathy in the diabetic mouse model.Dual contrast MEMRI-DEMRI was performed on weeks 1, 2, and 4 following initiation of telmisartan treatment in 24 left anterior descendent artery ligated diabetic mice. The MRI images were analyzed for core infarct, peri-infarct, left ventricular end-diastolic, end-systolic volumes, and the left ventricular ejection fraction (LVEF). Transmission electron microscopy (TEM) and real-time PCR were used for ex vivo analysis of the myocardium. Telmisartan vs. control groups demonstrated significantly improved LVEF at weeks 1, 2, and 4, respectively (33 � 7 %*** vs. 19 � 5 %, 29 � 3 %*** vs. 22 � 4 %, and 31 � 2 %*** vs 18 � 6 %, ***p < 0.001). The control group demonstrated significant differences in the scar volume measured by MEMRI and DEMRI, demonstrating peri-infarct injury. Telmisartan group significantly salvaged the peri-infarct injury. The myocardial effects were validated by TEM, which confirmed the presence of the injured but viable cardiomyocyte morphology in the peri-infarct region and by flow cytometry of venous blood, which demonstrated significantly increased circulating endothelial progenitor cells (EPCs).The improved cardiac function in ischemic cardiomyopathy of diabetic mice by telmisartan is attributed to the attenuation of the peri-infarct injury by the angiogenic effects of EPCs to salvage the injured cardiomyocytes. Dual-contrast MEMRI-DEMRI technique tracked the therapeutic effects of telmisartan on the injured myocardium longitudinally.

View details for DOI 10.1186/s12933-016-0348-y

View details for PubMedID 26846539
Infection-resistant MRI-visible scaffolds for tissue engineering applications. BioImpacts : BI Mahmoudi, M., Zhao, M., Matsuura, Y., Laurent, S., Yang, P. C., Bernstein, D., Ruiz-Lozano, P., Serpooshan, V. 2016; 6 (2): 111-115
Abstract

Tissue engineering utilizes porous scaffolds as template to guide the new tissue growth. Clinical application of scaffolding biomaterials is hindered by implant-associated infection and impaired in vivo visibility of construct in biomedical imaging modalities. We recently demonstrated the use of a bioengineered type I collagen patch to repair damaged myocardium. By incorporating superparamagnetic iron oxide nanoparticles into this patch, here, we developed an MRI-visible scaffold. Moreover, the embedded nanoparticles impeded the growth of Salmonella bacteria in the patch. Conferring anti-infection and MRI-visible activities to the engineered scaffolds can improve their clinical outcomes and reduce the morbidity/mortality of biomaterial-based regenerative therapies.

View details for DOI 10.15171/bi.2016.16

View details for PubMedID 27525229
in Patients with Non-ST Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: Results from a Multicentre, Placebo-Controlled, Randomized Trial. Evidence-based complementary and alternative medicine Wang, L., Zhao, X., Mao, S., Liu, S., Guo, X., Guo, L., Du, T., Yang, H., Zhao, F., Wu, K., Cong, H., Wu, Y., Yang, P. C., Chen, K., Zhang, M. 2016; 2016: 7960503-?
Abstract

This study seeks to investigate potential cardioprotection of Danlou Tablets in patients undergoing PCI with non-ST elevation acute coronary syndrome (NSTE-ACS). 219 patients with NSTE-ACS were randomised to Danlou Tablet pretreatment (n = 109) or placebo (n = 110). No patients received statins prior to PCI and all patients were given atorvastatin (10?mg/day) after procedure. The main endpoint was the composite incidence of major adverse cardiac events (MACEs) within 30 days after PCI. The proportion of patients with elevated levels of cTn I>5 � 99% of upper reference limit was significantly lower in the Danlou Tablet group at 8?h (22.0% versus 34.5%, p = 0.04) and 24?h (23.9% versus 38.2%, p = 0.02) after PCI. The 30-day MACEs occurred in 22.0% of the Danlou Tablet group and 33.6% in the placebo group (p = 0.06). The incidence of MACE at 90-day follow-up was significantly decreased in the Danlou Tablet group compared to the placebo group (23.9% versus 37.3%, p = 0.03). The difference between the groups at 90 days was the incidence of nonfatal myocardial infarction (22% versus 34.5%, p = 0.04). These findings might support that treatment with Danlou Tablet could reduce the incidence of periprocedural myocardial infarction in patients with ACS undergoing PCI.

View details for PubMedID 27895696
Efficacy of Danlou Tablet in Patients with Non-ST Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: Results from a Multicentre, Placebo-Controlled, Randomized Trial EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE Wang, L., Zhao, X., Mao, S., Liu, S., Guo, X., Guo, L., Du, T., Yang, H., Zhao, F., Wu, K., Cong, H., Wu, Y., Yang, P. C., Chen, K., Zhang, M. 2016
View details for DOI 10.1155/2016/7960503

View details for Web of Science ID 000388384800001
Novel MRI Contrast Agent from Magnetotactic Bacteria Enables In Vivo Tracking of iPSC-derived Cardiomyocytes. Scientific reports Mahmoudi, M., Tachibana, A., Goldstone, A. B., Woo, Y. J., Chakraborty, P., Lee, K. R., Foote, C. S., Piecewicz, S., Barrozo, J. C., Wakeel, A., Rice, B. W., Bell Iii, C. B., Yang, P. C. 2016; 6: 26960-?
Abstract

Therapeutic delivery of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) represents a novel clinical approach to regenerate the injured myocardium. However, methods for robust and accurate in vivo monitoring of the iCMs are still lacking. Although superparamagnetic iron oxide nanoparticles (SPIOs) are recognized as a promising tool for in vivo tracking of stem cells using magnetic resonance imaging (MRI), their signal persists in the heart even weeks after the disappearance of the injected cells. This limitation highlights the inability of SPIOs to distinguish stem cell viability. In order to overcome this shortcoming, we demonstrate the use of a living contrast agent, magneto-endosymbionts (MEs) derived from magnetotactic bacteria for the labeling of iCMs. The ME-labeled iCMs were injected into the infarcted area of murine heart and probed by MRI and bioluminescence imaging (BLI). Our findings demonstrate that the MEs are robust and effective biological contrast agents to track iCMs in an in vivo murine model. We show that the MEs clear within one week of cell death whereas the SPIOs remain over 2 weeks after cell death. These findings will accelerate the clinical translation of in vivo MRI monitoring of transplanted stem cell at high spatial resolution and sensitivity.

View details for DOI 10.1038/srep26960

View details for PubMedID 27264636

View details for PubMedCentralID PMC4893600
Magnetic Nanoparticles for Targeting and Imaging of Stem Cells in Myocardial Infarction STEM CELLS INTERNATIONAL Santoso, M. R., Yang, P. C. 2016
Abstract

Stem cell therapy has broad applications in regenerative medicine and increasingly within cardiovascular disease. Stem cells have emerged as a leading therapeutic option for many diseases and have broad applications in regenerative medicine. Injuries to the heart are often permanent due to the limited proliferation and self-healing capability of cardiomyocytes; as such, stem cell therapy has become increasingly important in the treatment of cardiovascular diseases. Despite extensive efforts to optimize cardiac stem cell therapy, challenges remain in the delivery and monitoring of cells injected into the myocardium. Other fields have successively used nanoscience and nanotechnology for a multitude of biomedical applications, including drug delivery, targeted imaging, hyperthermia, and tissue repair. In particular, superparamagnetic iron oxide nanoparticles (SPIONs) have been widely employed for molecular and cellular imaging. In this mini-review, we focus on the application of superparamagnetic iron oxide nanoparticles in targeting and monitoring of stem cells for the treatment of myocardial infarctions.

View details for DOI 10.1155/2016/4198790

View details for PubMedID 27127519
Rationale and Design of Sodium Tanshinone IIA Sulfonate in Left Ventricular Remodeling Secondary to Acute Myocardial Infarction (STAMP-REMODELING) Trial: A Randomized Controlled Study CARDIOVASCULAR DRUGS AND THERAPY Mao, S., Li, X., Wang, L., Yang, P. C., Zhang, M. 2015; 29 (6): 535-542
Abstract

Left ventricular (LV) remodeling in ischemic cardiomyopathy is the leading cause of heart failure and is an established prognostic factor for adverse cardiovascular events. Experimental studies suggest that sodium tanshinone IIA sulfonate attenuates cardiac remodeling in animal models of acute myocardial infarction (AMI). However, the effects of this drug in the clinical setting remain unclear. Therefore, the STAMP-REMODELING trial is set up to investigate whether treatment with sodium tanshinone IIA sulfonate would prevent the maladaptive progression to adverse LV remodeling in patients following ST-segment elevation myocardial infarction (STEMI).Approximately 80 patients with STEMI successfully treated with primary percutaneous coronary intervention (PCI) will be enrolled and randomized to receive sodium tanshinone IIA sulfonate (80�mg q.d. for 7�days) in addition to standard therapy or the same volume of hydration per day. The primary endpoint is the variation in LV end-diastolic volume index (LVEDVi) assessed with cardiac magnetic resonance imaging (CMR) at baseline and 6�months.This study will provide important clinical evidence on the efficacy of sodium tanshinone IIA sulfonate treatment in patients with STEMI when used in combination with current therapies that may significantly reduce adverse LV remodeling and potentially improve clinical outcomes.Clinical Trials.gov: NCT02524964.

View details for DOI 10.1007/s10557-015-6625-2

View details for Web of Science ID 000368454100005
Epicardial FSTL1 reconstitution regenerates the adult mammalian heart. Nature Wei, K., Serpooshan, V., Hurtado, C., Diez-Cu�ado, M., Zhao, M., Maruyama, S., Zhu, W., Fajardo, G., Noseda, M., Nakamura, K., Tian, X., Liu, Q., Wang, A., Matsuura, Y., Bushway, P., Cai, W., Savchenko, A., Mahmoudi, M., Schneider, M. D., van den Hoff, M. J., Butte, M. J., Yang, P. C., Walsh, K., Zhou, B., Bernstein, D., Mercola, M., Ruiz-Lozano, P. 2015; 525 (7570): 479-485
Abstract

The elucidation of factors that activate the regeneration of the adult mammalian heart is of major scientific and therapeutic importance. Here we found that epicardial cells contain a potent cardiogenic activity identified as follistatin-like 1 (Fstl1). Epicardial Fstl1 declines following myocardial infarction and is replaced by myocardial expression. Myocardial Fstl1 does not promote regeneration, either basally or upon transgenic overexpression. Application of the human Fstl1 protein (FSTL1) via an epicardial patch stimulates cell cycle entry and division of pre-existing cardiomyocytes, improving cardiac function and survival in mouse and swine models of myocardial infarction. The data suggest that the loss of epicardial FSTL1 is a maladaptive response to injury, and that its restoration would be an effective way to reverse myocardial death and remodelling following myocardial infarction in humans.

View details for DOI 10.1038/nature15372

View details for PubMedID 26375005
Epicardial FSTL1 reconstitution regenerates the adult mammalian heart NATURE Wei, K., Serpooshan, V., Hurtado, C., Diez-Cunado, M., Zhao, M., Maruyama, S., Zhu, W., Fajardo, G., Noseda, M., Nakamura, K., Tian, X., Liu, Q., Wang, A., Matsuura, Y., Bushway, P., Cai, W., Savchenko, A., Mahmoudi, M., Schneider, M. D., van den Hoff, M. J., Butte, M. J., Yang, P. C., Walsh, K., Zhou, B., Bernstein, D., Mercola, M., Ruiz-Lozano, P. 2015; 525 (7570): 479-?
Abstract

The elucidation of factors that activate the regeneration of the adult mammalian heart is of major scientific and therapeutic importance. Here we found that epicardial cells contain a potent cardiogenic activity identified as follistatin-like 1 (Fstl1). Epicardial Fstl1 declines following myocardial infarction and is replaced by myocardial expression. Myocardial Fstl1 does not promote regeneration, either basally or upon transgenic overexpression. Application of the human Fstl1 protein (FSTL1) via an epicardial patch stimulates cell cycle entry and division of pre-existing cardiomyocytes, improving cardiac function and survival in mouse and swine models of myocardial infarction. The data suggest that the loss of epicardial FSTL1 is a maladaptive response to injury, and that its restoration would be an effective way to reverse myocardial death and remodelling following myocardial infarction in humans.

View details for DOI 10.1038/nature15372

View details for Web of Science ID 000361599900042

View details for PubMedID 26375005
Protein Corona Influences Cell-Biomaterial Interactions in Nanostructured Tissue Engineering Scaffolds ADVANCED FUNCTIONAL MATERIALS Serpooshan, V., Mahmoudi, M., Zhao, M., Wei, K., Sivanesan, S., Motamedchaboki, K., Malkovskiy, A. V., Goldstone, A. B., Cohen, J. E., Yang, P. C., Rajadas, J., Bernstein, D., Woo, Y. J., Ruiz-Lozano, P. 2015; 25 (28): 4379-4389
Abstract

Biomaterials are extensively used to restore damaged tissues, in the forms of implants (e.g. tissue engineered scaffolds) or biomedical devices (e.g. pacemakers). Once in contact with the physiological environment, nanostructured biomaterials undergo modifications as a result of endogenous proteins binding to their surface. The formation of this macromolecular coating complex, known as 'protein corona', onto the surface of nanoparticles and its effect on cell-particle interactions are currently under intense investigation. In striking contrast, protein corona constructs within nanostructured porous tissue engineering scaffolds remain poorly characterized. As organismal systems are highly dynamic, it is conceivable that the formation of distinct protein corona on implanted scaffolds might itself modulate cell-extracellular matrix interactions. Here, we report that corona complexes formed onto the fibrils of engineered collagen scaffolds display specific, distinct, and reproducible compositions that are a signature of the tissue microenvironment as well as being indicative of the subject's health condition. Protein corona formed on collagen matrices modulated cellular secretome in a context-specific manner ex-vivo, demonstrating their role in regulating scaffold-cellular interactions. Together, these findings underscore the importance of custom-designing personalized nanostructured biomaterials, according to the biological milieu and disease state. We propose the use of protein corona as in situ biosensor of temporal and local biomarkers.

View details for DOI 10.1002/adfm.201500875

View details for Web of Science ID 000358504000001

View details for PubMedCentralID PMC4978190
Low-Dose FK506 (Tacrolimus) in End-Stage Pulmonary Arterial Hypertension. American journal of respiratory and critical care medicine Spiekerkoetter, E., Sung, Y. K., Sudheendra, D., Bill, M., Aldred, M. A., van de Veerdonk, M. C., Vonk Noordegraaf, A., Long-Boyle, J., Dash, R., Yang, P. C., Lawrie, A., Swift, A. J., Rabinovitch, M., Zamanian, R. T. 2015; 192 (2): 254-257
View details for DOI 10.1164/rccm.201411-2061LE

View details for PubMedID 26177174
Immunologic Network and Response to Intramyocardial CD34(+) Stem Cell Therapy in Patients With Dilated Cardiomyopathy JOURNAL OF CARDIAC FAILURE Haddad, F., Sever, M., Poglajen, G., Lezaic, L., Yang, P., Maecker, H., Davis, M., Kuznetsova, T., Wu, J. C., Vrtovec, B. 2015; 21 (7): 572-582
Abstract

Although stem cell therapy (SCT) is emerging as a potential treatment for patients with dilated cardiomyopathy (DCM), clinical response remains variable. Our objective was to determine whether baseline differences in circulating immunologic and nonimmunologic biomarkers may help to identify patients more likely to respond to intramyocardial injection of CD34(+)-based SCT.We enrolled from January 3, 2011 to March 5, 2012 37 patients with longstanding DCM (left ventricular ejection fraction [LVEF] <40%, New York Heart Association functional class III) who underwent peripheral CD34(+) stem cell mobilization with granulocyte colony-stimulating factor (G-CSF) and collection by means of apheresis. CD34(+) cells were labeled with (99m)Tc-hexamethylpropyleneamine oxime to allow assessment of stem cell retention at 18 hours. Response to SCT was predefined as an increase in LVEF of ?5% at 3 months. The majority (84%) of patients were male with an overall mean LVEF of 27 � 7% and a median N-terminal pro-B-type natriuretic peptide (NT-proBNP) level of 2,774 pg/mL. Nineteen patients (51%) were responders to SCT. There was no significant difference between responders and nonresponders regarding to age, sex, baseline LVEF, NT-proBNP levels, or 6-minute walking distance. With the use of a partial least squares (PLS) predictive model, we identified 9 baseline factors that were associated with both stem cell response and stem cell retention (mechanistic validation). Among the baseline factors positively associated with both clinical response and stem cell retention were G-CSF, SDF-1, LIF, MCP-1, and MCP-3. Among baseline factors negatively associated with both clinical response and retention were IL-12p70, FASL, ICAM-1, and GGT. A decrease in G-CSF at 3-month follow-up was also observed in responders compared with nonresponders (P�= .02).If further validated, baseline immunologic and nonimmunologic biomarkers may help to identify patients with DCM who are more likely to respond to CD34(+)-based SCT.

View details for DOI 10.1016/j.cardfail.2015.03.011

View details for Web of Science ID 000358105900007

View details for PubMedID 25863169
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
Direct evaluation of myocardial viability and stem cell engraftment demonstrates salvage of the injured myocardium. Circulation research Kim, P. J., Mahmoudi, M., Ge, X., Matsuura, Y., Toma, I., Metzler, S., Kooreman, N. G., Ramunas, J., Holbrook, C., McConnell, M. V., Blau, H., Harnish, P., Rulifson, E., Yang, P. C. 2015; 116 (7): e40-50
Abstract

Rationale: The mechanism of functional restoration by stem cell therapy remains poorly under-stood. Novel manganese-enhanced MRI and bioluminescence reporter gene imaging (BLI) were applied to follow myocardial viability and cell engraftment, respectively. Human-placenta-derived amniotic mesenchymal stem cells (AMCs) demonstrate unique immunoregulatory and pre-cardiac properties. In this study, the restorative effects of three AMC-derived sub-populations were exam-ined in a murine myocardial injury model: 1) unselected AMCs (uAMCs), 2) ckit+AMCs (c+AMCs), and 3) AMC-derived iPSCs (MiPSCs). Objective: Determine the differential restorative effects of the AMC-derived sub-populations in the murine myocardial injury model using multi-modality imaging. Methods and Results: SCID mice underwent left anterior descending artery ligation and were divid-ed into 4 treatment arms: 1) normal saline control (n=14), 2) uAMCs (n=10), 3) c+AMCs (n=13), and 4) MiPSCs (n=11). Cardiac MRI assessed myocardial viability and left ventricular (LV) func-tion while BLI assessed stem cell engraftment over a four-week period. Immunohistological label-ing and RT-PCR of the explanted myocardium were performed. The uAMC and c+AMC treated mice demonstrated transient LV functional improvement. However, the MiPSCs exhibited a signifi-cantly greater increase in LV function compared to all the other groups during the entire four-week period. LV functional improvement correlated with increased myocardial viability and sustained stem cell engraftment. The MiPSCs treated animals lacked any evidence of de novo cardiac differ-entiation. Conclusions: The functional restoration seen in MiPSCs was characterized by increased myocardial viability and sustained engraftment without de novo cardiac differentiation, indicating salvage of the injured myocardium.

View details for DOI 10.1161/CIRCRESAHA.116.304668

View details for PubMedID 25654979
Direct Evaluation of Myocardial Viability and Stem Cell Engraftment Demonstrates Salvage of the Injured Myocardium CIRCULATION RESEARCH Kim, P. J., Mahmoudi, M., Ge, X., Matsuura, Y., Toma, I., Metzler, S., Kooreman, N. G., Ramunas, J., Holbrook, C., McConnell, M. V., Blau, H., Harnish, P., Rulifson, E., Yang, P. C. 2015; 116 (7): E40-?
Abstract

Rationale: The mechanism of functional restoration by stem cell therapy remains poorly under-stood. Novel manganese-enhanced MRI and bioluminescence reporter gene imaging (BLI) were applied to follow myocardial viability and cell engraftment, respectively. Human-placenta-derived amniotic mesenchymal stem cells (AMCs) demonstrate unique immunoregulatory and pre-cardiac properties. In this study, the restorative effects of three AMC-derived sub-populations were exam-ined in a murine myocardial injury model: 1) unselected AMCs (uAMCs), 2) ckit+AMCs (c+AMCs), and 3) AMC-derived iPSCs (MiPSCs). Objective: Determine the differential restorative effects of the AMC-derived sub-populations in the murine myocardial injury model using multi-modality imaging. Methods and Results: SCID mice underwent left anterior descending artery ligation and were divid-ed into 4 treatment arms: 1) normal saline control (n=14), 2) uAMCs (n=10), 3) c+AMCs (n=13), and 4) MiPSCs (n=11). Cardiac MRI assessed myocardial viability and left ventricular (LV) func-tion while BLI assessed stem cell engraftment over a four-week period. Immunohistological label-ing and RT-PCR of the explanted myocardium were performed. The uAMC and c+AMC treated mice demonstrated transient LV functional improvement. However, the MiPSCs exhibited a signifi-cantly greater increase in LV function compared to all the other groups during the entire four-week period. LV functional improvement correlated with increased myocardial viability and sustained stem cell engraftment. The MiPSCs treated animals lacked any evidence of de novo cardiac differ-entiation. Conclusions: The functional restoration seen in MiPSCs was characterized by increased myocardial viability and sustained engraftment without de novo cardiac differentiation, indicating salvage of the injured myocardium.

View details for DOI 10.1161/CIRCRESAHA.116.304668

View details for Web of Science ID 000351834500001

View details for PubMedID 25654979
INCREASED MYOCARDIAL VIABILITY AND FUNCTION MEASURED BY MANGANESE-ENHANCED MRI (MEMRI) DEMONSTRATE MYOCARDIAL REGENERATION BY HUMAN PLURIPOTENT STEM CELL DERIVED CARDIOMYOCYTES (HPCMS) Tachibana, A., Rulifson, E., Matsuura, Y., Thakker, R., Wang, M., Wu, J., Dash, R., Yang, P. ELSEVIER SCIENCE INC. 2015: A2147
View details for DOI 10.1016/S0735-1097(15)62147-7

View details for Web of Science ID 000375328802469
USE OF HUMAN INDUCED PLURIPOTENT STEM CELL-DERIVED CARDIOMYOCYTES (ICMS) FOR HEART REGENERATION Mahmoudi, M., Rulifson, E., Tachibana, A., Wang, M., Wu, J., Yang, P. ELSEVIER SCIENCE INC. 2015: A848
View details for DOI 10.1016/S0735-1097(15)60848-8

View details for Web of Science ID 000375328801168
Small-molecule inhibitors targeting INK4 protein p18(INK4C) enhance ex vivo expansion of haematopoietic stem cells NATURE COMMUNICATIONS Gao, Y., Yang, P., Shen, H., Yu, H., Song, X., Zhang, L., Zhang, P., Cheng, H., Xie, Z., Hao, S., Dong, F., Ma, S., Ji, Q., Bartlow, P., Ding, Y., Wang, L., Liu, H., Li, Y., Cheng, H., Miao, W., Yuan, W., Yuan, Y., Cheng, T., Xie, X. 2015; 6
Abstract

Among cyclin-dependent kinase inhibitors that control the G1 phase in cell cycle, only p18 and p27 can negatively regulate haematopoietic stem cell (HSC) self-renewal. In this manuscript, we demonstrate that p18 protein is a more potent inhibitor of HSC self-renewal than p27 in mouse models and its deficiency promoted HSC expansion in long-term culture. Single-cell analysis indicated that deleting p18 gene favoured self-renewing division of HSC in vitro. Based on the structure of p18 protein and in-silico screening, we further identified novel smallmolecule inhibitors that can specifically block the activity of p18 protein. Our selected lead compounds were able to expand functional HSCs in a short-term culture. Thus, these putative small-molecule inhibitors for p18 protein are valuable for further dissecting the signalling pathways of stem cell self-renewal and may help develop more effective chemical agents for therapeutic expansion of HSC.

View details for DOI 10.1038/ncomms7328

View details for Web of Science ID 000350291300004

View details for PubMedID 25692908
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
Protein Corona Influences Cell-Biomaterial Interactions in Nanostructured Tissue Engineering Scaffolds. Advanced functional materials Serpooshan, V., Mahmoudi, M., Zhao, M., Wei, K., Sivanesan, S., Motamedchaboki, K., Malkovskiy, A. V., Gladstone, A. B., Cohen, J. E., Yang, P. C., Rajadas, J., Bernstein, D., Woo, Y. J., Ruiz-Lozano, P. 2015; 25 (28): 4379?89
Abstract

Biomaterials are extensively used to restore damaged tissues, in the forms of implants (e.g. tissue engineered scaffolds) or biomedical devices (e.g. pacemakers). Once in contact with the physiological environment, nanostructured biomaterials undergo modifications as a result of endogenous proteins binding to their surface. The formation of this macromolecular coating complex, known as 'protein corona', onto the surface of nanoparticles and its effect on cell-particle interactions are currently under intense investigation. In striking contrast, protein corona constructs within nanostructured porous tissue engineering scaffolds remain poorly characterized. As organismal systems are highly dynamic, it is conceivable that the formation of distinct protein corona on implanted scaffolds might itself modulate cell-extracellular matrix interactions. Here, we report that corona complexes formed onto the fibrils of engineered collagen scaffolds display specific, distinct, and reproducible compositions that are a signature of the tissue microenvironment as well as being indicative of the subject's health condition. Protein corona formed on collagen matrices modulated cellular secretome in a context-specific manner ex-vivo, demonstrating their role in regulating scaffold-cellular interactions. Together, these findings underscore the importance of custom-designing personalized nanostructured biomaterials, according to the biological milieu and disease state. We propose the use of protein corona as in situ biosensor of temporal and local biomarkers.

View details for PubMedID 27516731
Rationale and Design of Sodium Tanshinone IIA Sulfonate in Left Ventricular Remodeling Secondary to Acute Myocardial Infarction (STAMP-REMODELING) Trial: A Randomized Controlled Study. Cardiovascular drugs and therapy Mao, S., Li, X., Wang, L., Yang, P. C., Zhang, M. 2015; 29 (6): 535?42
Abstract

Left ventricular (LV) remodeling in ischemic cardiomyopathy is the leading cause of heart failure and is an established prognostic factor for adverse cardiovascular events. Experimental studies suggest that sodium tanshinone IIA sulfonate attenuates cardiac remodeling in animal models of acute myocardial infarction (AMI). However, the effects of this drug in the clinical setting remain unclear. Therefore, the STAMP-REMODELING trial is set up to investigate whether treatment with sodium tanshinone IIA sulfonate would prevent the maladaptive progression to adverse LV remodeling in patients following ST-segment elevation myocardial infarction (STEMI).Approximately 80 patients with STEMI successfully treated with primary percutaneous coronary intervention (PCI) will be enrolled and randomized to receive sodium tanshinone IIA sulfonate (80�mg q.d. for 7�days) in addition to standard therapy or the same volume of hydration per day. The primary endpoint is the variation in LV end-diastolic volume index (LVEDVi) assessed with cardiac magnetic resonance imaging (CMR) at baseline and 6�months.This study will provide important clinical evidence on the efficacy of sodium tanshinone IIA sulfonate treatment in patients with STEMI when used in combination with current therapies that may significantly reduce adverse LV remodeling and potentially improve clinical outcomes.Clinical Trials.gov: NCT02524964.

View details for PubMedID 26482376
Nonrigid autofocus motion correction for coronary MR angiography with a 3D cones trajectory. Magnetic resonance in medicine Ingle, R. R., Wu, H. H., Addy, N. O., Cheng, J. Y., Yang, P. C., Hu, B. S., Nishimura, D. G. 2014; 72 (2): 347-361
Abstract

To implement a nonrigid autofocus motion correction technique to improve respiratory motion correction of free-breathing whole-heart coronary magnetic resonance angiography acquisitions using an image-navigated 3D cones sequence.2D image navigators acquired every heartbeat are used to measure superior-inferior, anterior-posterior, and right-left translation of the heart during a free-breathing coronary magnetic resonance angiography scan using a 3D cones readout trajectory. Various tidal respiratory motion patterns are modeled by independently scaling the three measured displacement trajectories. These scaled motion trajectories are used for 3D translational compensation of the acquired data, and a bank of motion-compensated images is reconstructed. From this bank, a gradient entropy focusing metric is used to generate a nonrigid motion-corrected image on a pixel-by-pixel basis. The performance of the autofocus motion correction technique is compared with rigid-body translational correction and no correction in phantom, volunteer, and patient studies.Nonrigid autofocus motion correction yields improved image quality compared to rigid-body-corrected images and uncorrected images. Quantitative vessel sharpness measurements indicate superiority of the proposed technique in 14 out of 15 coronary segments from three patient and two volunteer studies.The proposed technique corrects nonrigid motion artifacts in free-breathing 3D cones acquisitions, improving image quality compared to rigid-body motion correction. Magn Reson Med, 2013. � 2013 Wiley Periodicals, Inc.

View details for DOI 10.1002/mrm.24924

View details for PubMedID 24006292
Mesenchymal stem cell therapy for cardiac repair. Current treatment options in cardiovascular medicine Thakker, R., Yang, P. 2014; 16 (7): 323
Abstract

OPINION STATEMENT: Owing to the prevalence of heart disease and the lack of effective long-term solutions for managing cardiac injury, research has turned to cell therapy as a potential mechanism for myocardial repair. Mesenchymal stem cells (MSC) in particular have become popular because their differentiative ability and their angiogenic and immunomodulatory properties make them attractive candidates for transplantation. However, there is still debate regarding the optimal strategy for the delivery of these cells. Recent clinical studies have isolated MSCs from a variety of tissue origins and have also tested the benefits of pretreatment with cardiogenic growth factors. Meanwhile, a newer school of thought instead supports the utilization of cardiomyocytes generated from MSC-derived induced pluripotent stem cells. This review will examine the promise of MSC therapy, discuss the results of past work, and propose steps that must be taken in the future.

View details for PubMedID 24898315
Graphite Oxide Nanoparticles with Diameter Greater than 20 nm Are Biocompatible with Mouse Embryonic Stem Cells and Can Be Used in a Tissue Engineering System. Small Wang, I. E., Robinson, J. T., Do, G., Hong, G., Gould, D. R., Dai, H., Yang, P. C. 2014; 10 (8): 1479-1484
Abstract

Graphite oxide sheets demonstrate size-dependent uptake and toxicity towards embryonic stem cells. Graphite oxide sheets larger than 20 nm are biocompatible and can be safely used with mouse embryonic stem cells, while graphite oxide sheets smaller than 20 nm in diameter reduced cell proliferation and increased cell toxicity.

View details for DOI 10.1002/smll.201303133

View details for PubMedID 24376186
Relationship between Echocardiographic and Magnetic Resonance Derived Measures of Right Ventricular Size and Function in Patients with Pulmonary Hypertension. Journal of the American Society of Echocardiography Shiran, H., Zamanian, R. T., McConnell, M. V., Liang, D. H., Dash, R., Heidary, S., Sudini, N. L., Wu, J. C., Haddad, F., Yang, P. C. 2014; 27 (4): 405-412
Abstract

Transthoracic echocardiographic (TTE) imaging is the mainstay of clinical practice for evaluating right ventricular (RV) size and function, but its accuracy in patients with pulmonary hypertension has not been well validated.Magnetic resonance imaging (MRI) and TTE images were retrospectively reviewed in 40 consecutive patients with pulmonary hypertension. RV and left ventricular volumes and ejection fractions were calculated using MRI. TTE areas and indices of RV ejection fraction (RVEF) were compared.The average age was 42 � 12 years, with a majority of women (85%). There was a wide range of mean pulmonary arterial pressures (27-81 mm Hg) and RV end-diastolic volumes (111-576 mL), RVEFs (8%-67 %), and left ventricular ejection fractions (26%-72%) by MRI. There was a strong association between TTE and MRI-derived parameters: RV end-diastolic area (by TTE imaging) and RV end-diastolic volume (by MRI), R(2)�= 0.78 (P < .001); RV fractional area change by TTE imaging and RVEF by MRI, R(2)�= 0.76 (P < .001); and tricuspid annular plane systolic excursion by TTE imaging and RVEF by MRI, R(2)�= 0.64 (P < .001). By receiver operating characteristic curve analysis, an RV fractional area change < 25% provided excellent discrimination of moderate systolic dysfunction (RVEF < 35%), with an area under the curve of 0.97 (P < .001). An RV end-diastolic area index of 18�cm(2)/m(2) provided excellent discrimination for moderate RV enlargement (area under the curve, 0.89; P < .001).Echocardiographic estimates of RV volume (by RV end-diastolic area) and function (by RV fractional area change and tricuspid annular plane systolic excursion) offer good approximations of RV size and function in patients with pulmonary hypertension and allow the accurate discrimination of normal from abnormal.

View details for DOI 10.1016/j.echo.2013.12.011

View details for PubMedID 24444659
Multi-cellular interactions sustain long-term contractility of human pluripotent stem cell-derived cardiomyocytes. Am J Transl Res PW, B., SA, M., KH, N., OJ, A., CS, S., MA, B., Y, M., PJ, K., JC, W., NF, H., PC, Y. 2014; 6 (6)
Multi-cellular interactions sustain long-term contractility of human pluripotent stem cell-derived cardiomyocytes. American journal of translational research Burridge, P. W., Metzler, S. A., Nakayama, K. H., Abilez, O. J., Simmons, C. S., Bruce, M. A., Matsuura, Y., Kim, P., Wu, J. C., Butte, M., Huang, N. F., Yang, P. C. 2014; 6 (6): 724-735
Abstract

Therapeutic delivery of cardiomyocytes derived from human pluripotent stem cells (hPSC-CMs) represents a novel clinical approach to regenerate the injured myocardium. However, poor survival and contractility of these cells are a significant bottleneck to their clinical use. To better understand the role of cell-cell communication in enhancing the phenotype and contractile properties of hPSC-CMs, we developed a three-dimensional (3D) hydrogel composed of hPSC-CMs, human pluripotent stem cell-derived endothelial cells (hPSC-ECs), and/or human amniotic mesenchymal stem cells (hAMSCs). The objective of this study was to examine the role of multi-cellular interactions among hPSC-ECs and hAMSCs on the survival and long-term contractile phenotype of hPSC-CMs in a 3D hydrogel. Quantification of spontaneous contractility of hPSC-CMs in tri-culture demonstrated a 6-fold increase in the area of contractile motion after 6 weeks with characteristic rhythmic contraction frequency, when compared to hPSC-CMs alone (P < 0.05). This finding was supported by a statistically significant increase in cardiac troponin T protein expression in the tri-culture hydrogel construct at 6 weeks, when compared to hPSC-CMs alone (P < 0.001). The sustained hPSC-CM survival and contractility in tri-culture was associated with a significant upregulation in the gene expression of L-type Ca(2+) ion channel, Cav1.2, and the inward-rectifier potassium channel, Kir2.1 (P < 0.05), suggesting a role of ion channels in mediating these processes. These findings demonstrate that multi-cellular interactions modulate hPSC-CM phenotype, function, and survival, and they will have important implications in engineering cardiac tissues for treatment of cardiovascular diseases.

View details for PubMedID 25628783
Effects of Frequent Hemodialysis on Ventricular Volumes and Left Ventricular Remodeling CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY Chan, C. T., Greene, T., Chertow, G. M., Kliger, A. S., Stokes, J. B., Beck, G. J., Daugirdas, J. T., Kotanko, P., Larive, B., Levin, N. W., Mehta, R. L., Rocco, M., Sanz, J., Yang, P. C., Rajagopalan, S. 2013; 8 (12): 2106-2116
Abstract

Higher left ventricular volume is associated with death in patients with ESRD. This work investigated the effects of frequent hemodialysis on ventricular volumes and left ventricular remodeling.The Frequent Hemodialysis Network daily trial randomized 245 patients to 12 months of six times per week versus three times per week in-center hemodialysis; the Frequent Hemodialysis Network nocturnal trial randomized 87 patients to 12 months of six times per week nocturnal hemodialysis versus three times per week predominantly home-based hemodialysis. Left and right ventricular end systolic and diastolic volumes, left ventricular mass, and ejection fraction at baseline and end of the study were ascertained by cardiac magnetic resonance imaging. The ratio of left ventricular mass/left ventricular end diastolic volume was used as a surrogate marker of left ventricular remodeling. In each trial, the effect of frequent dialysis on left or right ventricular end diastolic volume was tested between predefined subgroups.In the daily trial, frequent hemodialysis resulted in significant reductions in left ventricular end diastolic volume (-11.0% [95% confidence interval, -16.1% to -5.5%]), left ventricular end systolic volume (-14.8% [-22.7% to -6.2%]), right ventricular end diastolic volume (-11.6% [-19.0% to -3.6%]), and a trend for right ventricular end systolic volume (-11.3% [-21.4% to 0.1%]) compared with conventional therapy. The magnitude of reduction in left and right ventricular end diastolic volumes with frequent hemodialysis was accentuated among patients with residual urine output<100 ml/d (P value [interaction]=0.02). In the nocturnal trial, there were no significant changes in left or right ventricular volumes. The frequent dialysis interventions had no substantial effect on the ratio of left ventricular mass/left ventricular end diastolic volume in either trial.Frequent in-center hemodialysis reduces left and right ventricular end systolic and diastolic ventricular volumes as well as left ventricular mass, but it does not affect left ventricular remodeling.

View details for DOI 10.2215/CJN.03280313

View details for Web of Science ID 000327951100012

View details for PubMedID 23970131

View details for PubMedCentralID PMC3848394
Manganese-Enhanced MRI Enables Longitudinal in vivo Tracking of Transplanted Stem Cell Viability in the Murine Myocardium Dash, R., Subramanian, A., Matsuura, Y., Sohn, I., Yeh, T., McConnell, M. V., Wu, J. C., Yang, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2013
View details for Web of Science ID 000332162906073
Expert Consensus for Multi-Modality Imaging Evaluation of Cardiovascular Complications of Radiotherapy in Adults: A Report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Lancellotti, P., Nkomo, V. T., Badano, L. P., Bergler, J., Bogaert, J., Davin, L., Cosyns, B., Coucke, P., Dulgheru, R., Edvardsen, T., Gaemperli, O., Galderisi, M., Griffin, B., Heidenreich, P. A., Nieman, K., Plana, J. C., Port, S. C., Scherrer-Crosbie, M., Schwartz, R. G., Sebag, I. A., Voigt, J., Wann, S., Yang, P. C. 2013; 26 (9): 1013-1032
Abstract

Cardiac toxicity is one of the most concerning side effects of anti-cancer therapy. The gain in life expectancy obtained with anti-cancer therapy can be compromised by increased morbidity and mortality associated with its cardiac complications. While radiosensitivity of the heart was initially recognized only in the early 1970s, the heart is regarded in the current era as one of the most critical dose-limiting organs in radiotherapy. Several clinical studies have identified adverse clinical consequences of radiation-induced heart disease (RIHD) on the outcome of long-term cancer survivors. A comprehensive review of potential cardiac complications related to radiotherapy is warranted. An evidence-based review of several imaging approaches used to detect, evaluate, and monitor RIHD is discussed. Recommendations for the early identification and monitoring of cardiovascular complications of radiotherapy by cardiac imaging are also proposed.

View details for DOI 10.1016/j.echo.2013.07.005

View details for Web of Science ID 000324028300003

View details for PubMedID 23998694
Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. European heart journal cardiovascular Imaging Lancellotti, P., Nkomo, V. T., Badano, L. P., Bergler-Klein, J., Bogaert, J., Davin, L., Cosyns, B., Coucke, P., Dulgheru, R., Edvardsen, T., Gaemperli, O., Galderisi, M., Griffin, B., Heidenreich, P. A., Nieman, K., Plana, J. C., Port, S. C., Scherrer-Crosbie, M., Schwartz, R. G., Sebag, I. A., Voigt, J., Wann, S., Yang, P. C. 2013; 14 (8): 721-740
Abstract

Cardiac toxicity is one of the most concerning side effects of anti-cancer therapy. The gain in life expectancy obtained with anti-cancer therapy can be compromised by increased morbidity and mortality associated with its cardiac complications. While radiosensitivity of the heart was initially recognized only in the early 1970s, the heart is regarded in the current era as one of the most critical dose-limiting organs in radiotherapy. Several clinical studies have identified adverse clinical consequences of radiation-induced heart disease (RIHD) on the outcome of long-term cancer survivors. A comprehensive review of potential cardiac complications related to radiotherapy is warranted. An evidence-based review of several imaging approaches used to detect, evaluate, and monitor RIHD is discussed. Recommendations for the early identification and monitoring of cardiovascular complications of radiotherapy by cardiac imaging are also proposed.

View details for DOI 10.1093/ehjci/jet123

View details for PubMedID 23847385
Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING Lancellotti, P., Nkomo, V. T., Badano, L. P., Bergler, J., Bogaert, J., Davin, L., Cosyns, B., Coucke, P., Dulgheru, R., Edvardsen, T., Gaemperli, O., Galderisi, M., Griffin, B., Heidenreich, P. A., Nieman, K., Plana, J. C., Port, S. C., Scherrer-Crosbie, M., Schwartz, R. G., Sebag, I. A., Voigt, J., Wann, S., Yang, P. C. 2013; 14 (8): 721-740
Abstract

Cardiac toxicity is one of the most concerning side effects of anti-cancer therapy. The gain in life expectancy obtained with anti-cancer therapy can be compromised by increased morbidity and mortality associated with its cardiac complications. While radiosensitivity of the heart was initially recognized only in the early 1970s, the heart is regarded in the current era as one of the most critical dose-limiting organs in radiotherapy. Several clinical studies have identified adverse clinical consequences of radiation-induced heart disease (RIHD) on the outcome of long-term cancer survivors. A comprehensive review of potential cardiac complications related to radiotherapy is warranted. An evidence-based review of several imaging approaches used to detect, evaluate, and monitor RIHD is discussed. Recommendations for the early identification and monitoring of cardiovascular complications of radiotherapy by cardiac imaging are also proposed.

View details for DOI 10.1093/ehjci/jet123

View details for Web of Science ID 000321833100001

View details for PubMedID 23847385
Phase II Clinical Research Design in Cardiology Learning the Right Lessons Too Well: Observations and Recommendations From the Cardiovascular Cell Therapy Research Network (CCTRN) CIRCULATION Hare, J. M., Bolli, R., Cooke, J. P., Gordon, D. J., Henry, T. D., Perin, E. C., March, K. L., Murphy, M. P., Pepine, C. J., Simari, R. D., Skarlatos, S. I., Traverse, J. H., Willerson, J. T., Szady, A. D., Taylor, D. A., Vojvodic, R. W., Yang, P. C., Moye, L. A. 2013; 127 (15): 1630-1635
View details for DOI 10.1161/CIRCULATIONAHA.112.000779

View details for Web of Science ID 000317572700019

View details for PubMedID 23588961
A case of recurrent pericardial constriction presenting with severe pulmonary hypertension. Pulmonary circulation Brunner, N. W., Ramachandran, K., Kudelko, K. T., Sung, Y. K., Spiekerkoetter, E., Yang, P. C., Zamanian, R. T., Perez, V. d. 2013; 3 (2): 436-439
Abstract

Chronic constrictive pericarditis (CP) is a relatively rare condition in which the pericardium becomes fibrotic and noncompliant, eventually resulting in heart failure due to impaired ventricular filling. The only curative treatment is pericardiectomy. Classically, CP does not usually cause severe pulmonary hypertension. When attempting to differentiate CP from restrictive cardiomyopathy, the presence of severely elevated pulmonary arterial pressure is used as a diagnostic criterion ruling against CP. We present a case of proven recurrent pericardial constriction following pericardiectomy presenting with severe pulmonary hypertension.

View details for DOI 10.4103/2045-8932.114780

View details for PubMedID 24015347
SUSTAINED RESTORATION OF LV FUNCTION IN A PORCINE ISCHEMIA-REPERFUSION INJURY MODEL USING HUMAN PLACENTAL MESENCHYMAL STEM CELLS AND MANGANESE-ENHANCED MRI 62nd Annual Scientific Session of the American-College-of-Cardiology Dash, R., Kim, P., Matsuura, Y., Ikeno, F., Lyons, J., Ge, X., Metzler, S., Huang, N., Nguyen, P., Wu, J. C., Cooke, J., Luiz-Rozano, P., Robbins, R., McConnell, M., Yeung, A., Harnish, P., Yang, P. ELSEVIER SCIENCE INC. 2013: E1142?E1142
View details for Web of Science ID 000316555201247
DUAL CONTRAST CARDIAC MRI FOR EVALUATION OF TELMISARTAN AND AMLODIPINE COMBINATION THERAPY IN THE DIABETIC MURINE MYOCARDIAL INJURY MODEL 62nd Annual Scientific Session of the American-College-of-Cardiology Kim, P., Gong, Y., Harnish, P., Toma, I., Dash, R., Robbins, R., Yang, P. ELSEVIER SCIENCE INC. 2013: E941?E941
View details for Web of Science ID 000316555201046
REGENERATIVE CHANGES OF THE PERI-INFARCT INJURY ALLOWS SUSTAINED RESTORATION OF THE INJURED MYOCARDIUM 62nd Annual Scientific Session of the American-College-of-Cardiology Kim, P., Gong, Y., Ge, X., Harnish, P., Dash, R., Robbins, R., Yang, P. ELSEVIER SCIENCE INC. 2013: E1074?E1074
View details for Web of Science ID 000316555201179
VALIDATION OF INFARCT CHARACTERIZATION IN A PORCINE ISCHEMIA REPERFUSION INJURY MODEL 62nd Annual Scientific Session of the American-College-of-Cardiology Nakagawa, K., Ikeno, F., Matsuura, Y., Lyons, J., Nguyen, P., Wu, J., Yeung, A. C., Yang, P. C., Dash, R. ELSEVIER SCIENCE INC. 2013: E617?E617
View details for Web of Science ID 000316555200617
The Human Amniotic Mesenchymal Stem Cell-derived Ipscs Survive and Restore the Injured Hearts in an Immunocompetent Mouse Model of Myocardial Injury Ge, X., Chung, W., Kim, P. J., Gong, Y., Chang, P., Robbins, R., Dash, R., Yang, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2012
View details for Web of Science ID 000208885008107
Relationship Between Echocardiographic and MRI-derived Measures of RV Size and Function in Patients with Pulmonary Arterial Hypertension Shiran, H., Liang, D. H., Dash, R., Heidary, S., Sudini, N. L., Seo, H., Wu, J. C., Haddad, F., Yang, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2012
View details for Web of Science ID 000208885008050
Performing Dual Contrast Cardiac MRI to Determine the Underlying Mechanism of Cell-based Therapy Kim, P. J., Ge, X., Toma, I., Gong, Y., Chang, P., Harnish, P., Yang, P. LIPPINCOTT WILLIAMS & WILKINS. 2012
View details for Web of Science ID 000208885008020
Human amniotic mesenchymal stem cell-derived induced pluripotent stem cells may generate a universal source of cardiac cells. Stem cells and development Ge, X., Wang, I. E., Toma, I., Sebastiano, V., Liu, J., Butte, M. J., Reijo Pera, R. A., Yang, P. C. 2012; 21 (15): 2798-2808
Abstract

Human amniotic mesenchymal stem cells (hAMSCs) demonstrated partially pluripotent characteristics with a strong expression of Oct4 and Nanog genes and immunomodulatory properties characterized by the absence of HLA-DR and the presence of HLA-G and CD59. The hAMSCs were reprogrammed into induced pluripotent stem cells (iPSCs) that generate a promising source of universal cardiac cells. The hAMSC-derived iPSCs (MiPSCs) successfully underwent robust cardiac differentiation to generate cardiomyocytes. This study investigated 3 key properties of the hAMSCs and MiPSCs: (1) the reprogramming efficiency of the partially pluripotent hAMSCs to generate MiPSCs; (2) immunomodulatory properties of the hAMSCs and MiPSCs; and (3) the cardiac differentiation potential of the MiPSCs. The characteristic iPSC colony formation was observed within 10 days after the transduction of the hAMSCs with a single integration polycistronic vector containing 4 Yamanaka factors. Immunohistology and reverse transcription-polymerase chain reaction assays revealed that the MiPSCs expressed stem cell surface markers and pluripotency-specific genes. Furthermore, the hAMSCs and MiPSCs demonstrated immunomodulatory properties enabling successful engraftment in the SVJ mice. Finally, the cardiac differentiation of MiPSCs exhibited robust spontaneous contractility, characteristic calcium transience across the membrane, a high expression of cardiac genes and mature cardiac phenotypes, and a contractile force comparable to cardiomyocytes. Our results demonstrated that the hAMSCs are reprogrammed with a high efficiency into MiPSCs, which possess pluripotent, immunomodulatory, and precardiac properties. The MiPSC-derived cardiac cells express a c-kit cell surface marker, which may be employed to purify the cardiac cell population and enable allogeneic cardiac stem cell therapy.

View details for DOI 10.1089/scd.2011.0435

View details for PubMedID 22530853
Human Amniotic Mesenchymal Stem Cell-Derived Induced Pluripotent Stem Cells May Generate a Universal Source of Cardiac Cells STEM CELLS AND DEVELOPMENT Ge, X., Wang, I. E., Toma, I., Sebastiano, V., Liu, J., Butte, M. J., Pera, R. A., Yang, P. C. 2012; 21 (15): 2798-2808
Abstract

Human amniotic mesenchymal stem cells (hAMSCs) demonstrated partially pluripotent characteristics with a strong expression of Oct4 and Nanog genes and immunomodulatory properties characterized by the absence of HLA-DR and the presence of HLA-G and CD59. The hAMSCs were reprogrammed into induced pluripotent stem cells (iPSCs) that generate a promising source of universal cardiac cells. The hAMSC-derived iPSCs (MiPSCs) successfully underwent robust cardiac differentiation to generate cardiomyocytes. This study investigated 3 key properties of the hAMSCs and MiPSCs: (1) the reprogramming efficiency of the partially pluripotent hAMSCs to generate MiPSCs; (2) immunomodulatory properties of the hAMSCs and MiPSCs; and (3) the cardiac differentiation potential of the MiPSCs. The characteristic iPSC colony formation was observed within 10 days after the transduction of the hAMSCs with a single integration polycistronic vector containing 4 Yamanaka factors. Immunohistology and reverse transcription-polymerase chain reaction assays revealed that the MiPSCs expressed stem cell surface markers and pluripotency-specific genes. Furthermore, the hAMSCs and MiPSCs demonstrated immunomodulatory properties enabling successful engraftment in the SVJ mice. Finally, the cardiac differentiation of MiPSCs exhibited robust spontaneous contractility, characteristic calcium transience across the membrane, a high expression of cardiac genes and mature cardiac phenotypes, and a contractile force comparable to cardiomyocytes. Our results demonstrated that the hAMSCs are reprogrammed with a high efficiency into MiPSCs, which possess pluripotent, immunomodulatory, and precardiac properties. The MiPSC-derived cardiac cells express a c-kit cell surface marker, which may be employed to purify the cardiac cell population and enable allogeneic cardiac stem cell therapy.

View details for DOI 10.1089/scd.2011.0435

View details for Web of Science ID 000309593600006

View details for PubMedCentralID PMC3464077
Bone marrow cell therapy in clinical trials: a review of the literature. Reviews on recent clinical trials Kim, P. J., Yang, P. C. 2012; 7 (3): 204-213
Abstract

Spurred by remarkable findings in animal studies, there has been strong interest in evaluating the potential of adult stem cells to improve left ventricular function in the past decade. Driven by the need to treat the increasing number of patients with coronary artery disease, numerous studies have attempted to define a role for bone marrow cell therapy in clinical use. However, the conflicting results of these studies can be confusing. This article will review the landmark trials evaluating bone marrow cell therapy in the past decade and describe the current state of adult stem cell therapy and its future direction herein.

View details for PubMedID 22540909
Theranostic effect of serial manganese-enhanced magnetic resonance imaging of human embryonic stem cell derived teratoma MAGNETIC RESONANCE IN MEDICINE Chung, J., Dash, R., Kee, K., Barral, J. K., Kosuge, H., Robbins, R. C., Nishimura, D., Reijo-Pera, R. A., Yang, P. C. 2012; 68 (2): 595-599
Abstract

Although human embryonic stem cell (hESC) hold therapeutic potential, teratoma formation has deterred clinical translation. Manganese (Mn(2+)) enters metabolically active cells through voltage-gated calcium channels and subsequently, induces T(1) shortening. We hypothesized that serial manganese-enhanced MRI would have theranostic effect to assess hESC survival, teratoma formation, and hESC-derived teratoma reduction through intracellular accumulation of Mn(2+). Firefly luciferase transduced hESCs (hESC-Lucs) were transplanted into severe combined immunodeficient mouse hindlimbs to form teratoma. The chemotherapy group was injected with MnCl(2) intraperitoneally three times a week. The control group was given MnCl(2) only prior to manganese-enhanced MRI. Longitudinal evaluation by manganese-enhanced MRI and bioluminescence imaging was performed. The chemotherapy group showed significant reduction in the teratoma volume and luciferase activity at weeks 6 and 8. Histology revealed increased proportion of dead cells and caspase 3 positive cells in the chemotherapy group. Systemic administration of MnCl(2) enabled simultaneous monitoring and elimination of hESC-derived teratoma cells by higher intracellular accumulation of Mn(2+).

View details for DOI 10.1002/mrm.23262

View details for PubMedID 22190225
Is Reliable In Vivo Detection of Stem Cell Viability Possible in a Large Animal Model of Myocardial Injury? CIRCULATION Yang, P. C. 2012; 126 (4): 388-390
View details for DOI 10.1161/CIRCULATIONAHA.112.119305

View details for Web of Science ID 000306977200008

View details for PubMedID 22767660
Apelin Enhances Directed Cardiac Differentiation of Mouse and Human Embryonic Stem Cells PLOS ONE Wang, I. E., Wang, X., Ge, X., Anderson, J., Ho, M., Ashley, E., Liu, J., Butte, M. J., Yazawa, M., Dolmetsch, R. E., Quertermous, T., Yang, P. C. 2012; 7 (6)
Abstract

Apelin is a peptide ligand for an orphan G-protein coupled receptor (APJ receptor) and serves as a critical gradient for migration of mesodermal cells fated to contribute to the myocardial lineage. The present study was designed to establish a robust cardiac differentiation protocol, specifically, to evaluate the effect of apelin on directed differentiation of mouse and human embryonic stem cells (mESCs and hESCs) into cardiac lineage. Different concentrations of apelin (50, 100, 500 nM) were evaluated to determine its differentiation potential. The optimized dose of apelin was then combined with mesodermal differentiation factors, including BMP-4, activin-A, and bFGF, in a developmentally specific temporal sequence to examine the synergistic effects on cardiac differentiation. Cellular, molecular, and physiologic characteristics of the apelin-induced contractile embryoid bodies (EBs) were analyzed. It was found that 100 nM apelin resulted in highest percentage of contractile EB for mESCs while 500 nM had the highest effects on hESCs. Functionally, the contractile frequency of mESCs-derived EBs (mEBs) responded appropriately to increasing concentration of isoprenaline and diltiazem. Positive phenotype of cardiac specific markers was confirmed in the apelin-treated groups. The protocol, consisting of apelin and mesodermal differentiation factors, induced contractility in significantly higher percentage of hESC-derived EBs (hEBs), up-regulated cardiac-specific genes and cell surface markers, and increased the contractile force. In conclusion, we have demonstrated that the treatment of apelin enhanced cardiac differentiation of mouse and human ESCs and exhibited synergistic effects with mesodermal differentiation factors.

View details for DOI 10.1371/journal.pone.0038328

View details for PubMedID 22675543
Determinants of Left Ventricular Mass in Patients on Hemodialysis Frequent Hemodialysis Network (FHN) Trials CIRCULATION-CARDIOVASCULAR IMAGING Chan, C. T., Greene, T., Chertow, G. M., Kliger, A. S., Stokes, J. B., Beck, G. J., Daugirdas, J. T., Kotanko, P., Larive, B., Levin, N. W., Mehta, R. L., Rocco, M., Sanz, J., Schiller, B. M., Yang, P. C., Rajagopalan, S. 2012; 5 (2): 251-261
Abstract

An increase in left ventricular mass (LVM) is associated with mortality and cardiovascular morbidity in patients with end-stage renal disease.The Frequent Hemodialysis Network (FHN) Daily Trial randomized 245 patients to 12 months of 6 times per week daily in-center hemodialysis or conventional hemodialysis; the FHN Nocturnal Trial randomized 87 patients to 12 months of 6 times per week nocturnal hemodialysis or conventional hemodialysis. The main cardiac secondary outcome was change in LVM. In each trial, we examined whether several predefined baseline demographic or clinical factors as well as change in volume removal, blood pressure, or solute clearance influenced the effect of frequent hemodialysis on LVM. In the Daily Trial, frequent hemodialysis resulted in a significant reduction in LVM (13.1 g; 95% CI, 5.0-21.3 g; P=0.002), LVM index (6.9 g/m(2); 95% CI, 2.4-11.3 g/m(2); P=0.003), and percent change in geometric mean of LVM (7.0%; 95% CI, 1.0%-12.6; P=0.02). Similar trends were noted in the Nocturnal Trial but did not reach statistical significance. In the Daily Trial, a more pronounced effect of frequent hemodialysis on LVM was evident among patients with left ventricular hypertrophy at baseline. Changes in LVM were associated with changes in blood pressure (conventional hemodialysis: R=0.28, P=0.01, daily hemodialysis: R=0.54, P<0.001) and were not significantly associated with changes in other parameters.Frequent in-center hemodialysis reduces LVM. The benefit of frequent hemodialysis on LVM may be mediated by salutary effects on blood pressure. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00264758.

View details for DOI 10.1161/CIRCIMAGING.111.969923

View details for Web of Science ID 000302122700014

View details for PubMedID 22360996

View details for PubMedCentralID PMC3328963
Synthesis of an in vivo MRI-detectable apoptosis probe. Journal of visualized experiments : JoVE Lam, J., Simpson, P. C., Yang, P. C., Dash, R. 2012
Abstract

Cellular apoptosis is a prominent feature of many diseases, and this programmed cell death typically occurs before clinical manifestations of disease are evident. A means to detect apoptosis in its earliest, reversible stages would afford a pre-clinical 'window' during which preventive or therapeutic measures could be taken to protect the heart from permanent damage. We present herein a simple and robust method to conjugate human Annexin V (ANX), which avidly binds to cells in the earliest, reversible stages of apoptosis, to superparamagnetic iron oxide (SPIO) nanoparticles, which serve as an MRI-detectable contrast agent. The conjugation method begins with an oxidation of the SPIO nanoparticles, which oxidizes carboxyl groups on the polysaccharide shell of SPIO. Purified ANX protein is then added in the setting of a sodium borate solution to facilitate covalent interaction of ANX with SPIO in a reducing buffer. A final reduction step with sodium borohydride is performed to complete the reduction, and then the reaction is quenched. Unconjugated ANX is removed from the mix by microcentrifuge filtration. The size and purity of the ANX-SPIO product is verified by dynamic light scattering (DLS). This method does not require addition to, or modification of, the polysaccharide SPIO shell, as opposed to cross-linked iron oxide particle conjugation methods or biotin-labeled nanoparticles. As a result, this method represents a simple, robust approach that may be extended to conjugation of other proteins of interest.

View details for DOI 10.3791/3775

View details for PubMedID 22871963
Cardiovascular Magnetic Resonance Imaging Elucidates Genotype-Phenotype Relationships in Patients with Hypertrophic Cardiomyopathy Scientific Sessions of the American-Heart-Association/Resuscitation Science Symposium Heidary, S., Wheeler, M. T., Bennett, M. V., Chung, J., Pavlovic, A., Parent, M., Dash, R., McConnell, M. V., Ashley, E. A., Yang, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2011
View details for Web of Science ID 000299738705331
Robust Reprogramming Of human Placenta derived Mesenchymal Stem Cells Into Spontaneously Contractile Cardiomyocytes Ge, X., Toma, I., Wang, I. E., Sebastiano, V., Reijo-Pera, R., Yang, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2011
View details for Web of Science ID 000299738706250
In vivo Molecular MRI of Cell Survival and Teratoma Formation Following Embryonic Stem Cell Transplantation Into the Injured Murine Myocardium MAGNETIC RESONANCE IN MEDICINE Chung, J., Kee, K., Barral, J. K., Dash, R., Kosuge, H., Wang, X., Weissman, I., Robbins, R. C., Nishimura, D., Quertermous, T., Reijo-Pera, R. A., Yang, P. C. 2011; 66 (5): 1374-1381
Abstract

Embryonic stem cells (ESCs) have shown the potential to restore cardiac function after myocardial injury. Superparamagnetic iron oxide nanoparticles (SPIO) have been widely employed to label ESCs for cellular MRI. However, nonspecific intracellular accumulation of SPIO limits long-term in vivo assessment of the transplanted cells. To overcome this limitation, a novel reporter gene (RG) has been developed to express antigens on the ESC surface. By employing SPIO-conjugated monoclonal antibody against these antigens (SPIO-MAb), the viability of transplanted ESCs can be detected in vivo. This study aims to develop a new molecular MRI method to assess in vivo ESC viability, proliferation, and teratoma formation. The RG is designed to express 2 antigens (hemagglutinin A and myc) and luciferase on the ESC surface. The two antigens serve as the molecular targets for SPIO-MAb. The human and mouse ESCs were transduced with the RG (ESC-RGs) and transplanted into the peri-infarct area using the murine myocardial injury model. In vivo MRI was performed following serial intravenous administration of SPIO-MAb. Significant hypointense signal was generated from the viable and proliferating ESCs and subsequent teratoma. This novel molecular MRI technique enabled in vivo detection of early ESC-derived teratoma formation in the injured murine myocardium.

View details for DOI 10.1002/mrm.22929

View details for PubMedID 21604295
A Molecular MRI Probe to Detect Treatment of Cardiac Apoptosis In Vivo MAGNETIC RESONANCE IN MEDICINE Dash, R., Chung, J., Chan, T., Yamada, M., Barral, J., Nishimura, D., Yang, P. C., Simpson, P. C. 2011; 66 (4): 1152-1162
Abstract

Cell death by apoptosis is critical in myocardial diseases, and noninvasive detection of early, reversible apoptosis might be useful clinically. Exogenous Annexin-V (ANX) protein binds membrane phosphatidylserine, which is externalized in early apoptosis. A molecular MRI probe was constructed with superparamagnetic iron oxide (SPIO) conjugated to recombinant human ANX (ANX-SPIO). Apoptosis was induced with doxorubicin, a cardiotoxic cancer drug, in culture in neonatal rat ventricular myocytes, cardiac fibroblasts, and mesenchymal stem cells, and in vivo in the mouse heart. ANX-SPIO was validated using T2*-weighted 3T MRI. ANX-SPIO produced T2* signal loss, reflecting iron content, that correlated highly with independent apoptosis markers; bound with high affinity to apoptotic myocytes by competition assay (Ki 69 nM); detected apoptosis in culture much earlier than did TUNEL stain; and revealed fibroblast resistance to apoptosis. With apoptosis in vivo, ANX-SPIO produced diffuse myocardial T2* signal loss that correlated with increased iron stain and caspase activity. Treatment with an alpha-1-adrenergic agonist in vivo reversed apoptosis and eliminated the ANX-SPIO MRI signal. It is concluded that cardiac MRI of ANX-SPIO detects early, nonischemic cardiac apoptosis in culture and in vivo, and can identify reversibly injured cardiac cells in diseased hearts, when treatment is still possible.

View details for DOI 10.1002/mrm.22876

View details for Web of Science ID 000295356500027

View details for PubMedID 21360750

View details for PubMedCentralID PMC3138815
Contrast echocardiography: finding its place in stem cell therapy MINERVA CARDIOANGIOLOGICA Kim, P. J., Yang, P. C. 2011; 59 (5): 491-497
Abstract

To date, the underlying mechanism responsible for the restoration of the injured myocardium following transplantation of stem cells has not been clearly identified. Molecular imaging is essential to the continued progress of stem cell therapy by elucidating the biology of transplanted stem cells in vivo. Currently, several imaging modalities are in development in the rapidly evolving field of molecular imaging. Contrast echocardiography has the potential to define its role in shaping the future development of stem cell therapy. We describe the current state of contrast echocardiography and its future direction herein.

View details for Web of Science ID 000208662500009
Dual Manganese-Enhanced and Delayed Gadolinium-Enhanced MRI Detects Myocardial Border Zone Injury in a Pig Ischemia-Reperfusion Model CIRCULATION-CARDIOVASCULAR IMAGING Dash, R., Chung, J., Ikeno, F., Hahn-Windgassen, A., Matsuura, Y., Bennett, M. V., Lyons, J. K., Teramoto, T., Robbins, R. C., McConnell, M. V., Yeung, A. C., Brinton, T. J., Harnish, P. P., Yang, P. C. 2011; 4 (5): 574-582
Abstract

Gadolinium (Gd)-based delayed-enhancement MRI (DEMRI) identifies nonviable myocardium but is nonspecific and may overestimate nonviable territory. Manganese (Mn(2+))-enhanced MRI (MEMRI) denotes specific Mn(2+) uptake into viable cardiomyocytes. We performed a dual-contrast myocardial assessment in a porcine ischemia-reperfusion (IR) model to test the hypothesis that combined DEMRI and MEMRI identifies viable infarct border zone (BZ) myocardium in vivo.Sixty-minute left anterior descending coronary artery IR injury was induced in 13 adult swine. Twenty-one days post-IR, 3-T cardiac MRI was performed. MEMRI was obtained after injection of 0.7 mL/kg Mn(2+) contrast agent. DEMRI was then acquired after injection of 0.2 mmol/kg Gd. Left ventricular (LV) mass, infarct, and function were analyzed. Subtraction of MEMRI defect from DEMRI signal identified injured BZ myocardium. Explanted hearts were analyzed by 2,3,5-triphenyltetrazolium chloride stain and tissue electron microscopy to compare infarct, BZ, and remote myocardium. Average LV ejection fraction was reduced (30�7%). MEMRI and DEMRI infarct volumes correlated with 2,3,5-triphenyltetrazolium chloride stain analysis (MEMRI, r=0.78; DEMRI, r=0.75; P<0.004). MEMRI infarct volume percentage was significantly lower than that of DEMRI (14�4% versus 23�4%; P<0.05). BZ MEMRI signal-to-noise ratio (SNR) was intermediate to remote and core infarct SNR (7.5�2.8 versus 13.2�3.4 and 2.9�1.6; P<0.0001), and DEMRI BZ SNR tended to be intermediate to remote and core infarct SNR (8.4�5.4 versus 3.3�0.6 and 14.3�6.6; P>0.05). Tissue electron microscopy analysis exhibited preserved cell structure in BZ cardiomyocytes despite transmural DEMRI enhancement.The dual-contrast MEMRI-DEMRI detects BZ viability within DEMRI infarct zones. This approach may identify injured, at-risk myocardium in ischemic cardiomyopathy.

View details for DOI 10.1161/CIRCIMAGING.110.960591

View details for PubMedID 21719779
alpha B-Crystallin Improves Murine Cardiac Function and Attenuates Apoptosis in Human Endothelial Cells Exposed to Ischemia-Reperfusion ANNALS OF THORACIC SURGERY Velotta, J. B., Kimura, N., Chang, S. H., Chung, J., Itoh, S., Rothbard, J., Yang, P. C., Steinman, L., Robbins, R. C., Fischbein, M. P. 2011; 91 (6): 1907-1913
Abstract

This study investigates the protective effect of exogenous ?B-crystallin (CryAB) on myocardial function after ischemia-reperfusion injury.Mice underwent temporary left anterior descending artery occlusion for 30 minutes. Either CryAB (50 ?g) or phosphate-buffered saline (100 ?L [n=6, each group]) were injected in the intramyocardial medial and lateral perinfarct zone 15 minutes before reperfusion. Intraperitoneal injections were administered every other day. Left ventricular ejection fraction was evaluated on postoperative day 40 with magnetic resonance imaging. To investigate the effect of CryAB on apoptosis after hypoxia/reoxygenation in vitro, murine atrial cardiomyocytes (HL-1 cells) or human microvascular endothelial cells (HMEC-1) were incubated with either 50 ?g CryAB (500 ?g /10 mL) or phosphate-buffered saline in a hypoxia chamber for 6, 12, and 24 hours, followed by 30 minutes of reoxygenation at room air. Apoptosis was then assessed by western blot (Bcl-2, free bax, cleaved caspases-3, 9, PARP) and enzyme-linked immunosorbent assay analyses (cytoplasmic histone-associated DNA fragments and caspase-3 activity).On postoperative day 40, CryAB-treated mice had a 1.8-fold increase in left ventricular ejection fraction versus control mice (27%�6% versus 15%�4% SD, p<0.005). In vitro, (1) the HL-1 cells showed no significant difference in apoptotic protein expression, cytoplasmic histone-associated DNA fragments, or caspase-3 activity; (2) the HMEC-1 cells had increased but not significant apoptotic protein expression with, however, a significant decrease in cytoplasmic histone-associated DNA fragments (1.5-fold, p<0.01) and caspase-3 activity (2.7-fold, p<0.005).Exogenous CryAB administration significantly improves cardiac function after ischemia-reperfusion injury, in vivo. The protective anti-apoptotic affects of CryAB may target the endothelial cell.

View details for DOI 10.1016/j.athoracsur.2011.02.072

View details for Web of Science ID 000291019400043

View details for PubMedID 21619989
RevaTen platelet-rich plasma improves cardiac function after myocardial injury. Cardiovascular revascularization medicine : including molecular interventions Mishra, A., Velotta, J., Brinton, T. J., Wang, X., Chang, S., Palmer, O., Sheikh, A., Chung, J., Yang, P. C., Robbins, R., Fischbein, M. 2011; 12 (3): 158-163
Abstract

Cell therapy is an exciting area of investigation for repair of injured myocardial tissue. Platelet-rich plasma (PRP) is an autologous fractionation of whole blood containing high concentrations of growth factors including vascular endothelial growth factor and insulin-like growth factor, among many others. PRP has been shown to safely and effectively enhance healing of musculoskeletal tissue primarily by reparative cell signaling. Despite a growing body of evidence on PRP's safety and efficacy, limited studies have been performed using PRP in cardiovascular tissues. Utilizing a murine myocardial permanent ligation and ischemia/reperfusion model, this study sought to determine whether RevaTen PRP (Menlo Park, CA, USA), a proprietary formulation of PRP, improves cardiac function as measured by left ventricular ejection fraction (LVEF).Via thoracotomy, the left anterior descending arteries (LAD) of 28 mice were occluded by suture either permanently or for 45 min to induce ischemic injury and then reperfused. Mice undergoing permanent ligation had intramyocardial injections of either RevaTen PRP (n=5) or phosphate-buffered saline (PBS; n=4). Magnetic resonance (MR) imaging was performed to calculate LVEF at 7 days. Mice undergoing ischemia and reperfusion had intramyocardial injections of either PRP (n=10) or PBS (n=9) and underwent MR imaging to calculate LVEF at 21 days. Hearts were harvested for histologic examination following imaging.Compared with PBS controls, RevaTen PRP-treated animals that underwent LAD ligation had a 38% higher LVEF 7 days after injury (PRP=36.1�6.1%; PBS=26.4�3.6%, P=.027). Compared with PBS controls, PRP-treated animals who underwent ischemia-reperfusion of the LAD had a 28% higher LVEF 21 days after injury (PRP=37.6�4.8%, control=29.3�9.7%, P=.038). Histologic analysis suggested the presence of more scar tissue in the control group compared to the PRP-treated animals.MR imaging demonstrated a positive effect of RevaTen PRP on left ventricular function in both a ligation and ischemia-reperfusion murine model. Our results suggest RevaTen PRP should be investigated further as a potential point-of-care biologic treatment following myocardial injury.

View details for DOI 10.1016/j.carrev.2010.08.005

View details for PubMedID 21122486
RevaTen platelet-rich plasma improves cardiac function after myocardial injury CARDIOVASCULAR REVASCULARIZATION MEDICINE Mishra, A., Velotta, J., Brinton, T. J., Wang, X., Chang, S., Palmer, O., Sheikh, A., Chung, J., Yang, P., Robbins, R., Fischbein, M. 2011; 12 (3): 158?63
View details for DOI 10.1016/j.carrev.2010.08.005

View details for Web of Science ID 000213860500006
Detection of Injured Border Zone Myocardium Using Manganese-Enhanced and Delayed-Enhanced MRI in a Pig Ischemia-Reperfusion Model Dash, R., Chung, J., Hahn-Windgassen, A., Matsuura, Y., Ikeno, F., Lyons, J., Teramoto, T., Yeung, A. C., McConnell, M. V., Brinton, T. J., Harnish, P., Yang, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2010
View details for Web of Science ID 000208231600841
Apelin Enhances Cardiac Differentiation of Human Embryonic Stem Cells Wang, I. E., Chung, J., Yang, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2010
View details for Web of Science ID 000208231603454
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
Positive Contrast with Alternating Repetition Time SSFP (PARTS): A Fast Imaging Technique for SPIO-Labeled Cells MAGNETIC RESONANCE IN MEDICINE Cukur, T., Yamada, M., Overall, W. R., Yang, P., Nishimura, D. G. 2010; 63 (2): 427-437
Abstract

There has been recent interest in positive-contrast MRI methods for noninvasive tracking of cells labeled with superparamagnetic iron-oxide nanoparticles. Low-tip-angle balanced steady-state free precession sequences have been used for fast, high-resolution, and flow-insensitive positive-contrast imaging; however, the contrast can be compromised by the limited suppression of the on-resonant and fat signals. In this work, a new technique that produces positive contrast with alternating repetition time steady-state free precession is proposed to achieve robust background suppression for a broad range of tissue parameters. In vitro and in vivo experiments demonstrate the reliability of the generated positive contrast. The results indicate that the proposed method can enhance the suppression level by up to 18 dB compared with conventional balanced steady-state free precession.

View details for DOI 10.1002/mrm.22241

View details for PubMedID 20099331
Molecular Imaging of Stem Cell Transplantation in Myocardial Disease. Current cardiovascular imaging reports Chung, J., Yang, P. C. 2010; 3 (2): 106?12
Abstract

Stem cell therapy has been heralded as a novel therapeutic option for cardiovascular disease. In vivo molecular imaging has emerged as an indispensible tool in investigating stem cell biology post-transplantation into the myocardium and in evaluating the therapeutic efficacy. This review highlights the features of each molecular imaging modality and discusses how these modalities have been applied to evaluate stem cell therapy.

View details for PubMedID 20396619
In vivo Kinetics of Embryonic Stem Cell Viability Following Transplantation Into the Injured Murine Myocardium 82nd National Conference and Exhibitions and Scientific Sessions of the American-Heart-Association Chung, J., Kee, K., Barral, J. K., Dash, R., Weissman, I., Quertermous, T., Robbins, R. C., Nishimura, D. G., Reijo-Pera, R. A., Yang, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2009: S310?S311
View details for Web of Science ID 000271831500052
Manganese-Guided Cellular MRI of Human Embryonic Stem Cell and Human Bone Marrow Stromal Cell Viability MAGNETIC RESONANCE IN MEDICINE Yamada, M., Gurney, P. T., Chung, J., Kundu, P., Drukker, M., Smith, A. K., Weissman, I. L., Nishimura, D., Robbins, R. C., Yang, P. C. 2009; 62 (4): 1047-1054
Abstract

This study investigated the ability of MnCl(2) as a cellular MRI contrast agent to determine the in vitro viability of human embryonic stem cells (hESC) and human bone marrow stromal cells (hBMSC). Basic MRI parameters including T(1) and T(2) values of MnCl(2)-labeled hESC and hBMSC were measured and viability signal of manganese (Mn(2+))-labeled cells was validated. Furthermore, the biological activity of Ca(2+)-channels was modulated utilizing both Ca(2+)-channel agonist and antagonist to evaluate concomitant signal changes. Metabolic effects of MnCl(2)-labeling were also assessed using assays for cell viability, proliferation, and apoptosis. Finally, in vivo Mn(2+)-guided MRI of the transplanted hESC was successfully achieved and validated by bioluminescence imaging.

View details for DOI 10.1002/mrm.22071

View details for PubMedID 19526508
Magnetic resonance imaging of human embryonic stem cells. Current protocols in stem cell biology Chung, J., Yamada, M., Yang, P. C. 2009; Chapter 5: Unit 5A 3-?
Abstract

Magnetic resonance imaging (MRI) may emerge as an ideal non-invasive imaging modality to monitor stem cell therapy in the failing heart. This imaging modality generates any arbitrary tomographic view at high spatial and temporal resolution with exquisite intrinsic tissue contrast. This capability enables robust evaluation of both the cardiac anatomy and function. Traditionally, superparamagnetic iron oxide nanoparticle (SPIO) has been widely used for cellular MRI due to SPIO's ability to enhance sensitivity of MRI by inducing remarkable hypointense, negative signal, "blooming effect" on T2*-weighted MRI acquisition. Recently, manganese chloride (MnCl(2)) has been reported by our laboratory for its ability as a contrast agent to track biological activity of viable cells. Hyperintense, positive signals can be achieved from the Mn(2+)-labeled stem cells on T1-weighted MRI acquisition. Cytotoxicity is a potential drawback of Mn(2+) labeling of the cells. However, in our laboratory the labeling method has been optimized to minimize cytotoxic effects. This article describes two different magnetic labeling methods of human embryonic stem cells (hESC) using SPIO and MnCl(2).

View details for DOI 10.1002/9780470151808.sc05a03s10

View details for PubMedID 19653198
Self-Refocused Spatial-Spectral Pulse for Positive Contrast Imaging of Cells Labeled with SPIO Nanoparticles MAGNETIC RESONANCE IN MEDICINE Balchandani, P., Yamada, M., Pauly, J., Yang, P., Spielman, D. 2009; 62 (1): 183-192
Abstract

MRI has been used extensively to noninvasively track the location of cells labeled with superparamagnetic iron-oxide nanoparticles (SPIOs) in vivo. Typically, SPIOs are employed as a negative contrast agent which makes it difficult to differentiate labeled cells from extraneous sources of inhomogeneity and actual voids in the image. As a result, several novel approaches have been put forth to obtain positive contrast from SPIOs. One technique proposed by Cunningham et al. utilizes spectrally selective pulses to excite and refocus spins in the vicinity of the SPIOs. Although the frequency selectivity of this technique provides effective positive contrast, the lack of slice selectivity results in interfering signal from sources of off-resonance outside the slice of interest. We have developed a self-refocused spatial-spectral (SR-SPSP) pulse to achieve slice-selective spin-echo imaging of off-resonant spins. Using a self-refocused pulse affords flexibility in echo-time selection since the spin echo may be placed at any time after the end of the pulse. The spatial selectivity achieved by the SR-SPSP RF pulse eliminates background signal from out-of-slice regions and reduces the on-resonant water suppression requirements. Phantom and in vivo data demonstrate that positive contrast and slice-selectivity are achieved using this novel RF pulse.

View details for DOI 10.1002/mrm.21973

View details for PubMedID 19449385
Comparison of Optical Bioluminescence Reporter Gene and Superparamagnetic Iron Oxide MR Contrast Agent as Cell Markers for Noninvasive Imaging of Cardiac Cell Transplantation MOLECULAR IMAGING AND BIOLOGY Chen, I. Y., Greve, J. M., Gheysens, O., Willmann, J. K., Rodriguez-Porcel, M., Chu, P., Sheikh, A. Y., Faranesh, A. Z., Paulmurugan, R., Yang, P. C., Wu, J. C., Gambhir, S. S. 2009; 11 (3): 178-187
Abstract

In this study, we compared firefly luciferase (Fluc) reporter gene and superparamagnetic iron oxide (Feridex) as cell markers for longitudinal monitoring of cardiomyoblast graft survival using optical bioluminescence imaging (BLI) and magnetic resonance imaging (MRI), respectively.Rats (n = 31) underwent an intramyocardial injection of cardiomyoblasts (2 x 10(6)) labeled with Fluc, Feridex, or no marker (control) or an injection of Feridex alone (75 microg). Afterward, rats were serially imaged with BLI or MRI and killed at different time points for histological analysis.BLI revealed a drastically different cell survival kinetics (half-life = 2.65 days over 6 days) than that revealed by MRI (half-life = 16.8 days over 80 days). Injection of Feridex alone led to prolonged tissue retention of Feridex (> or =16 days) and persistent MR signal (> or =42 days).Fluc BLI reporter gene imaging is a more accurate gauge of transplanted cell survival as compared to MRI of Feridex-labeled cells.

View details for DOI 10.1007/s11307-008-0182-z

View details for PubMedID 19034584
Imaging Survival and Function of Transplanted Cardiac Resident Stem Cells JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Li, Z., Lee, A., Huang, M., Chun, H., Chung, J., Chu, P., Hoyt, G., Yang, P., Rosenberg, J., Robbins, R. C., Wu, J. C. 2009; 53 (14): 1229-1240
Abstract

The goal of this study is to characterize resident cardiac stem cells (CSCs) and investigate their therapeutic efficacy in myocardial infarction by molecular imaging methods.CSCs have been isolated and characterized in vitro. These cells offer a provocative method to regenerate the damaged myocardium. However, the survival kinetics and function of transplanted CSCs have not been fully elucidated.CSCs were isolated from L2G85 transgenic mice (FVB strain background) that constitutively express both firefly luciferase and enhanced green fluorescence protein reporter gene. CSCs were characterized in vitro and transplanted in vivo into murine infarction models. Multimodality noninvasive imaging techniques were used to assess CSC survival and therapeutic efficacy for restoration of cardiac function.CSCs can be isolated from L2G85 mice, and fluorescence-activated cell sorting analysis showed expression of resident CSC markers (Sca-1, c-Kit) and mesenchymal stem cell markers (CD90, CD106). Afterwards, 5 x 10(5) CSCs (n = 30) or phosphate-buffered saline control (n = 15) was injected into the hearts of syngeneic FVB mice undergoing left anterior descending artery ligation. Bioluminescence imaging showed poor donor cell survival by week 8. Echocardiogram, invasive hemodynamic pressure-volume analysis, positron emission tomography imaging with fluorine-18-fluorodeoxyglucose, and cardiac magnetic resonance imaging demonstrated no significant difference in cardiac contractility and viability between the CSC and control group. Finally, postmortem analysis confirmed transplanted CSCs integrated with host cardiomyocytes by immunohistology.In a mouse myocardial infarction model, Sca-1-positive CSCs provide no long-term engraftment and benefit to cardiac function as determined by multimodality imaging.

View details for DOI 10.1016/j.jacc.2008.12.036

View details for PubMedID 19341866
Magnetic Resonance Imaging With Targeted Iron-Oxide Labeling Detects Differential Cardiac Cell Survival After Doxorubicin and Myocardial Infarction in Culture and In Vivo Dash, R., Chan, T., Yamada, M., Paningbatan, M., Myagmar, B., Swigart, P. M., Yang, P. C., Simpson, P. C. ELSEVIER SCIENCE INC. 2009: A304
View details for Web of Science ID 000263864201261
In Vivo Serial Evaluation of Superparamagnetic Iron-Oxide Labeled Stem Cells by Off-Resonance Positive Contrast MAGNETIC RESONANCE IN MEDICINE Suzuki, Y., Cunningham, C. H., Noguchi, K., Chen, I. Y., Weissman, I. L., Yeung, A. C., Robbins, R. C., Yang, P. C. 2008; 60 (6): 1269-1275
Abstract

MRI is emerging as a diagnostic modality to track iron-oxide-labeled stem cells. This study investigates whether an off-resonance (OR) pulse sequence designed to generate positive contrast at 1.5T can assess the location, quantity, and viability of delivered stem cells in vivo. Using mouse embryonic stem cell transfected with luciferase reporter gene (luc-mESC), multimodality validation of OR signal was conducted to determine whether engraftment parameters of superparamagnetic iron-oxide labeled luc-mESC (SPIO-luc-mESC) could be determined after cell transplantation into the mouse hindlimb. A significant increase in signal- and contrast-to-noise of the SPIO-luc-mESC was achieved with the OR technique when compared to a gradient recalled echo (GRE) sequence. A significant correlation between the quantity of SPIO-luc-mESC and OR signal was observed immediately after transplantation (R(2) = 0.74, P < 0.05). The assessment of transplanted cell viability by bioluminescence imaging (BLI) showed a significant increase of luciferase activities by day 16, while the MRI signal showed no difference. No significant correlation between BLI and MRI signals of cell viability was observed. In conclusion, using an OR sequence the precise localization and quantitation of SPIO-labeled stem cells in both space and time were possible. However, the OR sequence did not allow evaluation of cell viability.

View details for DOI 10.1002/mrm.21816

View details for Web of Science ID 000261225100001

View details for PubMedID 19030159

View details for PubMedCentralID PMC2597338
Magnetic Resonance Imaging with Iran-Oxide Labeling Detects Differential Cell Survival after Doxorubicin Exposure in Cardiac Myocytes, Fibroblasts, and Stem Cells Dash, R., Chan, T., Yamada, M., Paningbatan, M., Swigart, P. M., Myagmar, B., Yang, P. C., Simpson, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2008: S996
View details for Web of Science ID 000262104503698
Multimodal evaluation of in vivo magnetic resonance imaging of myocardial restoration by mouse embryonic stem cells JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Hendry, S. L., van der Bogt, K. E., Sheikh, A. Y., Arai, T., Dylla, S. J., Drukker, M., McConnell, M. V., Kutschka, I., Hoyt, G., Cao, F., Weissman, I. L., Connolly, A. J., Pelletier, M. P., Wu, J. C., Robbins, R. C., Yang, P. C. 2008; 136 (4): 1028-U14
Abstract

Mouse embryonic stem cells have demonstrated potential to restore infarcted myocardium after acute myocardial infarction. Although the underlying mechanism remains controversial, magnetic resonance imaging has provided reliable in vivo assessment of functional recovery after cellular transplants. Multimodal comparison of the restorative effects of mouse embryonic stem cells and mouse embryonic fibroblasts was performed to validate magnetic resonance imaging data and provide mechanistic insight.SCID-beige mice (n = 55) underwent coronary artery ligation followed by injection of 2.5 x 10(5) mouse embryonic stem cells, 2.5 x 10(5) mouse embryonic fibroblasts, or normal saline solution. In vivo magnetic resonance imaging of myocardial restoration by mouse embryonic stem cells was evaluated by (1) in vivo pressure-volume loops, (2) in vivo bioluminescence imaging, and (3) ex vivo TaqMan (Roche Molecular Diagnostics, Pleasanton, Calif) polymerase chain reaction and immunohistologic examination.In vivo magnetic resonance imaging demonstrated significant improvement in left ventricular ejection fraction at 1 week in the mouse embryonic stem cell group. This finding was validated with (1) pressure-volume loop analysis demonstrating significantly improved systolic and diastolic functions, (2) bioluminescence imaging and polymerase chain reaction showing superior posttransplant survival of mouse embryonic stem cells, (3) immunohistologic identification of cardiac phenotype within engrafted mouse embryonic stem cells, and (4) polymerase chain reaction measuring increased expressions of angiogenic and antiapoptotic genes and decreased expressions of antifibrotic genes.This study validates in vivo magnetic resonance imaging as an effective means of evaluating the restorative potential of mouse embryonic stem cells.

View details for DOI 10.1016/j.jtcvs.2007.12.053

View details for PubMedID 18954646
Multimodality Evaluation of the Viability of Stem Cells Delivered Into Different Zones of Myocardial Infarction CIRCULATION-CARDIOVASCULAR IMAGING Hung, T., Suzuki, Y., Urashima, T., Caffarelli, A., Hoyt, G., Sheikh, A. Y., Yeung, A. C., Weissman, I., Robbins, R. C., Bulte, J. W., Yang, P. C. 2008; 1 (1): 6-13
Abstract

We tested the hypothesis that multimodality imaging of mouse embryonic stem cells (mESCs) provides accurate assessment of cellular location, viability, and restorative potential after transplantation into different zones of myocardial infarction.Mice underwent left anterior descending artery ligation followed by transplantation of dual-labeled mESCs with superparamagnetic iron oxide and luciferase via direct injection into 3 different zones of myocardial infarction: intra-infarction, peri-infarction, and normal (remote). One day after transplantation, magnetic resonance imaging enabled assessment of the precise anatomic locations of mESCs. Bioluminescence imaging allowed longitudinal analysis of cell viability through detection of luciferase activity. Subsequent evaluation of myocardial regeneration and functional restoration was performed by echocardiography and pressure-volume loop analysis. Using 16-segment analysis, we demonstrated precise localization of dual-labeled mESCs. A strong correlation between histology and magnetic resonance imaging was established (r=0.962, P=0.002). Bioluminescent imaging data demonstrated that cell viability in the remote group was significantly higher than in other groups. Echocardiography and pressure-volume loop analysis revealed improved functional restoration in animals treated with mESCs, although myocardial regeneration was not observed.Multimodality evaluation of mESC engraftment in the heterogeneous tissue of myocardial infarction is possible. Magnetic resonance imaging demonstrated accurate anatomic localization of dual-labeled mESCs. Bioluminescent imaging enabled assessment of variable viability of mESCs transplanted into the infarcted myocardium. Echocardiography and pressure-volume loop analysis validated the restorative potential of mESCs. Although mESCs transplanted into the remote zone demonstrated the highest viability, precise delivery of mESCs into the peri-infarction region might be equally critical in restoring the injured myocardium.

View details for DOI 10.1161/CIRCIMAGING.108.767343

View details for PubMedID 19808509
Human ESC vs. iPSC-Pros and Cons JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH Pappas, J. J., Yang, P. C. 2008; 1 (2): 96-99
View details for DOI 10.1007/s12265-008-9032-2

View details for PubMedID 20559900
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
Comparison of reporter gene and iron particle labeling for tracking fate of human embryonic stem cells and differentiated endothelial cells in living subjects STEM CELLS Li, Z., Suzuki, Y., Huang, M., Cao, F., Xie, X., Connolly, A. J., Yang, P. C., Wu, J. C. 2008; 26 (4): 864-873
Abstract

Human embryonic stem (hES) cells are pluripotent stem cells capable of self-renewal and differentiation into virtually all cell types. Thus, they hold tremendous potential as cell sources for regenerative therapies. The concurrent development of accurate, sensitive, and noninvasive technologies capable of monitoring hES cells engraftment in vivo can greatly expedite basic research prior to future clinical translation. In this study, hES cells were stably transduced with a lentiviral vector carrying a novel double-fusion reporter gene that consists of firefly luciferase and enhanced green fluorescence protein. Reporter gene expression had no adverse effects on cell viability, proliferation, or differentiation to endothelial cells (human embryonic stem cell-derived endothelial cells [hESC-ECs]). To compare the two popular imaging modalities, hES cells and hESC-ECs were then colabeled with superparamagnetic iron oxide particles before transplantation into murine hind limbs. Longitudinal magnetic resonance (MR) imaging showed persistent MR signals in both cell populations that lasted up to 4 weeks. By contrast, bioluminescence imaging indicated divergent signal patterns for hES cells and hESC-ECs. In particular, hESC-ECs showed significant bioluminescence signals at day 2, which decreased progressively over the following 4 weeks, whereas bioluminescence signals from undifferentiated hES cells increased dramatically during the same period. Post-mortem histology and immunohistochemistry confirmed teratoma formation after injection of undifferentiated hES cells but not hESC-ECs. From these data taken together, we concluded that reporter gene is a better marker for monitoring cell viability, whereas iron particle labeling is a better marker for high-resolution detection of cell location by MR. Furthermore, transplantation of predifferentiated rather than undifferentiated hES cells would be more suited for avoiding teratoma formation.

View details for DOI 10.1634/stemcells.2007-0843

View details for PubMedID 18218820
In vitro differentiation of mouse embryonic stem (mES) cells using the hanging drop method. Journal of visualized experiments : JoVE Wang, X., Yang, P. 2008
Abstract

Stem cells have the remarkable potential to develop into many different cell types. When a stem cell divides, each new cell has the potential to either remain a stem cell or become another type of cell with a more specialized function, This promising of science is leading scientists to investigate the possibility of cell-based therapies to treat disease. When culture in suspension without antidifferentiation factors, embryonic stem cells spontaneously differentiate and form three-dimensional multicellular aggregates. These cell aggregates are called embryoid bodies(EB). Hanging drop culture is a widely used EB formation induction method. The rounded bottom of hanging drop allows the aggregation of ES cells which can provide mES cells a good environment for forming EBs. The number of ES cells aggregatied in a hanging drop can be controlled by varying the number of cells in the initial cell suspension to be hung as a drop from the lid of Petri dish. Using this method we can reproducibly form homogeneous EBs from a predetermined number of ES cells.

View details for DOI 10.3791/825

View details for PubMedID 19066514
In vitro labeling of human embryonic stem cells for magnetic resonance imaging. Journal of visualized experiments : JoVE Yamada, M., Yang, P. 2008
Abstract

Human embryonic stem cells (hESC) have demonstrated the ability to restore the injured myocardium. Magnetic resonance imaging (MRI) has emerged as one of the predominant imaging modalities to assess the restoration of the injured myocardium. Furthermore, ex-vivo labeling agents, such as iron-oxide nanoparticles, have been employed to track and localize the transplanted stem cells. However, this method does not monitor a fundamental cellular biology property regarding the viability of transplanted cells. It has been known that manganese chloride (MnCl(2)) enters the cells via voltage-gated calcium (Ca(2+)) channels when the cells are biologically active, and accumulates intracellularly to generate T(1) shortening effect. Therefore, we suggest that manganese-guided MRI can be useful to monitor cell viability after the transplantation of hESC into the myocardium. In this video, we will show how to label hESC with MnCl(2) and how those cells can be clearly seen by using MRI in vitro. At the same time, biological activity of Ca(2+)-channels will be modulated utilizing both Ca(2+)-channel agonist and antagonist to evaluate concomitant signal changes.

View details for DOI 10.3791/827

View details for PubMedID 19066513
Gated micro computed tomography scanning: An emerging tool for longitudinal assessment of murine cardiac remodeling Sheikh, A. Y., Doyle, T. C., Sheikh, M. K., Cao, F., Ransolhoff, K. J., Yang, P. C., Robbins, R. C., Fischlbein, M. P., Wul, J. C. LIPPINCOTT WILLIAMS & WILKINS. 2007: 198
View details for Web of Science ID 000250394300881
In vitro comparison of the biological effects of three transfection methods for magnetically labeling mouse embryonic stem cells with ferumoxides MAGNETIC RESONANCE IN MEDICINE Suzuki, Y., Zhang, S., Kundu, P., Yeung, A. C., Robbins, R. C., Yang, P. C. 2007; 57 (6): 1173-1179
Abstract

In vivo MRI of stem cells (SCs) is an emerging application to evaluate the role of cell therapy in restoring the injured myocardium. The high spatial and temporal resolution combined with iron-oxide-based intracellular labeling techniques will provide a sensitive, noninvasive, dual imaging modality for both cells and myocardium. In order to facilitate this novel imaging approach, much effort has been directed towards developing efficient transfection methods. While techniques utilizing poly-L-lysine (PLL), protamine sulfate (PS), and electroporation (ELP) have been proposed, the fundamental biological effects of these methods on mouse embryonic SCs (mESC) have not been investigated systematically. In this study a longitudinal in vitro evaluation of cellular viability, apoptosis, proliferation, and cardiac differentiation of magnetically labeled mESC was conducted. No significant difference was seen in these biological parameters among the three transfection methods. However, cardiac differentiation was most attenuated by ELP, and iron uptake was most effective by PS.

View details for DOI 10.1002/mrm.21219

View details for PubMedID 17534917
Magnetic resonance imaging of progressive cardiomyopathic changes in the db/db mouse AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Yue, P., Arai, T., Terashima, M., Sheikh, A. Y., Cao, F., Charo, D., Hoyt, G., Robbins, R. C., Ashley, E. A., Wu, J., Yang, P. C., Tsao, P. S. 2007; 292 (5): H2106-H2118
Abstract

The db/db mouse is a well-established model of diabetes. Previous reports have documented contractile dysfunction (i.e., cardiomyopathy) in these animals, although the extant literature provides limited insights into cardiac structure and function as they change over time. To better elucidate the natural history of cardiomyopathy in db/db mice, we performed cardiac magnetic resonance (CMR) scans on these animals. CMR imaging was conducted with a 4.7-T magnet on female db/db mice and control db/+ littermates at 5, 9, 13, 17, and 22 wk of age. Gated gradient echo sequences were used to obtain cineographic short-axis slices from apex to base. From these images left ventricular (LV) mass (LVM), wall thickness, end-diastolic volume (LVEDV), and ejection fraction (LVEF) were determined. Additionally, cardiac [(18)F]fluorodeoxyglucose ([(18)F]FDG) PET scanning, pressure-volume loops, and real-time quantitative PCR on db/db myocardium were performed. Relative to control, db/db mice developed significant increases in LVM and wall thickness as early as 9 wk of age. LVEDV diverged slightly later, at 13 wk. Interestingly, compared with the baseline level, LVEF in the db/db group did not decrease significantly until 22 wk. Additionally, [(18)F]FDG metabolic imaging showed a 40% decrease in glucose uptake in db/db mice. Furthermore, contractile dysfunction was observed in 15-wk db/db mice undergoing pressure-volume loops. Finally, real-time quantitative PCR revealed an age-dependent recapitulation of the fetal gene program, consistent with a myopathic process. In summary, as assessed by CMR, db/db mice develop characteristic structural and functional changes consistent with cardiomyopathy.

View details for DOI 10.1152/ajpheart.00856.2006

View details for PubMedID 17122193
Cardiovascular MRI for stem cell therapy. Current cardiology reports Suzuki, Y., Yeung, A. C., Yang, P. C. 2007; 9 (1): 45-50
Abstract

Stem cell therapy may provide an alternative therapeutic option for severe congestive heart failure (CHF). Despite the promise generated by this novel approach, precise in vivo monitoring of the transplanted cells and of subsequent myocardial restoration remains a challenge. The development of a sensitive, noninvasive imaging technology to track stem cells while assessing cardiac function is critical to monitor therapeutic efficacy. In vivo cardiovascular MRI of stem cells is an emerging application to identify, localize, and monitor stem cells while simultaneously evaluating the restoration of the injured myocardium following stem cell therapy. Furthermore, advances in scanner technology, pulse sequence design, and associated hardware have resulted in real-time guidance of catheter-based intervention to deliver cells accurately to the regions of myocardial injury. These capabilities have positioned MRI as the primary comprehensive imaging modality to monitor cell therapy.

View details for PubMedID 17362684
FeCo/graphitic-shell nanocrystals as advanced magnetic-resonance-imaging and near-infrared agents NATURE MATERIALS Seo, W. S., Lee, J. H., Sun, X., Suzuki, Y., Mann, D., Liu, Z., Terashima, M., Yang, P. C., McConnell, M. V., Nishimura, D. G., Dai, H. 2006; 5 (12): 971-976
Abstract

Nanocrystals with advanced magnetic or optical properties have been actively pursued for potential biological applications, including integrated imaging, diagnosis and therapy. Among various magnetic nanocrystals, FeCo has superior magnetic properties, but it has yet to be explored owing to the problems of easy oxidation and potential toxicity. Previously, FeCo nanocrystals with multilayered graphitic carbon, pyrolytic carbon or inert metals have been obtained, but not in the single-shelled, discrete, chemically functionalized and water-soluble forms desired for biological applications. Here, we present a scalable chemical vapour deposition method to synthesize FeCo/single-graphitic-shell nanocrystals that are soluble and stable in water solutions. We explore the multiple functionalities of these core-shell materials by characterizing the magnetic properties of the FeCo core and near-infrared optical absorbance of the single-layered graphitic shell. The nanocrystals exhibit ultra-high saturation magnetization, r1 and r2 relaxivities and high optical absorbance in the near-infrared region. Mesenchymal stem cells are able to internalize these nanoparticles, showing high negative-contrast enhancement in magnetic-resonance imaging (MRI). Preliminary in vivo experiments achieve long-lasting positive-contrast enhancement for vascular MRI in rabbits. These results point to the potential of using these nanocrystals for integrated diagnosis and therapeutic (photothermal-ablation) applications.

View details for DOI 10.1038/nmat1775

View details for PubMedID 17115025
Apelin reverses pathologic ventricular remodeling in the db/db obese mouse Yue, P., Ernst, K., Terashima, M., Greve, J. M., Quertermous, T., Yang, P. C., Tsao, P. S. LIPPINCOTT WILLIAMS & WILKINS. 2006: 174
View details for Web of Science ID 000241792801133
Collagen matrices enhance survival of transplanted cardiomyoblasts and contribute to functional improvement of ischemic rat hearts 78th Annual Scientific Session of the American-Heart-Association Kutschka, I., Chen, I. Y., Kofidis, T., Arai, T., von Degenfeld, G., Sheikh, A. Y., Hendry, S. L., Pearl, J., Hoyt, G., Sista, R., Yang, P. C., Blau, H. M., Gambhir, S. S., Robbins, R. C. LIPPINCOTT WILLIAMS & WILKINS. 2006: I167?I173
Abstract

Cardiac cell transplantation is limited by poor graft viability. We aimed to enhance the survival of transplanted cardiomyoblasts using growth factor-supplemented collagen matrices.H9c2 cardiomyoblasts were lentivirally transduced to express firefly luciferase and green fluorescent protein (GFP). Lewis rats underwent ligation of the left anterior descending artery (LAD) ligation to induce an anterior wall myocardial infarction. Hearts (n=9/group) were harvested and restored ex vivo with 1 x 10(6) genetically labeled H9c2 cells either in (1) saline-suspension, or seeded onto (2) collagen-matrix (Gelfoam [GF];), (3) GF/Matrigel (GF/MG), (4) GF/MG/VEGF (10 microg/mL), or (5) GF/MG/FGF (10 microg/mL). Hearts were then abdominally transplanted into syngeneic recipients (working heart model). Controls (n=6/group) underwent infarction followed by GF implantation or saline injection. Cell survival was evaluated using optical bioluminescence on days 1, 5, 8, 14, and 28 postoperatively. At 4 weeks, fractional shortening and ejection fraction were determined using echocardiography and magnetic resonance imaging, respectively. Graft characteristics were assessed by immunohistology. Bioluminescence signals on days 5, 8, and 14 were higher for GF-based grafts compared with plain H9c2 injections (P<0.03). Signals were higher for GF/MG grafts compared with GF alone (P<0.02). GFP-positive, spindle-shaped H9c2 cells were found integrated in the infarct border zones at day 28. Left ventricular (LV) function of hearts implanted with collagen-based grafts was better compared with controls (P<0.05). Vascular endothelial growth factor or fibroblast growth factor did not further improve graft survival or heart function.Collagen matrices enhance early survival of H9c2 cardiomyoblasts after transplantation into ischemic hearts and lead to improved LV function. Further optimization of the graft design should make restoration of large myocardial infarctions by tissue engineering approaches effective.

View details for PubMedID 16820568
Cardiac magnetic resonance imaging for myocarditis - Effective use in medical decision making CIRCULATION Fenster, B. E., Chan, F. P., Valentine, H. A., Yang, E., McConnell, M. V., Berry, G. J., Yang, P. C. 2006; 113 (22): E842-E843
View details for DOI 10.1161/CIRCULATIONAHA.104.532481

View details for Web of Science ID 000238033400019
Images in cardiovascular medicine. Cardiac magnetic resonance imaging for myocarditis: effective use in medical decision making. Circulation Fenster, B. E., Chan, F. P., Valentine, H. A., Yang, E., McConnell, M. V., Berry, G. J., Yang, P. C. 2006; 113 (22): e842-3
View details for PubMedID 16754807
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
Indirect magnetic resonance lymphangiography to assess lymphatic function in experimental murine lymphedema. Lymphatic research and biology Pan, D., Suzuki, Y., Yang, P. C., Rockson, S. G. 2006; 4 (4): 211-216
Abstract

Recently, indirect magnetic resonance lymphangiography with gadolinium (Gd) has been demonstrated to offer the potential for safe, high-resolution visualization of the lymphatic vessels, in addition to the lymph nodes. In this study, the potential utility of indirect Gd contrast magnetic resonance imaging of lymphatic vascular function was investigated in the murine tail. Functional imaging of healthy mice is contrasted with the findings in experimentally-induced lymphatic vascular insufficiency.Postsurgical lymphedema was experimentally created in the murine tail. Normal and lymphedematous mouse tails were imaged following direct subcutaneous administration of Gadolinium-DTPA, 0.1 mmol/kg. Images were obtained in axial and coronal planes with a T1-weighted spin echo inversion-recovery sequence.In the normal tail, both of the bilateral major collecting lymphatics were clearly visualized as the Gd tracer was cleared from the interstitial compartment. In contrast, the Gd tracer accumulated at the prior surgical site in the lymphedematous tail. Quantitative assessment of Gd clearance demonstrates that accumulation of Gd correlates with the impedance to lymph flow proximal to the site of surgical lymphatic ablation.Magnetic resonance is a feasible and reliable method to be applied to quantitative functional imaging of the lymphatic vasculature in experimental models of lymphedema.

View details for PubMedID 17394404
Dual in vivo magnetic resonance evaluation of magnetically labeled mouse embryonic stem cells and cardiac function at 1.5 T MAGNETIC RESONANCE IN MEDICINE Arai, T., Kofidis, T., Bulte, J. W., de Bruin, J., Venook, R. D., Berry, G. J., McConnell, M. V., Quertermous, T., Robbins, R. C., Yang, P. C. 2006; 55 (1): 203-209
Abstract

Cell therapy has demonstrated the potential to restore injured myocardium. A reliable in vivo imaging method to localize transplanted cells and monitor their restorative effects will enable a systematic investigation of this therapeutic modality. The dual MRI capability of imaging both magnetically labeled mouse embryonic stem cells (mESC) and their restorative effects on cardiac function in a murine model of acute myocardial infarction is demonstrated. Serial in vivo MR detection of transplanted mESC and monitoring of the mESC-treated myocardium was conducted over a 4-week period using a 1.5 T clinical scanner. During the 4-week duration, the mESC-treated myocardium demonstrated sustained improvement of the left ventricular (LV) ejection fraction and conservation of LV mass. Furthermore, no significant difference of their restorative effects on the cardiac function was created by the magnetic labeling of mESC. Thus, in vivo MRI enables simultaneous detection of transplanted mESC and their therapeutic effect on the injured myocardium.

View details for DOI 10.1002/mrm.20702

View details for PubMedID 16315206
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
High-resolution real-time spiral MRI for guiding vascular interventions in a rabbit model at 1.5 T. Journal of magnetic resonance imaging : JMRI Terashima, M., Hyon, M., de la Pena-Almaguer, E., Yang, P. C., Hu, B. S., Nayak, K. S., Pauly, J. M., McConnell, M. V. 2005; 22 (5): 687-690
Abstract

To study the feasibility of a combined high spatial and temporal resolution real-time spiral MRI sequence for guiding coronary-sized vascular interventions.Eight New Zealand White rabbits (four normal and four with a surgically-created stenosis in the abdominal aorta) were studied. A real-time interactive spiral MRI sequence combining 1.1 x 1.1 mm(2) in-plane resolution and 189-msec total image acquisition time was used to image all phases of an interventional procedure (i.e., guidewire placement, balloon angioplasty, and stenting) in the rabbit aorta using coronary-sized devices on a 1.5 T MRI system.Real-time spiral MRI identified all rabbit aortic stenoses and provided high-temporal-resolution visualization of guide-wires crossing the stenoses in all animals. Angioplasty balloon dilatation and deployment of coronary-sized copper stents in the rabbit aorta were also successfully imaged by real-time spiral MRI.Combining high spatial and temporal resolution with spiral MRI allows real-time MR-guided vascular intervention using coronary-sized devices in a rabbit model. This is a promising approach for guiding coronary interventions.

View details for PubMedID 16217745
High-resolution real-time spiral MRI for guiding vascular interventions in a rabbit model at 1L.5T JOURNAL OF MAGNETIC RESONANCE IMAGING Terashima, M., Hyon, M., De La Pena-Almaguer, E., Yang, P. C., Hu, B. S., Nayalk, K. S., Pauly, J. M., McConnell, M. V. 2005; 22 (5): 687-690
Abstract

To study the feasibility of a combined high spatial and temporal resolution real-time spiral MRI sequence for guiding coronary-sized vascular interventions.Eight New Zealand White rabbits (four normal and four with a surgically-created stenosis in the abdominal aorta) were studied. A real-time interactive spiral MRI sequence combining 1.1 x 1.1 mm(2) in-plane resolution and 189-msec total image acquisition time was used to image all phases of an interventional procedure (i.e., guidewire placement, balloon angioplasty, and stenting) in the rabbit aorta using coronary-sized devices on a 1.5 T MRI system.Real-time spiral MRI identified all rabbit aortic stenoses and provided high-temporal-resolution visualization of guide-wires crossing the stenoses in all animals. Angioplasty balloon dilatation and deployment of coronary-sized copper stents in the rabbit aorta were also successfully imaged by real-time spiral MRI.Combining high spatial and temporal resolution with spiral MRI allows real-time MR-guided vascular intervention using coronary-sized devices in a rabbit model. This is a promising approach for guiding coronary interventions.

View details for DOI 10.1002/jmri.20409

View details for Web of Science ID 000233096000015
Magnetic resonance imaging of myocardial viability predicts future cardiovascular events in patients with severe ischemic cardiomyopathy 78th Annual Scientific Session of the American-Heart-Association Tsukiji, M., Nguyen, P., Narayan, G., Hellinger, J., Chan, F. P., Herfkens, R., McConnell, M. V., Yang, P. C. LIPPINCOTT WILLIAMS & WILKINS. 2005: U529?U530
View details for Web of Science ID 000232956403186
Collagen matrices enhance survival of embryonic cardiomyoblasts following transplantation into ischemic rat hearts Kutschka, Kofidis, T., Chen, I. Y., Arai, T., Sheikh, A. Y., Hendry, S. L., Pearl, J., Hoyt, G., Connolly, A., Yang, P. C., Gambhir, S. S., Robbins, R. C. LIPPINCOTT WILLIAMS & WILKINS. 2005: U805
View details for Web of Science ID 000232956405127
Myocardial restoration with embryonic stem cell transplantation in a murine myocardial infarction model 78th Annual Scientific Session of the American-Heart-Association Hendry, S. L., Arai, T., Dylla, S. J., Drukker, M., Sheikh, A. Y., Kutschka, I., Hoyt, G., Connolly, A., Pelletier, M., Wu, J. C., Yang, P. C., Robbins, R. C. LIPPINCOTT WILLIAMS & WILKINS. 2005: U37?U38
View details for Web of Science ID 000232956400031
Myocardial restoration with embryonic stem cell transplantation in a murine myocardial infarction model 78th Annual Scientific Session of the American-Heart-Association Hendry, S. L., Arai, T., Dylla, S. J., Drukker, M., Sheikh, A. Y., Kutschka, I., Hoyt, G., Connolly, A., Pelletier, M., Wu, J. C., Yang, P. C., Robbins, R. C. LIPPINCOTT WILLIAMS & WILKINS. 2005: U432?U432
View details for Web of Science ID 000232956402439
POsitive contrast magnetic resonance imaging of cells labeled with magnetic nanoparticles MAGNETIC RESONANCE IN MEDICINE Cunningham, C. H., Arai, T., Yang, P. C., McConnell, M. V., Pauly, J. M., Conolly, S. M. 2005; 53 (5): 999-1005
Abstract

Contrast agents incorporating superparamagnetic iron-oxide nanoparticles have shown promise as a means to visualize labeled cells using MRI. Labeled cells cause significant signal dephasing due to the magnetic field inhomogeneity induced in water molecules near the cell. With the resulting signal void as the means for detection, the particles behave as a negative contrast agent, which can suffer from partial-volume effects. In this paper, a new method is described for imaging labeled cells with positive contrast. Spectrally selective RF pulses are used to excite and refocus the off-resonance water surrounding the labeled cells so that only the fluid and tissue immediately adjacent to the labeled cells are visible in the image. Phantom, in vitro, and in vivo experiments show the feasibility of the new method. A significant linear correlation (r = 0.87, P < 0.005) between the estimated number of cells and the signal was observed.

View details for DOI 10.1002/mrm.20477

View details for PubMedID 15844142
Peri-infarct ischemia determined by comprehensive MR evaluation of myocardial viability and stress perfusion predicts future cardiovascular events in patients with severe ischemic cardiomyopathy 54th Annual Scientific Session of the American-College-of-Cardiology Tsukiji, M., Nguyen, P., Narayan, G., Hellinger, J., Chan, F., Herfkens, R., McConnell, M. V., Yang, P. ELSEVIER SCIENCE INC. 2005: 446A?446A
View details for Web of Science ID 000226808201931
Noninvasive assessment of coronary vasodilation using magnetic resonance angiography JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Terashima, M., Meyer, C. H., Keeffe, B. G., Putz, E. J., De La Pena-Almaguer, E., Yang, P. C., Hu, B. S., Nishimura, D. G., McConnell, M. V. 2005; 45 (1): 104-110
Abstract

The purpose of this study was to investigate the use of coronary magnetic resonance angiography (MRA) for assessing human epicardial coronary artery vasodilation.Coronary vasodilation plays a vital role in the human coronary circulation. Previous studies of epicardial coronary vasodilation have used invasive coronary angiography. Coronary MRA may provide an alternative noninvasive method to directly assess changes in coronary size.Thirty-two subjects were studied: 12 patients (age 55 +/- 18 years) and 20 healthy subjects (age 34 +/- 4 years). High-resolution multi-slice spiral coronary MRA (in-plane resolution of 0.52 to 0.75 mm) was performed before and after sublingual nitroglycerin (NTG). Quantitative analysis of coronary vasodilation was performed on cross-sectional images of the right coronary artery (RCA). A time-course analysis of coronary vasodilation was performed in a subset of eight subjects for 30 min after NTG. Signal-to-noise ratio was also measured on the in-plane RCA images.Coronary MRA demonstrated a 23% increase in cross-sectional area after NTG (16.9 +/- 7.8 mm2 to 20.8 +/- 8.9 mm2, p <0.0001), with significant vasodilation between 3 and 15 min after NTG on time-course analysis. The MRA measurements had low interobserver variability (< or =5%) and good correlation with X-ray angiography (r=0.98). The magnitude of vasodilation correlated with baseline cross-sectional area (r=0.52, p=0.03) and age (r=0.40, p=0.019). Post-NTG images also demonstrated a 31% improvement in coronary signal-to-noise ratio (p = 0.002).Nitroglycerin-enhanced coronary MRA can noninvasively measure coronary artery vasodilation and is a promising noninvasive technique to study coronary vasomotor function.

View details for DOI 10.1016/j.jacc.2004.09.057

View details for PubMedID 15629383
Early diagnosis of hemochromatosis-related cardiomyopathy with magnetic resonance imaging JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE Ptaszek, L. M., Price, E. T., Hu, M. Y., Yang, P. C. 2005; 7 (4): 689-692
Abstract

The hallmark of hemochromatosis is the deposition of iron in multiple tissue types, most notably the skin, liver, pancreas, thyroid, and heart. Definitive diagnosis of iron deposition generally requires invasive methods, such as direct tissue biopsy. We describe a 40 year-old woman with end-stage liver disease secondary to hereditary hemochromatosis and alcohol abuse, who was referred to the cardiology service as part of an evaluation for orthotopic liver transplant. The patient had no cardiac history but a dobutamine stress echocardiogram, performed as a portion of the pre-operative cardiac evaluation, could not be completed due to intermittent, supraventricular tachycardia. Additional cardiac testing, including electrocardiography and resting echocardiography, raised suspicion for cardiomyopathy related to hemochromatosis but was non-diagnostic. Cardiac magnetic resonance (MR) of this patient revealed deposition of iron in the myocardium and established the diagnosis of hemachromatosis-related cardiomyopathy. These findings suggest that cardiac MR may be more sensitive than other non-invasive, diagnostic tools in the initial evaluation of hemochromatosis-related cardiomyopathy and may be used as an alternative to myocardial biopsy. We propose that conventional T1- and T2-weighted spin echo MR sequences can be used routinely as non-invasive modalities to assess the presence of iron deposition in the tissues of patients with hemochromatosis.

View details for DOI 10.1081/JCMR-200065632

View details for PubMedID 16136860
In vivo magnetic resonance evaluation of the effects of mouse embryonic stem cells on cardiac function 53rd Annual Scientific Session of the American-College-of-Cardiology Arai, T., de Bruin, J., Kofidis, T., Venook, R., McConnell, M. V., Quertermous, T., Robbins, R., Yang, P. C. ELSEVIER SCIENCE INC. 2004: 532A?532A
View details for Web of Science ID 000189388502258
Spiral magnetic resonance coronary angiography - Direct comparison of 1.5 tesla vs. 3 tesla JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE Yang, P. C., Nguyen, P., Shimakawa, A., Brittain, J., Pauly, J., Nishimura, D., Hu, B., McConnell, M. 2004; 6 (4): 877-884
Abstract

MR coronary angiography (MRCA) has been demonstrated successfully at 3 Tesla (T). However, the advantages remain unclear. No systematic comparison of MRCA between 1.5 T and 3 T has been performed. Therefore, anatomic coverage, image quality, signal-to-noise ratio (SNR), contrast-to-noise ration (CNR), and susceptibility artifacts were compared in 23 subjects.Identical real-time (RT) and high-resolution (HR) sequences were implemented on the GE 1.5 T (Signa Twinspeed) and 3.0 T (Signa VH/i) whole body systems (GE, Milwaukee, WI). Both scanners were equipped with high-performance gradient systems capable of 40 mT/m peak amplitude and 150 mT/m/ms slew rate. Real-time localization of the coronary arteries was followed by a cardiac-gated, breath-hold HR sequence. Twenty-three subjects were recruited consecutively and underwent both 3 T and 1.5 T MRCA within one week. Coronary coverage based on the number of coronary segments visualized, image quality using a grading scale, SNR, CNR, and presence of susceptibility artifacts were analyzed. A significant improvement in SNR (47%), CNR (30%), and image quality were seen in 3 T. However, a significant increase in susceptibility artifacts was also noted.MRCA at 3 T significantly improves SNR, CNR, and image quality at the expense of susceptibility artifacts. Further optimization of the imaging parameters at 3 T may facilitate clinical implementation of MRCA.

View details for DOI 10.1081/JCMR.20036180

View details for PubMedID 15646891
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
A visual approach for the accurate determination of echocardiographic left ventricular ejection fraction by medical students JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Hope, M. D., de la Pena, E., Yang, P. C., Liang, D. H., McConnell, M. V., Rosenthal, D. N. 2003; 16 (8): 824-831
Abstract

Previously published reports show that there is significant intraobserver, interobserver, and interinstitutional variability in the determination of left ventricular (LV) ejection fraction (EF) by echocardiography. With the increased deployment of echocardiography (eg, handheld devices), there exists a need for developing a simple, intuitive approach for evaluating LVEF that allows a wider range of physicians to accurately and rapidly determine LVEF.We sought to create a system for assessing LVEF that relies on recognition and matching of patterns, rather than on mathematic calculations and geometric assumptions.A library of videoclips of cardiac function was compiled from 54 patients who spanned the spectrum of LVEF. LVEFs were calculated for these patients using standard echocardiographic methods, with further validation of a subsample using cardiac magnetic resonance imaging measurement of LVEF. The library of images was used to create a software tool for assessing LVEF on the basis of a "template-matching" approach. The software tool was then tested on medical students (N=13) to determine whether it enabled relatively untrained individuals to make accurate LVEF estimates.Using a template-matching approach for interpretation of echocardiograms, medical students were able to accurately estimate LVEF after only a limited introduction to echocardiography. Their LVEF estimates showed good correlation and agreement with gold standard (r = 0.88, standard square of the estimate = 6.0, limits of agreement = +12.0%, -15.6%).A new visual approach for assessing cardiac function using template matching can accurately estimate LVEF. With minimal training, medical students can make LVEF estimates that correlate well with gold standard. The application of this new approach includes allowing for the interpretation of LVEF from echocardiograms to be performed by a broader spectrum of physicians.

View details for DOI 10.1067/S0894-7317(03)00400-0

View details for Web of Science ID 000184604400007

View details for PubMedID 12878991
Spiral magnetic resonance coronary angiography with rapid real-time localization JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Yang, P. C., Meyer, C. H., Terashima, M., Kaji, S., McConnell, M. V., Macovski, A., Pauly, J. M., Nishimura, D. G., Hu, B. S. 2003; 41 (7): 1134-1141
Abstract

A spiral high-resolution coronary artery imaging sequence (SH) interfaced with real-time localization system (RT) has been developed. A clinical study of 40 patients suspected of coronary artery disease (CAD) was conducted. Segmented k-space acquisition techniques have dominated magnetic resonance coronary angiography (MRCA) over the last decade. Although a recent multicenter trial using this technique demonstrated encouraging results, the technique was hampered by low specificity. Spiral k-space acquisition had demonstrated several advantages for MRCA. Therefore, a first clinical trial implementing spiral high-resolution coronary imaging sequence with real-time localization (SH-RT) was performed.A clinical study of 40 patients suspected of CAD undergoing X-ray angiography was conducted to analyze the clinical reliability of this novel imaging system. The SH-RT had been designed to exploit the unique capability of two imaging sequences. The RT allowed a rapid localization of the coronary arteries. Then SH achieved multislice acquisition during a short breath-hold with submillimeter resolution. The MRCA data were analyzed for scan time, anatomic coverage, image quality, and accuracy in detecting CAD. In 40 subjects, SH achieved 0.7 to 0.9 mm resolution with 14-heartbeat breath-holds. Excellent or good image quality was achieved in 78% (263/337) of the coronary segments. Blinded consensus reading among three observers generated sensitivity of 76% and specificity of 91% in the detection of CAD compared with X-ray angiography. The MRCA imaging sequence implementing a novel spiral k-space acquisition technique enabled rapid and reliable imaging of the CAD in submillimeter resolution with short breath-holds.

View details for DOI 10.1016/S0735-1097(03)00079-2

View details for Web of Science ID 000181968900011

View details for PubMedID 12679213
Magnetic resonance coronary angiography. Current cardiology reports Yang, P. C., McConnell, M. V., Nishimura, D. G., Hu, B. S. 2003; 5 (1): 55-62
Abstract

Magnetic resonance coronary angiography (MRCA) has witnessed tremendous technical advances over the past decade. Although high-quality images of the coronary arteries have been demonstrated, this imaging modality is not performed routinely today. The fundamental properties of the coronary arteries deterring noninvasive imaging are well known. This article provides an overview of the developmental efforts to overcome these challenges, and highlights key technical and clinical advances. The future prospect of MRCA depends on clinical implementation of the technique. In order to meet this challenge, the following issues must be addressed: contrast- and signal-to-noise ratio, temporal and spatial resolution, and scan protocol.

View details for PubMedID 12493161
Contrast-enhanced MRI demonstrates acute response to vascular injury Terashima, M., De La Pena-Almaguer, E., Yang, P. C., Hu, B. S., McConnell, M. V. ELSEVIER SCIENCE INC. 2002: 389A?389A
View details for Web of Science ID 000174106701753
NTG-enhanced coronary MRA: Improved SNR and vasodilation time course Terashima, M., Keeffe, B. G., Putz, E. J., Yang, P. C., De La Pena-Almaguer, E., Hu, B. S., Nishimura, D. G., Meyer, C. H., McConnell, M. V. ELSEVIER SCIENCE INC. 2002: 218A?218A
View details for Web of Science ID 000174106700970
High-resolution real-time magnetic resonance imaging for vascular interventions. Terashima, M., De La Pena-Almaguer, E., Nayak, K., Pauly, J. M., Yang, P. C., Hu, B. S., McConnell, M. V. EXCERPTA MEDICA INC. 2001: 89G?89G
View details for Web of Science ID 000170893600229
Real-time interactive coronary MRA MAGNETIC RESONANCE IN MEDICINE Nayak, K. S., Pauly, J. M., Yang, P. C., Hu, B. S., Meyer, C. H., Nishimura, D. G. 2001; 46 (3): 430-435
Abstract

An interactive real-time imaging system capable of rapid coronary artery imaging is described. High-resolution spiral and circular echo planar trajectories were used to achieve 0.8 x 1.6 mm2 resolution in 135 ms (CEPI) or 1.13 x 1.13 mm2 resolution in 189 ms (spirals), over a 20-cm FOV. Using a sliding window reconstruction, display rates of up to 37 images/sec were achieved. Initial results indicate this technique can perform as a high-quality 2D coronary localizer and with SNR improvement may enable rapid screening of the coronary tree.

View details for Web of Science ID 000170740300004

View details for PubMedID 11550232
Rapid evaluation of left ventricular volume and mass without breath-holding using real-time interactive cardiac magnetic resonance imaging system JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Kaji, S., Yang, P. C., Kerr, A. B., Tang, W. H., Meyer, C. H., Macovski, A., Pauly, J. M., Nishimura, D. G., Hu, B. S. 2001; 38 (2): 527-533
Abstract

The purpose of this study was to validate cardiac measurements derived from real-time cardiac magnetic resonance imaging (MRI) as compared with well-validated conventional cine MRI.Although cardiac MRI provides accurate assessment of left ventricular (LV) volume and mass, most techniques have been relatively slow and required electrocardiogram (ECG) gating over many heart beats. A newly developed real-time MRI system allows continuous real-time dynamic acquisition and display without cardiac gating or breath-holding.Fourteen healthy volunteers and nine patients with heart failure underwent real-time and cine MRI in the standard short-axis orientation with a 1.5T MRI scanner. Nonbreath-holding cine MRI was performed with ECG gating and respiratory compensation. Left ventricular end-diastolic volume (LVEDV), left ventricular endsystolic volume (LVESV), ejection fraction (EF) and LV mass calculated from the images obtained by real-time MRI were compared to those obtained by cine MRI.The total study time including localization for real-time MRI was significantly shorter than cine MRI (8.6 +/- 2.3 vs. 24.7 +/- 3.5 min, p < 0.001). Both imaging techniques yielded good quality images allowing cardiac measurements. The measurements of LVEDV, LVESV, EF and LV mass obtained with real-time MRI showed close correlation with those obtained with cine MRI (LVEDV: r = 0.985, p < 0.001; LVESV: r = 0.994, p < 0.001; EF: r = 0.975, p < 0.001; LV mass: r = 0.977, p < 0.001).Real-time MRI provides accurate measurements of LV volume and mass in a time-efficient manner with respect to image acquisition.

View details for Web of Science ID 000170205800033

View details for PubMedID 11499748
New real-time interactive cardiac magnetic resonance imaging system complements echocardiography JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY Yang, P. C., Kerr, A. B., Liu, A. C., Liang, D. H., Hardy, C., Meyer, C. H., Macovski, A., Pauly, J. M., Hu, B. S. 1998; 32 (7): 2049-2056
Abstract

We conducted an initial clinical trial of a newly developed cardiac magnetic resonance imaging (CMRI) system. We evaluated left ventricular (LV) function in 85 patients to compare the clinical utility of the CMRI system with echocardiography, the current noninvasive gold standard.Conventional CMRI systems require cardiac-gating and respiratory compensation to synthesize a single image from data acquired over multiple cardiac cycles. In contrast, the new CMRI system allows continuous real-time dynamic acquisition and display of any scan plane at 16 images/s without the need for cardiac gating or breath-holding.A conventional 1.5T Signa MRI Scanner (GE, Milwaukee, Wisconsin) was modified by the addition of an interactive workstation and a bus adapter. The new CMRI system underwent clinical trial by testing its ability to evaluate global and regional LV function. The first group (A) consisted of 31 patients with acceptable echocardiography image quality. The second group (B) consisted of 31 patients with suboptimal echocardiography image quality. The third group (C) consisted of 29 patients with severe lung disease or congenital cardiac malformation who frequently have suboptimal echo study. Two independent observers scored wall motion and image quality using the standard 16-segment model and rank-order analysis.CMRI evaluation was complete in less than 15 min. In group A, no significant difference was found between ECHO and CMRI studies (p = NS). In group B, adequate visualization of wall segments was obtained 38% of the time using ECHO and 97% of the time using CMRI (p < 0.0001). When grouped into coronary segments, adequate visualization of at least one segment occurred in 18 of 30 patients (60%) with ECHO and in all 30 patients (100%) with CMRI (p < 0.0001). In group C, adequate visualization of the wall segments was obtained in 58% (CI 0.53-0.62) of the time using echocardiography and 99.7% (CI 0.99-1.0) of the time using CMRI (p < 0.0001).The new CMRI system provides clinically reliable evaluation of LV function and complements suboptimal echocardiography. In comparison with the conventional CMRI, the new CMRI system significantly reduces scan time, patient discomfort and associated cost.

View details for Web of Science ID 000077396200039

View details for PubMedID 9857892

Phillip C. Yang, MD

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

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