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\n \n \n\n \n \n \n \n \n Aggregation of Child Cardiac Progenitor Cells Into Spheres Activates Notch Signaling and Improves Treatment of Right Ventricular Heart Failure.\n \n \n \n\n\n \n Trac, D.; Maxwell, J. T.; Brown, M. E.; Xu, C.; and Davis, M. E.\n\n\n \n\n\n\n Circulation Research, 124(4): 526–538. February 2019.\n \n\n\n\n
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\n\n\n@article{trac_aggregation_2019,\n\ttitle = {Aggregation of {Child} {Cardiac} {Progenitor} {Cells} {Into} {Spheres} {Activates} {Notch} {Signaling} and {Improves} {Treatment} of {Right} {Ventricular} {Heart} {Failure}},\n\tvolume = {124},\n\tissn = {1524-4571},\n\tdoi = {10.1161/CIRCRESAHA.118.313845},\n\tabstract = {RATIONALE: Congenital heart disease can lead to life-threatening right ventricular (RV) heart failure. Results from clinical trials support expanding cardiac progenitor cell (CPC) based therapies. However, our recent data show that CPCs lose function as they age, starting as early as 1 year.\nOBJECTIVE: To determine whether the aggregation of child (1-5-year-old) CPCs into scaffold-free spheres can improve differentiation by enhancing Notch signaling, a known regulator of CPC fate. We hypothesized that aggregated (3-dimensional [3D]) CPCs will repair RV heart failure better than monolayer (2-dimensional [2D]) CPCs.\nMETHODS AND RESULTS: Spheres were produced with 1500 CPCs each using a microwell array. CPC aggregation significantly increased gene expression of Notch1 compared with 2D CPCs, accompanied by significant upregulation of cardiogenic transcription factors (GATA4, HAND1, MEF2C, NKX2.5, and TBX5) and endothelial markers (CD31, FLK1, FLT1, VWF). Blocking Notch receptor activation with the γ-secretase inhibitor DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) diminished these effects. To evaluate the therapeutic improvements of CPC aggregation, RV heart failure was induced in athymic rats by pulmonary artery banding, and cells were implanted into the RV free wall. Echocardiographic measurements 28 days postimplantation showed significantly improved RV function with 3D compared with 2D CPCs. Tracking implanted CPCs via DiR (1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide)-labeling showed improved retention of 3D CPCs. Transducing 3D CPCs with Notch1-shRNA (short hairpin RNA) did not reduce retention, but significantly reduced RV functional improvements. Histological analyses showed 3D treatment reduced RV fibrosis and increased angiogenesis. Although 3D CPCs formed CD31+ vessel-like cells in vivo, these effects are more likely because of improved 3D CPC exosome function compared with 2D CPC exosomes.\nCONCLUSIONS: Spherical aggregation improves child CPC function in a Notch-dependent manner. The strong reparative ability of CPC spheres warrants further investigation as a treatment for pediatric heart failure, especially in older children where reparative ability may be reduced.},\n\tlanguage = {eng},\n\tnumber = {4},\n\tjournal = {Circulation Research},\n\tauthor = {Trac, David and Maxwell, Joshua T. and Brown, Milton E. and Xu, Chunhui and Davis, Michael E.},\n\tmonth = feb,\n\tyear = {2019},\n\tpmid = {30590978},\n\tpmcid = {PMC6375764},\n\tkeywords = {child, exosomes, heart failure, stem cell transplantation},\n\tpages = {526--538},\n}\n\n\n\n RATIONALE: Congenital heart disease can lead to life-threatening right ventricular (RV) heart failure. Results from clinical trials support expanding cardiac progenitor cell (CPC) based therapies. However, our recent data show that CPCs lose function as they age, starting as early as 1 year. OBJECTIVE: To determine whether the aggregation of child (1-5-year-old) CPCs into scaffold-free spheres can improve differentiation by enhancing Notch signaling, a known regulator of CPC fate. We hypothesized that aggregated (3-dimensional [3D]) CPCs will repair RV heart failure better than monolayer (2-dimensional [2D]) CPCs. METHODS AND RESULTS: Spheres were produced with 1500 CPCs each using a microwell array. CPC aggregation significantly increased gene expression of Notch1 compared with 2D CPCs, accompanied by significant upregulation of cardiogenic transcription factors (GATA4, HAND1, MEF2C, NKX2.5, and TBX5) and endothelial markers (CD31, FLK1, FLT1, VWF). Blocking Notch receptor activation with the γ-secretase inhibitor DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester) diminished these effects. To evaluate the therapeutic improvements of CPC aggregation, RV heart failure was induced in athymic rats by pulmonary artery banding, and cells were implanted into the RV free wall. Echocardiographic measurements 28 days postimplantation showed significantly improved RV function with 3D compared with 2D CPCs. Tracking implanted CPCs via DiR (1,1'-dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine iodide)-labeling showed improved retention of 3D CPCs. Transducing 3D CPCs with Notch1-shRNA (short hairpin RNA) did not reduce retention, but significantly reduced RV functional improvements. Histological analyses showed 3D treatment reduced RV fibrosis and increased angiogenesis. Although 3D CPCs formed CD31+ vessel-like cells in vivo, these effects are more likely because of improved 3D CPC exosome function compared with 2D CPC exosomes. CONCLUSIONS: Spherical aggregation improves child CPC function in a Notch-dependent manner. The strong reparative ability of CPC spheres warrants further investigation as a treatment for pediatric heart failure, especially in older children where reparative ability may be reduced.\n
\n\n\n\n \n\n \n \n \n \n \n T Cells Play a Causal Role in Diastolic Dysfunction during Uremic Cardiomyopathy.\n \n \n \n\n\n \n Winterberg, P. D.; Robertson, J. M.; Kelleman, M. S.; George, R. P.; and Ford, M. L.\n\n\n \n\n\n\n Journal of the American Society of Nephrology: JASN. February 2019.\n \n\n\n\n
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\n\n\n@article{winterberg_t_2019,\n\ttitle = {T {Cells} {Play} a {Causal} {Role} in {Diastolic} {Dysfunction} during {Uremic} {Cardiomyopathy}},\n\tissn = {1533-3450},\n\tdoi = {10.1681/ASN.2017101138},\n\tabstract = {BACKGROUND: Uremic cardiomyopathy, characterized by left ventricular hypertrophy, diastolic dysfunction, and impaired myocardial strain, contributes to increased cardiovascular mortality in patients with CKD. Emerging evidence suggests a pathogenic role for T cells during chronic heart failure.\nMETHODS: To determine whether T cells contribute to uremic cardiomyopathy pathogenesis, we modeled this condition by inducing CKD via 5/6th nephrectomy in mice. We used flow cytometry to assess expression of markers of T cell memory or activation by lymphocytes from CKD mice and controls, as well as lymphocyte capacity for cytokine production. Flow cytometry was also used to quantify immune cells isolated from heart tissue. To test effects of T cell depletion on cardiac function, we gave CKD mice anti-CD3 antibody injections to deplete T cells and compared heart function (assessed by echocardiography) with that of controls. Finally, we correlated T cell phenotypes with structural and functional measures on clinically acquired echocardiograms in children with CKD.\nRESULTS: Mice with CKD accumulated T cells bearing markers of memory differentiation (CD44hi) and activation (PD-1, KLRG1, OX40), as reported previously in human CKD. In addition, mice with CKD showed T cells infiltrating the heart. T cell depletion significantly improved both diastolic function and myocardial strain in CKD mice without altering hypertension or degree of renal dysfunction. In children with CKD, increasing frequency of T cells bearing activation markers PD-1 and/or CD57 was associated with worsening diastolic function on echocardiogram.\nCONCLUSIONS: CKD results in an accumulation of proinflammatory T cells that appears to contribute to myocardial dysfunction.},\n\tlanguage = {eng},\n\tjournal = {Journal of the American Society of Nephrology: JASN},\n\tauthor = {Winterberg, Pamela D. and Robertson, Jennifer M. and Kelleman, Michael S. and George, Roshan P. and Ford, Mandy L.},\n\tmonth = feb,\n\tyear = {2019},\n\tpmid = {30728178},\n\tkeywords = {129 Mice, Diastolic Heart Failure, Doppler Echocardiography, T-Lymphocyte Subsets, chronic kidney disease},\n}\n\n\n\n BACKGROUND: Uremic cardiomyopathy, characterized by left ventricular hypertrophy, diastolic dysfunction, and impaired myocardial strain, contributes to increased cardiovascular mortality in patients with CKD. Emerging evidence suggests a pathogenic role for T cells during chronic heart failure. METHODS: To determine whether T cells contribute to uremic cardiomyopathy pathogenesis, we modeled this condition by inducing CKD via 5/6th nephrectomy in mice. We used flow cytometry to assess expression of markers of T cell memory or activation by lymphocytes from CKD mice and controls, as well as lymphocyte capacity for cytokine production. Flow cytometry was also used to quantify immune cells isolated from heart tissue. To test effects of T cell depletion on cardiac function, we gave CKD mice anti-CD3 antibody injections to deplete T cells and compared heart function (assessed by echocardiography) with that of controls. Finally, we correlated T cell phenotypes with structural and functional measures on clinically acquired echocardiograms in children with CKD. RESULTS: Mice with CKD accumulated T cells bearing markers of memory differentiation (CD44hi) and activation (PD-1, KLRG1, OX40), as reported previously in human CKD. In addition, mice with CKD showed T cells infiltrating the heart. T cell depletion significantly improved both diastolic function and myocardial strain in CKD mice without altering hypertension or degree of renal dysfunction. In children with CKD, increasing frequency of T cells bearing activation markers PD-1 and/or CD57 was associated with worsening diastolic function on echocardiogram. CONCLUSIONS: CKD results in an accumulation of proinflammatory T cells that appears to contribute to myocardial dysfunction.\n
\n\n\n\n \n\n \n \n \n \n \n Convergences of Life Sciences and Engineering in Understanding and Treating Heart Failure.\n \n \n \n\n\n \n Berry, J. L.; Zhu, W.; Tang, Y. L.; Krishnamurthy, P.; Ge, Y.; Cooke, J. P.; Chen, Y.; Garry, D. J.; Yang, H.; Rajasekaran, N. S.; Koch, W. J.; Li, S.; Domae, K.; Qin, G.; Cheng, K.; Kamp, T. J.; Ye, L.; Hu, S.; Ogle, B. M.; Rogers, J. M.; Abel, E. D.; Davis, M. E.; Prabhu, S. D.; Liao, R.; Pu, W. T.; Wang, Y.; Ping, P.; Bursac, N.; Vunjak-Novakovic, G.; Wu, J. C.; Bolli, R.; Menasché, P.; and Zhang, J.\n\n\n \n\n\n\n Circulation Research, 124(1): 161–169. January 2019.\n \n\n\n\n
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\n\n\n@article{berry_convergences_2019,\n\ttitle = {Convergences of {Life} {Sciences} and {Engineering} in {Understanding} and {Treating} {Heart} {Failure}},\n\tvolume = {124},\n\tissn = {1524-4571},\n\tdoi = {10.1161/CIRCRESAHA.118.314216},\n\tabstract = {On March 1 and 2, 2018, the National Institutes of Health 2018 Progenitor Cell Translational Consortium, Cardiovascular Bioengineering Symposium, was held at the University of Alabama at Birmingham. Convergence of life sciences and engineering to advance the understanding and treatment of heart failure was the theme of the meeting. Over 150 attendees were present, and {\\textgreater}40 scientists presented their latest work on engineering human functional myocardium for disease modeling, drug development, and heart failure research. The scientists, engineers, and physicians in the field of cardiovascular sciences met and discussed the most recent advances in their work and proposed future strategies for overcoming the major roadblocks of cardiovascular bioengineering and therapy. Particular emphasis was given for manipulation and using of stem/progenitor cells, biomaterials, and methods to provide molecular, chemical, and mechanical cues to cells to influence their identity and fate in vitro and in vivo. Collectively, these works are profoundly impacting and progressing toward deciphering the mechanisms and developing novel treatments for left ventricular dysfunction of failing hearts. Here, we present some important perspectives that emerged from this meeting.},\n\tlanguage = {eng},\n\tnumber = {1},\n\tjournal = {Circulation Research},\n\tauthor = {Berry, Joel L. and Zhu, Wuqiang and Tang, Yao Liang and Krishnamurthy, Prasanna and Ge, Ying and Cooke, John P. and Chen, Yabing and Garry, Daniel J. and Yang, Huang-Tian and Rajasekaran, Namakkal Soorapan and Koch, Walter J. and Li, Song and Domae, Keitaro and Qin, Gangjian and Cheng, Ke and Kamp, Timothy J. and Ye, Lei and Hu, Shijun and Ogle, Brenda M. and Rogers, Jack M. and Abel, E. Dale and Davis, Michael E. and Prabhu, Sumanth D. and Liao, Ronglih and Pu, William T. and Wang, Yibin and Ping, Peipei and Bursac, Nenad and Vunjak-Novakovic, Gordana and Wu, Joseph C. and Bolli, Roberto and Menasché, Philippe and Zhang, Jianyi},\n\tmonth = jan,\n\tyear = {2019},\n\tpmid = {30605412},\n\tpmcid = {PMC6350935},\n\tkeywords = {bioengineering, heart failure, myocardium, stem cells, tissue engineering},\n\tpages = {161--169},\n}\n\n\n\n On March 1 and 2, 2018, the National Institutes of Health 2018 Progenitor Cell Translational Consortium, Cardiovascular Bioengineering Symposium, was held at the University of Alabama at Birmingham. Convergence of life sciences and engineering to advance the understanding and treatment of heart failure was the theme of the meeting. Over 150 attendees were present, and \\textgreater40 scientists presented their latest work on engineering human functional myocardium for disease modeling, drug development, and heart failure research. The scientists, engineers, and physicians in the field of cardiovascular sciences met and discussed the most recent advances in their work and proposed future strategies for overcoming the major roadblocks of cardiovascular bioengineering and therapy. Particular emphasis was given for manipulation and using of stem/progenitor cells, biomaterials, and methods to provide molecular, chemical, and mechanical cues to cells to influence their identity and fate in vitro and in vivo. Collectively, these works are profoundly impacting and progressing toward deciphering the mechanisms and developing novel treatments for left ventricular dysfunction of failing hearts. Here, we present some important perspectives that emerged from this meeting.\n
\n\n\n\n \n\n \n \n \n \n \n Decellularized Extracellular Matrix Materials for Cardiac Repair and Regeneration.\n \n \n \n\n\n \n Bejleri, D.; and Davis, M. E.\n\n\n \n\n\n\n Advanced Healthcare Materials,e1801217. February 2019.\n \n\n\n\n
\n\n\n\n \n\n \n \n doi\n \n \n\n \n link\n \n \n\n bibtex\n \n\n \n \n \n abstract \n \n\n \n \n \n 4 downloads\n \n \n\n \n \n \n \n \n \n \n\n \n \n \n \n \n \n \n \n \n \n \n\n\n\n
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\n\n\n@article{bejleri_decellularized_2019,\n\ttitle = {Decellularized {Extracellular} {Matrix} {Materials} for {Cardiac} {Repair} and {Regeneration}},\n\tissn = {2192-2659},\n\tdoi = {10.1002/adhm.201801217},\n\tabstract = {Decellularized extracellular matrix (dECM) is a promising biomaterial for repairing cardiovascular tissue, as dECM most effectively captures the complex array of proteins, glycosaminoglycans, proteoglycans, and many other matrix components that are found in native tissue, providing ideal cues for regeneration and repair of damaged myocardium. dECM can be used in a variety of forms, such as solid scaffolds that maintain native matrix structure, or as soluble materials that can form injectable hydrogels for tissue repair. dECM has found recent success in many regeneration and repair therapies, such as for musculoskeletal, neural, and liver tissues. This review focuses on dECM in the context of cardiovascular applications, with variations in tissue and species sourcing, and specifically discusses advances in solid and soluble dECM development, in vitro studies, in vivo implementation, and clinical translation.},\n\tlanguage = {eng},\n\tjournal = {Advanced Healthcare Materials},\n\tauthor = {Bejleri, Donald and Davis, Michael E.},\n\tmonth = feb,\n\tyear = {2019},\n\tpmid = {30714354},\n\tkeywords = {cardiac patches, decellularized, extracellular matrices, injectable hydrogels},\n\tpages = {e1801217},\n}\n\n\n\n Decellularized extracellular matrix (dECM) is a promising biomaterial for repairing cardiovascular tissue, as dECM most effectively captures the complex array of proteins, glycosaminoglycans, proteoglycans, and many other matrix components that are found in native tissue, providing ideal cues for regeneration and repair of damaged myocardium. dECM can be used in a variety of forms, such as solid scaffolds that maintain native matrix structure, or as soluble materials that can form injectable hydrogels for tissue repair. dECM has found recent success in many regeneration and repair therapies, such as for musculoskeletal, neural, and liver tissues. This review focuses on dECM in the context of cardiovascular applications, with variations in tissue and species sourcing, and specifically discusses advances in solid and soluble dECM development, in vitro studies, in vivo implementation, and clinical translation.\n
\n\n\n\n \n\n \n \n \n \n \n Outcomes of Mechanical Mitral Valve Replacement in Children.\n \n \n \n\n\n \n Ibezim, C.; Sarvestani, A. L.; Knight, J. H.; Qayum, O.; Alshami, N.; Turk, E.; St Louis, J.; McCracken, C.; Moller, J. H.; Kochilas, L.; and Raghuveer, G.\n\n\n \n\n\n\n The Annals of Thoracic Surgery, 107(1): 143–150. January 2019.\n \n\n\n\n
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\n\n\n@article{ibezim_outcomes_2019,\n\ttitle = {Outcomes of {Mechanical} {Mitral} {Valve} {Replacement} in {Children}},\n\tvolume = {107},\n\tissn = {1552-6259},\n\tdoi = {10.1016/j.athoracsur.2018.07.069},\n\tabstract = {BACKGROUND: Mitral valve anomalies in children are rare but frequently severe, recalcitrant, and not often amenable to primary repair, necessitating mechanical mitral valve replacement (M-MVR). This study examined outcomes of a cohort undergoing a first M-MVR at age younger than 21 years.\nMETHODS: We queried the Pediatric Cardiac Care Consortium, a multi-institutional United States-based cardiac intervention registry, for patients undergoing first M-MVR for 2-ventricle congenital heart disease. Survival and transplant status through 2014 were obtained from Pediatric Cardiac Care Consortium and linkage with the National Death Index and the Organ Procurement and Transplantation Network.\nRESULTS: We identified 441 patients (median age, 4.3 years; interquartile range, 1.3 to 10.1 years) meeting study criteria. The commonest disease necessitating M-MVR was atrioventricular canal (44.3\\%). Early mortality (death {\\textless}90 days after M-MVR) was 11.1\\%; there was increased risk of early death if age at M-MVR was younger than 2 years (odds ratio, 7.8; 95\\% confidence interval [CI], 1.1 to 56.6) and with concurrent other mechanical valve placement (odds ratio, 8.5; 95\\% CI, 2.0 to 35.6). In those surviving more than 90 days after M-MVR, transplant-free survival was 76\\% at 20 years of follow-up (median follow-up, 16.6 years; interquartile range, 11.9 to 21.3 years). Adjusted analysis in those who survived more than 90 days showed elevated risk of death/transplant for boys (hazard ratio, 1.5; 95\\% CI, 1.0 to 2.3), age at M-MVR younger than 2 years (10-year survival: hazard ratio, 4.3; 95\\% CI, 1.2 to 15.1), and nonbileaflet prosthesis placement (hazard ratio, 2.4; 95\\% CI, 1.3 to 4.3).\nCONCLUSIONS: M-MVR is a viable strategy in children with unrepairable mitral valve disease. Age younger than 2 years at the first M-MVR is associated with significant early risk of death and poorer long-term survival.},\n\tlanguage = {eng},\n\tnumber = {1},\n\tjournal = {The Annals of Thoracic Surgery},\n\tauthor = {Ibezim, Chizitam and Sarvestani, Amber Leila and Knight, Jessica H. and Qayum, Omar and Alshami, Noor and Turk, Elizabeth and St Louis, James and McCracken, Courtney and Moller, James H. and Kochilas, Lazaros and Raghuveer, Geetha},\n\tmonth = jan,\n\tyear = {2019},\n\tpmid = {30267694},\n\tpages = {143--150},\n}\n\n\n\n BACKGROUND: Mitral valve anomalies in children are rare but frequently severe, recalcitrant, and not often amenable to primary repair, necessitating mechanical mitral valve replacement (M-MVR). This study examined outcomes of a cohort undergoing a first M-MVR at age younger than 21 years. METHODS: We queried the Pediatric Cardiac Care Consortium, a multi-institutional United States-based cardiac intervention registry, for patients undergoing first M-MVR for 2-ventricle congenital heart disease. Survival and transplant status through 2014 were obtained from Pediatric Cardiac Care Consortium and linkage with the National Death Index and the Organ Procurement and Transplantation Network. RESULTS: We identified 441 patients (median age, 4.3 years; interquartile range, 1.3 to 10.1 years) meeting study criteria. The commonest disease necessitating M-MVR was atrioventricular canal (44.3%). Early mortality (death \\textless90 days after M-MVR) was 11.1%; there was increased risk of early death if age at M-MVR was younger than 2 years (odds ratio, 7.8; 95% confidence interval [CI], 1.1 to 56.6) and with concurrent other mechanical valve placement (odds ratio, 8.5; 95% CI, 2.0 to 35.6). In those surviving more than 90 days after M-MVR, transplant-free survival was 76% at 20 years of follow-up (median follow-up, 16.6 years; interquartile range, 11.9 to 21.3 years). Adjusted analysis in those who survived more than 90 days showed elevated risk of death/transplant for boys (hazard ratio, 1.5; 95% CI, 1.0 to 2.3), age at M-MVR younger than 2 years (10-year survival: hazard ratio, 4.3; 95% CI, 1.2 to 15.1), and nonbileaflet prosthesis placement (hazard ratio, 2.4; 95% CI, 1.3 to 4.3). CONCLUSIONS: M-MVR is a viable strategy in children with unrepairable mitral valve disease. Age younger than 2 years at the first M-MVR is associated with significant early risk of death and poorer long-term survival.\n
\n\n\n\n \n\n \n \n \n \n \n Low cerebral blood flow is a non-invasive biomarker of neuroinflammation after repetitive mild traumatic brain injury.\n \n \n \n\n\n \n Sankar, S. B.; Pybus, A. F.; Liew, A.; Sanders, B.; Shah, K. J.; Wood, L. B.; and Buckley, E. M.\n\n\n \n\n\n\n Neurobiology of Disease, 124: 544–554. April 2019.\n \n\n\n\n
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\n\n\n@article{sankar_low_2019,\n\ttitle = {Low cerebral blood flow is a non-invasive biomarker of neuroinflammation after repetitive mild traumatic brain injury},\n\tvolume = {124},\n\tissn = {1095-953X},\n\tdoi = {10.1016/j.nbd.2018.12.018},\n\tabstract = {Previous work has shown that non-invasive optical measurement of low cerebral blood flow (CBF) is an acute biomarker of poor long-term cognitive outcome after repetitive mild traumatic brain injury (rmTBI). Herein, we explore the relationship between acute cerebral blood flow and underlying neuroinflammation. Specifically, because neuroinflammation is a driver of secondary injury after TBI, we hypothesized that both glial activation and inflammatory signaling are associated with acute CBF and, by extension, with long-term cognitive outcome after rmTBI. To test this hypothesis, cortical CBF was non-invasively measured in anesthetized mice 4 h after 3 repetitive closed head injuries spaced once-daily, at which time brains were collected. Right hemispheres were fixed for immunohistochemical staining for glial activation markers Iba1 and GFAP while left hemispheres were used to quantify Iba1 and GFAP expression via Western blot as well as 32 cytokines and 21 phospho-proteins in the MAPK, PI3K/Akt, and NF-κB pathways using a Luminex multiplexed immunoassay. N = 8/7 injured/sham C57/black-6 adult male mice were studied. Within the injured group, CBF inversely correlated with Iba1 expression (R = -0.86, p {\\textless} .01). Further, partial least squares regression analysis revealed significant correlations between CBF and expression of multiple pro-inflammatory cytokines, including RANTES and IL-17. Finally, within the injured group, phosphorylation of specific signals in the MAPK and NF-κB intracellular signaling pathways (e.g., p38 MAPK and NF-κB) were significantly positively correlated with Iba1. In total, our data indicate that acute cerebral blood flow after rmTBI is a biomarker of underlying neuroinflammatory pathology.},\n\tlanguage = {eng},\n\tjournal = {Neurobiology of Disease},\n\tauthor = {Sankar, Sitara B. and Pybus, Alyssa F. and Liew, Amanda and Sanders, Bharat and Shah, Kajol J. and Wood, Levi B. and Buckley, Erin M.},\n\tmonth = apr,\n\tyear = {2019},\n\tpmid = {30592976},\n\tkeywords = {Cerebral blood flow, Cytokines, Kinase signaling, Mild traumatic brain injury, Neuroinflammation},\n\tpages = {544--554},\n}\n\n\n\n Previous work has shown that non-invasive optical measurement of low cerebral blood flow (CBF) is an acute biomarker of poor long-term cognitive outcome after repetitive mild traumatic brain injury (rmTBI). Herein, we explore the relationship between acute cerebral blood flow and underlying neuroinflammation. Specifically, because neuroinflammation is a driver of secondary injury after TBI, we hypothesized that both glial activation and inflammatory signaling are associated with acute CBF and, by extension, with long-term cognitive outcome after rmTBI. To test this hypothesis, cortical CBF was non-invasively measured in anesthetized mice 4 h after 3 repetitive closed head injuries spaced once-daily, at which time brains were collected. Right hemispheres were fixed for immunohistochemical staining for glial activation markers Iba1 and GFAP while left hemispheres were used to quantify Iba1 and GFAP expression via Western blot as well as 32 cytokines and 21 phospho-proteins in the MAPK, PI3K/Akt, and NF-κB pathways using a Luminex multiplexed immunoassay. N = 8/7 injured/sham C57/black-6 adult male mice were studied. Within the injured group, CBF inversely correlated with Iba1 expression (R = -0.86, p \\textless .01). Further, partial least squares regression analysis revealed significant correlations between CBF and expression of multiple pro-inflammatory cytokines, including RANTES and IL-17. Finally, within the injured group, phosphorylation of specific signals in the MAPK and NF-κB intracellular signaling pathways (e.g., p38 MAPK and NF-κB) were significantly positively correlated with Iba1. In total, our data indicate that acute cerebral blood flow after rmTBI is a biomarker of underlying neuroinflammatory pathology.\n
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\n \n \n\n \n \n \n \n \n A Bioprinted Cardiac Patch Composed of Cardiac-Specific Extracellular Matrix and Progenitor Cells for Heart Repair.\n \n \n \n\n\n \n Bejleri, D.; Streeter, B. W.; Nachlas, A. L. Y.; Brown, M. E.; Gaetani, R.; Christman, K. L.; and Davis, M. E.\n\n\n \n\n\n\n Advanced Healthcare Materials, 7(23): e1800672. December 2018.\n \n\n\n\n
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\n\n\n@article{bejleri_bioprinted_2018,\n\ttitle = {A {Bioprinted} {Cardiac} {Patch} {Composed} of {Cardiac}-{Specific} {Extracellular} {Matrix} and {Progenitor} {Cells} for {Heart} {Repair}},\n\tvolume = {7},\n\tissn = {2192-2659},\n\tdoi = {10.1002/adhm.201800672},\n\tabstract = {Congenital heart defects are present in 8 of 1000 newborns and palliative surgical therapy has increased survival. Despite improved outcomes, many children develop reduced cardiac function and heart failure requiring transplantation. Human cardiac progenitor cell (hCPC) therapy has potential to repair the pediatric myocardium through release of reparative factors, but therapy suffers from limited hCPC retention and functionality. Decellularized cardiac extracellular matrix hydrogel (cECM) improves heart function in animals, and human trials are ongoing. In the present study, a 3D-bioprinted patch containing cECM for delivery of pediatric hCPCs is developed. Cardiac patches are printed with bioinks composed of cECM, hCPCs, and gelatin methacrylate (GelMA). GelMA-cECM bioinks print uniformly with a homogeneous distribution of cECM and hCPCs. hCPCs maintain {\\textgreater}75\\% viability and incorporation of cECM within patches results in a 30-fold increase in cardiogenic gene expression of hCPCs compared to hCPCs grown in pure GelMA patches. Conditioned media from GelMA-cECM patches show increased angiogenic potential ({\\textgreater}2-fold) over GelMA alone, as seen by improved endothelial cell tube formation. Finally, patches are retained on rat hearts and show vascularization over 14 d in vivo. This work shows the successful bioprinting and implementation of cECM-hCPC patches for potential use in repairing damaged myocardium.},\n\tlanguage = {eng},\n\tnumber = {23},\n\tjournal = {Advanced Healthcare Materials},\n\tauthor = {Bejleri, Donald and Streeter, Benjamin W. and Nachlas, Aline L. Y. and Brown, Milton E. and Gaetani, Roberto and Christman, Karen L. and Davis, Michael E.},\n\tmonth = dec,\n\tyear = {2018},\n\tpmid = {30379414},\n\tkeywords = {bioprinting, cardiac extracellular matrix, cardiac patches, cardiac progenitor cells, pediatric heart failure},\n\tpages = {e1800672},\n}\n\n\n\n Congenital heart defects are present in 8 of 1000 newborns and palliative surgical therapy has increased survival. Despite improved outcomes, many children develop reduced cardiac function and heart failure requiring transplantation. Human cardiac progenitor cell (hCPC) therapy has potential to repair the pediatric myocardium through release of reparative factors, but therapy suffers from limited hCPC retention and functionality. Decellularized cardiac extracellular matrix hydrogel (cECM) improves heart function in animals, and human trials are ongoing. In the present study, a 3D-bioprinted patch containing cECM for delivery of pediatric hCPCs is developed. Cardiac patches are printed with bioinks composed of cECM, hCPCs, and gelatin methacrylate (GelMA). GelMA-cECM bioinks print uniformly with a homogeneous distribution of cECM and hCPCs. hCPCs maintain \\textgreater75% viability and incorporation of cECM within patches results in a 30-fold increase in cardiogenic gene expression of hCPCs compared to hCPCs grown in pure GelMA patches. Conditioned media from GelMA-cECM patches show increased angiogenic potential (\\textgreater2-fold) over GelMA alone, as seen by improved endothelial cell tube formation. Finally, patches are retained on rat hearts and show vascularization over 14 d in vivo. This work shows the successful bioprinting and implementation of cECM-hCPC patches for potential use in repairing damaged myocardium.\n
\n\n\n\n \n\n \n \n \n \n \n Government continues to have an important role in promoting cardiovascular health.\n \n \n \n\n\n \n Tomaselli, G.; Roach, W. H.; Piña, I. L.; Oster, M. E.; Dietz, W. H.; Horton, K.; Borden, W. B.; Brownell, K.; Gibbons, R. J.; Otten, J. J.; Lee, C. S.; Hill, C.; Heidenreich, P. A.; Siscovick, D. S.; and Whitsel, L. P.\n\n\n \n\n\n\n American Heart Journal, 198: 160–165. 2018.\n \n\n\n\n
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\n\n\n\n@article{tomaselli_government_2018,\n\ttitle = {Government continues to have an important role in promoting cardiovascular health},\n\tvolume = {198},\n\tissn = {1097-6744},\n\tdoi = {10.1016/j.ahj.2017.11.002},\n\tlanguage = {eng},\n\tjournal = {American Heart Journal},\n\tauthor = {Tomaselli, Gordon and Roach, William H. and Piña, Ileana L. and Oster, Matthew E. and Dietz, William H. and Horton, Katie and Borden, William B. and Brownell, Kelly and Gibbons, Raymond J. and Otten, Jennifer J. and Lee, Christopher S. and Hill, Charles and Heidenreich, Paul A. and Siscovick, David S. and Whitsel, Laurie P.},\n\tyear = {2018},\n\tpmid = {29653638},\n\tkeywords = {Cardiovascular Diseases, Female, Government, Health Care Coalitions, Health Planning, Health Policy, Health Promotion, Humans, Male, Organizational Innovation, Policy Making, Program Development, Program Evaluation, Role, United States},\n\tpages = {160--165},\n}\n\n\n\n \n\n \n \n \n \n \n The utility of cardiac magnetic resonance imaging in post-Fontan surveillance.\n \n \n \n\n\n \n Zaki, N. C.; Kelleman, M. S.; James Parks, W.; Slesnick, T. C.; McConnell, M. E.; and Oster, M. E.\n\n\n \n\n\n\n Congenital Heart Disease. October 2018.\n \n\n\n\n
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\n\n\n@article{zaki_utility_2018,\n\ttitle = {The utility of cardiac magnetic resonance imaging in post-{Fontan} surveillance},\n\tissn = {1747-0803},\n\tdoi = {10.1111/chd.12692},\n\tabstract = {OBJECTIVE: Gated cardiac MRI offers the most detailed and accurate noninvasive method of assessing cardiac anatomy, particularly in patients with complex congenital heart disease. The proposed benefits of using cMRI as a routine screening tool in the Fontan population include early recognition of asymptomatic, postoperative anatomic and physiologic changes. In 2011, we therefore instituted at our center a recommended practice of cMRI screening in patients with Fontan physiology at 3 and 8 years post-Fontan operation. The purpose of this study was to determine the impact of this standardized practice of cMRI screening on the clinical management of a Fontan population.\nDESIGN: We retrospectively reviewed charts from our institutional Fontan database to determine which patients were eligible for cMRI under the current guidelines and who underwent imaging from November 2002 to June 2015. We reviewed the frequency of cMRI and number of changes in management based on the results. Statistical significance was determined using a chi-square test.\nRESULTS: There were 141 cMRIs performed on 121 patients who met inclusion criteria. The odds of a change in management were significantly greater after clinically indicated cMRI compared to screening cMRI (OR = 3.79, 95\\% CI: 1.48-9.66, P = .004). There were near significant odds of change in management if the cMRI occurred {\\textless}8 years after Fontan regardless of whether it was for screening or clinically indicated purposes (OR = 2.43, 95\\% CI: 0.97-6.08, P = .052). The most frequent change in management was referral for catheterization with pulmonary artery angioplasty.\nCONCLUSIONS: There is an important role for cMRI in routine surveillance of post-Fontan patients. Screening cMRI performed less than 8 years after Fontan palliation offers increased utility compared to studies performed later. The optimal timing of such imaging after Fontan palliation remains unclear.},\n\tlanguage = {eng},\n\tjournal = {Congenital Heart Disease},\n\tauthor = {Zaki, Neil C. and Kelleman, Michael S. and James Parks, W. and Slesnick, Timothy C. and McConnell, Michael E. and Oster, Matthew E.},\n\tmonth = oct,\n\tyear = {2018},\n\tpmid = {30378262},\n\tkeywords = {Fontan palliation, cardiac MRI, outcomes, surveillance},\n}\n\n\n\n OBJECTIVE: Gated cardiac MRI offers the most detailed and accurate noninvasive method of assessing cardiac anatomy, particularly in patients with complex congenital heart disease. The proposed benefits of using cMRI as a routine screening tool in the Fontan population include early recognition of asymptomatic, postoperative anatomic and physiologic changes. In 2011, we therefore instituted at our center a recommended practice of cMRI screening in patients with Fontan physiology at 3 and 8 years post-Fontan operation. The purpose of this study was to determine the impact of this standardized practice of cMRI screening on the clinical management of a Fontan population. DESIGN: We retrospectively reviewed charts from our institutional Fontan database to determine which patients were eligible for cMRI under the current guidelines and who underwent imaging from November 2002 to June 2015. We reviewed the frequency of cMRI and number of changes in management based on the results. Statistical significance was determined using a chi-square test. RESULTS: There were 141 cMRIs performed on 121 patients who met inclusion criteria. The odds of a change in management were significantly greater after clinically indicated cMRI compared to screening cMRI (OR = 3.79, 95% CI: 1.48-9.66, P = .004). There were near significant odds of change in management if the cMRI occurred \\textless8 years after Fontan regardless of whether it was for screening or clinically indicated purposes (OR = 2.43, 95% CI: 0.97-6.08, P = .052). The most frequent change in management was referral for catheterization with pulmonary artery angioplasty. CONCLUSIONS: There is an important role for cMRI in routine surveillance of post-Fontan patients. Screening cMRI performed less than 8 years after Fontan palliation offers increased utility compared to studies performed later. The optimal timing of such imaging after Fontan palliation remains unclear.\n
\n\n\n\n \n\n \n \n \n \n \n Detecting moderate or complex congenital heart defects in adults from an electronic health records system.\n \n \n \n\n\n \n Diallo, A. O.; Krishnaswamy, A.; Shapira, S. K.; Oster, M. E.; George, M. G.; Adams, J. C.; Walker, E. R.; Weiss, P.; Ali, M. K.; and Book, W.\n\n\n \n\n\n\n Journal of the American Medical Informatics Association: JAMIA, 25(12): 1634–1642. December 2018.\n \n\n\n\n
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\n\n\n@article{diallo_detecting_2018,\n\ttitle = {Detecting moderate or complex congenital heart defects in adults from an electronic health records system},\n\tvolume = {25},\n\tissn = {1527-974X},\n\tdoi = {10.1093/jamia/ocy127},\n\tabstract = {Background: The prevalence of moderate or complex (moderate-complex) congenital heart defects (CHDs) among adults is increasing due to improved survival, but many patients experience lapses in specialty care or their CHDs are undocumented in the medical system. There is, to date, no efficient approach to identify this population.\nObjective: To develop and assess the performance of a risk score to identify adults aged 20-60 years with undocumented specific moderate-complex CHDs from electronic health records (EHR).\nMethods: We used a case-control study (596 adults with specific moderate-complex CHDs and 2384 controls). We extracted age, race/ethnicity, electrocardiogram (EKG), and blood tests from routine outpatient visits (1/2009 through 12/2012). We used multivariable logistic regression models and a split-sample (4: 1 ratio) approach to develop and internally validate the risk score, respectively. We generated receiver operating characteristic (ROC) c-statistics and Brier scores to assess the ability of models to predict the presence of specific moderate-complex CHDs.\nResults: Out of six models, the non-blood biomarker model that included age, sex, and EKG parameters offered a high ROC c-statistic of 0.96 [95\\% confidence interval: 0.95, 0.97] and low Brier score (0.05) relative to the other models. The adult moderate-complex congenital heart defect risk score demonstrated good accuracy with 96.4\\% sensitivity and 80.0\\% specificity at a threshold score of 10.\nConclusions: A simple risk score based on age, sex, and EKG parameters offers early proof of concept and may help accurately identify adults with specific moderate-complex CHDs from routine EHR systems who may benefit from specialty care.},\n\tlanguage = {eng},\n\tnumber = {12},\n\tjournal = {Journal of the American Medical Informatics Association: JAMIA},\n\tauthor = {Diallo, Alpha Oumar and Krishnaswamy, Asha and Shapira, Stuart K. and Oster, Matthew E. and George, Mary G. and Adams, Jenna C. and Walker, Elizabeth R. and Weiss, Paul and Ali, Mohammed K. and Book, Wendy},\n\tmonth = dec,\n\tyear = {2018},\n\tpmid = {30541125},\n\tpmcid = {PMC6319253},\n\tpages = {1634--1642},\n}\n\n\n\n Background: The prevalence of moderate or complex (moderate-complex) congenital heart defects (CHDs) among adults is increasing due to improved survival, but many patients experience lapses in specialty care or their CHDs are undocumented in the medical system. There is, to date, no efficient approach to identify this population. Objective: To develop and assess the performance of a risk score to identify adults aged 20-60 years with undocumented specific moderate-complex CHDs from electronic health records (EHR). Methods: We used a case-control study (596 adults with specific moderate-complex CHDs and 2384 controls). We extracted age, race/ethnicity, electrocardiogram (EKG), and blood tests from routine outpatient visits (1/2009 through 12/2012). We used multivariable logistic regression models and a split-sample (4: 1 ratio) approach to develop and internally validate the risk score, respectively. We generated receiver operating characteristic (ROC) c-statistics and Brier scores to assess the ability of models to predict the presence of specific moderate-complex CHDs. Results: Out of six models, the non-blood biomarker model that included age, sex, and EKG parameters offered a high ROC c-statistic of 0.96 [95% confidence interval: 0.95, 0.97] and low Brier score (0.05) relative to the other models. The adult moderate-complex congenital heart defect risk score demonstrated good accuracy with 96.4% sensitivity and 80.0% specificity at a threshold score of 10. Conclusions: A simple risk score based on age, sex, and EKG parameters offers early proof of concept and may help accurately identify adults with specific moderate-complex CHDs from routine EHR systems who may benefit from specialty care.\n
\n\n\n\n \n\n \n \n \n \n \n Mortality Following Pediatric Congenital Heart Surgery: An Analysis of the Causes of Death Derived From the National Death Index.\n \n \n \n\n\n \n McCracken, C.; Spector, L. G.; Menk, J. S.; Knight, J. H.; Vinocur, J. M.; Thomas, A. S.; Oster, M. E.; St Louis, J. D.; Moller, J. H.; and Kochilas, L.\n\n\n \n\n\n\n Journal of the American Heart Association, 7(22): e010624. November 2018.\n \n\n\n\n
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\n\n\n@article{mccracken_mortality_2018,\n\ttitle = {Mortality {Following} {Pediatric} {Congenital} {Heart} {Surgery}: {An} {Analysis} of the {Causes} of {Death} {Derived} {From} the {National} {Death} {Index}},\n\tvolume = {7},\n\tissn = {2047-9980},\n\tshorttitle = {Mortality {Following} {Pediatric} {Congenital} {Heart} {Surgery}},\n\tdoi = {10.1161/JAHA.118.010624},\n\tabstract = {Background Prior research has focused on early outcomes after congenital heart surgery, but less is known about later risks. We aimed to determine the late causes of death among children ({\\textless}21 years of age) surviving their initial congenital heart surgery. Methods and Results This is a retrospective cohort study from the Pediatric Cardiac Care Consortium, a US-based registry of interventions for congenital heart defects (CHD). Excluding patients with chromosomal anomalies or inadequate identifiers, we matched those surviving their first congenital heart surgery (1982-2003) against the National Death Index through 2014. Causes of death were obtained from the National Death Index to calculate cause-specific standardized mortality ratios (SMRs). Among 31 132 patients, 2527 deaths (8.1\\%) occurred over a median follow-up period of 18 years. Causes of death varied by time after surgery and severity of CHD but, overall, 69.9\\% of deaths were attributed to the CHD or another cardiovascular disorder, with a SMR for CHD/cardiovascular disorder of 67.7 (95\\% confidence interval: 64.5-70.8). Adjusted odds ratios revealed increased risk of death from CHD/cardiovascular disorder in females [odds ratio=1.28; 95\\% confidence interval (1.04-1.58); P=0.018] with leading cardiovascular disorder contributing to death being cardiac arrest (16.8\\%), heart failure (14.8\\%), and arrhythmias (9.1\\%). Other major causes of death included coexisting congenital malformations (4.7\\%, SMR: 7.0), respiratory diseases (3.6\\%, SMR: 8.2), infections (3.4\\%, SMR: 8.2), and neoplasms (2.1\\%, SMR: 1.9). Conclusions Survivors of congenital heart surgery face long-term risks of premature mortality mostly related to residual CHD pathology, heart failure, and arrhythmias, but also to other noncardiac conditions. Ongoing monitoring is warranted to identify target factors to address residual morbidities and improve long-term outcomes.},\n\tlanguage = {eng},\n\tnumber = {22},\n\tjournal = {Journal of the American Heart Association},\n\tauthor = {McCracken, Courtney and Spector, Logan G. and Menk, Jeremiah S. and Knight, Jessica H. and Vinocur, Jeffrey M. and Thomas, Amanda S. and Oster, Matthew E. and St Louis, James D. and Moller, James H. and Kochilas, Lazaros},\n\tmonth = nov,\n\tyear = {2018},\n\tpmid = {30571499},\n\tkeywords = {congenital heart disease, mortality, outcomes research, surgery},\n\tpages = {e010624},\n}\n\n\n\n Background Prior research has focused on early outcomes after congenital heart surgery, but less is known about later risks. We aimed to determine the late causes of death among children (\\textless21 years of age) surviving their initial congenital heart surgery. Methods and Results This is a retrospective cohort study from the Pediatric Cardiac Care Consortium, a US-based registry of interventions for congenital heart defects (CHD). Excluding patients with chromosomal anomalies or inadequate identifiers, we matched those surviving their first congenital heart surgery (1982-2003) against the National Death Index through 2014. Causes of death were obtained from the National Death Index to calculate cause-specific standardized mortality ratios (SMRs). Among 31 132 patients, 2527 deaths (8.1%) occurred over a median follow-up period of 18 years. Causes of death varied by time after surgery and severity of CHD but, overall, 69.9% of deaths were attributed to the CHD or another cardiovascular disorder, with a SMR for CHD/cardiovascular disorder of 67.7 (95% confidence interval: 64.5-70.8). Adjusted odds ratios revealed increased risk of death from CHD/cardiovascular disorder in females [odds ratio=1.28; 95% confidence interval (1.04-1.58); P=0.018] with leading cardiovascular disorder contributing to death being cardiac arrest (16.8%), heart failure (14.8%), and arrhythmias (9.1%). Other major causes of death included coexisting congenital malformations (4.7%, SMR: 7.0), respiratory diseases (3.6%, SMR: 8.2), infections (3.4%, SMR: 8.2), and neoplasms (2.1%, SMR: 1.9). Conclusions Survivors of congenital heart surgery face long-term risks of premature mortality mostly related to residual CHD pathology, heart failure, and arrhythmias, but also to other noncardiac conditions. Ongoing monitoring is warranted to identify target factors to address residual morbidities and improve long-term outcomes.\n
\n\n\n\n \n\n \n \n \n \n \n Single ventricle, many arrhythmias.\n \n \n \n\n\n \n Whitehill, R.; Fischbach, P.; and Oster, M. E.\n\n\n \n\n\n\n Journal of Thoracic Disease, 10(Suppl 33): S4040–S4042. November 2018.\n \n\n\n\n
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\n\n\n\n@article{whitehill_single_2018,\n\ttitle = {Single ventricle, many arrhythmias},\n\tvolume = {10},\n\tissn = {2072-1439},\n\tdoi = {10.21037/jtd.2018.09.66},\n\tlanguage = {eng},\n\tnumber = {Suppl 33},\n\tjournal = {Journal of Thoracic Disease},\n\tauthor = {Whitehill, Robert and Fischbach, Peter and Oster, Matthew E.},\n\tmonth = nov,\n\tyear = {2018},\n\tpmid = {30631550},\n\tpmcid = {PMC6297542},\n\tpages = {S4040--S4042},\n}\n\n\n\n \n\n \n \n \n \n \n Human iPSC-derived mesenchymal stem cells encapsulated in PEGDA hydrogels mature into valve interstitial-like cells.\n \n \n \n\n\n \n Nachlas, A. L. Y.; Li, S.; Jha, R.; Singh, M.; Xu, C.; and Davis, M. E.\n\n\n \n\n\n\n Acta Biomaterialia, 71: 235–246. 2018.\n \n\n\n\n
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\n\n\n@article{nachlas_human_2018,\n\ttitle = {Human {iPSC}-derived mesenchymal stem cells encapsulated in {PEGDA} hydrogels mature into valve interstitial-like cells},\n\tvolume = {71},\n\tissn = {1878-7568},\n\tdoi = {10.1016/j.actbio.2018.02.025},\n\tabstract = {Despite recent advances in tissue engineered heart valves (TEHV), a major challenge is identifying a cell source for seeding TEHV scaffolds. Native heart valves are durable because valve interstitial cells (VICs) maintain tissue homeostasis by synthesizing and remodeling the extracellular matrix. This study demonstrates that induced pluripotent stem cells (iPSC)-derived mesenchymal stem cells (iMSCs) can be derived from iPSCs using a feeder-free protocol and then further matured into VICs by encapsulation within 3D hydrogels. The differentiation efficiency was characterized using flow cytometry, immunohistochemistry staining, and trilineage differentiation. Using our feeder-free differentiation protocol, iMSCs were differentiated from iPSCs and had CD90+, CD44+, CD71+, αSMA+, and CD45- expression. Furthermore, iMSCs underwent trilineage differentiation when cultured in induction media for 21 days. iMSCs were then encapsulated in poly(ethylene glycol)diacrylate (PEGDA) hydrogels grafted with adhesion peptide (RGDS) to promote remodeling and further maturation into VIC-like cells. VIC phenotype was assessed by the expression of alpha-smooth muscle actin (αSMA), vimentin, and collagen production after 28 days. When MSC-derived cells were encapsulated in PEGDA hydrogels that mimic the leaflet modulus, a decrease in αSMA expression and increase in vimentin was observed. In addition, iMSCs synthesized collagen type I after 28 days in 3D hydrogel culture. Thus, the results from this study suggest that iMSCs may be a promising cell source for TEHV.\nSTATEMENT OF SIGNIFICANCE: Developing a suitable cell source is a critical component for the success and durability of tissue engineered heart valves. The significance of this study is the generation of iPSCs-derived mesenchymal stem cells (iMSCs) that have the capacity to mature into valve interstitial-like cells when introduced into a 3D cell culture designed to mimic the layers of the valve leaflet. iMSCs were generated using a feeder-free protocol, which is one major advantage over other methods, as it is more clinically relevant. In addition to generating a potential new cell source for heart valve tissue engineering, this study also highlights the importance of a 3D culture environment to influence cell phenotype and function.},\n\tlanguage = {eng},\n\tjournal = {Acta Biomaterialia},\n\tauthor = {Nachlas, Aline L. Y. and Li, Siyi and Jha, Rajneesh and Singh, Monalisa and Xu, Chunhui and Davis, Michael E.},\n\tyear = {2018},\n\tpmid = {29505894},\n\tpmcid = {PMC5907941},\n\tkeywords = {Hydrogel, Induced pluripotent stem cells, Mesenchymal stem cells, PEG, Tissue engineering heart valves},\n\tpages = {235--246},\n}\n\n\n\n Despite recent advances in tissue engineered heart valves (TEHV), a major challenge is identifying a cell source for seeding TEHV scaffolds. Native heart valves are durable because valve interstitial cells (VICs) maintain tissue homeostasis by synthesizing and remodeling the extracellular matrix. This study demonstrates that induced pluripotent stem cells (iPSC)-derived mesenchymal stem cells (iMSCs) can be derived from iPSCs using a feeder-free protocol and then further matured into VICs by encapsulation within 3D hydrogels. The differentiation efficiency was characterized using flow cytometry, immunohistochemistry staining, and trilineage differentiation. Using our feeder-free differentiation protocol, iMSCs were differentiated from iPSCs and had CD90+, CD44+, CD71+, αSMA+, and CD45- expression. Furthermore, iMSCs underwent trilineage differentiation when cultured in induction media for 21 days. iMSCs were then encapsulated in poly(ethylene glycol)diacrylate (PEGDA) hydrogels grafted with adhesion peptide (RGDS) to promote remodeling and further maturation into VIC-like cells. VIC phenotype was assessed by the expression of alpha-smooth muscle actin (αSMA), vimentin, and collagen production after 28 days. When MSC-derived cells were encapsulated in PEGDA hydrogels that mimic the leaflet modulus, a decrease in αSMA expression and increase in vimentin was observed. In addition, iMSCs synthesized collagen type I after 28 days in 3D hydrogel culture. Thus, the results from this study suggest that iMSCs may be a promising cell source for TEHV. STATEMENT OF SIGNIFICANCE: Developing a suitable cell source is a critical component for the success and durability of tissue engineered heart valves. The significance of this study is the generation of iPSCs-derived mesenchymal stem cells (iMSCs) that have the capacity to mature into valve interstitial-like cells when introduced into a 3D cell culture designed to mimic the layers of the valve leaflet. iMSCs were generated using a feeder-free protocol, which is one major advantage over other methods, as it is more clinically relevant. In addition to generating a potential new cell source for heart valve tissue engineering, this study also highlights the importance of a 3D culture environment to influence cell phenotype and function.\n
\n\n\n\n \n\n \n \n \n \n \n N-Type 2D Organic Single Crystals for High-Performance Organic Field-Effect Transistors and Near-Infrared Phototransistors.\n \n \n \n\n\n \n Wang, C.; Ren, X.; Xu, C.; Fu, B.; Wang, R.; Zhang, X.; Li, R.; Li, H.; Dong, H.; Zhen, Y.; Lei, S.; Jiang, L.; and Hu, W.\n\n\n \n\n\n\n Advanced Materials (Deerfield Beach, Fla.), 30(16): e1706260. April 2018.\n \n\n\n\n
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\n\n\n@article{wang_n-type_2018,\n\ttitle = {N-{Type} {2D} {Organic} {Single} {Crystals} for {High}-{Performance} {Organic} {Field}-{Effect} {Transistors} and {Near}-{Infrared} {Phototransistors}},\n\tvolume = {30},\n\tissn = {1521-4095},\n\tdoi = {10.1002/adma.201706260},\n\tabstract = {Organic field-effect transistors and near-infrared (NIR) organic phototransistors (OPTs) have attracted world's attention in many fields in the past decades. In general, the sensitivity, distinguishing the signal from noise, is the key parameter to evaluate the performance of NIR OPTs, which is decided by responsivity and dark current. 2D single crystal films of organic semiconductors (2DCOS) are promising functional materials due to their long-range order in spite of only few molecular layers. Herein, for the first time, air-stable 2DCOS of n-type organic semiconductors (a furan-thiophene quinoidal compound, TFT-CN) with strong absorbance around 830 nm, by the facile drop-casting method on the surface of water are successfully prepared. Almost millimeter-sized TFT-CN 2DCOS are obtained and their thickness is below 5 nm. A competitive field-effect electron mobility (1.36 cm2 V-1 s-1 ) and high on/off ratio (up to 108 ) are obtained in air. Impressively, the ultrasensitive NIR phototransistors operating at the off-state exhibit a very low dark current of ≈0.3 pA and an ultrahigh detectivity (D*) exceeding 6 × 1014 Jones because the devices can operate in full depletion at the off-state, superior to the majority of the reported organic-based NIR phototransistors.},\n\tlanguage = {eng},\n\tnumber = {16},\n\tjournal = {Advanced Materials (Deerfield Beach, Fla.)},\n\tauthor = {Wang, Cong and Ren, Xiaochen and Xu, Chunhui and Fu, Beibei and Wang, Ruihao and Zhang, Xiaotao and Li, Rongjin and Li, Hongxiang and Dong, Huanli and Zhen, Yonggang and Lei, Shengbin and Jiang, Lang and Hu, Wenping},\n\tmonth = apr,\n\tyear = {2018},\n\tpmid = {29512238},\n\tkeywords = {2D, organic electronics, organic field-effect transistors, organic single crystals, phototransistors},\n\tpages = {e1706260},\n}\n\n\n\n Organic field-effect transistors and near-infrared (NIR) organic phototransistors (OPTs) have attracted world's attention in many fields in the past decades. In general, the sensitivity, distinguishing the signal from noise, is the key parameter to evaluate the performance of NIR OPTs, which is decided by responsivity and dark current. 2D single crystal films of organic semiconductors (2DCOS) are promising functional materials due to their long-range order in spite of only few molecular layers. Herein, for the first time, air-stable 2DCOS of n-type organic semiconductors (a furan-thiophene quinoidal compound, TFT-CN) with strong absorbance around 830 nm, by the facile drop-casting method on the surface of water are successfully prepared. Almost millimeter-sized TFT-CN 2DCOS are obtained and their thickness is below 5 nm. A competitive field-effect electron mobility (1.36 cm2 V-1 s-1 ) and high on/off ratio (up to 108 ) are obtained in air. Impressively, the ultrasensitive NIR phototransistors operating at the off-state exhibit a very low dark current of ≈0.3 pA and an ultrahigh detectivity (D*) exceeding 6 × 1014 Jones because the devices can operate in full depletion at the off-state, superior to the majority of the reported organic-based NIR phototransistors.\n
\n\n\n\n \n\n \n \n \n \n \n Stem-Cell-Derived Cardiomyocytes Grow Up: Start Young and Train Harder.\n \n \n \n\n\n \n Maxwell, J. T.; and Xu, C.\n\n\n \n\n\n\n Cell Stem Cell, 22(6): 790–791. June 2018.\n \n\n\n\n
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\n\n\n@article{maxwell_stem-cell-derived_2018,\n\ttitle = {Stem-{Cell}-{Derived} {Cardiomyocytes} {Grow} {Up}: {Start} {Young} and {Train} {Harder}},\n\tvolume = {22},\n\tissn = {1875-9777},\n\tshorttitle = {Stem-{Cell}-{Derived} {Cardiomyocytes} {Grow} {Up}},\n\tdoi = {10.1016/j.stem.2018.05.011},\n\tabstract = {Engineering cardiac tissue that accurately recapitulates adult myocardium is critical for advancing disease modeling, drug screening, and regenerative medicine. Ronaldson-Bouchard et al. report a new strategy for generating cardiac tissues from stem-cell-derived cardiomyocytes that reach a maturation level closer to human adult cardiac structure and function.},\n\tlanguage = {eng},\n\tnumber = {6},\n\tjournal = {Cell Stem Cell},\n\tauthor = {Maxwell, Joshua T. and Xu, Chunhui},\n\tmonth = jun,\n\tyear = {2018},\n\tpmid = {29859168},\n\tpages = {790--791},\n}\n\n\n\n Engineering cardiac tissue that accurately recapitulates adult myocardium is critical for advancing disease modeling, drug screening, and regenerative medicine. Ronaldson-Bouchard et al. report a new strategy for generating cardiac tissues from stem-cell-derived cardiomyocytes that reach a maturation level closer to human adult cardiac structure and function.\n
\n\n\n\n \n\n \n \n \n \n \n Targeted Elimination of Tumorigenic Human Pluripotent Stem Cells Using Suicide-Inducing Virus-like Particles.\n \n \n \n\n\n \n Rampoldi, A.; Crooke, S. N.; Preininger, M. K.; Jha, R.; Maxwell, J.; Ding, L.; Spearman, P.; Finn, M. G.; and Xu, C.\n\n\n \n\n\n\n ACS chemical biology, 13(8): 2329–2338. August 2018.\n \n\n\n\n
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\n\n\n@article{rampoldi_targeted_2018,\n\ttitle = {Targeted {Elimination} of {Tumorigenic} {Human} {Pluripotent} {Stem} {Cells} {Using} {Suicide}-{Inducing} {Virus}-like {Particles}},\n\tvolume = {13},\n\tissn = {1554-8937},\n\tdoi = {10.1021/acschembio.8b00490},\n\tabstract = {Sensitization to prodrugs via transgenic expression of suicide genes is a leading strategy for the selective elimination of potentially tumorigenic human pluripotent stem cells (hPSCs) in regenerative medicine, but transgenic modification poses safety risks such as deleterious mutagenesis. We describe here an alternative method of delivering suicide-inducing molecules explicitly to hPSCs using virus-like particles (VLPs) and demonstrate its use in eliminating undifferentiated hPSCs in vitro. VLPs were engineered from Qβ bacteriophage capsids to contain enhanced green fluorescent protein (EGFP) or cytosine deaminase (CD) and to simultaneously display multiple IgG-binding ZZ domains. After labeling with antibodies against the hPSC-specific surface glycan SSEA-5, EGFP-containing particles were shown to specifically bind undifferentiated cells in culture, and CD-containing particles were able to eliminate undifferentiated hPSCs with virtually no cytotoxicity to differentiated cells upon treatment with the prodrug 5-fluorocytosine.},\n\tlanguage = {eng},\n\tnumber = {8},\n\tjournal = {ACS chemical biology},\n\tauthor = {Rampoldi, Antonio and Crooke, Stephen N. and Preininger, Marcela K. and Jha, Rajneesh and Maxwell, Joshua and Ding, Lingmei and Spearman, Paul and Finn, M. G. and Xu, Chunhui},\n\tmonth = aug,\n\tyear = {2018},\n\tpmid = {29979576},\n\tpmcid = {PMC6343126},\n\tpages = {2329--2338},\n}\n\n\n\n Sensitization to prodrugs via transgenic expression of suicide genes is a leading strategy for the selective elimination of potentially tumorigenic human pluripotent stem cells (hPSCs) in regenerative medicine, but transgenic modification poses safety risks such as deleterious mutagenesis. We describe here an alternative method of delivering suicide-inducing molecules explicitly to hPSCs using virus-like particles (VLPs) and demonstrate its use in eliminating undifferentiated hPSCs in vitro. VLPs were engineered from Qβ bacteriophage capsids to contain enhanced green fluorescent protein (EGFP) or cytosine deaminase (CD) and to simultaneously display multiple IgG-binding ZZ domains. After labeling with antibodies against the hPSC-specific surface glycan SSEA-5, EGFP-containing particles were shown to specifically bind undifferentiated cells in culture, and CD-containing particles were able to eliminate undifferentiated hPSCs with virtually no cytotoxicity to differentiated cells upon treatment with the prodrug 5-fluorocytosine.\n
\n\n\n\n \n\n \n \n \n \n \n Aggregation of Child Cardiac Progenitor Cells into Spheres Activates Notch Signaling and Improves Treatment of Right Ventricular Heart Failure.\n \n \n \n\n\n \n Trac, D.; Maxwell, J. T.; Brown, M. E.; Xu, C.; and Davis, M. E.\n\n\n \n\n\n\n Circulation Research. December 2018.\n \n\n\n\n
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\n\n\n@article{trac_aggregation_2018,\n\ttitle = {Aggregation of {Child} {Cardiac} {Progenitor} {Cells} into {Spheres} {Activates} {Notch} {Signaling} and {Improves} {Treatment} of {Right} {Ventricular} {Heart} {Failure}},\n\tissn = {1524-4571},\n\tdoi = {10.1161/CIRCRESAHA.118.313845},\n\tabstract = {RATIONALE: Congenital heart disease can lead to life-threatening right ventricular heart failure (RVHF). Results from clinical trials support expanding cardiac progenitor cell (CPC) based therapies. However, our recent data show that CPCs lose function as they age, starting as early as 1 year.\nOBJECTIVE: To determine whether the aggregation of child (1 to 5-year-old) CPCs into scaffold-free spheres can improve differentiation by enhancing Notch signaling, a known regulator of CPC fate. We hypothesized that aggregated (3D) CPCs will repair RVHF better than monolayer (2D) CPCs.\nMETHODS AND RESULTS: Spheres were produced with 1500 CPCs each using a microwell array. CPC aggregation significantly increased gene expression of Notch1 compared to 2D CPCs, accompanied by significant upregulation of cardiogenic transcription factors (GATA4, HAND1, MEF2C, NKX2.5, and TBX5) and endothelial markers (CD31, FLK1, FLT1, vWF). Blocking Notch receptor activation with the γ-secretase inhibitor N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) diminished these effects. To evaluate the therapeutic improvements of CPC aggregation, RVHF was induced in athymic rats by pulmonary artery banding and cells were implanted into the RV free wall. Echocardiographic measurements 28 days post-implantation showed significantly improved RV function with 3D compared to 2D CPCs. Tracking implanted CPCs via DiR-labeling showed improved retention of 3D CPCs. Transducing 3D CPCs with Notch1-shRNA did not reduce retention, but significantly reduced RV functional improvements. Histological analyses showed 3D treatment reduced RV fibrosis and increased angiogenesis. While 3D CPCs formed CD31+ vessel-like cells in vivo, these effects are more likely due to improved 3D CPC exosome function compared to 2D CPC exosomes.\nCONCLUSIONS: Spherical aggregation improves child CPC function in a Notch-dependent manner. The strong reparative ability of CPC spheres warrants further investigation as a treatment for pediatric HF, especially in older children where reparative ability may be reduced.},\n\tlanguage = {eng},\n\tjournal = {Circulation Research},\n\tauthor = {Trac, David and Maxwell, Joshua T. and Brown, Milton E. and Xu, Chunhui and Davis, Michael E.},\n\tmonth = dec,\n\tyear = {2018},\n\tpmid = {30590978},\n\tkeywords = {Notch signaling, spherical aggregation},\n}\n\n\n\n RATIONALE: Congenital heart disease can lead to life-threatening right ventricular heart failure (RVHF). Results from clinical trials support expanding cardiac progenitor cell (CPC) based therapies. However, our recent data show that CPCs lose function as they age, starting as early as 1 year. OBJECTIVE: To determine whether the aggregation of child (1 to 5-year-old) CPCs into scaffold-free spheres can improve differentiation by enhancing Notch signaling, a known regulator of CPC fate. We hypothesized that aggregated (3D) CPCs will repair RVHF better than monolayer (2D) CPCs. METHODS AND RESULTS: Spheres were produced with 1500 CPCs each using a microwell array. CPC aggregation significantly increased gene expression of Notch1 compared to 2D CPCs, accompanied by significant upregulation of cardiogenic transcription factors (GATA4, HAND1, MEF2C, NKX2.5, and TBX5) and endothelial markers (CD31, FLK1, FLT1, vWF). Blocking Notch receptor activation with the γ-secretase inhibitor N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) diminished these effects. To evaluate the therapeutic improvements of CPC aggregation, RVHF was induced in athymic rats by pulmonary artery banding and cells were implanted into the RV free wall. Echocardiographic measurements 28 days post-implantation showed significantly improved RV function with 3D compared to 2D CPCs. Tracking implanted CPCs via DiR-labeling showed improved retention of 3D CPCs. Transducing 3D CPCs with Notch1-shRNA did not reduce retention, but significantly reduced RV functional improvements. Histological analyses showed 3D treatment reduced RV fibrosis and increased angiogenesis. While 3D CPCs formed CD31+ vessel-like cells in vivo, these effects are more likely due to improved 3D CPC exosome function compared to 2D CPC exosomes. CONCLUSIONS: Spherical aggregation improves child CPC function in a Notch-dependent manner. The strong reparative ability of CPC spheres warrants further investigation as a treatment for pediatric HF, especially in older children where reparative ability may be reduced.\n
\n\n\n\n \n\n \n \n \n \n \n Study rationale, design, and pretransplantation alloantibody status: A first report of Clinical Trials in Organ Transplantation in Children-04 (CTOTC-04) in pediatric heart transplantation.\n \n \n \n\n\n \n Zuckerman, W. A.; Zeevi, A.; Mason, K. L.; Feingold, B.; Bentlejewski, C.; Addonizio, L. J.; Blume, E. D.; Canter, C. E.; Dipchand, A. I.; Hsu, D. T.; Shaddy, R. E.; Mahle, W. T.; Demetris, A. J.; Briscoe, D. M.; Mohanakumar, T.; Ahearn, J. M.; Iklé, D. N.; Armstrong, B. D.; Morrison, Y.; Diop, H.; Odim, J.; and Webber, S. A.\n\n\n \n\n\n\n American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons, 18(9): 2135–2147. September 2018.\n \n\n\n\n
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\n\n\n@article{zuckerman_study_2018,\n\ttitle = {Study rationale, design, and pretransplantation alloantibody status: {A} first report of {Clinical} {Trials} in {Organ} {Transplantation} in {Children}-04 ({CTOTC}-04) in pediatric heart transplantation},\n\tvolume = {18},\n\tissn = {1600-6143},\n\tshorttitle = {Study rationale, design, and pretransplantation alloantibody status},\n\tdoi = {10.1111/ajt.14695},\n\tabstract = {Anti-HLA donor-specific antibodies are associated with worse outcomes after organ transplantation. Among sensitized pediatric heart candidates, requirement for negative donor-specific cytotoxicity crossmatch increases wait times and mortality. However, transplantation with positive crossmatch may increase posttransplantation morbidity and mortality. We address this clinical challenge in a prospective, multicenter, observational cohort study of children listed for heart transplantation (Clinical Trials in Organ Transplantation in Children-04 [CTOTC-04]). Outcomes were compared among sensitized recipients who underwent transplantation with positive crossmatch, nonsensitized recipients, and sensitized recipients without positive crossmatch. Positive crossmatch recipients received antibody removal and augmented immunosuppression, while other recipients received standard immunosuppression with corticosteroid avoidance. This first CTOTC-04 report summarizes study rationale and design and relates pretransplantation sensitization status using solid-phase technology. Risk factors for sensitization were explored. Of 317 screened patients, 290 were enrolled and 240 underwent transplantation. Core laboratory evaluation demonstrated that more than half of patients were anti-HLA sensitized. Greater than 80\\% of sensitized patients had class I (with or without class II) HLA antibodies, and one-third of sensitized patients had at least 1 HLA antibody with median fluorescence intensity of ≥8000. Logistic regression models demonstrated male sex, weight, congenital heart disease history, prior allograft, and ventricular assist device are independent risk factors for sensitization.},\n\tlanguage = {eng},\n\tnumber = {9},\n\tjournal = {American Journal of Transplantation: Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons},\n\tauthor = {Zuckerman, Warren A. and Zeevi, Adriana and Mason, Kristen L. and Feingold, Brian and Bentlejewski, Carol and Addonizio, Linda J. and Blume, Elizabeth D. and Canter, Charles E. and Dipchand, Anne I. and Hsu, Daphne T. and Shaddy, Robert E. and Mahle, William T. and Demetris, Anthony J. and Briscoe, David M. and Mohanakumar, Thalachallour and Ahearn, Joseph M. and Iklé, David N. and Armstrong, Brian D. and Morrison, Yvonne and Diop, Helena and Odim, Jonah and Webber, Steven A.},\n\tmonth = sep,\n\tyear = {2018},\n\tpmid = {29446208},\n\tpmcid = {PMC6093810},\n\tkeywords = {alloantibody, clinical research/practice, crossmatch, heart transplantation/cardiology, pediatrics, sensitization},\n\tpages = {2135--2147},\n}\n\n\n\n Anti-HLA donor-specific antibodies are associated with worse outcomes after organ transplantation. Among sensitized pediatric heart candidates, requirement for negative donor-specific cytotoxicity crossmatch increases wait times and mortality. However, transplantation with positive crossmatch may increase posttransplantation morbidity and mortality. We address this clinical challenge in a prospective, multicenter, observational cohort study of children listed for heart transplantation (Clinical Trials in Organ Transplantation in Children-04 [CTOTC-04]). Outcomes were compared among sensitized recipients who underwent transplantation with positive crossmatch, nonsensitized recipients, and sensitized recipients without positive crossmatch. Positive crossmatch recipients received antibody removal and augmented immunosuppression, while other recipients received standard immunosuppression with corticosteroid avoidance. This first CTOTC-04 report summarizes study rationale and design and relates pretransplantation sensitization status using solid-phase technology. Risk factors for sensitization were explored. Of 317 screened patients, 290 were enrolled and 240 underwent transplantation. Core laboratory evaluation demonstrated that more than half of patients were anti-HLA sensitized. Greater than 80% of sensitized patients had class I (with or without class II) HLA antibodies, and one-third of sensitized patients had at least 1 HLA antibody with median fluorescence intensity of ≥8000. Logistic regression models demonstrated male sex, weight, congenital heart disease history, prior allograft, and ventricular assist device are independent risk factors for sensitization.\n
\n\n\n\n \n\n \n \n \n \n \n Neutropenia in pediatric heart transplant recipients.\n \n \n \n\n\n \n Rose-Felker, K.; Mukhtar, A.; Kelleman, M. S.; Deshpande, S. R.; and Mahle, W. T.\n\n\n \n\n\n\n Pediatric Transplantation, 22(3): e13130. 2018.\n \n\n\n\n
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\n\n\n@article{rose-felker_neutropenia_2018,\n\ttitle = {Neutropenia in pediatric heart transplant recipients},\n\tvolume = {22},\n\tissn = {1399-3046},\n\tdoi = {10.1111/petr.13130},\n\tabstract = {Neutropenia has been reported in pediatric heart transplant recipients, but its association with infectious morbidity and mortality is unknown. We sought to determine neutropenia's prevalence and impact on infection, rejection, and survival. A retrospective analysis of pediatric heart transplant recipients from March 2005 to August 2015 was performed. Demographics, medications, infection, and rejection data were collected. Of 142 pediatric heart transplant recipients, 77 (54.2\\%) developed neutropenia within 4.7 months [3.3-12.1 months] of transplant. In all patients, the adjusted 5-year cumulative incidence of neutropenia was 30.2\\%. Fifty-one patients (66.2\\%) had recurrent neutropenia. Six of 14 tested had positive antineutrophil antibodies. Medications associated with neutropenia were decreased in 15 (19.5\\%) and discontinued in 42 (54.4\\%) patients with no change in 1-year rejection rates compared to published data. Fifteen patients developed infection within 30 days of neutropenia and two from 30 days to 1 year, with an infection rate similar to the non-neutropenic group. There was no significant difference in survival, ANC, rate of rejection or PTLD in neutropenic patients with and without infection at median follow-up (5.5 years). Neutropenia is common in pediatric heart transplant recipients. Neutropenia had {\\textless}20\\% risk of associated infection, similar to non-neutropenic patients. Infection in neutropenic patients did not increase mortality.},\n\tlanguage = {eng},\n\tnumber = {3},\n\tjournal = {Pediatric Transplantation},\n\tauthor = {Rose-Felker, Kirsten and Mukhtar, Ayesha and Kelleman, Michael S. and Deshpande, Shriprasad R. and Mahle, William T.},\n\tyear = {2018},\n\tpmid = {29473271},\n\tkeywords = {Adolescent, Child, Child, Preschool, Female, Follow-Up Studies, Graft Rejection, Graft Survival, Heart Transplantation, Humans, Incidence, Infant, Infection, Male, Neutropenia, Postoperative Complications, Prevalence, Retrospective Studies, Survival Analysis, children, heart transplantation, infectious risk, neutropenia},\n\tpages = {e13130},\n}\n\n\n\n Neutropenia has been reported in pediatric heart transplant recipients, but its association with infectious morbidity and mortality is unknown. We sought to determine neutropenia's prevalence and impact on infection, rejection, and survival. A retrospective analysis of pediatric heart transplant recipients from March 2005 to August 2015 was performed. Demographics, medications, infection, and rejection data were collected. Of 142 pediatric heart transplant recipients, 77 (54.2%) developed neutropenia within 4.7 months [3.3-12.1 months] of transplant. In all patients, the adjusted 5-year cumulative incidence of neutropenia was 30.2%. Fifty-one patients (66.2%) had recurrent neutropenia. Six of 14 tested had positive antineutrophil antibodies. Medications associated with neutropenia were decreased in 15 (19.5%) and discontinued in 42 (54.4%) patients with no change in 1-year rejection rates compared to published data. Fifteen patients developed infection within 30 days of neutropenia and two from 30 days to 1 year, with an infection rate similar to the non-neutropenic group. There was no significant difference in survival, ANC, rate of rejection or PTLD in neutropenic patients with and without infection at median follow-up (5.5 years). Neutropenia is common in pediatric heart transplant recipients. Neutropenia had \\textless20% risk of associated infection, similar to non-neutropenic patients. Infection in neutropenic patients did not increase mortality.\n
\n\n\n\n \n\n \n \n \n \n \n New Paradigms for Pulmonary Vein Stenosis Treatment: When Surgery and Transcatheter Therapy Aren't Good Enough.\n \n \n \n\n\n \n Kanaan, U. B.; and Mahle, W. T.\n\n\n \n\n\n\n The Journal of Pediatrics, 198: 12–13. July 2018.\n \n\n\n\n
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\n\n\n\n@article{kanaan_new_2018,\n\ttitle = {New {Paradigms} for {Pulmonary} {Vein} {Stenosis} {Treatment}: {When} {Surgery} and {Transcatheter} {Therapy} {Aren}'t {Good} {Enough}},\n\tvolume = {198},\n\tissn = {1097-6833},\n\tshorttitle = {New {Paradigms} for {Pulmonary} {Vein} {Stenosis} {Treatment}},\n\tdoi = {10.1016/j.jpeds.2018.01.082},\n\tlanguage = {eng},\n\tjournal = {The Journal of Pediatrics},\n\tauthor = {Kanaan, Usama B. and Mahle, William T.},\n\tmonth = jul,\n\tyear = {2018},\n\tpmid = {29551312},\n\tpages = {12--13},\n}\n\n\n\n \n\n \n \n \n \n \n Heart failure after the Norwood procedure: An analysis of the Single Ventricle Reconstruction Trial.\n \n \n \n\n\n \n Mahle, W. T.; Hu, C.; Trachtenberg, F.; Menteer, J.; Kindel, S. J.; Dipchand, A. I.; Richmond, M. E.; Daly, K. P.; Henderson, H. T.; Lin, K. Y.; McCulloch, M.; Lal, A. K.; Schumacher, K. R.; Jacobs, J. P.; Atz, A. M.; Villa, C. R.; Burns, K. M.; Newburger, J. W.; and Pediatric Heart Network Investigators\n\n\n \n\n\n\n The Journal of Heart and Lung Transplantation: The Official Publication of the International Society for Heart Transplantation, 37(7): 879–885. July 2018.\n \n\n\n\n
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\n\n\n@article{mahle_heart_2018,\n\ttitle = {Heart failure after the {Norwood} procedure: {An} analysis of the {Single} {Ventricle} {Reconstruction} {Trial}},\n\tvolume = {37},\n\tissn = {1557-3117},\n\tshorttitle = {Heart failure after the {Norwood} procedure},\n\tdoi = {10.1016/j.healun.2018.02.009},\n\tabstract = {BACKGROUND: Heart failure results in significant morbidity and mortality in young children with hypoplastic left heart syndrome (HLHS) after the Norwood procedure.\nMETHODS: We studied subjects enrolled in the prospective Single Ventricle Reconstruction (SVR) Trial who survived to hospital discharge after a Norwood operation and were followed up to age 6 years. The primary outcome was heart failure, defined as heart transplant listing after Norwood hospitalization, death attributable to heart failure, or symptomatic heart failure (New York Heart Association [NYHA] Class IV). Multivariate modeling was undertaken using Cox regression methodology to determine variables associated with heart failure.\nRESULTS: Of the 461 subjects discharged home following a Norwood procedure, 66 (14.3\\%) met the criteria for heart failure. Among these, 15 died from heart failure, 39 were listed for transplant (22 had a transplant, 12 died after listing, and 5 were alive and not yet transplanted), and 12 had NYHA Class IV heart failure but were never listed. The median age at heart failure identification was 1.28 (interquartile range 0.30 to 4.69) years. Factors associated with early heart failure included post-Norwood lower fractional area change, need for extracorporeal membrane oxygenation, non-Hispanic ethnicity, Norwood perfusion type, and total support time (p {\\textless} 0.05).\nCONCLUSIONS: By 6 years of age, heart failure developed in nearly 15\\% of children after the Norwood procedure. Although transplant listing was common, many patients died from heart failure before receiving a transplant or without being listed. Shunt type did not impact the risk of developing heart failure.},\n\tlanguage = {eng},\n\tnumber = {7},\n\tjournal = {The Journal of Heart and Lung Transplantation: The Official Publication of the International Society for Heart Transplantation},\n\tauthor = {Mahle, William T. and Hu, Chenwei and Trachtenberg, Felicia and Menteer, JonDavid and Kindel, Steven J. and Dipchand, Anne I. and Richmond, Marc E. and Daly, Kevin P. and Henderson, Heather T. and Lin, Kimberly Y. and McCulloch, Michael and Lal, Ashwin K. and Schumacher, Kurt R. and Jacobs, Jeffrey P. and Atz, Andrew M. and Villa, Chet R. and Burns, Kristin M. and Newburger, Jane W. and {Pediatric Heart Network Investigators}},\n\tmonth = jul,\n\tyear = {2018},\n\tpmid = {29571602},\n\tpmcid = {PMC6015519},\n\tkeywords = {Norwood procedure, cardiac surgery, congenital heart defect, congenital heart disease, single ventricle},\n\tpages = {879--885},\n}\n\n\n\n BACKGROUND: Heart failure results in significant morbidity and mortality in young children with hypoplastic left heart syndrome (HLHS) after the Norwood procedure. METHODS: We studied subjects enrolled in the prospective Single Ventricle Reconstruction (SVR) Trial who survived to hospital discharge after a Norwood operation and were followed up to age 6 years. The primary outcome was heart failure, defined as heart transplant listing after Norwood hospitalization, death attributable to heart failure, or symptomatic heart failure (New York Heart Association [NYHA] Class IV). Multivariate modeling was undertaken using Cox regression methodology to determine variables associated with heart failure. RESULTS: Of the 461 subjects discharged home following a Norwood procedure, 66 (14.3%) met the criteria for heart failure. Among these, 15 died from heart failure, 39 were listed for transplant (22 had a transplant, 12 died after listing, and 5 were alive and not yet transplanted), and 12 had NYHA Class IV heart failure but were never listed. The median age at heart failure identification was 1.28 (interquartile range 0.30 to 4.69) years. Factors associated with early heart failure included post-Norwood lower fractional area change, need for extracorporeal membrane oxygenation, non-Hispanic ethnicity, Norwood perfusion type, and total support time (p \\textless 0.05). CONCLUSIONS: By 6 years of age, heart failure developed in nearly 15% of children after the Norwood procedure. Although transplant listing was common, many patients died from heart failure before receiving a transplant or without being listed. Shunt type did not impact the risk of developing heart failure.\n
\n\n\n\n \n\n \n \n \n \n \n Posterior Cerebellar Volume and Executive Function in Young Adults With Congenital Heart Disease.\n \n \n \n\n\n \n Semmel, E. S.; Dotson, V. M.; Burns, T. G.; Mahle, W. T.; and King, T. Z.\n\n\n \n\n\n\n Journal of the International Neuropsychological Society: JINS, 24(9): 939–948. October 2018.\n \n\n\n\n
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\n\n\n@article{semmel_posterior_2018,\n\ttitle = {Posterior {Cerebellar} {Volume} and {Executive} {Function} in {Young} {Adults} {With} {Congenital} {Heart} {Disease}},\n\tvolume = {24},\n\tissn = {1469-7661},\n\tdoi = {10.1017/S1355617718000310},\n\tabstract = {OBJECTIVES: As the number of adolescents and young adults (AYAs) surviving congenital heart disease (CHD) grows, studies of long-term outcomes are needed. CHD research documents poor executive function (EF) and cerebellum (CB) abnormalities in children. We examined whether AYAs with CHD exhibit reduced EF and CB volumes. We hypothesized a double dissociation such that the posterior CB is related to EF while the anterior CB is related to motor function. We also investigated whether the CB contributes to EF above and beyond processing speed.\nMETHODS: Twenty-two AYAs with CHD and 22 matched healthy controls underwent magnetic resonance imaging and assessment of EF, processing speed, and motor function. Volumetric data were calculated using a cerebellar atlas (SUIT) developed for SPM. Group differences were compared with t tests, relationships were tested with Pearson's correlations and Fisher's r to z transformation, and hierarchical regression was used to test the CB's unique contributions to EF.\nRESULTS: CHD patients had reduced CB total, lobular, and white matter volume (d=.52-.99) and poorer EF (d=.79-1.01) compared to controls. Significant correlations between the posterior CB and EF (r=.29-.48) were identified but there were no relationships between the anterior CB and motor function nor EF. The posterior CB predicted EF above and beyond processing speed (ps{\\textless}.001).\nCONCLUSIONS: This study identified a relationship between the posterior CB and EF, which appears to be particularly important for inhibitory processes and abstract reasoning. The unique CB contribution to EF above and beyond processing speed alone warrants further study. (JINS, 2018, 24, 939-948).},\n\tlanguage = {eng},\n\tnumber = {9},\n\tjournal = {Journal of the International Neuropsychological Society: JINS},\n\tauthor = {Semmel, Eric S. and Dotson, Vonetta M. and Burns, Thomas G. and Mahle, William T. and King, Tricia Z.},\n\tmonth = oct,\n\tyear = {2018},\n\tpmid = {29843839},\n\tkeywords = {Cerebellum, Congenital, Heart defects, Hypoxia, Inhibition, Magnetic resonance imaging, Motor skills},\n\tpages = {939--948},\n}\n\n\n\n OBJECTIVES: As the number of adolescents and young adults (AYAs) surviving congenital heart disease (CHD) grows, studies of long-term outcomes are needed. CHD research documents poor executive function (EF) and cerebellum (CB) abnormalities in children. We examined whether AYAs with CHD exhibit reduced EF and CB volumes. We hypothesized a double dissociation such that the posterior CB is related to EF while the anterior CB is related to motor function. We also investigated whether the CB contributes to EF above and beyond processing speed. METHODS: Twenty-two AYAs with CHD and 22 matched healthy controls underwent magnetic resonance imaging and assessment of EF, processing speed, and motor function. Volumetric data were calculated using a cerebellar atlas (SUIT) developed for SPM. Group differences were compared with t tests, relationships were tested with Pearson's correlations and Fisher's r to z transformation, and hierarchical regression was used to test the CB's unique contributions to EF. RESULTS: CHD patients had reduced CB total, lobular, and white matter volume (d=.52-.99) and poorer EF (d=.79-1.01) compared to controls. Significant correlations between the posterior CB and EF (r=.29-.48) were identified but there were no relationships between the anterior CB and motor function nor EF. The posterior CB predicted EF above and beyond processing speed (ps\\textless.001). CONCLUSIONS: This study identified a relationship between the posterior CB and EF, which appears to be particularly important for inhibitory processes and abstract reasoning. The unique CB contribution to EF above and beyond processing speed alone warrants further study. (JINS, 2018, 24, 939-948).\n
\n\n\n\n \n\n \n \n \n \n \n The mammalian phosphate carrier SLC25A3 is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis.\n \n \n \n\n\n \n Boulet, A.; Vest, K. E.; Maynard, M. K.; Gammon, M. G.; Russell, A. C.; Mathews, A. T.; Cole, S. E.; Zhu, X.; Phillips, C. B.; Kwong, J. Q.; Dodani, S. C.; Leary, S. C.; and Cobine, P. A.\n\n\n \n\n\n\n The Journal of Biological Chemistry, 293(6): 1887–1896. 2018.\n \n\n\n\n
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\n\n\n@article{boulet_mammalian_2018,\n\ttitle = {The mammalian phosphate carrier {SLC25A3} is a mitochondrial copper transporter required for cytochrome c oxidase biogenesis},\n\tvolume = {293},\n\tissn = {1083-351X},\n\tdoi = {10.1074/jbc.RA117.000265},\n\tabstract = {Copper is required for the activity of cytochrome c oxidase (COX), the terminal electron-accepting complex of the mitochondrial respiratory chain. The likely source of copper used for COX biogenesis is a labile pool found in the mitochondrial matrix. In mammals, the proteins that transport copper across the inner mitochondrial membrane remain unknown. We previously reported that the mitochondrial carrier family protein Pic2 in budding yeast is a copper importer. The closest Pic2 ortholog in mammalian cells is the mitochondrial phosphate carrier SLC25A3. Here, to investigate whether SLC25A3 also transports copper, we manipulated its expression in several murine and human cell lines. SLC25A3 knockdown or deletion consistently resulted in an isolated COX deficiency in these cells, and copper addition to the culture medium suppressed these biochemical defects. Consistent with a conserved role for SLC25A3 in copper transport, its heterologous expression in yeast complemented copper-specific defects observed upon deletion of PIC2 Additionally, assays in Lactococcus lactis and in reconstituted liposomes directly demonstrated that SLC25A3 functions as a copper transporter. Taken together, these data indicate that SLC25A3 can transport copper both in vitro and in vivo.},\n\tlanguage = {eng},\n\tnumber = {6},\n\tjournal = {The Journal of Biological Chemistry},\n\tauthor = {Boulet, Aren and Vest, Katherine E. and Maynard, Margaret K. and Gammon, Micah G. and Russell, Antoinette C. and Mathews, Alexander T. and Cole, Shelbie E. and Zhu, Xinyu and Phillips, Casey B. and Kwong, Jennifer Q. and Dodani, Sheel C. and Leary, Scot C. and Cobine, Paul A.},\n\tyear = {2018},\n\tpmid = {29237729},\n\tpmcid = {PMC5808751},\n\tkeywords = {copper, copper transport, cytochrome c oxidase (complex IV), membrane transport, mitochondria},\n\tpages = {1887--1896},\n}\n\n\n\n Copper is required for the activity of cytochrome c oxidase (COX), the terminal electron-accepting complex of the mitochondrial respiratory chain. The likely source of copper used for COX biogenesis is a labile pool found in the mitochondrial matrix. In mammals, the proteins that transport copper across the inner mitochondrial membrane remain unknown. We previously reported that the mitochondrial carrier family protein Pic2 in budding yeast is a copper importer. The closest Pic2 ortholog in mammalian cells is the mitochondrial phosphate carrier SLC25A3. Here, to investigate whether SLC25A3 also transports copper, we manipulated its expression in several murine and human cell lines. SLC25A3 knockdown or deletion consistently resulted in an isolated COX deficiency in these cells, and copper addition to the culture medium suppressed these biochemical defects. Consistent with a conserved role for SLC25A3 in copper transport, its heterologous expression in yeast complemented copper-specific defects observed upon deletion of PIC2 Additionally, assays in Lactococcus lactis and in reconstituted liposomes directly demonstrated that SLC25A3 functions as a copper transporter. Taken together, these data indicate that SLC25A3 can transport copper both in vitro and in vivo.\n
\n\n\n\n \n\n \n \n \n \n \n Long-Term Transplant-Free Survival After Repair of Total Anomalous Pulmonary Venous Connection.\n \n \n \n\n\n \n St Louis, J. D.; McCracken, C. E.; Turk, E. M.; Hancock, H. S.; Menk, J. S.; Harvey, B. A.; Vinocur, J. M.; Oster, M. E.; Moller, J. H.; Spector, L. G.; and Kochilas, L. K.\n\n\n \n\n\n\n The Annals of Thoracic Surgery, 105(1): 186–192. January 2018.\n \n\n\n\n
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\n\n\n@article{st_louis_long-term_2018,\n\ttitle = {Long-{Term} {Transplant}-{Free} {Survival} {After} {Repair} of {Total} {Anomalous} {Pulmonary} {Venous} {Connection}},\n\tvolume = {105},\n\tissn = {1552-6259},\n\tdoi = {10.1016/j.athoracsur.2017.05.052},\n\tabstract = {BACKGROUND: Long-term survival, risk of transplantation, and causes of death after repair of total anomalous pulmonary venous connection (TAPVC) remain unknown. By linking the Pediatric Cardiac Care Consortium with the National Death Index and the United Network for Organ Sharing, we evaluated long-term transplant-free survival in children undergoing repair of TAPVC.\nMETHODS: We identified 777 infants within the Pediatric Cardiac Care Consortium who underwent TAPVC repair (median 21 days; interquartile range, 5 to 80) and had sufficient personal identifiers for linkage with the National Death Index and United Network for Organ Sharing. Sixty-six deaths, ten cardiac transplantations, and one bilateral lung transplantation had occurred by the end of 2014. Data collected included age and weight at time of procedure, TAPVC type, associated cardiac lesions, and postoperative length of stay. The study cohort was divided into simple and complex TAPVC based on the presence of an associated cardiac lesion. Parametric survival plots were constructed, and risk factor analyses were performed to identify demographic and clinical characteristics associated with long-term outcomes.\nRESULTS: Mortality or need for transplantation was 9.7\\% with a median follow-up of 18.4 years and a median age of death or transplant of 0.74 years. The risk of mortality and transplant after TAPVC repair was highest during the first 18 months after hospital discharge. Cardiac causes accounted for the majority of deaths. Multivariate regression models for transplant-free survival demonstrated that complex TAPVC, mixed TAPVC, and postoperative length of stay were associated with increased risk of death/transplant.\nCONCLUSIONS: Transplant-free survival after TAPVC repair is excellent, with most deaths or transplant events occurring early. Factors associated with the worst long-term outcomes included complex TAPVC, mixed TAPVC, and prolonged postoperative length of stay.},\n\tlanguage = {eng},\n\tnumber = {1},\n\tjournal = {The Annals of Thoracic Surgery},\n\tauthor = {St Louis, James D. and McCracken, Courtney E. and Turk, Elizabeth M. and Hancock, Hayley S. and Menk, Jeremiah S. and Harvey, Brian A. and Vinocur, Jeffrey M. and Oster, Matthew E. and Moller, James H. and Spector, Logan G. and Kochilas, Lazaros K.},\n\tmonth = jan,\n\tyear = {2018},\n\tpmid = {28847536},\n\tpmcid = {PMC5729081},\n\tkeywords = {Cohort Studies, Disease-Free Survival, Female, Heart Transplantation, Humans, Infant, Infant, Newborn, Male, Scimitar Syndrome, Time Factors, Vascular Surgical Procedures},\n\tpages = {186--192},\n}\n\n\n\n BACKGROUND: Long-term survival, risk of transplantation, and causes of death after repair of total anomalous pulmonary venous connection (TAPVC) remain unknown. By linking the Pediatric Cardiac Care Consortium with the National Death Index and the United Network for Organ Sharing, we evaluated long-term transplant-free survival in children undergoing repair of TAPVC. METHODS: We identified 777 infants within the Pediatric Cardiac Care Consortium who underwent TAPVC repair (median 21 days; interquartile range, 5 to 80) and had sufficient personal identifiers for linkage with the National Death Index and United Network for Organ Sharing. Sixty-six deaths, ten cardiac transplantations, and one bilateral lung transplantation had occurred by the end of 2014. Data collected included age and weight at time of procedure, TAPVC type, associated cardiac lesions, and postoperative length of stay. The study cohort was divided into simple and complex TAPVC based on the presence of an associated cardiac lesion. Parametric survival plots were constructed, and risk factor analyses were performed to identify demographic and clinical characteristics associated with long-term outcomes. RESULTS: Mortality or need for transplantation was 9.7% with a median follow-up of 18.4 years and a median age of death or transplant of 0.74 years. The risk of mortality and transplant after TAPVC repair was highest during the first 18 months after hospital discharge. Cardiac causes accounted for the majority of deaths. Multivariate regression models for transplant-free survival demonstrated that complex TAPVC, mixed TAPVC, and postoperative length of stay were associated with increased risk of death/transplant. CONCLUSIONS: Transplant-free survival after TAPVC repair is excellent, with most deaths or transplant events occurring early. Factors associated with the worst long-term outcomes included complex TAPVC, mixed TAPVC, and prolonged postoperative length of stay.\n
\n\n\n\n \n\n \n \n \n \n \n Outcomes after surgical coronary artery revascularisation in children with congenital heart disease.\n \n \n \n\n\n \n Thammineni, K.; Vinocur, J. M.; Harvey, B.; Menk, J. S.; Kelleman, M. S.; Korakiti, A.; Thomas, A. S.; Moller, J. H.; St Louis, J. D.; and Kochilas, L. K.\n\n\n \n\n\n\n Heart (British Cardiac Society), 104(17): 1417–1423. 2018.\n \n\n\n\n
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\n\n\n@article{thammineni_outcomes_2018,\n\ttitle = {Outcomes after surgical coronary artery revascularisation in children with congenital heart disease},\n\tvolume = {104},\n\tissn = {1468-201X},\n\tdoi = {10.1136/heartjnl-2017-312652},\n\tabstract = {OBJECTIVE: Surgical coronary revascularisation in children with congenital heart disease (CHD) is a rare event for which limited information is available. In this study, we review the indications and outcomes of surgical coronary revascularisation from the Pediatric Cardiac Care Consortium, a large US-based multicentre registry of interventions for CHD.\nMETHODS: This is a retrospective cohort study of children ({\\textless}18 years old) with CHD who underwent surgical coronary revascularisation between 1982 and 2011. In-hospital mortality and graft patency data were obtained from the registry. Long-term transplant-free survival through 2014 was achieved for patients with adequate identifiers via linkage with the US National Death Index and the Organ Procurement and Transplantation Network.\nRESULTS: Coronary revascularisation was accomplished by bypass grafting (n=72, median age 6.8 years, range 3 days-17.4 years) or other operations (n=65, median age 2.6 years, range 5 days-16.7 years) in 137 patients. Most revascularisations were related to the aortic root (61.3\\%) or coronary anomalies (27.7\\%), but 10.9\\% of them were unrelated to either of them. Twenty in-hospital deaths occurred, 70\\% of them after urgent 'rescue' revascularisation in association with another operation. Long-term outcomes were available by external linkage for 54 patients surviving to hospital discharge (median follow-up time 15.0 years, max follow-up 29.8 years) with a 15-year transplant-free survival of 91\\% (95\\% CI 83\\% to 99\\%).\nCONCLUSIONS: Surgical coronary revascularisation can be performed in children with CHD with acceptable immediate and long-term survival. Outcomes are dependent on indication, with the highest mortality in rescue procedures.},\n\tlanguage = {eng},\n\tnumber = {17},\n\tjournal = {Heart (British Cardiac Society)},\n\tauthor = {Thammineni, Kalpana and Vinocur, Jeffrey M. and Harvey, Brian and Menk, Jeremiah S. and Kelleman, Michael Scott and Korakiti, Anna-Maria and Thomas, Amanda S. and Moller, James H. and St Louis, James D. and Kochilas, Lazaros K.},\n\tyear = {2018},\n\tpmid = {29472291},\n\tpmcid = {PMC6092219},\n\tkeywords = {congenital heart disease, congenital heart disease surgery},\n\tpages = {1417--1423},\n}\n\n\n\n OBJECTIVE: Surgical coronary revascularisation in children with congenital heart disease (CHD) is a rare event for which limited information is available. In this study, we review the indications and outcomes of surgical coronary revascularisation from the Pediatric Cardiac Care Consortium, a large US-based multicentre registry of interventions for CHD. METHODS: This is a retrospective cohort study of children (\\textless18 years old) with CHD who underwent surgical coronary revascularisation between 1982 and 2011. In-hospital mortality and graft patency data were obtained from the registry. Long-term transplant-free survival through 2014 was achieved for patients with adequate identifiers via linkage with the US National Death Index and the Organ Procurement and Transplantation Network. RESULTS: Coronary revascularisation was accomplished by bypass grafting (n=72, median age 6.8 years, range 3 days-17.4 years) or other operations (n=65, median age 2.6 years, range 5 days-16.7 years) in 137 patients. Most revascularisations were related to the aortic root (61.3%) or coronary anomalies (27.7%), but 10.9% of them were unrelated to either of them. Twenty in-hospital deaths occurred, 70% of them after urgent 'rescue' revascularisation in association with another operation. Long-term outcomes were available by external linkage for 54 patients surviving to hospital discharge (median follow-up time 15.0 years, max follow-up 29.8 years) with a 15-year transplant-free survival of 91% (95% CI 83% to 99%). CONCLUSIONS: Surgical coronary revascularisation can be performed in children with CHD with acceptable immediate and long-term survival. Outcomes are dependent on indication, with the highest mortality in rescue procedures.\n
\n\n\n\n \n\n \n \n \n \n \n A Modified Algorithm for Critical Congenital Heart Disease Screening Using Pulse Oximetry.\n \n \n \n\n\n \n Diller, C. L.; Kelleman, M. S.; Kupke, K. G.; Quary, S. C.; Kochilas, L. K.; and Oster, M. E.\n\n\n \n\n\n\n Pediatrics, 141(5). May 2018.\n \n\n\n\n
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\n\n\n@article{diller_modified_2018,\n\ttitle = {A {Modified} {Algorithm} for {Critical} {Congenital} {Heart} {Disease} {Screening} {Using} {Pulse} {Oximetry}},\n\tvolume = {141},\n\tissn = {1098-4275},\n\tdoi = {10.1542/peds.2017-4065},\n\tabstract = {: media-1vid110.1542/5727212367001PEDS-VA\\_2017-4065Video Abstract OBJECTIVES: Determine the performance of the American Academy of Pediatrics (AAP) critical congenital heart disease (CCHD) newborn screening algorithm and the impact of an alternative algorithm.\nMETHODS: Screening was performed on term infants without a known CCHD diagnosis at or near 24 hours of age at a tertiary birth hospital by using the AAP algorithm from 2013 to 2016. Retrospective review from the birth hospital and the area's sole pediatric cardiac center identified true- and false-positives and true- and false-negatives. A simulation study modeled the results of a modified screening algorithm with a single repeat pulse oximetry test instead of 2.\nRESULTS: Screening results were collected on 77 148 newborns . By using the current AAP algorithm, 77 114 (99.96\\%) infants passed screening, 18 infants failed for an initial saturation of {\\textless}90\\%, and 16 failed after not attaining a passing pulse oximetry level after 3 tests. There was 1 true-positive (total anomalous pulmonary venous return), 33 false-positives, and 6 false-negatives, yielding an overall specificity of 99.96\\%, a sensitivity of 14.3\\%, and a false-positive rate of 0.043\\%. Among false-positives, 10 (31.3\\%) had significant non-CCHD disease. Simulating the modified algorithm, sensitivity remained at 14.3\\%, and the false-positive rate increased to 0.054\\%.\nCONCLUSIONS: Although CCHD screening in a tertiary care birth hospital may not detect many new cases of CCHD, it can detect other important diseases in newborns. Modifying the screening algorithm to 1 repeat pulse oximetry test instead of 2 may detect additional infants with significant disease without a substantial increase in the false-positive rate.},\n\tlanguage = {eng},\n\tnumber = {5},\n\tjournal = {Pediatrics},\n\tauthor = {Diller, Christina L. and Kelleman, Michael S. and Kupke, Kenneth G. and Quary, Sharon C. and Kochilas, Lazaros K. and Oster, Matthew E.},\n\tmonth = may,\n\tyear = {2018},\n\tpmid = {29691284},\n}\n\n\n\n : media-1vid110.1542/5727212367001PEDS-VA_2017-4065Video Abstract OBJECTIVES: Determine the performance of the American Academy of Pediatrics (AAP) critical congenital heart disease (CCHD) newborn screening algorithm and the impact of an alternative algorithm. METHODS: Screening was performed on term infants without a known CCHD diagnosis at or near 24 hours of age at a tertiary birth hospital by using the AAP algorithm from 2013 to 2016. Retrospective review from the birth hospital and the area's sole pediatric cardiac center identified true- and false-positives and true- and false-negatives. A simulation study modeled the results of a modified screening algorithm with a single repeat pulse oximetry test instead of 2. RESULTS: Screening results were collected on 77 148 newborns . By using the current AAP algorithm, 77 114 (99.96%) infants passed screening, 18 infants failed for an initial saturation of \\textless90%, and 16 failed after not attaining a passing pulse oximetry level after 3 tests. There was 1 true-positive (total anomalous pulmonary venous return), 33 false-positives, and 6 false-negatives, yielding an overall specificity of 99.96%, a sensitivity of 14.3%, and a false-positive rate of 0.043%. Among false-positives, 10 (31.3%) had significant non-CCHD disease. Simulating the modified algorithm, sensitivity remained at 14.3%, and the false-positive rate increased to 0.054%. CONCLUSIONS: Although CCHD screening in a tertiary care birth hospital may not detect many new cases of CCHD, it can detect other important diseases in newborns. Modifying the screening algorithm to 1 repeat pulse oximetry test instead of 2 may detect additional infants with significant disease without a substantial increase in the false-positive rate.\n
\n\n\n\n \n\n \n \n \n \n \n Long-Term Survival After Arterial Versus Atrial Switch in d-Transposition of the Great Arteries.\n \n \n \n\n\n \n Kiener, A.; Kelleman, M.; McCracken, C.; Kochilas, L.; St Louis, J. D.; and Oster, M. E.\n\n\n \n\n\n\n The Annals of Thoracic Surgery, 106(6): 1827–1833. December 2018.\n \n\n\n\n
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\n\n\n@article{kiener_long-term_2018,\n\ttitle = {Long-{Term} {Survival} {After} {Arterial} {Versus} {Atrial} {Switch} in d-{Transposition} of the {Great} {Arteries}},\n\tvolume = {106},\n\tissn = {1552-6259},\n\tdoi = {10.1016/j.athoracsur.2018.06.084},\n\tabstract = {BACKGROUND: The arterial switch operation (ASO) became the procedure of choice for dextro-transposition of the great arteries (d-TGA) nearly 30 years ago, but the long-term results of this operation are unknown. We aimed to compare the long-term transplant-free survival of patients with d-TGA who underwent ASO versus atrial switch in the Pediatric Cardiac Care Consortium.\nMETHODS: We performed a retrospective cohort study of d-TGA patients undergoing ASO or atrial switch in the United States between 1982 and 1991. Long-term transplant-free survival was obtained by linking Pediatric Cardiac Care Consortium data with the National Death Index and the Organ Procurement and Transplant Network. Kaplan-Meier survival plots were constructed, and multivariable regression was used to compare long-term transplant-free survival.\nRESULTS: Of 554 d-TGA patients who underwent ASO (n = 259) or atrial switch (n = 295), the 20-year overall transplant-free survival was 82.1\\% for those undergoing ASO and 76.3\\% for those who had atrial switch procedure. Adjusted overall transplant-free survival beyond 10 years after operation was superior for ASO compared with atrial switch (hazard ratio 0.07, 95\\% confidence interval: 0.01 to 0.52, p = 0.009). During this period, the ASO had higher in-hospital mortality than the atrial switch (21.6\\% versus 12.9\\%, p = 0.007). After excluding patients with in-hospital mortality, the transplant-free survival 20 years after repair was 97.7\\% for the ASO patients versus 86.3\\% for the atrial switch patients.\nCONCLUSIONS: Despite initial higher in-hospital mortality for ASO during the study period, there is a significant long-term transplant-free survival advantage for ASO as compared with atrial switch for d-TGA surgery. Ongoing monitoring is required to assess late risk of cardiovascular disease.},\n\tlanguage = {eng},\n\tnumber = {6},\n\tjournal = {The Annals of Thoracic Surgery},\n\tauthor = {Kiener, Alexander and Kelleman, Michael and McCracken, Courtney and Kochilas, Lazaros and St Louis, James D. and Oster, Matthew E.},\n\tmonth = dec,\n\tyear = {2018},\n\tpmid = {30172857},\n\tpmcid = {PMC6240478},\n\tpages = {1827--1833},\n}\n\n\n\n BACKGROUND: The arterial switch operation (ASO) became the procedure of choice for dextro-transposition of the great arteries (d-TGA) nearly 30 years ago, but the long-term results of this operation are unknown. We aimed to compare the long-term transplant-free survival of patients with d-TGA who underwent ASO versus atrial switch in the Pediatric Cardiac Care Consortium. METHODS: We performed a retrospective cohort study of d-TGA patients undergoing ASO or atrial switch in the United States between 1982 and 1991. Long-term transplant-free survival was obtained by linking Pediatric Cardiac Care Consortium data with the National Death Index and the Organ Procurement and Transplant Network. Kaplan-Meier survival plots were constructed, and multivariable regression was used to compare long-term transplant-free survival. RESULTS: Of 554 d-TGA patients who underwent ASO (n = 259) or atrial switch (n = 295), the 20-year overall transplant-free survival was 82.1% for those undergoing ASO and 76.3% for those who had atrial switch procedure. Adjusted overall transplant-free survival beyond 10 years after operation was superior for ASO compared with atrial switch (hazard ratio 0.07, 95% confidence interval: 0.01 to 0.52, p = 0.009). During this period, the ASO had higher in-hospital mortality than the atrial switch (21.6% versus 12.9%, p = 0.007). After excluding patients with in-hospital mortality, the transplant-free survival 20 years after repair was 97.7% for the ASO patients versus 86.3% for the atrial switch patients. CONCLUSIONS: Despite initial higher in-hospital mortality for ASO during the study period, there is a significant long-term transplant-free survival advantage for ASO as compared with atrial switch for d-TGA surgery. Ongoing monitoring is required to assess late risk of cardiovascular disease.\n
\n\n\n\n \n\n \n \n \n \n \n Factors Associated With Interstage Mortality Following Neonatal Single Ventricle Palliation.\n \n \n \n\n\n \n Alsoufi, B.; McCracken, C.; Kochilas, L. K.; Clabby, M.; and Kanter, K.\n\n\n \n\n\n\n World Journal for Pediatric & Congenital Heart Surgery, 9(6): 616–623. 2018.\n \n\n\n\n
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\n\n\n@article{alsoufi_factors_2018,\n\ttitle = {Factors {Associated} {With} {Interstage} {Mortality} {Following} {Neonatal} {Single} {Ventricle} {Palliation}},\n\tvolume = {9},\n\tissn = {2150-136X},\n\tdoi = {10.1177/2150135118787723},\n\tabstract = {BACKGROUND: Several advances have led to improved hospital survival following neonatal palliation (NP) of single ventricle (SV) anomalies. Nonetheless, a number of patients continue to suffer from interstage mortality (ISM) prior to subsequent Glenn. We aim to study patients' characteristics and anatomic, surgical, and clinical details associated with ISM.\nMETHODS: A total of 453 SV neonates survived to hospital discharge following NP. Competing risk analysis modeled events after NP (Glenn, transplantation, or death) and examined variables associated with ISM.\nRESULTS: Competing risk analysis showed that one year following NP, 10\\% of patients had died, 87\\% had progressed to Glenn, 1\\% had received heart transplantation, and 2\\% were alive without subsequent surgery. On multivariable analysis, factors associated with ISM were as follows: weight ≤2.5 kg (hazard ratio, HR = 2.4 [1.2-4.6], P = .013), premature birth ≤36 weeks (HR = 2.0 [1.0-4.0], P = .05), genetic syndromes (HR = 3.2 [1.7-6.1], P {\\textless} .001), unplanned cardiac reoperation (HR = 2.1 [1.0-4.4], P = .05), and prolonged intensive care unit (ICU) stay {\\textgreater}30 days following NP (HR = 2.5 [1.4-4.5], P {\\textless} .001). Palliative surgery type (shunt, Norwood, band) was not associated with ISM, although aortopulmonary shunt circulation after Norwood was (HR = 5.4 [1.5-19.2] P = .01). Of interest, underlying SV anatomy was not associated with ISM (HR = 1.1 [0.6-2.2], P = .749).\nCONCLUSIONS: In our series, ISM following NP occurred in 10\\% of hospital survivors. As opposed to hospital death, underlying SV anomaly was not associated with ISM. Conversely, several patient factors (prematurity, low weight, and genetic syndromes) and clinical factors (unplanned reoperation and prolonged ICU stay following NP) were associated with ISM. Vigilant outpatient management that is individualized to specific clinical and social needs, taking into account all associated factors, is warranted to improve survival in high-risk patients.},\n\tlanguage = {eng},\n\tnumber = {6},\n\tjournal = {World Journal for Pediatric \\& Congenital Heart Surgery},\n\tauthor = {Alsoufi, Bahaaldin and McCracken, Courtney and Kochilas, Lazaros K. and Clabby, Martha and Kanter, Kirk},\n\tyear = {2018},\n\tpmid = {30322369},\n\tkeywords = {Cardiac Surgical Procedures, Female, Heart Ventricles, Humans, Hypoplastic Left Heart Syndrome, Infant, Low Birth Weight, Infant, Newborn, Male, Norwood procedure, Palliative Care, Risk Factors, Survival Rate, Treatment Outcome, United States, cavopulmonary anastomosis, shunts (indicate location), single ventricle},\n\tpages = {616--623},\n}\n\n\n\n BACKGROUND: Several advances have led to improved hospital survival following neonatal palliation (NP) of single ventricle (SV) anomalies. Nonetheless, a number of patients continue to suffer from interstage mortality (ISM) prior to subsequent Glenn. We aim to study patients' characteristics and anatomic, surgical, and clinical details associated with ISM. METHODS: A total of 453 SV neonates survived to hospital discharge following NP. Competing risk analysis modeled events after NP (Glenn, transplantation, or death) and examined variables associated with ISM. RESULTS: Competing risk analysis showed that one year following NP, 10% of patients had died, 87% had progressed to Glenn, 1% had received heart transplantation, and 2% were alive without subsequent surgery. On multivariable analysis, factors associated with ISM were as follows: weight ≤2.5 kg (hazard ratio, HR = 2.4 [1.2-4.6], P = .013), premature birth ≤36 weeks (HR = 2.0 [1.0-4.0], P = .05), genetic syndromes (HR = 3.2 [1.7-6.1], P \\textless .001), unplanned cardiac reoperation (HR = 2.1 [1.0-4.4], P = .05), and prolonged intensive care unit (ICU) stay \\textgreater30 days following NP (HR = 2.5 [1.4-4.5], P \\textless .001). Palliative surgery type (shunt, Norwood, band) was not associated with ISM, although aortopulmonary shunt circulation after Norwood was (HR = 5.4 [1.5-19.2] P = .01). Of interest, underlying SV anatomy was not associated with ISM (HR = 1.1 [0.6-2.2], P = .749). CONCLUSIONS: In our series, ISM following NP occurred in 10% of hospital survivors. As opposed to hospital death, underlying SV anomaly was not associated with ISM. Conversely, several patient factors (prematurity, low weight, and genetic syndromes) and clinical factors (unplanned reoperation and prolonged ICU stay following NP) were associated with ISM. Vigilant outpatient management that is individualized to specific clinical and social needs, taking into account all associated factors, is warranted to improve survival in high-risk patients.\n
\n\n\n\n \n\n \n \n \n \n \n Long-term Outcomes of Tetralogy of Fallot: A Study From the Pediatric Cardiac Care Consortium.\n \n \n \n\n\n \n Smith, C. A.; McCracken, C.; Thomas, A. S.; Spector, L. G.; St Louis, J. D.; Oster, M. E.; Moller, J. H.; and Kochilas, L.\n\n\n \n\n\n\n JAMA cardiology. December 2018.\n \n\n\n\n
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\n\n\n@article{smith_long-term_2018,\n\ttitle = {Long-term {Outcomes} of {Tetralogy} of {Fallot}: {A} {Study} {From} the {Pediatric} {Cardiac} {Care} {Consortium}},\n\tissn = {2380-6591},\n\tshorttitle = {Long-term {Outcomes} of {Tetralogy} of {Fallot}},\n\tdoi = {10.1001/jamacardio.2018.4255},\n\tabstract = {Importance: Tetralogy of Fallot (TOF) is a surgically repairable form of cyanotic congenital heart disease. Multicenter data for long-term survival following repair are sparse.\nObjective: To evaluate the long-term transplant-free survival of TOF by surgical strategy adjusted for era and patient characteristics.\nDesign, Setting, and Participants: Retrospective cohort study enriched with data from the National Death Index and the Organ Procurement and Transplantation Network through 2014. Multicenter cohort from the Pediatric Cardiac Care Consortium (PCCC), a large, US-based clinical registry for interventions for congenital heart disease. The cohort included patients with adequate identifiers for linkage with the National Death Index and the Organ Procurement and Transplantation Network who were enrolled in the PCCC registry between 1982 and 2003 and survived surgical repair of simple TOF. Data were analyzed between September 2015 and April 2018.\nExposures: We examined patient-associated and surgery-associated risk factors affecting survival.\nMain Outcomes and Measures: We analyzed the transplant-free survival during early ({\\textless}6 years) and late (≥6 years) phase after TOF surgical repair.\nResults: Of the 3283 patients who survived repair for simple TOF and met the study's inclusion criteria, 56.4\\% were male and 43.6\\% were female. Twenty-five-year survival following TOF repair was 94.5\\%. Multivariable analysis demonstrated increased risk of early mortality with staged repair (HR, 2.68; 95\\% CI, 1.59-4.49) and non-valve-sparing operation (HR, 3.76; 95\\% CI, 1.53-9.19). Presence of a genetic abnormality was associated with increased risk of death both in the early (HR, 3.64; 95\\% CI, 2.05-6.47) and late postoperative phase (HR, 4.41; 95\\% CI, 2.62-7.44).\nConclusions and Relevance: Long-term survival after simple TOF repair is excellent. Staged repair and non-valve-sparing operations were negatively associated with survival in the early postrepair phase but not the late postrepair phase. These data are important for patients with repaired TOF and their caretakers and may guide surgical strategies for optimizing the long-term outcomes of this population.},\n\tlanguage = {eng},\n\tjournal = {JAMA cardiology},\n\tauthor = {Smith, Clayton A. and McCracken, Courtney and Thomas, Amanda S. and Spector, Logan G. and St Louis, James D. and Oster, Matthew E. and Moller, James H. and Kochilas, Lazaros},\n\tmonth = dec,\n\tyear = {2018},\n\tpmid = {30566184},\n}\n\n\n\n Importance: Tetralogy of Fallot (TOF) is a surgically repairable form of cyanotic congenital heart disease. Multicenter data for long-term survival following repair are sparse. Objective: To evaluate the long-term transplant-free survival of TOF by surgical strategy adjusted for era and patient characteristics. Design, Setting, and Participants: Retrospective cohort study enriched with data from the National Death Index and the Organ Procurement and Transplantation Network through 2014. Multicenter cohort from the Pediatric Cardiac Care Consortium (PCCC), a large, US-based clinical registry for interventions for congenital heart disease. The cohort included patients with adequate identifiers for linkage with the National Death Index and the Organ Procurement and Transplantation Network who were enrolled in the PCCC registry between 1982 and 2003 and survived surgical repair of simple TOF. Data were analyzed between September 2015 and April 2018. Exposures: We examined patient-associated and surgery-associated risk factors affecting survival. Main Outcomes and Measures: We analyzed the transplant-free survival during early (\\textless6 years) and late (≥6 years) phase after TOF surgical repair. Results: Of the 3283 patients who survived repair for simple TOF and met the study's inclusion criteria, 56.4% were male and 43.6% were female. Twenty-five-year survival following TOF repair was 94.5%. Multivariable analysis demonstrated increased risk of early mortality with staged repair (HR, 2.68; 95% CI, 1.59-4.49) and non-valve-sparing operation (HR, 3.76; 95% CI, 1.53-9.19). Presence of a genetic abnormality was associated with increased risk of death both in the early (HR, 3.64; 95% CI, 2.05-6.47) and late postoperative phase (HR, 4.41; 95% CI, 2.62-7.44). Conclusions and Relevance: Long-term survival after simple TOF repair is excellent. Staged repair and non-valve-sparing operations were negatively associated with survival in the early postrepair phase but not the late postrepair phase. These data are important for patients with repaired TOF and their caretakers and may guide surgical strategies for optimizing the long-term outcomes of this population.\n
\n\n\n\n \n\n \n \n \n \n \n Long-Term Outcomes in Single-Ventricle Congenital Heart Disease.\n \n \n \n\n\n \n Oster, M. E.; Knight, J. H.; Suthar, D.; Amin, O.; and Kochilas, L. K.\n\n\n \n\n\n\n Circulation, 138(23): 2718–2720. December 2018.\n \n\n\n\n
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\n\n\n\n@article{oster_long-term_2018,\n\ttitle = {Long-{Term} {Outcomes} in {Single}-{Ventricle} {Congenital} {Heart} {Disease}},\n\tvolume = {138},\n\tissn = {1524-4539},\n\tdoi = {10.1161/CIRCULATIONAHA.118.036821},\n\tlanguage = {eng},\n\tnumber = {23},\n\tjournal = {Circulation},\n\tauthor = {Oster, Matthew E. and Knight, Jessica H. and Suthar, Divya and Amin, Omayma and Kochilas, Lazaros K.},\n\tmonth = dec,\n\tyear = {2018},\n\tpmid = {30571273},\n\tpmcid = {PMC6309811},\n\tkeywords = {heart defects, congenital, heart transplantation, heart ventricles, hypoplastic left heart syndrome, mortality, survival analysis, thoracic surgery},\n\tpages = {2718--2720},\n}\n\n\n\n \n\n \n \n \n \n \n 1024-Pixel CMOS Multimodality Joint Cellular Sensor/Stimulator Array for Real-Time Holistic Cellular Characterization and Cell-Based Drug Screening.\n \n \n \n\n\n \n Park, J. S.; Aziz, M. K.; Li, S.; Chi, T.; Grijalva, S. I.; Sung, J. H.; Cho, H. C.; and Wang, H.\n\n\n \n\n\n\n IEEE transactions on biomedical circuits and systems, 12(1): 80–94. 2018.\n \n\n\n\n
\n\n\n\n \n\n \n \n doi\n \n \n\n \n link\n \n \n\n bibtex\n \n\n \n \n \n abstract \n \n\n \n\n \n \n \n \n \n \n \n\n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n \n\n\n\n
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\n\n\n@article{park_1024-pixel_2018,\n\ttitle = {1024-{Pixel} {CMOS} {Multimodality} {Joint} {Cellular} {Sensor}/{Stimulator} {Array} for {Real}-{Time} {Holistic} {Cellular} {Characterization} and {Cell}-{Based} {Drug} {Screening}},\n\tvolume = {12},\n\tissn = {1940-9990},\n\tdoi = {10.1109/TBCAS.2017.2759220},\n\tabstract = {This paper presents a fully integrated CMOS multimodality joint sensor/stimulator array with 1024 pixels for real-time holistic cellular characterization and drug screening. The proposed system consists of four pixel groups and four parallel signal-conditioning blocks. Every pixel group contains 16 × 16 pixels, and each pixel includes one gold-plated electrode, four photodiodes, and in-pixel circuits, within a pixel footprint. Each pixel supports real-time extracellular potential recording, optical detection, charge-balanced biphasic current stimulation, and cellular impedance measurement for the same cellular sample. The proposed system is fabricated in a standard 130-nm CMOS process. Rat cardiomyocytes are successfully cultured on-chip. Measured high-resolution optical opacity images, extracellular potential recordings, biphasic current stimulations, and cellular impedance images demonstrate the unique advantages of the system for holistic cell characterization and drug screening. Furthermore, this paper demonstrates the use of optical detection on the on-chip cultured cardiomyocytes to real-time track their cyclic beating pattern and beating rate.},\n\tlanguage = {eng},\n\tnumber = {1},\n\tjournal = {IEEE transactions on biomedical circuits and systems},\n\tauthor = {Park, Jong Seok and Aziz, Moez Karim and Li, Sensen and Chi, Taiyun and Grijalva, Sandra Ivonne and Sung, Jung Hoon and Cho, Hee Cheol and Wang, Hua},\n\tyear = {2018},\n\tpmid = {29377798},\n\tkeywords = {Animals, Cell Culture Techniques, Drug Evaluation, Preclinical, Electric Impedance, Electrodes, Image Processing, Computer-Assisted, Lab-On-A-Chip Devices, Membrane Potentials, Myocytes, Cardiac, Rats, Rats, Sprague-Dawley},\n\tpages = {80--94},\n}\n\n\n\n This paper presents a fully integrated CMOS multimodality joint sensor/stimulator array with 1024 pixels for real-time holistic cellular characterization and drug screening. The proposed system consists of four pixel groups and four parallel signal-conditioning blocks. Every pixel group contains 16 × 16 pixels, and each pixel includes one gold-plated electrode, four photodiodes, and in-pixel circuits, within a pixel footprint. Each pixel supports real-time extracellular potential recording, optical detection, charge-balanced biphasic current stimulation, and cellular impedance measurement for the same cellular sample. The proposed system is fabricated in a standard 130-nm CMOS process. Rat cardiomyocytes are successfully cultured on-chip. Measured high-resolution optical opacity images, extracellular potential recordings, biphasic current stimulations, and cellular impedance images demonstrate the unique advantages of the system for holistic cell characterization and drug screening. Furthermore, this paper demonstrates the use of optical detection on the on-chip cultured cardiomyocytes to real-time track their cyclic beating pattern and beating rate.\n
\n\n\n\n \n\n \n \n \n \n \n Multi-parametric cell profiling with a CMOS quad-modality cellular interfacing array for label-free fully automated drug screening.\n \n \n \n\n\n \n Park, J. S.; Grijalva, S. I.; Aziz, M. K.; Chi, T.; Li, S.; Sayegh, M. N.; Wang, A.; Cho, H. C.; and Wang, H.\n\n\n \n\n\n\n Lab on a Chip, 18(19): 3037–3050. 2018.\n \n\n\n\n
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\n\n\n@article{park_multi-parametric_2018,\n\ttitle = {Multi-parametric cell profiling with a {CMOS} quad-modality cellular interfacing array for label-free fully automated drug screening},\n\tvolume = {18},\n\tissn = {1473-0189},\n\tdoi = {10.1039/c8lc00156a},\n\tabstract = {Cells are complex systems with concurrent multi-physical responses, and cell physiological signals are often encoded with spatiotemporal dynamics and further coupled with multiple cellular activities. However, most existing electronic sensors are only single-modality and cannot capture multi-parametric cellular responses. In this paper, a 1024-pixel CMOS quad-modality cellular interfacing array that enables multi-parametric cell profiling for drug development is presented. The quad-modality CMOS array features cellular impedance characterization, optical detection, extracellular potential recording, and biphasic current stimulation. The fibroblast transparency and surface adhesion are jointly monitored by cellular impedance and optical sensing modalities for comprehensive cell growth evaluation. Simultaneous current stimulation and opto-mechanical monitoring based on cardiomyocytes are demonstrated without any stimulation/sensing dead-zone. Furthermore, drug dose-dependent multi-parametric feature extractions in cardiomyocytes from their extracellular potentials and opto-mechanical signals are presented. The CMOS array demonstrates great potential for fully automated drug screening and drug safety assessments, which may substantially reduce the drug screening time and cost in future new drug development.},\n\tlanguage = {eng},\n\tnumber = {19},\n\tjournal = {Lab on a Chip},\n\tauthor = {Park, Jong Seok and Grijalva, Sandra I. and Aziz, Moez K. and Chi, Taiyun and Li, Sensen and Sayegh, Michael N. and Wang, Adam and Cho, Hee Cheol and Wang, Hua},\n\tyear = {2018},\n\tpmid = {30168827},\n\tkeywords = {Automation, Drug Evaluation, Preclinical, Fibroblasts, Metals, Oxides, Semiconductors, Tissue Array Analysis},\n\tpages = {3037--3050},\n}\n\n\n\n Cells are complex systems with concurrent multi-physical responses, and cell physiological signals are often encoded with spatiotemporal dynamics and further coupled with multiple cellular activities. However, most existing electronic sensors are only single-modality and cannot capture multi-parametric cellular responses. In this paper, a 1024-pixel CMOS quad-modality cellular interfacing array that enables multi-parametric cell profiling for drug development is presented. The quad-modality CMOS array features cellular impedance characterization, optical detection, extracellular potential recording, and biphasic current stimulation. The fibroblast transparency and surface adhesion are jointly monitored by cellular impedance and optical sensing modalities for comprehensive cell growth evaluation. Simultaneous current stimulation and opto-mechanical monitoring based on cardiomyocytes are demonstrated without any stimulation/sensing dead-zone. Furthermore, drug dose-dependent multi-parametric feature extractions in cardiomyocytes from their extracellular potentials and opto-mechanical signals are presented. The CMOS array demonstrates great potential for fully automated drug screening and drug safety assessments, which may substantially reduce the drug screening time and cost in future new drug development.\n
\n\n\n\n \n\n \n \n \n \n \n Gene Therapy Approaches to Biological Pacemakers.\n \n \n \n\n\n \n Farraha, M.; Kumar, S.; Chong, J.; Cho, H. C.; and Kizana, E.\n\n\n \n\n\n\n Journal of Cardiovascular Development and Disease, 5(4). October 2018.\n \n\n\n\n
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\n\n\n@article{farraha_gene_2018,\n\ttitle = {Gene {Therapy} {Approaches} to {Biological} {Pacemakers}},\n\tvolume = {5},\n\tissn = {2308-3425},\n\tdoi = {10.3390/jcdd5040050},\n\tabstract = {Bradycardia arising from pacemaker dysfunction can be debilitating and life threatening. Electronic pacemakers serve as effective treatment options for pacemaker dysfunction. They however present their own limitations and complications. This has motivated research into discovering more effective and innovative ways to treat pacemaker dysfunction. Gene therapy is being explored for its potential to treat various cardiac conditions including cardiac arrhythmias. Gene transfer vectors with increasing transduction efficiency and biosafety have been developed and trialed for cardiovascular disease treatment. With an improved understanding of the molecular mechanisms driving pacemaker development, several gene therapy targets have been identified to generate the phenotypic changes required to correct pacemaker dysfunction. This review will discuss the gene therapy vectors in use today along with methods for their delivery. Furthermore, it will evaluate several gene therapy strategies attempting to restore biological pacing, having the potential to emerge as viable therapies for pacemaker dysfunction.},\n\tlanguage = {eng},\n\tnumber = {4},\n\tjournal = {Journal of Cardiovascular Development and Disease},\n\tauthor = {Farraha, Melad and Kumar, Saurabh and Chong, James and Cho, Hee Cheol and Kizana, Eddy},\n\tmonth = oct,\n\tyear = {2018},\n\tpmid = {30347716},\n\tpmcid = {PMC6306875},\n\tkeywords = {atrioventricular node, bradycardia, gene therapy, heart, pacemaker, sinoatrial node, viral vector},\n}\n\n\n\n Bradycardia arising from pacemaker dysfunction can be debilitating and life threatening. Electronic pacemakers serve as effective treatment options for pacemaker dysfunction. They however present their own limitations and complications. This has motivated research into discovering more effective and innovative ways to treat pacemaker dysfunction. Gene therapy is being explored for its potential to treat various cardiac conditions including cardiac arrhythmias. Gene transfer vectors with increasing transduction efficiency and biosafety have been developed and trialed for cardiovascular disease treatment. With an improved understanding of the molecular mechanisms driving pacemaker development, several gene therapy targets have been identified to generate the phenotypic changes required to correct pacemaker dysfunction. This review will discuss the gene therapy vectors in use today along with methods for their delivery. Furthermore, it will evaluate several gene therapy strategies attempting to restore biological pacing, having the potential to emerge as viable therapies for pacemaker dysfunction.\n
\n\n\n\n \n\n \n \n \n \n \n Small separation diffuse correlation spectroscopy for measurement of cerebral blood flow in rodents.\n \n \n \n\n\n \n Sathialingam, E.; Lee, S. Y.; Sanders, B.; Park, J.; McCracken, C. E.; Bryan, L.; and Buckley, E. M.\n\n\n \n\n\n\n Biomedical Optics Express, 9(11): 5719–5734. November 2018.\n \n\n\n\n
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\n\n\n@article{sathialingam_small_2018,\n\ttitle = {Small separation diffuse correlation spectroscopy for measurement of cerebral blood flow in rodents},\n\tvolume = {9},\n\tissn = {2156-7085},\n\tdoi = {10.1364/BOE.9.005719},\n\tabstract = {Diffuse correlation spectroscopy (DCS) has shown promise as a means to non-invasively measure cerebral blood flow in small animal models. Here, we characterize the validity of DCS at small source-detector reflectance separations needed for small animal measurements. Through Monte Carlo simulations and liquid phantom experiments, we show that DCS error increases as separation decreases, although error remains below 12\\% for separations {\\textgreater} 0.2 cm. In mice, DCS measures of cerebral blood flow have excellent intra-user repeatability and strongly correlate with MRI measures of blood flow (R = 0.74, p{\\textless}0.01). These results are generalizable to other DCS applications wherein short-separation reflectance geometries are desired.},\n\tlanguage = {eng},\n\tnumber = {11},\n\tjournal = {Biomedical Optics Express},\n\tauthor = {Sathialingam, Eashani and Lee, Seung Yup and Sanders, Bharat and Park, Jaekeun and McCracken, Courtney E. and Bryan, Leah and Buckley, Erin M.},\n\tmonth = nov,\n\tyear = {2018},\n\tpmid = {30460158},\n\tpmcid = {PMC6238900},\n\tpages = {5719--5734},\n}\n\n\n\n Diffuse correlation spectroscopy (DCS) has shown promise as a means to non-invasively measure cerebral blood flow in small animal models. Here, we characterize the validity of DCS at small source-detector reflectance separations needed for small animal measurements. Through Monte Carlo simulations and liquid phantom experiments, we show that DCS error increases as separation decreases, although error remains below 12% for separations \\textgreater 0.2 cm. In mice, DCS measures of cerebral blood flow have excellent intra-user repeatability and strongly correlate with MRI measures of blood flow (R = 0.74, p\\textless0.01). These results are generalizable to other DCS applications wherein short-separation reflectance geometries are desired.\n
\n\n\n\n \n\n \n \n \n \n \n A novel, highly discriminatory risk model predicting acute severe right ventricular failure in patients undergoing continuous-flow left ventricular assist device implant.\n \n \n \n\n\n \n Tchantchaleishvili, V.; Maltais, S.; Sharma, S.; Haglund, N. A.; Davis, M. E.; Cowger, J.; Shah, P.; Desai, S. S.; Aaronson, K. D.; Pagani, F. D.; Dunlay, S. M.; and Stulak, J. M.\n\n\n \n\n\n\n Artificial Organs. December 2018.\n \n\n\n\n
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\n\n\n@article{tchantchaleishvili_novel_2018,\n\ttitle = {A novel, highly discriminatory risk model predicting acute severe right ventricular failure in patients undergoing continuous-flow left ventricular assist device implant},\n\tissn = {1525-1594},\n\tdoi = {10.1111/aor.13413},\n\tabstract = {Various risk models with differing discriminatory power and predictive accuracy have been used to predict right ventricular failure (RVF) after left ventricular assist device (LVAD) placement. There remains an unmet need for a contemporary risk score for continuous flow (CF)-LVADs. We sought to independently validate and compare existing risk models in a large cohort of patients and develop a simple, yet highly predictive risk score for acute, severe RVF. Data from the Mechanical Circulatory Support Research Network (MCSRN) registry, consisting of patients who underwent CF-LVAD implantation, were randomly divided into equal-sized derivation and validation samples. RVF scores were calculated for the entire sample, and the need for a right ventricular assist device (RVAD) was the primary endpoint. Candidate predictors from the derivation sample were subjected to backward stepwise logistic regression until the model with lowest Akaike information criterion value was identified. A risk score was developed based on the identified variables and their respective regression coefficients. Between May 2004 and September 2014, 734 patients underwent implantation of CF-LVADs [HeartMate II LVAD, 76\\% (n = 560), HeartWare HVAD, 24\\% (n = 174)]. A RVAD was required in 4.5\\% (n = 33) of the patients [Derivation cohort, n = 15 (4.3\\%); Validation cohort, n = 18 (5.2\\%); P = 0.68)]. 19.5\\% of the patients (n = 143) were female, median age at implant was 59 years (IQR, 49.4-65.3), and median INTERMACS profile was 3 (IQR, 2-3). RVAD was required in 4.5\\% (n = 33) of the patients. Correlates of acute, severe RVF in the final model included heart rate, albumin, BUN, WBC, cardiac index, and TR severity. Areas under the curves (AUC) for most commonly used risk predictors ranged from 0.61 to 0.78. The AUC for the new model was 0.89 in the derivation and 0.92 in the validation cohort. Proposed risk model provides very high discriminatory power predicting acute severe right ventricular failure and can be reliably applied to patients undergoing placement of contemporary continuous flow left ventricular assist devices.},\n\tlanguage = {eng},\n\tjournal = {Artificial Organs},\n\tauthor = {Tchantchaleishvili, Vakhtang and Maltais, Simon and Sharma, Shashank and Haglund, Nicholas A. and Davis, Mary E. and Cowger, Jennifer and Shah, Palak and Desai, Shashank S. and Aaronson, Keith D. and Pagani, Francis D. and Dunlay, Shannon M. and Stulak, John M.},\n\tmonth = dec,\n\tyear = {2018},\n\tpmid = {30592069},\n\tkeywords = {left ventricular assist device, right ventricular assist device, right ventricular failure, risk score},\n}\n\n\n Various risk models with differing discriminatory power and predictive accuracy have been used to predict right ventricular failure (RVF) after left ventricular assist device (LVAD) placement. There remains an unmet need for a contemporary risk score for continuous flow (CF)-LVADs. We sought to independently validate and compare existing risk models in a large cohort of patients and develop a simple, yet highly predictive risk score for acute, severe RVF. Data from the Mechanical Circulatory Support Research Network (MCSRN) registry, consisting of patients who underwent CF-LVAD implantation, were randomly divided into equal-sized derivation and validation samples. RVF scores were calculated for the entire sample, and the need for a right ventricular assist device (RVAD) was the primary endpoint. Candidate predictors from the derivation sample were subjected to backward stepwise logistic regression until the model with lowest Akaike information criterion value was identified. A risk score was developed based on the identified variables and their respective regression coefficients. Between May 2004 and September 2014, 734 patients underwent implantation of CF-LVADs [HeartMate II LVAD, 76% (n = 560), HeartWare HVAD, 24% (n = 174)]. A RVAD was required in 4.5% (n = 33) of the patients [Derivation cohort, n = 15 (4.3%); Validation cohort, n = 18 (5.2%); P = 0.68)]. 19.5% of the patients (n = 143) were female, median age at implant was 59 years (IQR, 49.4-65.3), and median INTERMACS profile was 3 (IQR, 2-3). RVAD was required in 4.5% (n = 33) of the patients. Correlates of acute, severe RVF in the final model included heart rate, albumin, BUN, WBC, cardiac index, and TR severity. Areas under the curves (AUC) for most commonly used risk predictors ranged from 0.61 to 0.78. The AUC for the new model was 0.89 in the derivation and 0.92 in the validation cohort. Proposed risk model provides very high discriminatory power predicting acute severe right ventricular failure and can be reliably applied to patients undergoing placement of contemporary continuous flow left ventricular assist devices.\n
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\n \n \n\n \n \n \n \n \n \n We Can Learn From the Past, but We Must Pave the Future of Congenital Heart Disease Research-Reply. - PubMed - NCBI.\n \n \n \n \n\n\n \n \n\n\n \n\n\n\n \n \n\n\n\n
\n\n\n\n \n \n![\"We](\"//bibbase.org/img/filetypes/link.svg\"\n\t "\\"Paper\\"\n\t")
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\n\n\n\n@misc{noauthor_we_nodate,\n\ttitle = {We {Can} {Learn} {From} the {Past}, but {We} {Must} {Pave} the {Future} of {Congenital} {Heart} {Disease} {Research}-{Reply}. - {PubMed} - {NCBI}},\n\turl = {https://www.ncbi.nlm.nih.gov/pubmed/31017614},\n\turldate = {2019-05-10},\n}\n\n\n\n \n\n \n \n \n \n \n \n Electrospun Nanofiber-Based Patches for the Delivery of Cardiac Progenitor Cells. - PubMed - NCBI.\n \n \n \n \n\n\n \n \n\n\n \n\n\n\n \n \n\n\n\n
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\n\n\n\n@misc{noauthor_electrospun_nodate,\n\ttitle = {Electrospun {Nanofiber}-{Based} {Patches} for the {Delivery} of {Cardiac} {Progenitor} {Cells}. - {PubMed} - {NCBI}},\n\turl = {https://www.ncbi.nlm.nih.gov/pubmed?term=Electrospun%5BTitle%5D+AND+Nanofiber-Based%5BTitle%5D+AND+Patches%5BTitle%5D+AND+Delivery%5BTitle%5D+AND+Cardiac%5BTitle%5D+AND+Progenitor%5BTitle%5D+AND+Cells%5BTitle%5D&cmd=DetailsSearch},\n\turldate = {2019-05-10},\n}\n\n\n\n \n\n \n \n \n \n \n \n Cardiac Toxicity From Ethanol Exposure in Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes. - PubMed - NCBI.\n \n \n \n \n\n\n \n \n\n\n \n\n\n\n \n \n\n\n\n
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\n\n\n\n@misc{noauthor_cardiac_nodate,\n\ttitle = {Cardiac {Toxicity} {From} {Ethanol} {Exposure} in {Human}-{Induced} {Pluripotent} {Stem} {Cell}-{Derived} {Cardiomyocytes}. - {PubMed} - {NCBI}},\n\turl = {https://www.ncbi.nlm.nih.gov/pubmed/31059573},\n\turldate = {2019-05-10},\n}\n\n\n