41 results on '"Reemtsen B"'
Search Results
2. Novel techniques in the use of bivalirudin for cardiopulmonary bypass anticoagulation in a child with heparin-induced thrombocytopenia
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Dragomer, D, Chalfant, A, Biniwale, R, Reemtsen, B, and Federman, M
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- 2011
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3. Transition to Adulthood: Heart Transplant (HT) Recipient Outcomes By Age Group
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Reardon, L., primary, Alejos, J., additional, Deng, M., additional, Nsair, A., additional, Reemtsen, B., additional, Biniwale, R., additional, and Depasquale, E., additional
- Published
- 2015
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4. Post Heart Transplant (HT) Survival in Pediatric Patients with Left Ventricular and Biventricular Assist Devices (LVAD/BIVAD): UNOS Registry Analysis
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Reardon, L.C., primary, Alejos, J.C., additional, Nsair, A.A., additional, Biniwale, R.M., additional, Deng, M.C., additional, Reemtsen, B., additional, Ardehali, A., additional, and Depasquale, E.C., additional
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- 2014
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5. (141) - Transition to Adulthood: Heart Transplant (HT) Recipient Outcomes By Age Group
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Reardon, L., Alejos, J., Deng, M., Nsair, A., Reemtsen, B., Biniwale, R., and Depasquale, E.
- Published
- 2015
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- View/download PDF
6. (850) - Post Heart Transplant (HT) Survival in Pediatric Patients with Left Ventricular and Biventricular Assist Devices (LVAD/BIVAD): UNOS Registry Analysis
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Reardon, L.C., Alejos, J.C., Nsair, A.A., Biniwale, R.M., Deng, M.C., Reemtsen, B., Ardehali, A., and Depasquale, E.C.
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- 2014
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7. INFECTIOUS TRANSPLANTATION TOLERANCE: CENTRAL INDUCTION AND PERIPHERAL MAINTENANCE
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Reemtsen, B., primary, Kato, H., additional, Goss, J. A., additional, Busuttil, R. W., additional, and Kupiec-Weglinski, J. W., additional
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- 1999
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8. IMMUNOGENICITY OF THE ??1-HELICAL REGION OF RAT RT1.A CLASS I MHC ANTIGENS
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Reemtsen, B., primary, Zhai, Y., additional, Wang, M., additional, Stepkowski, S., additional, Kahan, B. D., additional, Busuttil, R. W., additional, Kupiec-Weglinski, J. W., additional, and Ghobrial, R., additional
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- 1999
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9. ANTIGEN REACTIVATED REGULATORY T CELLS MAINTAIN INFECTIOUS TOLERANCE IN TRANSPLANT RECIPIENTS
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Reemtsen, B., primary, Kato, H., additional, Ghobrial, M., additional, Goss, J. A., additional, Volk, H. D., additional, Busuttil, R. W., additional, and Kupiec-Weglinski, J. W., additional
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- 1999
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10. DIVERGENT EFFECTS OF INTRATHYMIC IMMUNOMODULATION ON CELLULAR AND HUMORAL ALLOREACTIVITY IN TRANSPLANT RECIPIENTS
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Reemtsen, B L, primary, Maggard, M, additional, Kato, H, additional, Wang, T, additional, Coito, A J, additional, Busuttil, R W, additional, Kupiec-Weglinski, J W, additional, and Goss, J A, additional
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- 1998
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11. ORTHOTOPIC LIVER TRANSPLANTATION FOR METABOLIC LIVER DISEASE IN THE PEDIATRIC PATIENT
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Goss, J A, primary, Shackleton, C R, additional, McDiarmid, S V, additional, Reemtsen, B L, additional, Dulkanchainun, T S, additional, Seu, P, additional, Farmer, D G, additional, Ghobrial, R M, additional, Markmann, J F, additional, Imagawa, D K, additional, and Busuttil, R W, additional
- Published
- 1998
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12. Gadolinium Chloride Induced Blockade of Kupffer Cells (KC) Ameliorates Ischemia/Reperfusion (I/R) Injury in the Steatotic Liver
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Dulkanchainun, T S, primary, Goss, J A, additional, Imagawa, D K, additional, Busuttil, A A, additional, Reemtsen, B L, additional, Kato, H, additional, Wang, T, additional, Murray, NGB, additional, Kupiec-Weglinski, J W, additional, and Busuttil, R W, additional
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- 1998
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13. IMMUNOGENICITY OF THE α1-HELICAL REGION OF RAT RT1.A CLASS I MHC ANTIGENS.
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Reemtsen, B., Zhai, Y., Wang, M., Stepkowski, S., Kahan, B. D., Busuttil, R. W., Kupiec-Weglinski, J. W., and Ghobrial, R.
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- 1999
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14. IMMUNOGENICITY OF THE α1-HELICAL REGION OF RAT RT1.A CLASS I MHC ANTIGENS
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Reemtsen, B., Zhai, Y., Wang, M., Stepkowski, S., Kahan, B. D., Busuttil, R. W., Kupiec-Weglinski, J. W., and Ghobrial, R.
- Published
- 1999
15. Anomalous Aortic Origin of the Right Coronary Artery: When to Intervene.
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Nissen T, Renno MS, Reemtsen B, and Rajab TK
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- Humans, Aorta, Thoracic abnormalities, Aorta, Thoracic diagnostic imaging, Aorta, Thoracic surgery, Male, Female, Coronary Angiography, Coronary Vessel Anomalies surgery, Coronary Vessel Anomalies diagnosis, Coronary Vessel Anomalies diagnostic imaging
- Published
- 2024
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16. Aberrant right subclavian artery: a novel approach and an overview of operative techniques.
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Heye T, Greiten L, Story-Hefta L, Reemtsen B, and Moursi M
- Abstract
An aberrant right subclavian artery (ARSA) is a rare variation of normal anatomy occurring in 0.5% to 1.8% of the population. No current guidelines are available regarding ARSA management, and surgical intervention should be evaluated carefully. Moreover, symptomatic patients with a dominant left arch and aberrant ARSA require a surgical approach from the right side of the chest for ligation and division of the aberrant artery at its origin on the aorta. The ARSA can then be reimplanted onto the right common carotid artery via a supraclavicular incision. The extensive mobilization in the chest allows for easy reimplantation in the supraclavicular region and eliminates reliance on the collateral circulation. Postoperative monitoring is reliable and easy with radial pulse examinations., Competing Interests: None.
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- 2023
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17. Arterial switch operation for complex d-transposition of the great arteries with aortopulmonary window.
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McKay M, Eisenring C, Greiten L, and Reemtsen B
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- 2023
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18. The MITRIS RESILIA mitral valve is a safe and effective option for mitral valve replacement in young patients requiring mitral valve replacement.
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Heye T, Reemtsen B, and Greiten L
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We report the first successful implantation in the United States of a novel mitral valve (MITRIS RESILIA by Edwards Lifesciences) in a patient with history of mitral valve replacement at a young age. This new bioprosthetic valve offers a unique profile and innovative option for mitral valve replacement in patients who are at risk of left ventricular outflow tract obstruction.
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- 2022
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19. Coronary Sinus Ostial Obstruction in Single-Ventricle Congenital Heart Disease: Two Patients With Different Outcomes.
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Dalby ST, Mitchell WM, Greiten LE, Reemtsen B, Eisenring C, and Zakaria D
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Coronary sinus ostial obstruction is an exceedingly rare anomaly that is particularly important to diagnose in patients with single-ventricle heart disease before surgical palliation. We present 2 cases, an infant and an adult, diagnosed with coronary sinus ostial obstruction, with different clinical outcomes due to timing of diagnosis. ( Level of Difficulty: Intermediate. )., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
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- 2021
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20. Gene-environment regulation of chamber-specific maturation during hypoxemic perinatal circulatory transition.
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Zhao Y, Kang X, Barsegian A, He J, Guzman A, Lau RP, Biniwale R, Wadhra M, Reemtsen B, Garg M, Halnon N, Quintero-Rivera F, Grody WW, Van Arsdell G, Nelson SF, and Touma M
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- Animals, Animals, Newborn, Cell Proliferation genetics, Epithelial-Mesenchymal Transition genetics, Female, Gene Expression Profiling methods, Heart Defects, Congenital physiopathology, Male, Mice, Mice, Inbred C57BL, Signal Transduction genetics, Transcriptome genetics, Heart Defects, Congenital genetics, Heart Ventricles physiopathology, Hypoxia genetics
- Abstract
Chamber-specific and temporally regulated perinatal cardiac growth and maturation is critical for functional adaptation of the heart and may be altered significantly in response to perinatal stress, such as systemic hypoxia (hypoxemia), leading to significant pathology, even mortality. Understanding transcriptome regulation of neonatal heart chambers in response to hypoxemia is necessary to develop chamber-specific therapies for infants with cyanotic congenital heart defects (CHDs). We sought to determine chamber-specific transcriptome programming during hypoxemic perinatal circulatory transition. We performed transcriptome-wide analysis on right ventricle (RV) and left ventricle (LV) of postnatal day 3 (P3) mouse hearts exposed to perinatal hypoxemia. Hypoxemia decreased baseline differences between RV and LV leading to significant attenuation of ventricular patterning (AVP), which involved several molecular pathways, including Wnt signaling suppression and cell cycle induction. Notably, robust changes in RV transcriptome in hypoxemic condition contributed significantly to the AVP. Remarkably, suppression of epithelial mesenchymal transition (EMT) and dysregulation of the TP53 signaling were prominent hallmarks of the AVP genes in neonatal mouse heart. Furthermore, members of the TP53-related gene family were dysregulated in the hypoxemic RVs of neonatal mouse and cyanotic Tetralogy of Fallot hearts. Integrated analysis of chamber-specific transcriptome revealed hypoxemia-specific changes that were more robust in RVs compared with LVs, leading to previously uncharacterized AVP induced by perinatal hypoxemia. Remarkably, reprogramming of EMT process and dysregulation of the TP53 network contributed to transcriptome remodeling of neonatal heart during hypoxemic circulatory transition. These insights may enhance our understanding of hypoxemia-induced pathogenesis in newborn infants with cyanotic CHD phenotypes. KEY MESSAGES: During perinatal circulatory transition, transcriptome programming is a major driving force of cardiac chamber-specific maturation and adaptation to hemodynamic load and external environment. During hypoxemic perinatal transition, transcriptome reprogramming may affect chamber-specific growth and development, particularly in newborns with congenital heart defects (CHDs). Chamber-specific transcriptome changes during hypoxemic perinatal transition are yet to be fully elucidated. Systems-based analysis of hypoxemic neonatal hearts at postnatal day 3 reveals chamber-specific transcriptome signatures during hypoxemic perinatal transition, which involve attenuation of ventricular patterning (AVP) and repression of epithelial mesenchymal transition (EMT). Key regulatory circuits involved in hypoxemia response were identified including suppression of Wnt signaling, induction of cellular proliferation and dysregulation of TP53 network.
- Published
- 2020
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21. An International Survey Comparing Different Physician Models for Health Care Delivery to Critically Ill Children With Heart Disease.
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Bhaskar P, Rettiganti M, Sadot E, Paul T, Garros D, Frankel LR, Reemtsen B, Butt W, and Gupta P
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- Child, Critical Care, Cross-Sectional Studies, Delivery of Health Care, Humans, Surveys and Questionnaires, Critical Illness therapy, Physicians
- Abstract
Objectives: To explore relationships between the training background of cardiac critical care attending physicians and self-reported perceived strengths and weaknesses in their ability to provide clinical care., Design: Cross-sectional observational survey sent worldwide to ~550 practicing cardiac ICU attending physicians., Setting: Hospitals providing cardiac critical care., Subjects: Practicing cardiac critical care physicians., Interventions: None., Measurements and Main Results: We received responses from 243 ICU attending physicians from 82 centers (14 countries). The primary training background of the respondents included critical care (62%), dual training in critical care and cardiology (16%), cardiology (14%), and other (8%). We received 49 responses from medical directors in nine countries, who reported that the predominant training background for attending physicians who provide cardiac intensive care at their institutions were critical care (58%), dual trained (18%), cardiology (12%), and other (11%). A greater proportion of physicians trained in either critical care or dual-training reported feeling confident managing multiple organ failure, neurologic conditions, brain death, cardiac arrest, and performing procedures like advanced airway placement and inserting chest- and abdominal-drains. In contrast, physicians with cardiology and dual-training reported feeling more confident managing intractable arrhythmias, understanding cardiopulmonary interactions, and interpreting echocardiogram, electrocardiogram, and cardiac catheterization. Overall, only 57% of the respondents felt comfortable based on their current training background to manage patients with complex cardiac issues without collaboration with other specialists., Conclusions: Our survey demonstrates that intensivists trained in critical care are more comfortable with critical care skills, cardiology-trained intensivists are more comfortable with cardiology skills, and dual-trained physicians are comfortable with both critical care skills and cardiology skills. These findings may help inform future efforts to optimize the educational curriculum and training pathways for future cardiac intensivists. These data may also be used to shape continuing medical education activities for cardiac intensivists who have already completed their training.
- Published
- 2020
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22. Gene-environment regulatory circuits of right ventricular pathology in tetralogy of fallot.
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Zhao Y, Kang X, Gao F, Guzman A, Lau RP, Biniwale R, Wadehra M, Reemtsen B, Garg M, Halnon N, Quintero-Rivera F, Van Arsdell G, Coppola G, Nelson SF, and Touma M
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- Child, Child, Preschool, Cohort Studies, Cyclic AMP Response Element-Binding Protein metabolism, E2F1 Transcription Factor metabolism, Epithelial-Mesenchymal Transition genetics, Female, Gene Expression Profiling, Gene Expression Regulation genetics, Gene Regulatory Networks genetics, Genome, Heart Ventricles pathology, Humans, Infant, Male, Signal Transduction genetics, Tetralogy of Fallot genetics, Transcriptome physiology, Wnt Proteins metabolism, Heart Ventricles metabolism, Hypoxia metabolism, Tetralogy of Fallot metabolism, Transcriptome genetics
- Abstract
The phenotypic spectrum of congenital heart defects (CHDs) is contributed by both genetic and environmental factors. Their interactions are profoundly heterogeneous but may operate on common pathways as in the case of hypoxia signaling during postnatal heart development in the context of CHDs. Tetralogy of Fallot (TOF) is the most common cyanotic (hypoxemic) CHD. However, how the hypoxic environment contributes to TOF pathogenesis after birth is poorly understood. We performed Genome-wide transcriptome analysis on right ventricle outflow tract (RVOT) specimens from cyanotic and noncyanotic TOF. Co-expression network analysis identified gene modules specifically associated with clinical diagnosis and hypoxemia status in the TOF hearts. In particular, hypoxia-dependent induction of myocyte proliferation is associated with E2F1-mediated cell cycle regulation and repression of the WNT11-RB1 axis. Genes enriched in epithelial mesenchymal transition (EMT), fibrosis, and sarcomere were also repressed in cyanotic TOF patients. Importantly, transcription factor analysis of the hypoxia-regulated modules suggested CREB1 as a putative regulator of hypoxia/WNT11-RB1 circuit. The study provides a high-resolution landscape of transcriptome programming associated with TOF phenotypes and unveiled hypoxia-induced regulatory circuit in cyanotic TOF. Hypoxia-induced cardiomyocyte proliferation involves negative modulation of CREB1 activity upstream of the WNT11-RB1 axis. KEY MESSAGES: Genetic and environmental factors contribute to congenital heart defects (CHDs). How hypoxia contributes to Tetralogy of Fallot (TOF) pathogenesis after birth is unclear. Systems biology-based analysis revealed distinct molecular signature in CHDs. Gene expression modules specifically associated with cyanotic TOF were uncovered. Key regulatory circuits induced by hypoxia in TOF pathogenesis after birth were unveiled.
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- 2019
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23. Trans-apical systemic tricuspid valve-in-ring replacement.
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Ghobrial J, Reemtsen B, Levi DS, and Aboulhosn J
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- Female, Hemodynamics, Humans, Middle Aged, Prosthesis Design, Recovery of Function, Severity of Illness Index, Treatment Outcome, Tricuspid Valve diagnostic imaging, Tricuspid Valve physiopathology, Tricuspid Valve Insufficiency diagnostic imaging, Tricuspid Valve Insufficiency physiopathology, Cardiac Valve Annuloplasty instrumentation, Heart Valve Prosthesis, Heart Valve Prosthesis Implantation adverse effects, Tricuspid Valve surgery, Tricuspid Valve Insufficiency surgery
- Abstract
Transcatheter valve replacement offers a safe and effective alternative to traditional surgical techniques in patients with congenital heart disease, especially those at high surgical risk. The most common causes of morbidity and mortality in patients with D-transposition of the great arteries status post Senning or Mustard repair is severe tricuspid valve (TV) regurgitation. Replacement of the systemic TV may be useful in those without severe systemic ventricular dysfunction. We present a case of a patient with D-loop transposition of the great arteries status post Mustard repair and TV ring placement with subsequent severe systemic TV regurgitation, at high surgical risk, who underwent a transcatheter valve replacement via a trans-apical approach using an Edwards Sapien XT valve., (© 2018 Wiley Periodicals, Inc.)
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- 2019
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24. Impact of Regional Cerebral Perfusion on Outcomes Among Neonates Undergoing Norwood Operation.
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Migally K, Rettiganti M, Gossett JM, Reemtsen B, and Gupta P
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- Circulatory Arrest, Deep Hypothermia Induced methods, Female, Heart Defects, Congenital mortality, Hospital Mortality trends, Humans, Incidence, Infant, Newborn, Male, Norwood Procedures mortality, Postoperative Complications epidemiology, Prospective Studies, Risk Factors, Survival Rate trends, United States epidemiology, Cerebrovascular Circulation physiology, Heart Defects, Congenital surgery, Norwood Procedures methods, Perfusion methods
- Abstract
Objectives: To evaluate the impact of regional cerebral perfusion (RCP) during heart operation on outcomes in neonates undergoing Norwood operation., Methods: We performed a retrospective cohort study using data from the Single Ventricle Reconstruction trial data set. The adjusted effect of RCP use on each outcome was studied using a penalized logistic regression model with bootstrap validation., Results: Of 549 patients included in the study, 252 patients (45.9%) received RCP during their heart operation. In univariate comparisons, the majority of the baseline characteristics and preoperative risk factors were similar in the RCP and No RCP group. The total cardiopulmonary bypass (CPB) time and the total cross-clamp (CC) time were longer in the RCP group (RCP vs No RCP, median CPB time: 161 minutes vs 109 minutes; median CC time: 63 minutes vs 43 minutes). In adjusted models, the use of RCP was not associated with decreased mortality and/or need for heart transplant at hospital discharge (odds ratio [OR]: 0.73; 95% confidence interval [CI]: 0.43-1.25) or prolonged mechanical ventilation (OR: 1.20, 95% CI: 0.62-2.28) or prolonged hospital length of stay (OR: 1.30, 95% CI: 0.73-2.30). We demonstrated that use of RCP was associated with longer CPB times, increased use of ultrafiltration, and higher probability of open chest after Norwood operation., Conclusions: This study did not demonstrate any impact of RCP on in-hospital mortality and/or heart transplantation, prolonged mechanical ventilation, and prolonged hospital length of stay among neonates undergoing Norwood operation.
- Published
- 2019
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25. Double whammy: A case of bilateral bicuspid arterial valves in transposition, with a review of the literature.
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Shivaram P, Shah K, Dossey A, Reemtsen B, and Anderson RH
- Abstract
Bicuspidity of both the semilunar valves is rarely reported. We report the first ever case of bilateral bicuspid semilunar valves in a case of transposition., Competing Interests: There are no conflicts of interest.
- Published
- 2019
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26. Incidence and outcome of infective endocarditis following percutaneous versus surgical pulmonary valve replacement.
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Lluri G, Levi DS, Miller E, Hageman A, Sinha S, Sadeghi S, Reemtsen B, Laks H, Biniwale R, Salem M, Fishbein GA, and Aboulhosn J
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- Adolescent, Adult, Cardiac Catheterization instrumentation, Cardiac Catheterization methods, Child, Endocarditis diagnosis, Endocarditis therapy, Female, Heart Valve Prosthesis Implantation instrumentation, Heart Valve Prosthesis Implantation methods, Humans, Incidence, Los Angeles epidemiology, Male, Pulmonary Valve diagnostic imaging, Pulmonary Valve physiopathology, Retrospective Studies, Risk Factors, Time Factors, Treatment Outcome, Young Adult, Cardiac Catheterization adverse effects, Endocarditis epidemiology, Heart Valve Prosthesis Implantation adverse effects, Pulmonary Valve surgery
- Abstract
Objectives: To provide a comparison of the outcome of infective endocarditis (IE) in patients undergoing transcatheter pulmonary valve replacement (TPVR) versus surgical pulmonary valve replacement (SPVR)., Background: Although TPVR is thought to be associated with a higher risk of IE than SPVR, there is paucity of data to support this., Methods: Patients who underwent TPVR or SPVR at UCLA between October 2010 and September 2016 were included and retrospectively analyzed., Results: Three hundred forty-two patients underwent PVR at UCLA including 134 SPVR and 208 TPVR. Patients undergoing TPVR were more likely to have had a history of endocarditis than those undergoing SPVR (5.3% vs. 0.7%, P = 0.03) and a right ventricle to pulmonary artery (RV to PA) conduit (37% vs. 17%, P = 0.0001). Two SPVR and seven TPVR patients developed IE with a 4-year freedom from endocarditis of 94.0% in the SPVR versus 84% in the TPVR group (P = 0.13). In patients who underwent TPVR and developed endocarditis, the mean gradient across the RVOT prior to intervention was higher (28.1 ± 4.5 vs. 17.4 ± 0.6 mmHg, P = 0.02) and were more likely to have a conduit (71% vs. 36%, P = 0.049)., Conclusions: In this study, patients undergoing TPVR were not at a higher risk of IE than patients undergoing SPVR. TPVR patients were more likely to have had a prior history of IE and RV-PA conduit. The patients at highest risk were those with stenotic RV to PA conduits who were treated with TPVR., (© 2017 Wiley Periodicals, Inc.)
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- 2018
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27. Efficacy of an Extracellular Matrix in Systemic Loading Conditions in Congenital Heart Surgery.
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Ashfaq A, Iyengar A, Kwon OJ, Soroya MS, Nguyen S, Ou R, and Reemtsen B
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- Cardiac Surgical Procedures adverse effects, Echocardiography methods, Female, Follow-Up Studies, Graft Survival, Heart Defects, Congenital mortality, Humans, Infant, Male, Postoperative Complications epidemiology, Reoperation statistics & numerical data, Retrospective Studies, Survival Rate, Treatment Outcome, Cardiac Surgical Procedures methods, Extracellular Matrix transplantation, Heart Defects, Congenital surgery
- Abstract
Extracellular matrices (ECM) are commonly used to repair congenital heart defects; however, there is a lack of literature pertaining to outcomes with ECM use in high-pressure conditions. Between 2011 and 2014, a total of 202 patients underwent congenital heart disease repair using the ECM placed in a systemic pressure condition. The operative sites included: defects in the ventricular septum, mitral valve, aortic valve, ascending aorta, and aortic arch. Patients were followed and evaluated for mortality and reoperations due to loss of ECM integrity. Echocardiograms were evaluated for graft malfunction such as aneurysmal dilation, VSD formation, valve malfunction, or outflow tract obstruction. Patients were followed for an average of 1492 days (Median = 1583). Out of the 202 patients, 7 (3.5%) died due to complications unrelated to ECM, and 10 (5%) underwent reoperations due to complications of ECM integrity. Reoperations were as follows: two of 6 patients receiving aortic leaflet replacement required reoperation for leaflet failure; four of 12 patients receiving mitral valve leaflet repairs required reoperation for leaflet failure; and four of 142 patients with VSD repair required reoperation for residual shunting. The average time to reoperation was 208 days. There were no outflow tract obstructions or aneurysmal dilatations observed. This modern case series suggests that the ECM is efficacious and sustainable under systemic conditions in congenital heart defect repair. However, concerns remain about the use of ECM in aortic valve repair and infant mitral valve repair. Further studies are needed to evaluate long-term ECM integrity.
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- 2017
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28. Wnt11 regulates cardiac chamber development and disease during perinatal maturation.
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Touma M, Kang X, Gao F, Zhao Y, Cass AA, Biniwale R, Xiao X, Eghbali M, Coppola G, Reemtsen B, and Wang Y
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- Animals, Animals, Newborn, Down-Regulation, Female, Gene Expression, Genes, cdc, Heart growth & development, Heart Defects, Congenital metabolism, Humans, Hypoxia metabolism, Male, Mice, Mice, Inbred C57BL, Phosphorylation, Retinoblastoma Protein metabolism, Retinoblastoma Protein physiology, Signal Transduction, Wnt Proteins metabolism, Cell Proliferation physiology, Heart embryology, Wnt Proteins physiology
- Abstract
Ventricular chamber growth and development during perinatal circulatory transition is critical for functional adaptation of the heart. However, the chamber-specific programs of neonatal heart growth are poorly understood. We used integrated systems genomic and functional biology analyses of the perinatal chamber specific transcriptome and we identified Wnt11 as a prominent regulator of chamber-specific proliferation. Importantly, downregulation of Wnt11 expression was associated with cyanotic congenital heart defect (CHD) phenotypes and correlated with O2 saturation levels in hypoxemic infants with Tetralogy of Fallot (TOF). Perinatal hypoxia treatment in mice suppressed Wnt11 expression and induced myocyte proliferation more robustly in the right ventricle, modulating Rb1 protein activity. Wnt11 inactivation was sufficient to induce myocyte proliferation in perinatal mouse hearts and reduced Rb1 protein and phosphorylation in neonatal cardiomyocytes. Finally, downregulated Wnt11 in hypoxemic TOF infantile hearts was associated with Rb1 suppression and induction of proliferation markers. This study revealed a previously uncharacterized function of Wnt11-mediated signaling as an important player in programming the chamber-specific growth of the neonatal heart. This function influences the chamber-specific development and pathogenesis in response to hypoxia and cyanotic CHDs. Defining the underlying regulatory mechanism may yield chamber-specific therapies for infants born with CHDs.
- Published
- 2017
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29. Childhood Obesity and Extracorporeal Membrane Oxygenation: Special Considerations for Successful Outcomes.
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Iyengar A, Zhu A, Samson J, Reemtsen B, and Biniwale R
- Abstract
The effects of obesity on venoarterial extracorporeal membrane oxygenation (VA-ECMO) outcomes in pediatric population are unknown. We performed retrospective analysis of 41 children (age 2-18 years) undergoing VA-ECMO. The percentage difference between actual body weight and lean body weight, referred to as Δmass, was calculated. Ratios of Δmass to ECMO flow were calculated at 4 and 24 hours. In patients with Δmass:flow ≥ 0.1 at 4 hours, higher 24-hour lactates (20.0 vs. 14.5 mg/dL; p = 0.002) and inotrope scores (17.3 vs. 11.2; p = 0.015) were observed. However, elevated Δmass:flow was not associated with mortality, and in-hospital mortality rates between groups were similar (53 vs. 45%; p = 0.647). In obese pediatric patients requiring VA-ECMO, increased flow is necessary to avoid complications of hypoperfusion and related complications.
- Published
- 2017
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30. A Path to Implement Precision Child Health Cardiovascular Medicine.
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Touma M, Reemtsen B, Halnon N, Alejos J, Finn JP, Nelson SF, and Wang Y
- Abstract
Congenital heart defects (CHDs) affect approximately 1% of live births and are a major source of childhood morbidity and mortality even in countries with advanced healthcare systems. Along with phenotypic heterogeneity, the underlying etiology of CHDs is multifactorial, involving genetic, epigenetic, and/or environmental contributors. Clear dissection of the underlying mechanism is a powerful step to establish individualized therapies. However, the majority of CHDs are yet to be clearly diagnosed for the underlying genetic and environmental factors, and even less with effective therapies. Although the survival rate for CHDs is steadily improving, there is still a significant unmet need for refining diagnostic precision and establishing targeted therapies to optimize life quality and to minimize future complications. In particular, proper identification of disease associated genetic variants in humans has been challenging, and this greatly impedes our ability to delineate gene-environment interactions that contribute to the pathogenesis of CHDs. Implementing a systematic multileveled approach can establish a continuum from phenotypic characterization in the clinic to molecular dissection using combined next-generation sequencing platforms and validation studies in suitable models at the bench. Key elements necessary to advance the field are: first, proper delineation of the phenotypic spectrum of CHDs; second, defining the molecular genotype/phenotype by combining whole-exome sequencing and transcriptome analysis; third, integration of phenotypic, genotypic, and molecular datasets to identify molecular network contributing to CHDs; fourth, generation of relevant disease models and multileveled experimental investigations. In order to achieve all these goals, access to high-quality biological specimens from well-defined patient cohorts is a crucial step. Therefore, establishing a CHD BioCore is an essential infrastructure and a critical step on the path toward precision child health cardiovascular medicine.
- Published
- 2017
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31. Repair of Complete Atrioventricular Septal Defects With Decellularized Extracellular Matrix: Initial and Midterm Outcomes.
- Author
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Ashfaq A, Brown T, and Reemtsen B
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- California epidemiology, Child, Preschool, Echocardiography, Female, Follow-Up Studies, Heart Septal Defects, Heart Ventricles diagnostic imaging, Humans, Infant, Male, Mitral Valve Insufficiency diagnosis, Mitral Valve Insufficiency mortality, Retrospective Studies, Survival Rate trends, Time Factors, Treatment Outcome, Cardiac Surgical Procedures methods, Extracellular Matrix, Heart Ventricles surgery, Mitral Valve Insufficiency surgery, Postoperative Complications epidemiology
- Abstract
Objective: Since April 2010, our institution has repaired complete atrioventricular septal defects (CAVSDs) with a two-patch technique utilizing CorMatrix extracellular material. This material is potentially an attractive patch because of its theorized eventual integration with the host tissue. We sought to analyze initial outcomes of CAVSD repair with CorMatrix., Methods: Data were collected on consecutive pediatric (age <18) patients receiving two-patch CAVSD repairs with CorMatrix at a single institution from April 2010 to July 2014. Baseline and perioperative characteristics were evaluated. Echocardiograms were evaluated in both the immediate postoperative period and the most recent postoperative follow-up. Variables analyzed included left AV valve performance, residual shunting, left ventricular outflow tract (LVOT) gradient, morbidity, and mortality., Results: Fifteen patients were identified. The average age at operation was 205 days, with mean follow-up time at 1,364 days. Echocardiograms revealed the following: 12 (80%) patients showed either improved or stable left AV valve performance remaining at "mild" or less insufficiency, while two (13%) declined from "none" to mild and one (7%) from mild to "severe," which required reoperation. There was no residual shunting or LVOT obstruction at follow-up. The single (7%) reoperation was performed after three years due to left AV valve zone of apposition dehiscence. No permanent pacemakers were needed, and no deaths were reported., Conclusion: Our initial experience with CorMatrix in the repair of CAVSD in children has resulted in good initial and midterm outcomes. The CorMatrix patch remained stable through midterm follow-up, thus may be efficacious for use in CAVSD repair.
- Published
- 2017
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32. Decoding the Long Noncoding RNA During Cardiac Maturation: A Roadmap for Functional Discovery.
- Author
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Touma M, Kang X, Zhao Y, Cass AA, Gao F, Biniwale R, Coppola G, Xiao X, Reemtsen B, and Wang Y
- Subjects
- Animals, Animals, Newborn, Cells, Cultured, Connectin genetics, Connectin metabolism, Dopamine and cAMP-Regulated Phosphoprotein 32 genetics, Dopamine and cAMP-Regulated Phosphoprotein 32 metabolism, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Heart Defects, Congenital metabolism, Heart Defects, Congenital pathology, Heart Defects, Congenital physiopathology, Heart Ventricles abnormalities, Heart Ventricles metabolism, Humans, Male, Mice, Inbred C57BL, Myoblasts, Cardiac metabolism, Myocardium pathology, RNA, Long Noncoding metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Time Factors, Gene Expression Profiling methods, Heart Defects, Congenital genetics, Heart Ventricles growth & development, Myocardium metabolism, RNA, Long Noncoding genetics, Transcriptome
- Abstract
Background: Cardiac maturation during perinatal transition of heart is critical for functional adaptation to hemodynamic load and nutrient environment. Perturbation in this process has major implications in congenital heart defects. Transcriptome programming during perinatal stages is an important information but incomplete in current literature, particularly, the expression profiles of the long noncoding RNAs (lncRNAs) are not fully elucidated., Methods and Results: From comprehensive analysis of transcriptomes derived from neonatal mouse heart left and right ventricles, a total of 45 167 unique transcripts were identified, including 21 916 known and 2033 novel lncRNAs. Among these lncRNAs, 196 exhibited significant dynamic regulation along maturation process. By implementing parallel weighted gene co-expression network analysis of mRNA and lncRNA data sets, several lncRNA modules coordinately expressed in a developmental manner similar to protein coding genes, while few lncRNAs revealed chamber-specific patterns. Out of 2262 lncRNAs located within 50 kb of protein coding genes, 5% significantly correlate with the expression of their neighboring genes. The impact of Ppp1r1b-lncRNA on the corresponding partner gene Tcap was validated in cultured myoblasts. This concordant regulation was also conserved in human infantile hearts. Furthermore, the Ppp1r1b-lncRNA/Tcap expression ratio was identified as a molecular signature that differentiated congenital heart defect phenotypes., Conclusions: The study provides the first high-resolution landscape on neonatal cardiac lncRNAs and reveals their potential interaction with mRNA transcriptome during cardiac maturation. Ppp1r1b-lncRNA was identified as a regulator of Tcap expression, with dynamic interaction in postnatal cardiac development and congenital heart defects., (© 2016 American Heart Association, Inc.)
- Published
- 2016
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33. Effects of acute kidney injury and chronic hypoxemia on fibroblast growth factor 23 levels in pediatric cardiac surgery patients.
- Author
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Hanudel MR, Wesseling-Perry K, Gales B, Ramos G, Campbell V, Ethridge K, Scotti M, Elashoff DA, Alejos J, Reemtsen B, and Salusky IB
- Subjects
- Acute Kidney Injury diagnosis, Acute Kidney Injury etiology, Biomarkers blood, Child, Child, Preschool, Chronic Disease, Female, Fibroblast Growth Factor-23, Humans, Hypoxia diagnosis, Hypoxia etiology, Infant, Male, Predictive Value of Tests, Risk Factors, Time Factors, Treatment Outcome, Acute Kidney Injury blood, Cardiac Surgical Procedures adverse effects, Cardiopulmonary Bypass adverse effects, Fibroblast Growth Factors blood, Hypoxia blood, Peptide Fragments blood
- Abstract
Background: Fibroblast growth factor-23 (FGF23) levels are elevated in cardiopulmonary bypass (CPB)-associated acute kidney injury (AKI); however, it is unknown how much of the circulating FGF23 is intact and bioactive. Hypoxia may induce FGF23 production, yet its impact in humans is unknown. Pediatric cardiac surgery patients have both a high incidence of CPB-associated AKI and a high prevalence of chronic hypoxemia., Methods: We assessed the effects of hypoxemia and CPB-associated AKI on C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) levels in 32 pediatric cardiac surgery patients with normal estimated glomerular filtration rate (eGFR). Plasma cFGF23 and iFGF23 were measured preoperatively and serially postoperatively., Results: Despite normal renal and ventricular function, preoperative cFGF23 levels were high and elevated out of proportion to iFGF23 levels. Preoperative oxygen saturation measurements correlated inversely with FGF23 levels. Preoperative cFGF23 and oxygen saturation both predicted postoperative AKI. Postoperatively, cFGF23 and iFGF23 increased by 2 h postreperfusion; iFGF23 then returned to baseline, but cFGF23 remained elevated through 24 h postreperfusion. Group status (AKI vs. non-AKI) modified the effect of time on changes in iFGF23 levels but not cFGF23 levels., Conclusions: Preoperative cFGF23 may predict CPB-associated kidney dysfunction. Changes over time in cFGF23 and iFGF23 levels post-CPB differ. Chronic hypoxemia may affect FGF23 production in humans.
- Published
- 2016
- Full Text
- View/download PDF
34. Histologic examination of decellularized porcine intestinal submucosa extracellular matrix (CorMatrix) in pediatric congenital heart surgery.
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Woo JS, Fishbein MC, and Reemtsen B
- Subjects
- Adolescent, Calcinosis etiology, Child, Child, Preschool, Databases, Factual, Extracellular Matrix pathology, Female, Fibrosis, Foreign-Body Reaction etiology, Heart Defects, Congenital pathology, Heart Septum pathology, Heart Valves pathology, Heterografts, Humans, Infant, Inflammation etiology, Intestinal Mucosa pathology, Los Angeles, Male, Necrosis, Treatment Outcome, Calcinosis pathology, Cardiac Surgical Procedures adverse effects, Extracellular Matrix transplantation, Foreign-Body Reaction pathology, Heart Defects, Congenital surgery, Heart Septum surgery, Heart Valves surgery, Inflammation pathology, Intestinal Mucosa transplantation
- Abstract
Background: CorMatrix is a decellularized porcine small intestinal submucosa extracellular matrix that has gained attention as a promising alternative to current materials used in cardiac repair. While animal models demonstrate integration of CorMatrix material with host tissue, the histologic characteristics of CorMatrix used in humans are less well-characterized. In this retrospective study, we report our experience with CorMatrix material used in pediatric congenital heart surgery and describe the histology of CorMatrix material and of surrounding native tissue in explanted specimens., Methods: Records were reviewed of all pediatric patients implanted with CorMatrix from a single institution (2011-2014). Histologic examinations were performed on CorMatrix and other tissues removed. Explanted samples of CorMatrix and adherent tissues were evaluated for inflammation (acute and chronic), fibrosis, necrosis, degenerative changes, eosinophil response, foreign-body giant cell reaction, neovascularization, and calcification of tissues on a semiquantitative basis (0, none; 1, mild; 2, moderate; 3, marked). Presence of degeneration within CorMatrix and necrosis of surrounding tissue were noted., Results: CorMatrix was utilized in 532 pediatric heart reconstruction procedures since 2011. Twelve explanted CorMatrix specimens from 11 pediatric patients including 4 valves (2 mitral and 2 aortic) and 8 outflow/septal/conduit patches were identified and evaluated. Six cases (5 patients) demonstrated clinical evidence of graft failure prior to surgery (n=6, 1%). Chronic inflammation was seen in adjacent native tissue in 11/12 cases and consisted predominantly of a mixed population of lymphocytes, macrophages, and plasma cells. Acute inflammation was seen in three cases (3/12). Fibrosis of the surrounding native tissue was seen in all CorMatrix specimens. Eosinophils were present in 6/12 cases. Calcification in surrounding tissue was present in 3/12 cases. Giant cell reaction in adjacent native tissue was seen in 8/12 cases. Neovascularization was seen in surrounding native tissue in 5/12 cases. Degeneration of CorMatrix material was seen in 9/12 cases. Necrosis of surrounding tissue was also identified in 5/12 cases. CorMatrix was not resorbed and no cases demonstrated any remodeling of CorMatrix material by integration of native mesenchymal cells or myocytes., Conclusion: CorMatrix may be associated with a marked inflammatory response, including a foreign-body giant cell reaction and fibrosis of the surrounding native tissue. Degenerative changes of CorMatrix material are also seen in a majority of explanted specimens. No histologic differences were seen between patients with clinical evidence of graft failure versus patients requiring graft removal due to other factors. Additionally, no cases showed evidence of tissue integration or recellularization of patch material. Our overall clinical experience with CorMatrix demonstrates a favorable outcome for pediatric patients undergoing cardiac reconstructive surgery. However, there is no histologic evidence that CorMatrix acts as a scaffold for reconstitution of the native cardiovascular structures., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2016
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35. Use of bivalirudin for anticoagulation during implantation of total artificial heart.
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Federman M, Dragomer D, Grant S, Reemtsen B, and Biniwale R
- Subjects
- Adult, Antithrombins administration & dosage, Humans, Male, Prosthesis Implantation adverse effects, Recombinant Proteins administration & dosage, Treatment Outcome, Cardiopulmonary Bypass adverse effects, Heart, Artificial adverse effects, Hirudins administration & dosage, Peptide Fragments administration & dosage, Premedication methods, Prosthesis Implantation methods, Thrombosis etiology, Thrombosis prevention & control
- Abstract
Heparin-induced thrombocytopenia presents a challenge for anticoagulation techniques during cardiac surgery and ventricular assist device implantation. Bivalirudin is currently recommended for use during cardiopulmonary bypass for patients with heparin-induced thrombocytopenia but requires the use of special techniques to avoid blood stagnation. We report the successful use of bivalirudin during cardiopulmonary bypass for implantation of the Total Artificial Heart with late operative bleeding likely resulting from heavy cell saver use.
- Published
- 2014
36. Berlin Heart EXCOR pediatric ventricular assist device for bridge to heart transplantation in US children.
- Author
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Almond CS, Morales DL, Blackstone EH, Turrentine MW, Imamura M, Massicotte MP, Jordan LC, Devaney EJ, Ravishankar C, Kanter KR, Holman W, Kroslowitz R, Tjossem C, Thuita L, Cohen GA, Buchholz H, St Louis JD, Nguyen K, Niebler RA, Walters HL 3rd, Reemtsen B, Wearden PD, Reinhartz O, Guleserian KJ, Mitchell MB, Bleiweis MS, Canter CE, and Humpl T
- Subjects
- Body Size, Cause of Death, Child, Child, Preschool, Comorbidity, Compassionate Use Trials, Equipment Design, Extracorporeal Membrane Oxygenation statistics & numerical data, Female, Heart Defects, Congenital blood, Heart Defects, Congenital surgery, Heart Diseases blood, Heart Diseases surgery, Hemorrhage epidemiology, Humans, Hyperbilirubinemia epidemiology, Infant, Kidney Diseases epidemiology, Liver Diseases epidemiology, Male, Mortality, Multiple Organ Failure epidemiology, Proportional Hazards Models, Risk, Stroke epidemiology, Survival Rate, Treatment Outcome, Waiting Lists, Heart Transplantation statistics & numerical data, Heart-Assist Devices
- Abstract
Background: Recent data suggest that the Berlin Heart EXCOR Pediatric ventricular assist device is superior to extracorporeal membrane oxygenation for bridge to heart transplantation. Published data are limited to 1 in 4 children who received the device as part of the US clinical trial. We analyzed outcomes for all US children who received the EXCOR to characterize device outcomes in an unselected cohort and to identify risk factors for mortality to facilitate patient selection., Methods and Results: This multicenter, prospective cohort study involved all children implanted with the Berlin Heart EXCOR Pediatric ventricular assist device at 47 centers from May 2007 through December 2010. Multiphase nonproportional hazards modeling was used to identify risk factors for early (<2 months) and late mortality. Of 204 children supported with the EXCOR, the median duration of support was 40 days (range, 1-435 days). Survival at 12 months was 75%, including 64% who reached transplantation, 6% who recovered, and 5% who were alive on the device. Multivariable analysis identified lower weight, biventricular assist device support, and elevated bilirubin as risk factors for early mortality and bilirubin extremes and renal dysfunction as risk factors for late mortality. Neurological dysfunction occurred in 29% and was the leading cause of death., Conclusions: Use of the Berlin Heart EXCOR has risen dramatically over the past decade. The EXCOR has emerged as a new treatment standard in the United States for pediatric bridge to transplantation. Three-quarters of children survived to transplantation or recovery; an important fraction experienced neurological dysfunction. Smaller patient size, renal dysfunction, hepatic dysfunction, and biventricular assist device use were associated with mortality, whereas extracorporeal membrane oxygenation before implantation and congenital heart disease were not.
- Published
- 2013
- Full Text
- View/download PDF
37. Arrhythmia recurrence in adult patients with single ventricle physiology following surgical Fontan conversion.
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Aboulhosn J, Williams R, Shivkumar K, Barkowski R, Plunkett M, Miner P, Houser L, Laks H, Reemtsen B, Shannon K, and Child J
- Subjects
- Adolescent, Adult, Female, Heart Defects, Congenital mortality, Heart Ventricles abnormalities, Hospital Mortality, Humans, Los Angeles, Male, Middle Aged, Palliative Care, Recurrence, Retrospective Studies, Risk Assessment, Risk Factors, Tachycardia, Supraventricular etiology, Tachycardia, Supraventricular mortality, Time Factors, Treatment Outcome, Young Adult, Catheter Ablation adverse effects, Catheter Ablation mortality, Fontan Procedure adverse effects, Fontan Procedure mortality, Heart Defects, Congenital surgery, Heart Ventricles surgery, Tachycardia, Supraventricular surgery
- Abstract
Objectives: To evaluate the incidence of atrial tachy-arrhythmia (AT) recurrence following conversion from right atrial-pulmonary artery (RA-PA) Fontan to total cavopulmonary connection (TCPC) in adults., Background: AT is a recognized sequel of Fontan palliation, especially in RA-PA Fontans, and is associated with significant morbidity. While catheter ablation achieves fairly reliable short-term success with low morbidity, conversion to TCPC with arrhythmia surgery is a highly effective treatment option for the classical Fontan patients with incessant AT., Methods: Single center retrospective review., Results: Twenty-seven adults underwent Fontan conversion from RA-PA to TCPC, mostly for AT indications (n = 24). Nine (33%) underwent conversion to a lateral tunnel (LT) and 18 (67%) to an extracardiac (EC) Fontan. Two patients died <30 days post-operatively. Both had liver failure and had been turned down for cardiac/liver transplantation. In-hospital complications occurred in 15/27 patients (55%), including recurrence of AT requiring cardioversion in six patients (22%) and persistent pleural effusions in 4 (15%). Mean follow-up was 4.2 years (range 3 months-14 years). Functional capacity improved from mean New York Heart Association (NYHA) class 1.8 pre-conversion to 1.2 post-conversion (P= 0.008). Twenty-one patients had concomitant arrhythmia surgery (MAZE in 12 patients with IART and Cox-MAZE in nine patients with A-Fib +/- IART). Of these, 3/21 (14%) had AT recurrence >3 months following conversion., Conclusions: Conversion from RA-PA Fontan to TCPC, with arrhythmia surgery, decreases AT recurrence and improves functional capacity. The risk of peri-operative mortality is highest in patients with cirrhosis. AT recurred in 14% of patients.
- Published
- 2010
- Full Text
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38. Role of clinically indicated transbronchial lung biopsies in the management of pediatric post-lung transplant patients.
- Author
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Greene CL, Reemtsen B, Polimenakos A, Horn M, and Wells W
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Cohort Studies, Female, Follow-Up Studies, Graft Survival, Humans, Immunohistochemistry, Infant, Lung Transplantation adverse effects, Male, Monitoring, Physiologic methods, Retrospective Studies, Sensitivity and Specificity, Transplantation, Homologous, Biopsy, Needle methods, Bronchoscopy, Graft Rejection diagnosis, Graft Rejection therapy, Lung Transplantation methods
- Abstract
Background: Although transbronchial biopsy (TBB) is the definitive method for diagnosing graft dysfunction after pediatric lung transplantation, concern over procedural complications has limited its use. We reviewed our institutional experience with clinically indicated TBB to determine its safety and efficacy with emphasis on how biopsy findings altered management., Methods: A retrospective chart review was done of 61 pediatric lung transplantation patients undergoing 179 TBB procedures. Data were collected on pre-TBB symptoms, pulmonary function testing, and imaging studies. The prebiopsy diagnosis was noted and compared with the findings from TBB to see how frequently treatment changed after biopsy., Results: Age at TBB ranged from 2 months to 20 years, with an average of 3 biopsies per patient. There was no procedure-related mortality. The incidence of complications was 9% and included important bleeding with spontaneous resolution in 6% and pneumothorax in 3%. The usual indication for TBB was a change in the chest roentgenogram, frequently accompanied by a decrease in flows on spirometry. The TBB specimens were adequate for pathologic analysis 92% of the time, and a specific pathologic diagnosis could be made in 54% of cases. The findings from TBB altered the clinical management of the patient 64% of the time., Conclusions: In pediatric lung transplant recipients presenting with graft dysfunction, TBB is a low-risk diagnostic procedure that yields clinically useful information in a majority of cases. In our experience, the findings from TBB altered medical treatment in 64% of patients. Treatment was most often changed in the group diagnosed with rejection as the probable cause of graft dysfunction.
- Published
- 2008
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39. Force required to elevate the sternum of pectus excavatum patients.
- Author
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Fonkalsrud EW and Reemtsen B
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Female, Humans, Male, Middle Aged, Minimally Invasive Surgical Procedures, Orthopedic Procedures methods, Postoperative Complications, Traction, Funnel Chest surgery, Sternum surgery
- Published
- 2002
- Full Text
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40. Allochimeric class I MHC molecules prevent chronic rejection and attenuate alloantibody responses.
- Author
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Singer JS, Mhoyan A, Fishbein MC, Shen XD, Gao F, Zhao D, Coito AJ, Reemtsen BL, Amersi F, Busuttil RW, Kupiec-Weglinski JW, and Ghobrial RM
- Subjects
- Amino Acid Sequence, Animals, Chronic Disease, Cyclosporine pharmacology, Graft Survival, Immunoglobulin G biosynthesis, Immunoglobulin G classification, Immunohistochemistry, Male, Molecular Sequence Data, Muscle, Smooth, Vascular pathology, Myocardium pathology, Rats, Rats, Inbred ACI, Rats, Inbred WF, Graft Rejection prevention & control, Heart Transplantation immunology, Histocompatibility Antigens immunology, Isoantibodies biosynthesis, Recombinant Fusion Proteins immunology
- Abstract
Background: We have shown that treatment with molecularly engineered, allochimeric [alpha1 hl/u]-RT1.Aa class I MHC antigens bearing donor-type Wistar-Furth (WF, RT1.Au) amino acid substitutions for host-type ACI (RTI.Aa) sequences in the alpha1-helical region induces donor-specific tolerance to cardiac allografts in rat recipients. This study examined the effect of allochimeric molecules on the development of chronic rejection., Methods: Allochimeric [alpha1 hl/u]-RT1.Aa class I MHC antigenic extracts (1 mg) were administered via the portal vein into ACI recipients of WF hearts on the day of transplantation in conjunction with subtherapeutic oral cyclosporine (CsA, 10 mg/kg/day, days 0-2). Control groups included recipients of syngeneic grafts and ACI recipients of WF heart allografts treated with high-dose CsA (10 mg/kg/day, days 0-6)., Results: WF hearts in ACI rats receiving 7 days of CsA exhibited myocardial fibrosis, perivascular inflammation, and intimal hyperplasia at day 80. At day 120, these grafts displayed severe chronic rejection with global architectural disorganization, ventricular fibrosis, intimal hyperplasia, and progressive luminal narrowing. In contrast, WF hearts in rats treated with [alpha1 hl/u]-RT1.Aa molecules revealed only mild perivascular fibrosis, minimal intimal thickening, and preserved myocardial architecture. Alloantibody analysis demonstrated no IgM alloantibodies in all groups. An attenuated, but detectable, anti-WF IgG response was present in recipients receiving allochimeric molecules, with IgG1 and IgG2a subclasses predominating. Immunohistochemical analysis of allografts demonstrated minimal T cell infiltration and IgG binding to vascular endothelium., Conclusion: Treatment with allochimeric molecules prevents the development of chronic rejection. Such effect may be in part caused by deviation of host alloantibody responses.
- Published
- 2001
- Full Text
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41. Intrathymic immunomodulation and the "infectious" tolerance pathway in allograft recipients.
- Author
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Reemtsen BL, Kato H, Wang TS, Busuttil RW, Kupiec-Weglinski JW, and Goss JA
- Subjects
- Animals, Antibody Formation physiology, Cytokines metabolism, Isoantibodies immunology, Kinetics, Male, Rats, Rats, Inbred Strains, Th1 Cells metabolism, Th2 Cells metabolism, Transplantation Immunology physiology, Transplantation, Homologous immunology, Heart Transplantation immunology, Immune System physiopathology, Immune Tolerance physiology, Infections immunology, Thymus Gland immunology
- Abstract
Background: We have previously shown that >75% of LEW cardiac allografts survive indefinitely in BUF rats pretreated at Day -21 intrathymically (IT) with donor alloantigen in conjunction with a single intravenous dose of ALS. Spleen cells can adoptively transfer the tolerant state to new cohorts of test recipients. This study was designed to analyze cellular and humoral events contributing to the "infectious" tolerance pathway in this model., Methods: Spleen cells (25 x 10(6)) harvested from BUF recipients bearing long-term cardiac allografts were injected intravenously into lightly irradiated (450 R) secondary BUF rats, followed 24 h later by transplantation of LEW of ACl hearts. Cardiac allografts were then analyzed serially by reverse transcription polymerase chain reaction for Th1 and Th2 cytokine gene expression. Donor-specific IgM and IgG alloantibody responses in host serum were screened by flow cytometry., Results: Transfer of regulatory spleen cells harvested between Days 80 and 140 from tolerant hosts induced tolerance to heart grafts in a donor-specific manner. In the early posttransplant period, selective sparing of Th2 cytokines was noted. Adoptively transferred hosts showed overall depression of IgM, but a vigorous IgG1 and IgG2a alloantibody response., Conclusion: IT + ALS-induced tolerance can be transferred in a donor-specific "infectious" manner to new cohorts of engrafted recipients. The development of tolerance is nontemporally bound, and associates with an early Th2-type immune deviation at the graft site. The elevated levels of T cell-dependent IgG1 and IgG2 may interfere with the antigen reactivity and alloresponsive effector functions, contributing to graft acceptance in the "infectious" tolerance pathway., (Copyright 1999 Academic Press.)
- Published
- 1999
- Full Text
- View/download PDF
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