Bio

Clinical Focus


  • Pediatric Cardiothoracic Surgery
  • Pediatric Cardiac Transplantation
  • Cardiothoracic Surgery

Academic Appointments


Administrative Appointments


  • Chief, Division of Pediatric Cardiac Surgery, Children's Hospital and Research Center Oakland (2004 - Present)
  • Chief, Pediatric Heart Transplantation, Department of Cardiothoracic Surgery (2007 - Present)

Professional Education


  • Residency:UCSF School of Medicine (2002) CA
  • Residency:University of Illinois at Chicago (1998) IL
  • Residency:Martin Luther University (1997) Germany
  • Fellowship:UCSF School of Medicine (1996) CA
  • Internship:Bradford Royal Infirmary (1994) UK
  • Internship:Fachbereich Medizin (1993) Germany
  • Medical Education:Freie University Berlin (1992) Germany
  • MD, Free University of Berlin, Medicine (1992)
  • CT boards, German Board of Medicine, Cardiothoracic Surgery (2001)

Research & Scholarship

Current Research and Scholarly Interests


1.Axial flow pump support in total cavopulmonary connection. Stanford 2006-2010. American Heart Association National Scientist Development Grant 0635219N, PI: Olaf Reinhartz, Total amount $ 280,000
2.Pathophysiologic response to fetal cardiac surgery. Co-PI. NIH RO1 grant 5RO1HL043357-10, PI: Frank Hanley, UCSF/Stanford 2000+
3.Berlin Heart Ventricular Assist Devices in Children. Multicenter study in 10 US centers. 2007+. Co-PI, Stanford site. (local PI: D. Rosenthal)
4.Triostat in children during CPB. Sub-Investigator; Multicenter trial incl. Childrens Hospital & Research Center Oakland 2003+, Funding through Dept. of Health and Human Services, Food and Drug Administration, IND55367; PI: M. Portman, Seattle
5.CLARINET: Clopidogrel to lower arterial thrombotic risk in neonates and infants trial. Sub-Investigator; Multicenter trial incl. Childrens Hospital & Research Center Oakland 2007+; EFC5314; Funding through Sanofi Aventis; Study Director: Sylvie Fontecave
6.Maturation and differentiation of the human cardiomyocyte in the first month of life. PI: Kirk Riemer, Internal funding, Stanford/Children’s Hospital Oakland 2004+
7.Adrenal axis of infants undergoing congenital heart disease surgery. Internal funding, Childrens Hospital & Research Center Oakland 2003+, PI: P. Sekar
8.Identification, isolation, purification and testing of Pulmonary-Arteriovenous-Malformation-Inhibiting factor. Internal funding, Stanford 2003+
9.Arterio-venous malformations after superior cavopulmonary anastomosis in the sheep model. Internal funding, UCSF/Stanford 2000+

Teaching

2013-14 Courses


Graduate and Fellowship Programs


Publications

Journal Articles


  • Lower socioeconomic status is associated with worse outcomes after both listing and transplanting children with heart failure PEDIATRIC TRANSPLANTATION Davies, R. R., Russo, M. J., Reinhartz, O., Maeda, K., Rosenthal, D. N., Chin, C., Bernstein, D., Mallidi, H. R. 2013; 17 (6): 573-581

    Abstract

    The relationship between SES and outcomes surrounding pediatric cardiac transplantation is complex and influenced by recipient race. Broad-based studies of SES have not been performed. A retrospective review of all 5125 primary pediatric heart transplants performed in the United States between 2000 and 2011. Patients were stratified by SES based on zip code of residence and U.S. census data (low SES: 1637; mid-SES: 2253; high SES: 1235). Survival following listing and transplantation was compared across strata. Risk-adjusted long-term mortality on the waitlist was higher among low SES patients (hazard 1.32, CI 1.07-1.63). The relationship between SES and outcomes varied by race. Early risk-adjusted post-transplant outcomes were worst among high SES patients (10.8% vs. low SES: 8.9%, p < 0.05). The incidence of non-compliance was higher among low SES patients (p < 0.0001). Long-term risk-adjusted patient survival was poorer among low (hazard 1.41, CI 1.10-1.80) and mid-SES (1.29, 1.04-1.59) groups. Low SES is associated with worse outcomes on both the waitlist and late following transplantation. Higher SES patients had more complex transplants with higher early mortality. Further research should be directed at identifying and addressing underlying causal factors for these disparities.

    View details for DOI 10.1111/petr.12117

    View details for Web of Science ID 000322317700015

    View details for PubMedID 23834560

  • Berlin Heart EXCOR Pediatric Ventricular Assist Device for Bridge to Heart Transplantation in US Children CIRCULATION Almond, C. S., Morales, D. L., Blackstone, E. H., Turrentine, M. W., Imamura, M., Massicotte, M. P., Jordan, L. C., Devaney, E. J., Ravishankar, C., Kanter, K. R., Holman, W., Kroslowitz, R., Tjossem, C., Thuita, L., Cohen, G. A., Buchholz, H., St Louis, J. D., Khanh Nguyen, K., Niebler, R. A., Walters, H. L., Reemtsen, B., Wearden, P. D., Reinhartz, O., Guleserian, K. J., Mitchell, M. B., Bleiweis, M. S., Canter, C. E., Humpl, T. 2013; 127 (16): 1702-?

    Abstract

    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.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.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.

    View details for DOI 10.1161/CIRCULATIONAHA.112.000685

    View details for Web of Science ID 000318031800012

    View details for PubMedID 23538380

  • Intermediate-term outcomes after combined heart-liver transplantation in children with a univentricular heart JOURNAL OF HEART AND LUNG TRANSPLANTATION Hollander, S. A., Reinhartz, O., Maeda, K., Hurwitz, M., Rosenthal, D. N., Bernstein, D. 2013; 32 (3): 368-370

    Abstract

    For patients with end-stage hepatic failure secondary to failing hemodynamics, combined heart-liver transplant (H-LT) remains the only option for long-term survival. We report a series of three pediatric patients who successfully underwent orthotopic H-LT for failed single-ventricle palliation. All three patients are currently living, now two, three, and five years post-transplant, and remain completely free of cardiac cellular allograft rejection despite reduced immunosuppression protocols. One patient, however, did develop acute antibody-mediated rejection in the immediate post-transplant period, suggesting that this protective effect may be less effective in attenuating humoral mechanisms of rejection.

    View details for DOI 10.1016/j.healun.2012.11.023

    View details for Web of Science ID 000315664600014

    View details for PubMedID 23415318

  • Cognitive outcomes in pediatric heart transplant recipients bridged to transplantation with ventricular assist devices JOURNAL OF HEART AND LUNG TRANSPLANTATION Stein, M. L., Bruno, J. L., Konopacki, K. L., Kesler, S., Reinhartz, O., Rosenthal, D. 2013; 32 (2): 212-220

    Abstract

    Ventricular assist devices (VADs) have been associated with high rates of neurologic injury in pediatric patients during the period of support, but the delayed consequences of this type of injury have not been described in the literature.In this study we assess cognitive outcomes with indices of general intellectual functioning, including working memory, processing speed, perceptual reasoning and verbal comprehension, for pediatric heart transplant recipients who required VAD support as a bridge to transplant (n = 9). We present an aggregate of these VAD patients combined with heart transplant recipients who did not require mechanical circulatory support (n = 11), and compare the performance of all transplant patients (n = 20) to typically developing, healthy comparators (n = 12). We also present a post hoc analysis of those transplant recipients with significant medical morbidity in the first year of life, referred to as the "high-risk" transplant group (n = 5), and compare them with the "low-risk" transplant group (n = 15) and the typically developing comparators (n = 12).The mean performance of the VAD patients was in the average range for each of the examined indices of cognitive functioning. A total of 11% of the VAD patients performed in the impaired range and 78% performed in the average range, with 11% in the superior range on measures of general intellectual functioning. The typically developing participants performed significantly better than the aggregated transplant recipients on all indices except verbal comprehension. Lower cognitive performance in the combined transplant group appears to be associated with medical morbidity in the first year of life.Despite significant neurologic risk factors, this cohort of pediatric patients who were bridged to transplant with VAD demonstrated resiliency in terms of cognitive outcomes. In this heterogeneous population, it is likely that multiple factors contributed to the cognitive outcomes. As VAD use becomes more common in pediatric patients, a prospective evaluation of cognitive outcomes is warranted.

    View details for DOI 10.1016/j.healun.2012.11.006

    View details for Web of Science ID 000314445800006

    View details for PubMedID 23352393

  • Midterm Results of the Modified Ross/Konno Procedure in Neonates and Infants ANNALS OF THORACIC SURGERY Maeda, K., Rizal, R. E., Lavrsen, M., Malhotra, S. P., Akram, S. A., Davies, R., Suleman, S., Reinhartz, O., Murphy, D. J., Hanley, F. L., Reddy, V. M. 2012; 94 (1): 156-163

    Abstract

    The management of congenital aortic stenosis in neonates and infants continues to be a surgical challenge. We have performed the modified Ross-Konno procedure for patients who have severe aortic insufficiency or significant residual stenosis after balloon aortic dilation. The midterm results of this procedure were evaluated in this subset of patients.Between 1994 and 2010, a total of 24 patients younger than 1 year of age underwent the modified Ross-Konno procedure. The diagnoses were aortic stenosis with or without subaortic stenosis (n = 16), Shone's complex (n = 7), and interrupted aortic arch with subaortic stenosis (n = 1). The aortic root was replaced with a pulmonary autograft, and the left ventricular outflow tract (LVOT) was enlarged with a right ventricular infundibular free wall muscular extension harvested with the autograft.Age at operation ranged from 1 to 236 days (median 28 days). The median follow-up period was 81 months (range 1-173 months). There was 1 early death and no late mortality. Overall the 1-, 2-, and 5-year survival rate was 95% ± 4.5%. Freedom from aortic stenosis was 94.7% ± 5.1% at 1, 2, and 5 years. Less than mild aortic insufficiency was 93.3% ± 6.4% at 2 years, and 74.7% ± 12.9% at 5 years. In total, 23 reoperations and reinterventions were performed; 14 were allograft conduit replacements. Two patients required aortic valve plasty. None required valve replacement. The reintervention-free rate was 64.6% ± 10.8% at 2 years and 36.9% ± 11.3% at 5 years.Pulmonary autografts demonstrated good durability with low mortality and morbidity. This study shows that the modified Ross-Konno procedure can be a practical choice in selective cases for complex LVOT stenosis in neonates and infants.

    View details for DOI 10.1016/j.athoracsur.2012.03.007

    View details for Web of Science ID 000305801600033

    View details for PubMedID 22626750

  • Use of the Impella 5.0 as a bridge from ECMO to implantation of the HeartMate II left ventricular assist device in a pediatric patient PEDIATRIC TRANSPLANTATION Hollander, S. A., Reinhartz, O., Chin, C., Yeh, J., Maeda, K., Mallidi, H., Bernstein, D., Rosenthal, D. 2012; 16 (2): 205-206
  • Maintenance Dose of Warfarin in Sheep and Effect of Diet: A Preliminary Report JOURNAL OF INVESTIGATIVE SURGERY Sasaki, T., Tsuda, S., Trujillo, M., Riemer, R. K., Reinhartz, O. 2012; 25 (1): 29-32

    Abstract

    Sheep models are widely used to evaluate the feasibility of various cardiac assist devices. Anticoagulation therapy postoperatively, however, is seldomly reported on. Continuous heparin infusion is often used, but is cumbersome due to long-term line management with the risk of infection and dislodgement. We contemplated using warfarin instead and started a pilot dose-finding study. Three sheep were given oral warfarin between 0.1 and 0.3 mg/kg/day. Prothrombin time was monitored and INR was calculated daily. If the INR did not reach a target of 2.5-3.5, warfarin dose was doubled. We found that sheep required a dose of warfarin between 1.6 and 2.4 mg/kg/day to raise the INR to the target zone. In a subsequent study to evaluate the effect of diet on INR in sheep, three sheep were fed alfalfa hay or alfalfa pellets in a crossover design. All the animals were given warfarin at the dose of 1.6 mg/kg. The diet was switched when the INR reached the target zone of 2.5-3.5. Hay-fed animals reached the target INR on days 6 and 7. On the other hand, pellet-fed animals did not reach the target value by day 7 with the initial dose and required 2.4 mg/kg of warfarin to achieve the goal. Hay raised the INR faster and higher than pellets with the same warfarin dose. Hay may be advantageous when using oral warfarin therapy in sheep.

    View details for DOI 10.3109/08941939.2011.598219

    View details for Web of Science ID 000299424500006

    View details for PubMedID 22272634

  • Challenges in Longer-Term Mechanical Support of Fontan Circulation in Sheep ASAIO JOURNAL Boni, L., Sasaki, T., Ferrier, W. T., Yeung, J. T., Reichenbach, S. H., Riemer, R. K., Reinhartz, O. 2012; 58 (1): 60-64

    Abstract

    Single ventricle congenital heart defects are usually palliated with the end result of a Fontan circulation. Despite improving results, this circulation is still associated with long-term failure. We previously developed an animal model of mechanical cavopulmonary circulation support that was successful in the acute and mid-term period. In the current study, we evaluated longer support durations in five Western-breed sheep. Through a right thoracotomy we instituted mechanical support from the inferior vena cava to the pulmonary artery, using a Heartmate II axial flow pump (Thoratec Corp., Pleasanton, CA). Postoperatively, the animals were anticoagulated with heparin iv. Hemodynamics, pump flow, anticoagulation, and hepatic and renal function were monitored daily. All animals survived the operation. Signs of moderate liver and kidney injury in general reversed quickly. Two animals had a fatal pump thrombosis. When anticoagulation was effective, hemodynamics and pump flow were maintained to normal values. Effective anticoagulation was difficult to achieve because of the high variability in response to heparin. Survival up to 18 days was accomplished. This study is the longest reported survival of animals with a mechanically assisted cavopulmonary circulation. The performance of the Thoratec Heartmate II has been good, but the issue of effective anticoagulation has not yet been solved.

    View details for DOI 10.1097/MAT.0b013e31823c0aa4

    View details for Web of Science ID 000298643200011

    View details for PubMedID 22210652

  • Surgical Results in Patients With Pulmonary Atresia-Major Aortopulmonary Collaterals in Association With Total Anomalous Pulmonary Venous Connection ANNALS OF THORACIC SURGERY Mainwaring, R. D., Reddy, M., Reinhartz, O., Punn, R., Tacy, T., Hanley, F. L. 2011; 92 (5): 1756-1760

    Abstract

    Pulmonary atresia and major aortopulmonary collaterals (PA/MAPCAs) is a complex form of congenital heart disease. One to two percent of patients with PA/MAPCAs will also have total anomalous pulmonary venous connection (TAPVC). This study summarizes our surgical experience with this rare combination of life-threatening congenital heart defects.A retrospective review was performed to identify patients who had surgery for PA/MAPCAs in association with TAPVC. From November 2001 to March 2011, 9 patients presented with this combination of defects. Eight of the 9 patients had heterotaxy with an unbalanced atrioventricular canal and functional single ventricle. The ninth patient had double outlet right ventricle (two ventricles). Timing of surgical intervention was typically predicated on the degree of pulmonary venous obstruction. The median age at surgery was 14 days. All nine patients had surgical correction of TAPVC, unifocalization of MAPCA's into a central confluence, and placement of a shunt.There was one early mortality (< 30 days) and two late mortalities. For the 6 survivors, 5 have subsequently undergone a bidirectional Glenn procedure, and 3 had completion of their Fontan. Two patients are currently at the bidirectional Glenn stage; one is a good candidate for Fontan completion while the other is not suitable. The sixth patient is awaiting further assessment.The PA/MAPCAs, in association with TAPVC, is a challenging combination of defects. The data suggest that the combination of PA/MAPCAs and TAPVC can be undertaken with a reasonable midterm prognosis.

    View details for DOI 10.1016/j.athoracsur.2011.06.020

    View details for Web of Science ID 000296925400045

    View details for PubMedID 21944736

  • Anomalous Aortic Origin of a Coronary Artery: Medium-Term Results After Surgical Repair in 50 Patients ANNALS OF THORACIC SURGERY Mainwaring, R. D., Reddy, V. M., Reinhartz, O., Petrossian, E., Macdonald, M., Nasirov, T., Miyake, C. Y., Hanley, F. L. 2011; 92 (2): 691-697

    Abstract

    Anomalous aortic origin of a coronary artery (AAOCA) is a rare congenital heart defect that has been associated with myocardial ischemia and sudden death. Controversies exist regarding the diagnosis, treatment, and long-term recommendations for patients with AAOCA. The purpose of this study is to evaluate the medium-term results of surgical repair for AAOCA.From January 1999 through August 2010, 50 patients underwent surgical repair of AAOCA. The median age at surgery was 14 years (range, 5 days to 47 years). Thirty-one patients had the right coronary originate from the left sinus of Valsalva, 17 had the left coronary originate from the right sinus, and 2 had an eccentric single coronary ostium. Twenty six of the 50 patients had symptoms of myocardial ischemia preoperatively, and 14 patients had associated congenital heart defects. Repair was accomplished by unroofing in 35, reimplantation in 6, and pulmonary artery translocation in 9.There was no operative mortality. The median time of follow-up has been 5.7 years. Two patients were lost to follow-up, and 1 patient required heart transplantation 1 year after AAOCA repair. In the remaining 47 postoperative patients, all have remained free of cardiac symptoms and no one has experienced a sudden death event.The surgical treatment of AAOCA is safe and appears to be highly effective in eliminating ischemic symptoms. These medium-term results are encouraging and suggest that many patients may be able to resume normal activities.

    View details for DOI 10.1016/j.athoracsur.2011.03.127

    View details for Web of Science ID 000293221000050

    View details for PubMedID 21718962

  • Clinical usefulness of a novel C1q assay to detect immunoglobulin G antibodies capable of fixing complement in sensitized pediatric heart transplant patients JOURNAL OF HEART AND LUNG TRANSPLANTATION Chin, C., Chen, G., Sequeria, F., Berry, G., Siehr, S., Bernstein, D., Rosenthal, D., Reinhartz, O., Tyan, D. 2011; 30 (2): 158-163

    Abstract

    Donor-specific antibodies (DSA) against human leukocyte antigens complicate transplantation with the potential for acute antibody-mediated rejection (AMR). Complement-fixing antibodies are required to initiate the complement cascade. Not all DSAs, however, can fix complement.A novel C1q assay was developed to detect the sub-set of immunoglobulin G (IgG) antibodies capable of fixing complement. Sera from 18 pediatric heart transplant patients were analyzed for DSAs using a Luminex platform (Luminex Inc, Austin, TX) and commercially available single-antigen bead assay kits. Biopsy specimens were assessed for AMR using histopathologic criteria and immunohistochemical staining.During the study period, 5 patients had AMR; of these, 2 were C1q virtual crossmatch positive (VXM+) and had persistent C1q DSAs after transplant, and 3 were C1q VXM- but antibody developed immediately after transplant. A positive C1q assay in the immediate post-transplant period had a positive predictive value (PPV) of 100% and a negative predictive value (NPV) of 100%, with 100% sensitivity and 100% specificity (Fisher exact p = 0.001). Of 11 patients who were IgG VXM+, 5 had AMR; the IgG VXM had a PPV of 45% and NPV of 100%, with 100% sensitivity and 54% specificity (Fisher exact p = 0.101).The C1q assay can detect a sub-set of antibodies capable of fixing complement and predicts AMR early after transplant. Avoiding only the donor antigens that would be recognized by the C1q assay may accelerate time to transplant by expansion of the donor pool and potentially allows transplantation of previously "incompatible" organs.

    View details for DOI 10.1016/j.healun.2010.08.020

    View details for Web of Science ID 000286545200008

    View details for PubMedID 20951058

  • Imaging and Surgical Repair of a Bifurcating Aortico-Left Ventricle Tunnel ANNALS OF THORACIC SURGERY Kaiser, C. A., Chung, T., Rosenfeld, H. M., Reinhartz, O. 2011; 91 (2): E23-E25

    Abstract

    Aortico-left ventricle tunnels are rare congenital anomalies with variable anatomy; however, by definition, they consist of an abnormal connection between the ascending aorta and the left ventricle. Diagnosis is usually by echocardiography, and treatment typically uses a two-patch surgical repair. Herein, we describe a case of an aortico-left ventricle tunnel, with the tunnel bifurcating before entering the left ventricle. Preoperative echocardiography and magnetic resonance imaging show the lesion in great detail. Two patches were required on the left-ventricular side of the tunnel for closure. A bifurcating aortico-left ventricle tunnel has not yet been described in the literature. The preoperative imaging and surgical management are discussed.

    View details for DOI 10.1016/j.athoracsur.2010.10.033

    View details for Web of Science ID 000286456400004

    View details for PubMedID 21256259

  • Bridging children of all sizes to cardiac transplantation: The initial multicenter North American experience with the Berlin Heart EXCOR ventricular assist device JOURNAL OF HEART AND LUNG TRANSPLANTATION Morales, D. L., Almond, C. S., Jaquiss, R. D., Rosenthal, D. N., Naftel, D. C., Massicotte, M. P., Humpl, T., Turrentine, M. W., Tweddell, J. S., Cohen, G. A., Kroslowitz, R., Devaney, E. J., Canter, C. E., Fynn-Thompson, F., Reinhartz, O., Imamura, M., Ghanayem, N. S., Buchholz, H., Furness, S., Mazor, R., Gandhi, S. K., Fraser, C. D. 2011; 30 (1): 1-8

    Abstract

    Beginning in 2000 and accelerating in 2004, the Berlin Heart EXCOR (Berlin Heart Inc Woodlands, TX) became the first pediatric-specific ventricular assist device (VAD) applied throughout North America for children of all sizes. This retrospective study analyzed the initial Berlin Heart EXCOR pediatric experience as a bridge to transplantation.Between June 2000 and May 2007, 97 EXCOR VADs were implanted in North America at 29 different institutions. The analysis is limited to 73 patients (75%) from 17 institutions, for which retrospective data were available.Median age and weight at VAD implant were 2.1 years (range, 12 days-17.8 years) and 11 kg (range, 3-87.6 kg), respectively. The primary diagnoses were dilated cardiomyopathy in 42 (58%), congenital heart disease in 19 (26%), myocarditis in 7 (10%), and other cardiomyopathies in 5 (7%). Pre-implant clinical condition was critical cardiogenic shock in 38 (52%), progressive decline in 33 (45%), or other in 2 (3%). Extracorporeal membrane oxygenation was used as a bridge to EXCOR in 22 patients (30%). Device selection was left VAD (LVAD) in 42 (57%) and biventricular assist devices (BiVAD) in 31 (43%). The EXCOR bridged 51 patients (70%) to transplant and 5 (7%) to recovery. Mortality on the EXCOR was 23% (n = 17) overall, including 35% (11 of 31) in BiVAD vs 14% (6 of 42) in LVAD patients (p = 0.003). Multivariate analysis showed younger age and BiVAD support were significant risk factors for death while on the EXCOR.This limited but large preliminary North American experience with the Berlin Heart EXCOR VAD as a bridge to cardiac transplantation for children of all ages and sizes points to the feasibility of this approach. The prospective investigational device evaluation trial presently underway will further characterize the safety and efficacy of the EXCOR as a bridge to pediatric cardiac transplantation.

    View details for DOI 10.1016/j.healun.2010.08.033

    View details for Web of Science ID 000286287000001

    View details for PubMedID 21145473

  • The hemi-Mustard/bidirectional Glenn atrial switch procedure in the double-switch operation for congenitally corrected transposition of the great arteries: Rationale and midterm results JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Malhotra, S. P., Reddy, V. M., Qiu, M., Pirolli, T. J., Barboza, L., Reinhartz, O., Hanley, F. L. 2011; 141 (1): 162-170

    Abstract

    This study was undertaken to assess the risks and benefits of the double-switch operation using a hemi-Mustard atrial switch procedure and the bidirectional Glenn operation for congenitally corrected transposition of the great arteries. To avoid complications associated with the complete Senning and Mustard procedures and to assist right-heart hemodynamics, we favor a modified atrial switch procedure, consisting of a hemi-Mustard procedure to baffle inferior vena caval return to the tricuspid valve in conjunction with a bidirectional Glenn operation.Between January 1994 and September 2009, anatomic repair was achieved in 48 patients. The Rastelli-atrial switch procedure was performed in 25 patients with pulmonary atresia and the arterial-atrial switch procedure was performed in 23 patients. A hemi-Mustard procedure was the atrial switch procedure for 70% (33/48) of anatomic repairs.There was 1 in-hospital death after anatomic repair. There were no late deaths or transplantation. At a median follow-up of 59.2 months, 43 of 47 survivors are in New York Heart Association class I. Bidirectional Glenn operation complications were uncommon (2/33), limited to the perioperative period, and seen in patients less than 4 months of age. Atrial baffle-related reoperations or sinus node dysfunction have not been observed. Tricuspid regurgitation decreased from a mean grade of 2.3 to 1.2 after repair (P = .00002). Right ventricle-pulmonary artery conduit longevity is significantly improved.We describe a 15-year experience with the double-switch operation using a modified atrial switch procedure with favorable midterm results. The risks of the hemi-mustard and bidirectional Glenn operation are minimal and are limited to a well-defined patient subset. The benefits include prolonged conduit life, reduced baffle- and sinus node-related complications, and technical simplicity.

    View details for DOI 10.1016/j.jtcvs.2010.08.063

    View details for Web of Science ID 000285407500029

    View details for PubMedID 21055773

  • Behcet's disease and heart transplantation: A word of caution JOURNAL OF HEART AND LUNG TRANSPLANTATION Hollander, S. A., Yasnovsky, J. R., Reinhartz, O., Chan, F., Sandborg, C., Hunt, S., Bernstein, D., Chin, C. 2010; 29 (11): 1306-1308

    Abstract

    Behcet's disease is a rare autoimmune disease characterized by oral and genital ulcers, and by multisystem disease, including arthritis, neurologic complications and vasculitis. Large-vessel and coronary artery aneurysms are often an indication for surgery, but the return of aneurysms, thrombosis, and the tendency to exhibit an exaggerated inflammatory response at puncture sites (pathergy) complicate surgical recovery. As such, cardiac transplantation, which requires atrial and large-vessel anastomoses, has not been reported in patients with Behcet's disease. We report the first orthotopic heart transplant with >1-year survival in a patient with Behcet's disease despite major complications. The investigators remain pessimistic about cardiac transplantation in patients with Behcet's disease until advances in preventing recurrent vascular pathology ensue.

    View details for DOI 10.1016/j.healun.2010.07.010

    View details for Web of Science ID 000284030700015

    View details for PubMedID 20822920

  • Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS)-Defined Morbidity and Mortality Associated With Pediatric Ventricular Assist Device Support at a Single US Center The Stanford Experience CIRCULATION-HEART FAILURE Stein, M. L., Robbins, R., Sabati, A. A., Reinhartz, O., Chin, C., Liu, E., Bernstein, D., Roth, S., Wright, G., Reitz, B., Rosenthal, D. 2010; 3 (6): 682-688

    Abstract

    The use of ventricular assist devices (VADs) to bridge pediatric patients to heart transplantation has increased dramatically over the last 15 years. In this report, we present the largest US single-center report of pediatric VAD use to date. We present detailed descriptions of morbidity and mortality associated with VAD support, using standard Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) criteria for pediatrics to facilitate the comparison of these results to other studies.We retrospectively identified 25 patients younger than 18 years with 27 episodes of mechanical circulatory support using VADs as bridge to heart transplantation from January 1998 to December 2007. Survival to transplant for the entire cohort was 74%. The most common major morbidities, as defined by INTERMACS criteria for a pediatric population, were respiratory failure, major localized infections, major bleeding events, hepatic dysfunction, and right heart failure. Major neurological events occurred in 48% of the study population. The median time to the first occurrence of an adverse event was less than 14 days for respiratory failure, right heart failure, major localized infection, and major bleeding. Patients who died before transplantation had significantly more adverse events per day of support than did those who were successfully transplanted. Episodes of major bleeding, tamponade, acute renal failure, respiratory failure, and right heart failure were all associated with increased risk of mortality.INTERMACS criteria can be successfully used to analyze pediatric VAD outcomes. These data serve as a baseline for future studies of VAD support in children and indicate good survival rates but considerable morbidity.

    View details for DOI 10.1161/CIRCHEARTFAILURE.109.918672

    View details for Web of Science ID 000284261600011

    View details for PubMedID 20807863

  • Unusual Manifestations of Vascular Rings JOURNAL OF CARDIAC SURGERY Mainwaring, R. D., Jacobson, J. L., Reinhartz, O., Gates, R. L. 2010; 25 (1): 79-83

    Abstract

    Vascular rings are a relatively rare entity caused by abnormal development of the fetal aortic arches. Most patients with vascular rings present in infancy or early childhood with respiratory (inspiratory) symptoms. The treatment of patients with symptomatic vascular rings is generally straight-forward, focusing on surgical division of the ring. The majority of patients are "cured" by this simple procedure. However, a small percentage of patients do not follow this typical course. The purpose of this manuscript is to review and discuss three patients who demonstrated unusual manifestations of vascular rings. Two patients required reoperation after double aortic arch repair and one had successful treatment of an aberrant right subclavian artery.

    View details for DOI 10.1111/j.1540-8191.2009.00947.x

    View details for Web of Science ID 000273164700023

    View details for PubMedID 19874418

  • Recovery During Mid-Term Mechanical Support of Fontan Circulation in Sheep ASAIO JOURNAL Tsuda, S., Sasaki, T., Maeda, K., Riemer, R. K., Reichenbach, S. H., Reinhartz, O. 2009; 55 (4): 406-411

    Abstract

    Total cavopulmonary connection (CPC) has a significant incidence of late failure due to increased systemic venous pressure and low cardiac output. Mechanical support could prevent failure by correcting hemodynamics. We established a model of inferior CPC using an axial flow pump (Thoratec HeartMate II, Thoratec Corp. Pleasanton, CA) in a group of ten 47-57 kg sheep and assessed hemodynamics and metabolism as a potential chronic treatment option for failed Fontan circulation. After pilot studies (n = 7), three animals underwent pump-supported inferior CPC to assess hemodynamic and metabolic responses. Pump inflow was connected to the inferior vena cava (IVC) and outflow to the main pulmonary artery. The IVC was ligated at the right atrium. Hemodynamic and biochemical parameters were recorded over four days. The first seven animals died from pump-related causes (graft kinking, three; pump thrombosis, one) or other causes (GI bleeding, one; suspected stroke, two). The subsequent three animals were electively euthanized on postoperative day four due to IRB requirements. Over the four day postoperative period, pump flow was 3.43 +/- 0.62 L/min and IVC pressure 4.05 +/- 3.21 mm Hg (mean +/- SD). Lactate levels remained normal. Low pressure and high-volume IVC flow was sustained by mechanical support. We will next attempt chronic pump implantation.

    View details for DOI 10.1097/MAT.0b013e3181a0a570

    View details for Web of Science ID 000267559100016

    View details for PubMedID 19471161

  • Outcome Analysis for a Small, Start-up Congenital Heart Surgery Program JOURNAL OF CARDIAC SURGERY Mainwaring, R. D., Reddy, V. M., Reinhartz, O., Lamberti, J. J., Jacobson, J. G., Jimenez, D. L., Hanley, F. L. 2008; 23 (6): 622-626

    Abstract

    There will be a continuing need to start new congenital heart surgery programs to serve communities experiencing significant population growth. However, small congenital heart programs frequently underperform their larger counterparts. This study summarizes the clinical outcome data for the first 42 months of a small, start-up congenital heart surgery program. Clinical outcomes were summarized from the start of the program in September 2003 through March 2007. Risk adjustment analysis was performed using the risk adjustment in congenital heart surgery (Rachs-1) risk adjustment model and Society of Thoracic Surgeons (STS) congenital database. Three hundred eighty-six operations have been performed during this time period, including 47 newborns, 96 infants, 217 children/adolescents, and 26 adults (greater than 18 years). There have been two operative mortalities (0.5%). Assigning these cases to the Rachs-1 categories, there were 64 level I, 188 level II, 90 level III, 12 level IV cases, with 32 "others." The predicted mortality for the 354 categorized cases calculates to be 17.4 (Rachs-1) and 10.2 (STS). The data demonstrate that a start-up program with a relatively modest surgical volume can achieve satisfactory clinical results. This model has relied upon careful case selection and direct, senior-level surgeon involvement through an affiliation with a university-based program. These results suggest that a small congenital heart surgery program can be successfully started if the circumstances are carefully controlled.

    View details for DOI 10.1111/j.1540-8191.2008.00675.x

    View details for Web of Science ID 000260499400007

    View details for PubMedID 19016985

  • Dynamics of human myocardial progenitor cell Populations in the neonatal period ANNALS OF THORACIC SURGERY Amir, G., Ma, X., Reddy, V. M., Hanley, F. L., Reinhartz, O., Ramamoorthy, C., Riemer, R. K. 2008; 86 (4): 1311-1320

    Abstract

    Pluripotent cardiac progenitor cells resident in myocardium offer a potentially promising role in promoting recovery from injury. In pediatric congenital heart disease (CHD) patients, manipulation of resident progenitor cells may provide important new approaches to improving outcomes. Our study goals were to identify and quantitate populations of progenitor cells in human neonatal myocardium during the early postnatal period and determine the proliferative capacity of differentiated cardiac myocytes.Immunologic markers of cell lineage (stage-specific embryonic antigen 4 [SSEA-4], islet cell antigen 1 [Isl1], c-kit, Nkx2.5, sarcoplasmic reticulum calcium-regulated ATPase type 2 [SERCA2]) and proliferation (Ki67) were localized in right ventricular biopsies from 32 CHD patients aged 2 to 93 days.Neonatal myocardium contains progenitor cells and transitional cells expressing progenitor and differentiated myocyte marker proteins. Some cells expressed the pluripotent cell marker c-kit and also coexpressed the myocyte marker SERCA2. Multipotent progenitor cells, identified by the expression of Isl1, were found. Ki67 was expressed in some myocytes and in nonmyocyte cells. A few cells expressing SSEA-4 and Isl1 were observed during the early postnatal period. Cells expressing c-kit, the premyocyte marker Nkx2.5, and Ki67 were found throughout the first postnatal month. A progressive decline in cell density during the first postnatal month was observed for c-kit+ cells (p = 0.0013) and Nkx2.5+ cells (p = 0.0001). The percentage of cells expressing Ki67 declined during the first 3 postnatal months (p = 0.0030).Cells in an incomplete state of cardiomyocyte differentiation continue to reside in the infant heart. However, the relative density of progenitor cells declines during the first postnatal month.

    View details for DOI 10.1016/j.athoracsur.2008.06.058

    View details for Web of Science ID 000259848000036

    View details for PubMedID 18805183

  • Surgical management of coronary artery arising from the wrong coronary sinus, using standard and novel approaches JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Gulati, R., Reddy, V. M., Culbertson, C., Helton, G., Suleman, S., Reinhartz, O., Silverman, N., Hanley, F. L. 2007; 134 (5): 1171-U12

    Abstract

    Patients with a coronary artery arising from the wrong sinus are susceptible to ischemia and sudden death. Risk is higher when the artery courses interarterially--between the pulmonary artery and aorta--has an intramural course, or has an abnormal orifice. In single coronary ostium without intramural course, unroofing and coronary reimplantation are inappropriate, and coronary artery bypass grafting is suboptimal. For this variant, we have devised pulmonary artery translocation.A retrospective review of 18 patients undergoing repair between January 1999 and March 2005 was performed. Mean age was 8.1 years (range 6 weeks-16 years). All anomalous arteries coursed interarterially. Ten patients had a right coronary artery from the left coronary sinus; 8 had a left coronary artery from the right sinus. Eleven had an intramural course, and 4 had a single coronary ostium without an intramural course. Ten (56%) patients had symptoms: chest pain (9/10), syncope (3/10), or dyspnea (2/10). Repair was implemented by unroofing (n = 11), reimplantation (n = 3), or pulmonary artery translocation (1 lateral, 3 anterior). All patients were followed up clinically and echocardiographically.At a mean of 2.2 years (2 weeks-5 years), there was no mortality. Symptoms improved and function remained normal in all but 1 patient. He had sustained multiple infarcts in the anomalous artery's distribution and required transplantation despite repair.Repair is indicated in all patients with coronary insufficiency and in asymptomatic patients with high-risk morphologic abnormalities. We recommend unroofing when an intramural component (or slit-like orifice) is present, reimplantation for separate ostia without an intramural course, and pulmonary artery translocation for single ostium without an intramural course. Coronary artery bypass grafting is thus avoided.

    View details for DOI 10.1016/j.jtcvs.2007.02.051

    View details for Web of Science ID 000250576200011

    View details for PubMedID 17976445

  • The extracardiac conduit Fontan operation using minimal approach extracorporeal circulation: Early and midterm outcomes JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Petrossian, E., Reddy, V. M., Collins, K. K., Culbertson, C. B., MacDonald, M. J., Lamberti, J. J., Reinhartz, O., Mainwaring, R. D., Francis, P. D., Malhotra, S. P., Gremmels, D. B., Suleman, S., Hanley, F. L. 2006; 132 (5): 1054-1063

    Abstract

    Our approach to the extracardiac conduit Fontan operation has evolved over time from full-pump, to partial-pump, to completely off-pump. This study is designed to report our overall experience with the extracardiac conduit Fontan operation and to evaluate the evolution in bypass technique on postoperative outcomes.From September 1992 to April 2005, 285 patients, median age 4.5 years (1.4-44 years), median weight 16 kg (9.4-94 kg), underwent a primary extracardiac conduit Fontan procedure. Early and late outcomes were analyzed for the entire cohort and for 2 patient groups depending on whether an oxygenator was used in the bypass circuit (166 patients; 58%) or not (119 patients; 42%).Early failure (including death and takedown) occurred in 7 patients (2.5%). Prevalence of new early postoperative sinus node dysfunction necessitating a permanent pacemaker was 0.4%, and that of new tachyarrhythmias necessitating discharge home on a regimen of antiarrhythmia medications was 2.5%. Ten-year actuarial freedom from Fontan failure, new sinus node dysfunction necessitating a permanent pacemaker, and reoperation for conduit thrombosis or stenosis was 90%, 96%, and 98%, respectively. Fenestration rate was lower (P = .001) in the no-oxygenator group (8%) than in the oxygenator group (25%). Patients in the no-oxygenator group had lower intraoperative Fontan pressure (12.0 +/- 2.3 vs 13.5 +/- 2.4 mm Hg, P < .001), common atrial pressure (4.6 +/- 1.8 vs 5.3 +/- 1.8 mm Hg, P = .003), and transpulmonary gradient (7.5 +/- 2.1 vs 8.3 +/- 2.2 mm Hg, P = .013) than did the oxygenator group.The extracardiac conduit Fontan operation coupled with minimal use of extracorporeal circulation is associated with favorable intraoperative hemodynamics, low fenestration rate, minimal risk of thrombosis or stenosis, and minimal early and late rhythm disturbance.

    View details for DOI 10.1016/j.jtcvs.2006.05.066

    View details for Web of Science ID 000241497500009

    View details for PubMedID 17059923

  • Unifocalization of major aortopulmonary collaterals in single-ventricle patients ANNALS OF THORACIC SURGERY Reinhartz, O., Reddy, V. M., Petrossian, E., Suleman, S., Mainwaring, R. D., Rosenthal, D. N., Feinstein, J. A., Gulati, R., Hanley, F. L. 2006; 82 (3): 934-939

    Abstract

    Unifocalization of major aortopulmonary collateral arteries (MAPCAs) in pulmonary atresia with ventricular septal defect and intracardiac repair has become the standard of care. However, there are no reports addressing unifocalization of MAPCAs in single-ventricle patients. It is unknown whether their pulmonary vascular bed can be reconstructed and low enough pulmonary vascular resistance achieved to allow for superior or total cavopulmonary connections.We reviewed data on all patients with functional single ventricles and unifocalization procedures of MAPCAs. From 1997 to 2005, 14 consecutive children with various single-ventricle anatomies were operated on.Patients had a median of three surgical procedures (range, 1 to 5). Two patients had absent, all others diminutive central pulmonary arteries, with an average of 3.5 +/- 1.2 MAPCAs. Seven patients (50%) had bidirectional Glenn procedures, and 3 of these had Fontan procedures. Median postoperative pulmonary artery pressures measured 12.5 mm Hg (Glenn) and 14 mm Hg (Fontan), respectively. Six patients are alive today (46%), with 1 patient lost to follow-up. Three patients died early and 3 late after initial unifocalization to shunts. One other patient survived unifocalization, but was not considered a candidate for a Glenn procedure and died after high-risk two-ventricle repair. Another patient with right-ventricle-dependent coronary circulation died of sepsis late after Glenn.In selected patients with functional single ventricles and MAPCAs, the pulmonary vascular bed can be reconstructed sufficiently to allow for cavopulmonary connections. Venous flow to the pulmonary vasculature decreases cardiac volume load and is likely to increase life expectancy and quality of life for these patients.

    View details for DOI 10.1016/j.athoracsur.2006.03.063

    View details for Web of Science ID 000239996300025

    View details for PubMedID 16928512

  • Homograft valved right ventricle to pulmonary artery conduit as a modification of the Norwood procedure CIRCULATION Reinhartz, O., Reddy, V. M., Petrossian, E., Macdonald, M., Lamberti, J. J., Roth, S. J., Wright, G. E., Perry, S. B., Suleman, S., Hanley, F. L. 2006; 114: I594-I599

    Abstract

    The use of a right ventricle to pulmonary artery (RV-PA) conduit in the Norwood procedure has been proposed to increase postoperative hemodynamic stability. A valve within the conduit should further decrease RV volume load. We report our clinical experience with this modification.From February 2002 through August 2005, we performed 88 consecutive Norwood procedures using RV-PA conduits. We used composite valved conduits made from cryopreserved homograft and polytetrafluoroethylene (PTFE) in 66 cases (54 pulmonary, 12 aortic homografts), other valved conduits in 14, and unvalved PTFE in 8 cases. Hospital survival was 88.6% overall and increased to 93.1% after the initial year. Early interventions were required in 18 patients (16 for cyanosis). Prestage II cardiac catheterization was performed at a mean age of 126 days. Mean Qp/Qs was 1, with mean aortic saturation 71%, mean O2 extraction 24%, and mean right ventricular end-diastolic pressure 9 mm Hg. Patient weight, use of an aortic homograft valve in the conduit, stage I palliation within the first year of our experience, and low O2 extraction and high transpulmonary gradient prestage II were risk factors for overall death. Early interventions were more frequent in aortic valve conduits compared with all other conduits.The valved RV-PA conduit was associated with low early mortality after the Norwood procedure. The majority of these patients had normal cardiac output and well-maintained RV function. There may be a higher risk for early conduit interventions and death when aortic valve homografts are used in the RV-PA conduit.

    View details for DOI 10.1161/CIRCULATIONAHA.105.001438

    View details for Web of Science ID 000238688200097

    View details for PubMedID 16820644

  • Thoratec ventricular assist devices in pediatric patients: Update on clinical results ASAIO JOURNAL Reinhartz, O., Hill, J. D., Al-Khaldi, A., Pelletier, M. P., Robbins, R. C., Farrar, D. J. 2005; 51 (5): 501-503

    Abstract

    Particularly in pediatric patients, mechanical circulatory support remains a clinical challenge. We analyzed the Stanford experience with use of the Thoratec ventricular assist device (VAD) in children and adolescents and data from the company's voluntary database. Through January 2005, 209 patients up to 18 years of age have been supported with the Thoratec VAD worldwide. Mean age was 14.5 years (range 5-18 years), mean weight was 57 kg (range 17-118 kg), and mean body surface area was 1.6 m2 (range 0.7-2.3 m2). The majority of patients were supported for cardiomyopathies (55%) and acute myocarditis (25%). A minority (6%) was treated for end-stage congenital heart disease. Average duration of support was 44 days (0-434 days). Overall survival to transplantation or weaning off the device was 68%. Survival rates were higher for patients with cardiomyopathies (74%) and acute myocarditis (86%) compared with patients with congenital heart disease (27%). We performed a subanalysis in small children with a body surface area of less 1.3 m2. This subgroup had a higher incidence of congenital heart disease and a slightly lower survival (52%). Aspects of the particular risks and device management in these small patients are discussed.

    View details for DOI 10.1097/01.mat.0000178214.95010.c0

    View details for Web of Science ID 000238586400009

    View details for PubMedID 16322705

  • Mechanical support of total cavopulmonary connection with an axial flow pump JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Riemer, R. K., Amir, G., Reichenbach, S. H., Reinhartz, O. 2005; 130 (2): 351-354

    Abstract

    Even under optimal circumstances, total cavopulmonary connection is associated with a continuous late risk of death. Hemodynamics are distinctly abnormal, with increased systemic venous pressures and frequent low cardiac output. Our study uses a sheep model of total cavopulmonary connection to test the response to axial flow pump (Thoratec HeartMate II; Thoratec Corporation (Pleasanton, Calif)) support of total cavopulmonary connection, which might be suitable to treat patients with failing Fontan circulation.Eight sheep (42-48 kg) were studied. After pilot studies in 3 animals, 5 underwent both pump-supported and nonsupported total cavopulmonary connection in alternating sequence for up to 2 hours. This was achieved with a 12-mm polytetrafluoroethylene graft from the (distally ligated) superior vena cava to the main pulmonary artery and a cannula placed in the inferior vena cava with an attached 16-mm Dacron graft to the main pulmonary artery. Pressures (arterial, inferior vena cava, left atrium, and pulmonary artery) and flows (ascending aorta and inferior vena cava) were recorded over 1 hour both with unsupported total cavopulmonary connection and after placing an axial flow pump (Thoratec HeartMate II) between the inferior vena caval inflow cannula and the main pulmonary artery.Under nonsupported total cavopulmonary connection circulation, inferior vena caval and aortic blood flow decreased by nearly 50%. Inferior vena caval pressure nearly doubled, whereas arterial pressure decreased by one third. Pulmonary artery pressure became nonpulsatile; however, mean pulmonary artery pressure and left atrial pressure did not change significantly. With pump-supported Fontan circulation, cardiac output, inferior vena caval flow, and arterial pressure returned to baseline. Inferior vena caval pressure decreased to below baseline levels. Mean pulmonary artery pressure and left atrial pressure again remained unchanged.Axial flow pump support from the inferior vena cava to the pulmonary artery can prevent the substantial decrease of aortic flow and pressure associated with total cavopulmonary connection and can reverse its poor hemodynamics. This is a simple model that can be used to further evaluate the potential of mechanical support as a treatment option in failing Fontan circulation.

    View details for DOI 10.1016/j.jtcvs.2004.12.037

    View details for Web of Science ID 000231069700019

    View details for PubMedID 16077398

  • Chronic endothelin A receptor blockade in lambs with increased pulmonary blood flow and pressure AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Fratz, S., Meyrick, B., Ovadia, B., Johengen, M. J., Reinhartz, O., Azakie, A., Ross, G., Fitzgerald, R., Oishi, P., Hess, J., Black, S. M., Fineman, J. R. 2004; 287 (3): L592-L597

    Abstract

    Endothelin receptor blockade is an emerging therapy for pulmonary hypertension. However, hemodynamic and structural effects and potential changes in endogenous nitric oxide (NO)-cGMP and endothelin-1 signaling of chronic endothelin A receptor blockade in pulmonary hypertension secondary to congenital heart disease are unknown. Therefore, the objectives of this study were to determine hemodynamic and structural effects and potential changes in endogenous NO-cGMP and endothelin-1 signaling of chronic endothelin A receptor blockade in a lamb model of increased pulmonary blood flow following in utero placement of an aortopulmonary shunt. Immediately after spontaneous birth, shunt lambs were treated lifelong with either an endothelin A receptor antagonist (PD-156707) or placebo. At 4 wk of age, PD-156707-treated shunt lambs (n = 6) had lower pulmonary vascular resistance and right atrial pressure than placebo-treated shunt lambs (n = 8, P < 0.05). Smooth muscle thickness or arterial number per unit area was not different between the two groups. However, the number of alveolar profiles per unit area was increased in the PD-156707-treated shunt lambs (190.7 +/- 5.6 vs. 132.9 +/- 10.0, P < 0.05). Plasma endothelin-1 and cGMP levels and lung NOS activity, cGMP, eNOS, preproendothelin-1, endothelin-converting enzyme-1, endothelin A, and endothelin B receptor protein levels were similar in both groups. We conclude that chronic endothelin A receptor blockade attenuates the progression of pulmonary hypertension and augments alveolar growth in lambs with increased pulmonary blood flow.

    View details for DOI 10.1152/ajplung.00093.2004

    View details for Web of Science ID 000223251000021

    View details for PubMedID 15155268

  • Pulmonary expression of the hepatocyte growth factor receptor c-Met shifts from medial to intimal layer after cavopulmonary anastomosis JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Ikai, A., Riemer, R. K., Ma, X. Y., Reinhartz, O., Hanley, F. L., Reddy, V. M. 2004; 127 (5): 1442-1449

    Abstract

    Pulmonary arteriovenous malformations occur in up to 60% of patients after cavopulmonary anastomosis. We compared the effects of cavopulmonary anastomosis and pulmonary artery banding on lung gene expression in an ovine model to study the abnormal pulmonary vascular remodeling after the exclusion of inferior vena caval blood independent of reduced pulmonary blood flow. We previously demonstrated by contrast echocardiography that pulmonary arteriovenous malformations develop by 8 weeks after cavopulmonary anastomosis but not after pulmonary artery banding. Hepatocyte growth factor, a pleiotropic factor with morphogenic, mitogenic, and angiogenic activities, signals via its specific receptor c-Met to induce the antiapoptotic factor Bcl-2. In this study, we examined pulmonary artery expression of these factors and their potential role in pulmonary artery remodeling after cavopulmonary anastomosis and pulmonary artery banding.Eighteen lambs aged 35 to 45 days were placed into 3 groups: cavopulmonary anastomosis, pulmonary artery banding, and control (n = 6/group). In the cavopulmonary anastomosis group, the superior vena cava was anastomosed to the right pulmonary artery in an end-to-end fashion. In the pulmonary artery banding group, the left pulmonary artery was banded to reduce blood flow to 20% of control. The control group had a simple right pulmonary artery clamp for 30 minutes. Lung was harvested for Western blot, reverse transcriptase-polymerase chain reaction, and immunostaining at 2 weeks (n = 3/group) and 5 weeks (n = 3/group) after surgery.The expression of c-Met mRNA after cavopulmonary anastomosis was increased by twofold compared with the control or pulmonary artery banding group. The total lung expression of c-Met by Western blot was also up regulated at 2 weeks (P <.05). However, total lung expression of hepatocyte growth factor and Bcl-2 by Western and reverse transcriptase-polymerase chain reaction was not different from the control and pulmonary artery banding groups at both 2 and 5 weeks after surgery. Immunohistochemical analysis revealed that c-Met expression was localized to the intimal layer of the pulmonary artery in the cavopulmonary anastomosis, while its expression in the control and pulmonary artery banding lungs was localized to the medial layer. Localization of Bcl-2 on the intimal layer in lambs with cavopulmonary anastomosis followed the same pattern as c-Met.After cavopulmonary anastomosis, pulmonary artery expression of the hepatocyte growth factor receptor c-Met and one of its downstream effectors, Bcl-2, had increased in the intimal layer and decreased in the medial layer. Because the hepatocyte growth factor signaling promotes increased endothelial cell survival, it may have a role in pulmonary artery remodeling following cavopulmonary anastomosis. In addition, the change of c-Met expression in the medial layer after cavopulmonary anastomosis suggests a possible mechanism for the smooth muscle cell alteration related to abnormal angiogenesis.

    View details for DOI 10.1016/j.jtcvs.2003.09.009

    View details for Web of Science ID 000221134600031

    View details for PubMedID 15116006

  • Thoratec ventricular assist devices in children with less than 1.3 m(2) of body surface area ASAIO JOURNAL Reinhartz, O., Copeland, J. G., Farrar, D. J. 2003; 49 (6): 727-730

    Abstract

    This report summarizes the multicenter experience with the Thoratec paracorporeal pneumatic ventricular assist device (VAD) (Thoratec Corp., Pleasanton, CA) in small children. Between October 1988 and August 2001, 19 children (11 male, 8 female) with less than 1.3 (mean 1.09, range 0.73-1.29) m2 body surface area (BSA) have been supported with univentricular (9) or biventricular (10) Thoratec VADs in 12 centers in the United States and Germany. Mean patient age was 10 (range 7-14) years, mean weight 31 (range 17-41) kg. Indications for support were end-stage cardiomyopathy in eight patients, myocarditis in three, end-stage congenital heart disease in seven, and transplant graft failure in one patient. Mean duration of support was 43 (range 0-120) days. In patients with cardiomyopathies and myocarditis, survival through discharge occurred in 8 of 11 (72%) patients; however, only 1 of 7 patients with congenital disease survived. Outcome appeared independent of patient size. Neurologic complications were significant and predominant in the congenital disease group. Our experience suggests that the Thoratec VAD can be successfully used in these difficult patients, particularly in children with cardiomyopathies and myocarditis. Congenital disease is associated with increased risk. To reduce thromboembolic risk, we recommend left ventricular as opposed to left atrial inflow cannulation and higher device rates with partial stroke volumes.

    View details for DOI 10.1097/01.MAT.0000093965.33300.83

    View details for Web of Science ID 000186745400022

    View details for PubMedID 14655743

  • Emergence of smooth muscle cell endothelin B-Mediated vasoconstriction in lambs with experimental congenital heart disease and increased pulmonary blood flow CIRCULATION Black, S. M., Mata-Greenwood, E., Dettman, R. W., Ovadia, B., Fitzgerald, R. K., Reinhartz, O., Thelitz, S., Steinhorn, R. H., Gerrets, R., Hendricks-Munoz, K., Ross, G. A., Bekker, J. M., Johengen, M. J., Fineman, J. R. 2003; 108 (13): 1646-1654

    Abstract

    Endothelin-1 (ET-1) has been implicated in the pathophysiology of pulmonary hypertension. In 1-month-old lambs with increased pulmonary blood flow, we have demonstrated early alterations in the ET-1 cascade. The objective of this study was to investigate the role of potential later alterations of the ET cascade in the pathophysiology of pulmonary hypertension secondary to increased pulmonary blood flow.Eighteen fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 8 weeks after spontaneous delivery. Compared with age-matched control lambs, lung tissue ET-1 levels were increased in shunt lambs (317.2+/-113.8 versus 209.8+/-61.8 pg/g, P<0.05). In shunt lambs (n=9), exogenous ET-1 induced potent pulmonary vasoconstriction, which was blocked by the ETA receptor antagonist PD 156707 (n=3). This pulmonary vasoconstriction was mimicked by exogenous Ala1,3,11,15 ET-1 (4 Ala ET-1), the ETB receptor agonist, and was blocked by the ETB receptor antagonist BQ 788 (n=3). However, in control lambs (n=7), ET-1 and 4 Ala ET-1 did not change pulmonary vascular tone. In contrast to 4-week-old shunt lambs, immunohistochemistry revealed the emergence of ETB receptors on smooth muscle cells in the vasculature of 8-week-old shunt lambs.Over time, increased pulmonary blood flow and/or pressure results in the emergence of ETB-mediated vasoconstriction, which coincides with the emergence of ETB receptors on smooth muscle cells. These data suggest an important role for ETB receptors in the pathophysiology of pulmonary hypertension in this animal model of increased pulmonary blood flow.

    View details for DOI 10.1161/01.CIR.0000087596.01416.2F

    View details for Web of Science ID 000185624500033

    View details for PubMedID 12963646

  • Alterations in ET-1, not nitric oxide, in 1-week-old lambs with increased pulmonary blood flow AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Ovadia, B., Reinhartz, O., Fitzgerald, R., Bekker, J. M., Johengen, M. J., Azakie, A., Thelitz, S., Black, S. M., Fineman, J. R. 2003; 284 (2): H480-H490

    Abstract

    Altered pulmonary vascular reactivity is a source of morbidity and mortality for children with congenital heart disease and increased pulmonary blood flow. Nitric oxide (NO) and endothelin (ET)-1 are important mediators of pulmonary vascular reactivity. We hypothesize that early alterations in endothelial function contribute to the altered vascular reactivity associated with congenital heart disease. The objective of this study was to characterize endothelial function in our lamb model of increased pulmonary blood flow at 1 wk of life. Eleven fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt) and were studied 7 days after delivery. The pulmonary vasodilator response to both intravenous ACh (endothelium dependent) and inhaled NO (endothelium independent) was similar in shunted and control lambs. In addition, tissue NO(x), NO synthase (NOS) activity, and endothelial NOS protein levels were similar. Conversely, the vasodilator response to both ET-1 and 4Ala-ET-1 (an ET(B) receptor agonist) were attenuated in shunted lambs, and tissue ET-1 concentrations were increased (P < 0.05). Associated with these changes were an increase in ET-converting enzyme-1 protein and a decrease in ET(B) receptor protein levels (P < 0.05). These data demonstrate that increased pulmonary blood flow induces alterations in ET-1 signaling before NO signaling and suggest an early role for ET-1 in the altered vascular reactivity associated with increased pulmonary blood flow.

    View details for DOI 10.1152/ajpheart.00493.2002

    View details for Web of Science ID 000180400800008

    View details for PubMedID 12399254

  • Pulmonary vascular K+ channel expression and vasoreactivity in a model of congenital heart disease AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY Cornfield, D. N., Resnik, E. R., Herron, J. M., Reinhartz, O., Fineman, J. R. 2002; 283 (6): L1210-L1219

    Abstract

    K+ channels play an important role in mediating pulmonary vasodilation caused by increased oxygen tension, nitric oxide, alkalosis, and shear stress. To test the hypothesis that lung K+ channel gene expression may be altered by chronic increases in pulmonary blood flow, we measured gene and protein expression of calcium-sensitive (K Ca ) and voltage-gated (Kv2.1) K+ channels, and a pH-sensitive K+ channel (TASK), in distal lung from fetal lambs in which an aortopulmonary shunt was placed at 139 days gestation. Under baseline conditions, animals with an aortopulmonary shunt showed elevated pulmonary artery pressure and pulmonary blood flow compared with twin controls. Hypoxia caused a greater increase in pulmonary vascular tone in shunt animals compared with controls. Alkalosis caused pulmonary vasodilation in control but not shunt animals. To determine lung K+ channel mRNA levels, we performed quantitative RT-PCR. In comparison with control animals, lung K Ca channel mRNA content was increased in shunt animals, whereas TASK mRNA levels were decreased. There was no difference in Kv2.1 mRNA levels. Channel protein expression was consistent with these findings. We conclude that, in the presence of elevated pulmonary blood flow, K Ca channel expression is increased and TASK is decreased.

    View details for DOI 10.1152/ajplung.00428.2001

    View details for Web of Science ID 000179082700008

    View details for PubMedID 12388350

  • Current clinical status of pulsatile pediatric circulatory support ASAIO JOURNAL Reinhartz, O., Stiller, B., Eilers, R., Farrar, D. J. 2002; 48 (5): 455-459

    Abstract

    Whereas circulatory support with pulsatile assist devices is an established therapy in adults today, it remains unusual and extremely challenging in children. Specifically designed smaller size pumps are, to date, only available in Europe. This review summarizes the experience with both adult size pumps in the U.S. and pediatric pumps in Europe. Thoratec ventricular assist devices (VADs) were implanted in 101 patients worldwide who were between 7 and 17 years of age. Survival in this group was 68.8%, which is comparable with that in adult patients and was independent of age or body size. Berlin Heart VADs, available in several sizes, were implanted at the Deutsches Herzzentrum Berlin in 45 patients between 2 days and 16 years old. Survival in patients with myocarditis and cardiomyopathy was 66.7% and 71.4%, respectively; overall survival was 48.9%. In a number of European centers, 64 children up to 16 years of age received Medos devices, which are also available in several sizes, with an overall survival of 36.2%, similar for all pump sizes. End-stage congenital heart defects or failure to wean off bypass carried a poorer prognosis than cardiomyopathies or myocarditis for all devices.

    View details for DOI 10.1097/01.MAT.0000026978.02458.4F

    View details for Web of Science ID 000178040500002

    View details for PubMedID 12296561

  • Alterations in nitric oxide production in 8-week-old lambs with increased pulmonary blood flow PEDIATRIC RESEARCH Black, S. M., Bekker, J. M., McMullan, D. M., Parry, A. J., Ovadia, B., Reinhartz, O., Lakshminrushimha, S., Mata-Greenwood, E., Steinhorn, R. H., Fineman, J. R. 2002; 52 (2)

    Abstract

    Nitric oxide (NO) is an important mediator of pulmonary vascular reactivity, and decreased NO synthase expression has been demonstrated in children with advanced pulmonary hypertension secondary to congenital heart disease and increased pulmonary blood flow. Using aortopulmonary vascular graft placement in the fetal lamb, we have established a unique animal model of pulmonary hypertension with increased pulmonary blood flow. At 4 wk of age, these lambs display an early, selective impairment in agonist-induced NO responses, but an up-regulation of basal NO activity and gene expression. We hypothesized that further exposure to increased flow and/or pressure results in progressive endothelial dysfunction and a subsequent decrease in basal NO production. The objective of this study was to characterize potential later alterations in agonist-induced NO responses and basal NO activity and gene expression induced by 8 wk of increased pulmonary blood flow and pulmonary hypertension. Twenty-two fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt), and were studied 8 wk after delivery. Both in vivo and in isolated pulmonary arteries, the pulmonary vasodilating response to endothelium-dependent agents was attenuated in shunted lambs (p < 0.05), whereas the response to endothelium-independent agents was unchanged. The pulmonary vasoconstricting responses to Nomega-nitro-L-arginine, and lung tissue endothelial NO synthase mRNA, endothelial NO synthase protein, NO synthase activity, and NO(X) levels were all unchanged. These data suggest that the increase in basal NO activity demonstrated after 4 wk of increased pulmonary blood flow is lost by 8 wk of age, whereas the attenuation of agonist-induced responses persists. We speculate that the progressive decrease in basal NO activity participates in the development of pulmonary hypertension secondary to increased pulmonary blood flow.

    View details for DOI 10.1023/01.PDR.0000023495.70201.55

    View details for Web of Science ID 000177067600014

    View details for PubMedID 12149501

  • Management of neonatal bronchovenous fistula after cardiopulmonary bypass ANNALS OF THORACIC SURGERY Reinhartz, O., DeSilva, A. M., Hanley, F. L. 2002; 73 (4): 1320-1322

    Abstract

    Bronchovenous fistula is occasionally encountered after traumatic lung injury or, in neonates, due to ventilation injuries with high ventilatory pressures. We report a case of massive air embolism associated with a bronchopulmonary venous communication in an infant post-repair of truncus arteriosus. Selective ventilation of the opposite lung for 3 days sealed the fistula.

    View details for Web of Science ID 000174807400080

    View details for PubMedID 11996288

  • Multicenter experience with the Thoratec ventricular assist device in children and adolescents JOURNAL OF HEART AND LUNG TRANSPLANTATION Reinhartz, O., Keith, F. M., El-Banayosy, A., McBride, L. R., Robbins, R. C., Copeland, J. G., Farrar, D. J. 2001; 20 (4): 439-448

    Abstract

    Patient size is 1 determinant in selecting a mechanical circulatory support device. The current pulsatile ventricular assist devices (VADs) were designed primarily for average-sized adults. The flexibility of the Thoratec VAD, however, has encouraged physicians to use it in a significant number of intermediate-sized older children and adolescents.We conducted a retrospective study in 58 children and adolescents <18 years (41 boys, 17 girls) who had been supported with the Thoratec VAD in 27 centers worldwide as of December 1999. Mean patient age was 13.8 years (range, 7 to 17 years), and mean patient weight and body surface area were 51.6 kg (range, 17 to 93 kg) and 1.5 m(2) (range, 0.7 to 2.1 m(2)), respectively.Thirty-five patients (60%) survived to transplantation and 6 (10%) to recovery of the native heart, respectively; 38 were discharged from the hospital (66%). In the transplanted group, post-transplantation survival was 97%. Patient age and size were not associated with significantly increased risk for death or adverse events. Fifteen patients (27%) had 18 neurologic events during support, and 6 of these were fatal. Left atrial cannulation proved a risk factor for neurologic complications.The Thoratec VAD has successfully been used in a large number of children and adolescents with similar morbidity and mortality results as with adults. The risk of neurologic complications may be increased, particularly in patients cannulated in the left atria.

    View details for Web of Science ID 000168040900008

    View details for PubMedID 11295582

  • Importance of preoperative liver function as a predictor of survival in patients supported with thoratec ventricular assist devices as a bridge to transplantation JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY Reinhartz, O., Farrar, D. J., Hershon, J. H., Avery, G. J., Haeusslein, E. A., Hill, J. D. 1998; 116 (4): 633-640

    Abstract

    Patient selection is crucial for the success of ventricular assist devices as a bridge to heart transplantation.The objective of this study was to identify preoperative markers for survival and end-organ recovery in patients having a ventricular assist device.A retrospective study was performed on 32 severely ill patients with end-stage cardiac failure being mechanically bridged to heart transplantation with the Thoratec Ventricular Assist Device System (Thoratec Laboratories Corporation, Pleasanton, Calif) in a single center between 1984 and 1995. The preoperative cardiac index averaged 1.6 L/min per square meter with a pulmonary capillary wedge pressure of 29 mm Hg. Because of a high incidence of hepatic or renal dysfunction, or both (total bilirubin: 3.5 +/- 6.2 mg/dL; creatinine: 2.0 +/- 1.3 mg/dL), biventricular support was used in most patients (28/32). A total of 30 preoperative and 4 perioperative variables were evaluated for their association with survival and liver recovery.Nineteen patients (59.4%) survived to transplantation and 13 died. All 19 patients undergoing transplantation were discharged alive with a 1-year survival of 94.4%. All patients without liver recovery died of multiorgan failure. Direct and indirect bilirubin measurements were the only significant predictors for survival to discharge (P = .036, .045); all other factors failed to show significance. As direct bilirubin levels increased (normal range, 3 times normal, and >3 times normal), patient survival decreased (82 %, 56%, and 33 %, respectively). In addition, bilirubin and liver enzyme levels before insertion of the assist device were significantly associated with liver recovery during support with the device.In our patient population with ventricular assist devices, liver function is the most predictive factor of patient survival in bridging to transplantation.

    View details for Web of Science ID 000076224600014

    View details for PubMedID 9766593

  • Timing of surgery in patients with acute infective endocarditis JOURNAL OF CARDIOVASCULAR SURGERY Reinhartz, O., Herrmann, M., Redling, F., Zerkowski, H. R. 1996; 37 (4): 397-400

    Abstract

    Surgical intervention in patients with active infective endocarditis is generally considered as indicated in few high-risk patients who have developed severe complications such as heart failure, persistent septicemia or recurrent arterial embolism, but the question of when to intervene is still subject to discussion.Retrospective study.Cardio-Thoracic Surgery Unit, University clinic. PATIENTS, INTERVENTIONS AND RESULTS: From 1984 to 1994, 130 patients (87 male, mean age 43.2 +/- 12.7 years) underwent heart valve replacement or reconstruction for infective endocarditis of native or prosthetic valves. 89 of them had acute infection requiring urgent surgical treatment. Over-all operative mortality was 12.3%. Certain preoperative factors were investigated regarding their influence on postoperative death. Statistical analysis revealed functional class according to NYHA as well as extravalvular involvement of the infection as significant risk factors or mortality. Emergency operation was not significantly associated with increased operative mortality, neither were the causative organism, a history of arterial embolism or persistent septicemia.In active infective endocarditis the optimal time to perform surgery is before the onset of severe end-stage heart failure or spread of the infection to extravalvular tissue. If one of these complications is imminent, urgent intervention is indicated.

    View details for Web of Science ID A1996UZ09600013

    View details for PubMedID 8698786

  • BACTERIAL AND FUNGAL COLONIZATION AND INFECTIONS USING ORAL SELECTIVE BOWEL DECONTAMINATION IN ORTHOTOPIC LIVER TRANSPLANTATIONS TRANSPLANT INTERNATIONAL Steffen, R., Reinhartz, O., BLUMHARDT, G., Bechstein, W. O., Raakow, R., Langrehr, J. M., Rossaint, R., Slama, K., Neuhaus, P. 1994; 7 (2): 101-108

    Abstract

    Bacterial and fungal infections are a major cause of morbidity and mortality after orthotopic liver transplantation. In the immunocompromised host, infections are thought to arise from the gut, which is almost always colonized with potential pathogens. Using oral selective bowel decontamination (SBD), potential pathogens can be eradicated from the gut and infections prevented. In this catamnestic study we have reviewed gastrointestinal colonization, bacterial and fungal infections, and bacterial resistance to standard antibiotics in our first 206 liver transplant patients while under SBD. With few exceptions, gram-negatives were eradicated from the gastrointestinal tract and secondary colonization was inhibited. In spite of unsatisfactory elimination of Candida, probably because nystatin doses were too low, Candida infections were rare (n = 4) and none was fatal. One and two-year survival rates were 93% and 92%, respectively. The bacterial and fungal infection rate was 27.8% with an infection-related mortality of 1.95%. Infections with aerobic gram-positive bacteria prevailed and only 11 gram-negative and 11 fungal infections occurred; among the latter, Aspergillus and Mucor were the most serious and responsible for three of the six deaths in this series. With regard to the development of resistance, we found an increasing number of enterococci and coagulase-negative staphylococci resistant to ciprofloxacin and imipenem, respectively, but unlikely as a consequence of SBD.

    View details for Web of Science ID A1994MW94900006

    View details for PubMedID 8179797

Conference Proceedings


  • Selective Right Ventricular Unloading and Novel Technical Concepts in Ebstein's Anomaly Malhotra, S. P., Petrossian, E., Reddy, V. M., Qiu, M., Maeda, K., Suleman, S., Macdonald, M., Reinhartz, O., Hanley, F. L. ELSEVIER SCIENCE INC. 2009: 1975-1981

    Abstract

    Favorable outcomes in Ebstein's anomaly are predicated on tricuspid valve competence and right ventricular function. Successful valve repair should be aggressively pursued to avoid the morbidity of prosthetic tricuspid valve replacement. We report our experience with valve-sparing intracardiac repair, emphasizing novel concepts and techniques of valve repair supplemented by selective bidirectional Glenn (BDG).Between June 1993 and December 2008, 57 nonneonatal patients underwent Ebstein's anomaly repairs. The median age at operation was 8.1 years. All were symptomatic in New York Heart Association (NYHA) functional class II (n = 38), III (n = 17), or IV (n = 1). Preoperatively, 26 had mild or moderate cyanosis at rest. We used a number of valve reconstructive techniques that differed substantially from those currently described. BDG was performed in 31 patients (55%) who met specific criteria.No early or late deaths occurred. At the initial repair, 3 patients received a prosthetic valve. Four patients required reoperation for severe tricuspid regurgitation. Repeat repairs were successful in 2 patients. At follow-up (range, 3 months to 6 years), all patients were acyanotic and in NYHA class I. Tricuspid regurgitation was mild or less in 49 (86%) and moderate in 6 (11%). Freedom from a prosthesis was 91% (52 of 57).Following a protocol using BDG for ventricular unloading in selected patients with Ebstein's anomaly can achieve a durable valve-sparing repair using the techniques described. Excellent functional midterm outcomes can be obtained with a selective one and a half ventricle approach to Ebstein's anomaly.

    View details for DOI 10.1016/j.athoracsur.2009.07.019

    View details for Web of Science ID 000272029100037

    View details for PubMedID 19932271

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