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Primary pericardial mesothelioma is a rare malignancy of the mesothelial lining of the pericardium. This study aimed to evaluate the clinical characteristics and survival outcomes of these patients using a United States population-based cancer database. We queried the Surveillance, Epidemiology, and End Results program (1973-2015). Primary pericardial mesothelioma patients with complete follow-up data were included, and primary pleural mesothelioma patients were identified as controls. Propensity-score matching was used to balance individual characteristics. Kaplan-Meier analysis and log-rank tests were performed to compare overall survival. Forty-one primary pericardial mesothelioma and 15,970 primary pleural mesothelioma patients were identified. Before matching, when compared to the pleural mesothelioma counterparts, primary pericardial mesothelioma patients were younger (median 57 vs 73 years, P0.001), more likely to be female (46.3% vs 20.2%, P0.001), more likely to be nonwhite (24.4% vs 8.4%, P = 0.001), and less likely to have been diagnosed in the most recent study decade (2006-2015, 34.1% vs 43.5%, P = 0.002). The overall 1- and 2-year survival rates were 22.0% and 12.2%, with a median survival of 2 months (IQR: 1-6). After 1:2 nearest neighbor propensity-score matching, 38 pericardial mesothelioma and 76 matched pleural mesothelioma cases were identified. The 2 matched groups had comparable baseline characteristics, including age, sex, race, year of diagnosis, histological type, and cancer history. Compared to their pleural mesothelioma counterparts, primary pericardial mesothelioma patients were less likely to receive chemotherapy (23.7% vs 50.0%, P = 0.01) and had worse overall survival (median survival: 2 vs 10 months, log-rank P = 0.006). Primary pericardial mesothelioma has worse survival outcomes than pleural mesothelioma, with a median survival of only 2 months. These patients should seek care from experienced multidisciplinary teams at tertiary care centers that handle high volumes of mesothelioma patients.

Traumatic thoracic or chest wall hernias are relatively uncommon but highly challenging injuries that can be seen after a variety of injury mechanisms. Despite their description throughout history there remains scant literature on this topic that is primarily limited to case reports or series. Until recently, there also has been no effort to create a reliable grading system that can assess severity, predict outcomes, and guide the choice of surgical repair. The purpose of this article is to review the reported literature on this topic and to analyze the history, common injury mechanisms, likely presentations, and optimal management strategies to guide clinicians who are faced with these challenging cases. We also report a modified and updated version of our previously developed grading system for traumatic chest wall hernias that can be utilized to guide surgical management techniques and approaches.

Pulmonary valve infective endocarditis (PVIE) represents a rare subset of right-sided IE. This study aimed to evaluate the population-level surgical outcomes of PVIE in the United States.We performed a retrospective observational study using the 2002-2017 National Inpatient Sample database. We included hospitalizations with both IE and PV interventions. We excluded Tetralogy of Fallot, congenital PV malformation, and those who underwent the Ross procedure. The primary outcome was in-hospital mortality. The secondary outcomes included major complications and length of hospital stay.We identified 677 PVIE hospitalizations that underwent surgical treatment, accounting for 0.06% of all IE hospitalizations. The mean age was 35.2 ± 1.7 years; 60.0% were White, 30.3% were women, and 11.4% were intravenous drug users. Most were treated in large-sized (70.1%) urban teaching (88.8%) hospitals. Close to 30% of patients received at least one concomitant valve procedure. The in-hospital mortality was 5.5% for the entire cohort, and the median length of stay was 16 days. Major complications included complete heart block (8.7%), acute kidney injury (8.1%), and stroke (1.3%). The differences in mortality and complications rate comparing PV repair and replacement were not statistically significant. PV repair was associated with a longer length of hospital stay compared to PV replacement (median: 25 vs. 16 days, p = 0.03).This study defines the population-level in-hospital outcomes after surgical intervention of PVIE. Surgically treated PVIE patients are associated with relatively low mortality and morbidities. The outcomes between PV replacement and repair are similar.

Granulomatosis with polyangiitis (GPA, also known as Wegener's granulomatosis) is a type of systematic vasculitis that primarily involves the lung and kidney. Diffuse alveolar hemorrhage (DAH) and associated acute respiratory failure are uncommon but devastating complications of GPA. Experience in using extracorporeal membrane oxygenation (ECMO) to manage DAH caused by GPA is limited. We report two GPA patients with DAH that were successfully managed using ECMO support. Examining 13 cases identified in the literature and two of our own, we observed that most patients experienced rapid deterioration in respiratory function in conjunction with a precedent respiratory infection. All 15 patients received veno-venous ECMO support. The median duration of ECMO support was 11 days (interquartile range: 7.5-20.75 days). Bleeding was the most common complication, seen in four (26.7%) cases. All patients were successfully weaned off ECMO after a median length of hospital stay of 42 days (interquartile range: 30-78 days). We demonstrated that the use of ECMO is a reasonable and effective support option in the management of GPA patients with DAH. The risk of bleeding is high but maybe reduced using a lower anticoagulation goal.

Background: Aortic dissection (AD) during pregnancy and puerperium is a rare yet potentially fatal catastrophe for both parent and fetus, yet population-level trends in incidence and outcomes are undetermined. Objectives: To investigate the incidence and in-hospital outcomes of AD during pregnancy and puerperium in a US national database. Methods: The National Inpatient Sample, a large and publicly available all-payer inpatient care database, was queried to identify pregnancy-related AD hospitalizations using codes from the International Classification of Diseases (ICD-9 and ICD-10). Identified hospitalizations were stratified into Stanford type A AD (TAAD) and type B AD (TBAD) using the associated procedure codes. The weighted values of the hospitalizations were used to generate national estimates. Results: From January 2002 to December 2017, a total of 471 pregnancy-related AD hospitalizations were identified, with 106 (22.5%) being TAAD and 365 (77.5%) being TBAD. The mean age of the entire cohort was 30.9 ± 0.6 years; 52.1% were White, 20.6% were Hispanic, and 9.4% were Black. Marfan syndrome, primary hypertension, and pre-eclampsia/eclampsia were found in 21.9%, 11.3%, and 13.2%. Although trimester information was only available in hospitalizations with ICD-10 codes (18.0% of the entire cohort), we found that 58.8% of AD occurred in the third trimester. Overall, the incidences of AD, TAAD, and TBAD were 0.66, 0.15, and 0.51 per 100,000 pregnancy-related hospitalizations. We observed a trend of increasing incidence for pregnancy-related AD (Fig 1) during the 16-year study period - predominantly driven by TBAD. The in-hospital mortalities of AD, TAAD, and TBAD were 7.3%, 4.3%, and 8.1%. Conclusions: For the first time, we quantified the population-level incidence and in-hospital outcomes of AD during pregnancy and puerperium in the US; while its incidence is increasing, its in-hospital mortality appears better than that of the general population.

Epidemiologic variation with respect to sex has been established in aortic dissection. However, current literature on sex-based outcomes in patients with aortic dissection is conflicting. In this study we aimed to compare perioperative outcomes according to sex in patients treated surgically for acute type A aortic dissection.PubMed/MEDLINE, Embase, and Web of Science were searched for studies that reported sex-based differences in postoperative outcomes among patients with acute type A aortic dissection. The primary outcome was in-hospital/30-day mortality, and secondary outcomes included postoperative stroke, renal failure requiring dialysis, and reoperation for bleeding. Data were aggregated using the random effects model as pooled risk ratio (RR). Meta-regression was applied to identify sources of heterogeneity between studies.Nine of 1022 studies were included for final analysis comprising 3338 female and 5979 male participants. Compared with male sex, female sex was associated with similar in-hospital/30-day mortality (RR, 1.04; 95% CI, 0.85-1.28; P = .67), postoperative stroke risk (RR, 1.07; 95% CI, 0.91-1.25; P = .43), and postoperative risk of acute renal failure requiring dialysis (RR, 0.84; 95% CI, 0.59-1.19; P = .32). A decreased risk of reoperation for bleeding (RR, 0.84; 95% CI, 0.75-0.94; P .01) was observed in female participants. Meta-regression analysis indicated that differences in preoperative shock were a source of heterogeneity in the sex difference in in-hospital/30-day mortality across studies.Among patients treated surgically for acute type A aortic dissection, female sex was not associated with increased risk of short-term mortality nor with major postoperative complications. Male sex was associated with a greater risk of postoperative bleeding.

OBJECTIVES:. Extracorporeal membrane oxygenator support is a powerful clinical tool that is currently enjoying a resurgence in popularity. Wider use of extracorporeal membrane oxygenator support is limited by its significant risk profile and extreme consumption of resources. This study examines the role of markers of liver dysfunction in predicting outcomes of adult patients requiring extracorporeal membrane oxygenator support. DESIGN:. Retrospective review. SETTING:. Large extracorporeal membrane oxygenator center, Chicago, IL. PATIENTS:. This study reports a single institution experience examining all adult patients for whom extracorporeal membrane oxygenator support was used over an 8-year period. Data were collected regarding patient demographics, details of extracorporeal membrane oxygenator support provided, laboratory data, and outcomes. Trends in liver function were examined for their ability to predict survival. INTERVENTION:. Extracorporeal membrane oxygenator support, critical care. MEASUREMENTS AND MAIN RESULTS:. Mean age was 50 years (range, 19–82 yr). There were 86 male patients (56.6%) and 66 female patients (43.4%). Indications for initiation of extracorporeal membrane oxygenator support included cardiac 76 patients (50.0%), respiratory 48 patients (31.6%), extracorporeal cardiopulmonary resuscitation 21 patients (13.3%), and combined cardiac/respiratory seven patients (4.6%). Mean duration of extracorporeal membrane oxygenator support was 17 days (range 1–223 d) or median 8 days (interquartile range, 4–17 d). Overall, in-hospital mortality was 56% (86/152). Forty-five percent of adult patients (68/152) surpassed at least one of the following established liver dysfunction thresholds: total bilirubin greater than 15 mg/dL, aspartate aminotransferase greater than 20× upper limit of normal, and alanine aminotransferase greater than 20× upper limit of normal. The multivariable logistic analysis yielded three significant findings associated with in-hospital mortality: highest total bilirubin greater than 15 (adjusted odds ratio = 4.40; 95% CI, 1.19–21.87; p = 0.04), age (adjusted odds ratio = 1.03; 95% CI, 1.00–1.05; p = 0.04), and highest lactate (adjusted odds ratio = 1.15; 95% CI, 1.06–1.26; p = 0.002). CONCLUSIONS:. Increases in age, highest total bilirubin, and lactate all correlated with in-hospital mortality in multivariable analysis of patients requiring extracorporeal membrane oxygenator support.

This study aimed to understand the population-level treatment modalities and to evaluate the survival benefits of surgical resection in primary cardiac lymphoma.We queried the Surveillance, Epidemiology, and End Results Program database, which covers 35% of the US population. Patients with a histologic diagnosis of primary cardiac lymphoma from 1973 to 2015 were included. Multivariable accelerated failure time regression was performed to evaluate the associations between clinical factors and overall survival.A total of 184 patients were identified. The median age was 68 years, 80% were White, and 46% were women. Diffuse large B-cell lymphoma (80%) was the most common histology, and the majority (65%) was low-stage lymphoma (Ann Arbor stage I or II). Median survival was 2.2 years. Seventy-three percent of patients received chemotherapy. Only 10% of patients received local resection or debulking. Multivariable analysis demonstrated that local resection or debulking was not independently associated with overall survival (adjusted hazard ratio, 0.67; 95% confidence interval, 0.30-1.48; P = .32). Instead, chemotherapy (adjusted hazard ratio, 0.4; 95% confidence interval, 0.23-0.69; P .001) was independently associated with improved survival, whereas increasing age (adjusted hazard ratio of 5-year increment, 1.13; 95% confidence interval, 1.04-1.22; P.001) and advanced stage (adjusted hazard ratio, 2.18; 95% confidence interval, 1.33-3.56; P .001) were independently associated with worse survival.Surgical resection was not independently associated with survival in patients with primary cardiac lymphoma. Chemotherapy was the predominant treatment option and associated with improved survival, whereas increasing age and advanced stage were independently associated with worse outcomes.

We report a rare case of prosthetic valve fungal endocarditis caused by Lichtheimia, a subspecies of the order Mucorales. The patient experienced complicated prosthetic valve endocarditis less than 2 months after uneventful coronary artery bypass grafting (CABG) and 2 aortic valve replacements. Ultimately surgical management required aortic root replacement and lifelong antimicrobial agents. We believe this is the first case of fungal endocarditis caused by Lichtheimia.

Objective: The lung allocation score (LAS) has changed the distribution of donor lungs for transplantation. This study was undertaken to evaluatethe impact of the LASon a uniquepatientpopulation undergoing lung transplantation(LTX) at the single nationalVeterans Affairs(VA) LT center. Methods: One hundred and ten consecutive VA patients underwent LTX between 1994 and 2007. Patients transplanted using the LAS (LAS, n = 26) were compared to patients transplanted prior to introduction of the LAS (pre-LAS, n = 84). Results: Waiting time decreased from 353.8 254.7 (pre-LAS) to 238.0 306.6 (LAS) days (p < 0.01). Recipient diagnoses have changed with an increase in idiopathic pulmonary fibrosis [11% (9/84) pre-LAS vs 46% (12/26) LAS, p < 0.01] and a decrease in emphysema [57% (48/84) pre-LAS vs 35% (9/26) LAS, p < 0.01]. Mean LAS calculation was 33.1 2.9 for pre-LAS versus 41.9 9.8 for the LAS (p < 0.01). Postoperative complications did not differ between the groups. Length of hospital stay decreased from 44.3 42.9 (pre-LAS) to 18.1 12.3 (LAS) days (p < 0.01). Hospital mortality and 1-year survival did not differ between the pre-LAS and LAS groups (7% vs 8%; p = 0.72 and 92% [95% confidence interval (CI) 86—98] vs 92% [CI 82—100]; p = 0.23, respectively). Conclusions: The LAS appears to be achieving its objectives by reducing waitlist time and altering the distribution of lung disease being transplanted on the basis of medical necessity in the U.S. VA population. In addition, the LAS does not appear to have adversely affected short-term post-transplant outcomes in our recipient cohort. # 2009 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Objective: Percutaneous valve replacement was recently introduced, and reports of early clinical experience have already been published. To date, this technique is limitedto the replacement of pulmonaryand aortic valves in a strictly selectedgroup of patients. The aim of this study was to analyse a self-expanding valved stent for minimally invasive replacement of the mitral valve in animals. Methods: A newly designed nitinol stent was specially designed for this experimental acute study. It comprised of a left ventricular tubular stent with star shaped left atrial anchoring springs and carried a trileaflet bovine pericardial valve. A polytetrafluoroethylene membrane was sutured to envelop the atrial springs and the outside of the ventricular stent. The ventricular anchoring system was the same as in our previously reported results with a similar mitral valved stent. Seven pigs underwent minimally invasive off-pump mitral valved stent implantation. This was performed through a lower ministernotomyandastandardtransapicalapproachundertransoesophagealechocardiographic(TEE)guidancewasused.Results:Thevalvedstentis fully retrievable and precise deployment and accurate adjustment of its intra-annular position is achievable to eliminate paravalvular leakage. The deployment time ranged from 127 to 255 s and the blood loss from 70 to 220 cc. One animal died of intractable ventricular fibrillation. Mitral regurgitation in all surviving animals was minimal (trace in 5/6 and mild in 1/6 during echo examination; on the contrast ventriculogram no mitral insufficiency was observed except in one documented as mild paravalvular regurgitation). These animals remained haemodynamically stable (6/ 6) and without TEE or ventriculographic changes for 1 h. Conclusion: Implantation of a tricuspid bovine pericardial valved stent in the mitral position is feasible in pigs through a transcatheter approach. This was possible through a smaller delivery system than previously reported. Additional studies are required to demonstrate long-term feasibility, durability, and heart function. # 2009 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Objective: This study was undertaken to evaluate outcomes of redo lung transplantation (LT) for acute and chronic graft failure. Methods: Between 1988 and 2007, 388 LT procedures were performed on 369 patients. From those, 17 (4.6%) patients had redo LTonce and 2 patients had redo LT twice. Patient survival and recurrence of bronchiolitis obliterans syndrome (BOS) after redo LT were reviewed. Results: The overall survival rates of the 17 redo LTrecipients at 1, 2 and 5 years were 59 23%, 59 23% and 42 25%, respectively. For the chronic graft failure group (n = 12), survival rates at 1, 2 and 5 years were 67 26%, 67 26% and 44 30%, respectively. These survival rates were significantly lower than the survival rates observed in our experience after primary LT (n = 352, 1-, 2- and 5-year survival rates of 88 4%, 80 4% and 65 5%, respectively. For the acute graft failure group (n = 5), the 1-year survival rate was 40%; two patients remain free from BOS. Two patients had a second redo LT, one died from multi-organ failure on postoperative day 86 and the other died from pulmonary aspergillosis on postoperative day 214. Conclusions: Redo LT is a valid therapeutic option for selected patients with BOS and might be an option for highly selected patients with acute lung graft failure. Outcomes from a second redo LTare poor, and a second lung retransplantation must be used very cautiously, if at all. Published by Elsevier B.V. on behalf of European Association for Cardio-Thoracic Surgery.

Background Transcatheter aortic and pulmonary valve replacement is currently being tested in human trials. Efforts to create a valved stent to replace the atrioventricular valves have shown limited success. This is due to their their complex anatomy and function. Methods A self-expanding valved stent was created for transapical replacement of the atrioventricular valve. Ten pigs underwent transapical off-pump mitral valved stent implantation. Data were gathered to assess the animals' hemodynamic stability for 60 minutes after implantation. The valved stent function was assessed by transesophageal echocardiography (TEE) and contrast left ventriculogram. Results All animals exhibited normal hemodynamics immediately after mitral valved stent implantation and maintained stability for the entire period of monitoring. Accurate positioning of the valved stent was established in all animals. Mild paravalvular regurgitation was found in three out of ten animals by TEE and in two animals during left ventriculogram. No left ventricular outflow tract obstruction was encountered. Conclusions Transapical off-pump mitral valved stent implantation is feasible in an acute experimental setting. Long-term function of the new valved stent remains to be established.

Objective: Ventricularassistdevices(VADs)have beenimplantedsince 1990inour institution,becomingan increasinglycommontreatmentfor end-stage heart failure. Beginning in 1997, VAD patients were discharged home when feasible. In August 2003, a dedicated multidisciplinary VAD team (cardiac surgeons, cardiologists, VAD coordinators, nurses, rehabilitation specialists, nutrition experts, psychologists, pharmacists, social workers,andadministrators)wascreatedto optimizethemanagement ofVADpatients.Thepurposeofthisstudyis toanalyzethe impactofthese changes in care at our center over the last 17 years. Methods: We retrospectively studied 107 consecutive VAD recipients between June 1990 and August 2006. VADs were implanted as bridge to recovery, bridge to transplant and destination therapy. The cohort was divided by care plans into early (n = 37, June 1990—1996), mid (n = 32, 1997—July 2003), and late groups (n = 38, August 2003—August 2006). Demographic profile, survival and complications were assessed. Results: Patient demographics tended to show an increased severity of illness over time. Post-VAD survival rate significantly improved in the late group (post-VAD 1- and 3-year survival rates; early: 54.1% and 40.5%; mid: 51.6% and 41.9%; late: 86.8% and 82.5%, p < 0.001, respectively). The incidence of complications including re-operation, major bleeding and major infection, significantly decreased in the late group (p < 0.05). Conclusions: Outcomes have improved dramatically in recent VAD patients, despite an increasingly highrisk patient population. These data suggest that advances in device technology and medical therapies, as well as a multidisciplinary approach, have improved survival on VAD therapy. # 2008 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Background The shortage of available donors limits cardiac transplantation. Use of hearts from patients with hepatitis-B core antibodies could expand the donor pool but are usually avoided because of concern about virus transmission. We conducted a retrospective review to determine the safety of transplanting hearts from donors with hepatitis-B core antibodies. Methods We reviewed donor and recipient charts for patients who underwent transplantation at our center between January 1, 1997, and December 1, 2002. Results A total of 541 heart transplantations were performed in this time period. Thirty-three patients (aged 47.5 ± 18.8 years) received hearts from core-antibody-positive donors (aged 37.7 ± 10.8 years). Of these, 5 patients received prophylactic antibiotic treatment with lamivudine after transplantation. Only 1 patient (baseline surface-antigen-negative and without prophylaxis) experienced donor-transmitted hepatitis B infection 10 months after transplantation that was treated with lamivudine. Two patients (baseline surface-antibody-negative) had hepatitis B seroconversion, becoming surface-antibody positive without evidence of infection. None of the 5 patients who received prophylaxis with lamivudine had donor-transmitted hepatitis, and only 1 lamivudine-treated patient had surface antibodies. Post-transplant survival in this small cohort was similar to that for all patients who underwent transplantation at our center during this time period. Conclusions Transplantation of hearts from donors with hepatitis-B core antibodies is associated with a small viral-transmission risk, with or without post-transplant, anti-viral prophylaxis. Use of these donor hearts should be considered safe and may help to augment the available donor pool.

Objectives This study investigates the outcomes of cardiac transplantation using older donors. Background Despite high mortality rates on waiting lists, transplanting hearts from older donors remains a relative contraindication. Methods We retrospectively reviewed data on 479 adult heart transplant recipients, 352 status I patients, and 534 status II patients enrolled on a waiting list between 1992 and 1999. The Cox proportional hazards model was used for statistical analysis. Results Of all donors, 20% were 40 to 50 years old and 8% were ≥50 years old. The risk of six-month mortality on the waiting list for patients who were not transplanted (status I: relative risk [RR] 8.5; status II: RR 3.7) significantly outweighed the risk of transplanting patients with a heart from donors >40 years old (status I: RR 1.6; status II: RR 2.1). Recipients of cardiac allografts from donors 40 years, respectively. Conclusions Despite a strong association between older donor age and increased post-operative mortality and TCAD, it is more beneficial in terms of patient survival to receive an allograft from a donor >40 years old than to remain on the waiting list.

Background— Cardiac transplantation vasculopathy is the leading cause of late death in heart transplantation recipients. Rapamycin is an immunosuppressant drug with potent antiproliferative and antimigratory effects. We investigated whether rapamycin could prevent progression of graft vasculopathy in 46 patients (age, 54±10 years; 4.3±2.3 years after transplantation) with severe disease. Methods and Results— At annual cardiac catheterization, patients were randomly assigned to treatment with rapamycin (n=22) versus continued current immunosuppression (n=24). Clinical characteristics including recipient age and sex, underlying cause of congestive heart failure, donor age and sex, and ischemic time were recorded. Cardiac catheterization was graded with the use of a semiquantitative scale and repeated annually. Clinically significant adverse events were defined as death, need for angioplasty or bypass surgery, myocardial infarction, and a >25% worsening of the catheterization score. These events were monitored as primary study end points. Anti-HLA class I and II antibody production and lymphocyte growth assays were measured with each biopsy. Patients selected for rapamycin had azathioprine or mycophenolate mofetil discontinued and were given rapamycin. Outcomes were compared by means of log-rank analysis. There were no significant differences in baseline characteristics. Duration of follow-up was comparable (rapamycin, 689±261; control, 630±207 days; NS). In the rapamycin group, 3 patients reached primary end points versus 14 patients in the control group ( P Conclusions— In this patient cohort with cardiac vasculopathy, treatment with rapamycin slowed disease progression probably by its antiproliferative and antimigratory effects.

Background: Mechanical support for pre-transplant stabilization is established, but its use in peri-operative graft failure (PGF) has not been well documented. With liberal acceptance criteria being used to enlarge the donor pool, an increased incidence of graft failure might be expected. We evaluated the incidence and outcome of PGF at our institution. Methods: A retrospective review of 462 consecutive adult heart transplants performed between January 1993 and December 1999 revealed 20 cases of PGF. Donor-, surgery- and device-related variables were evaluated for association with operative mortality, survival and successful device weaning. Results: Transplant recipients included 17 men and 3 women, median age 56.5 years (20 to 66 years). PGF etiology included primary graft failure ( n = 9); right heart failure (RHF) secondary to pulmonary hypertension, coagulopathy/intra-operative hemorrhage or sepsis ( n = 9); and hyperacute rejection ( n = 2). Device types included RVAD ( n = 11), LVAD ( n = 4), BIVAD ( n = 3) and IABP ( n = 2). The wean rate was 45%. Duration of device support ranged from 2 to 965 hours. Early ventricular recovery (within 96 hours) was associated with significantly better 30-day and 2-year survival. Weaned patients had an 88% 30-day and 67% 2-year survival, whereas the overall survival rate was 79% at 2 years ( p = not significant). Conclusions: Early ventricular recovery is an important predictor of successful weaning and survival. In view of the prohibitive mortality associated with PGF and the dismal prognosis with re-transplantation, we advocate aggressive use of mechanical assistance for PGF, with an acceptable survival benefit.

Background. Because allograft rejection results from specific T-cell activation by donor human leukocyte antigens (HLA), new immunomodulatory therapies for organ-transplant recipients are used to selectively block T-cell activity without global immunosuppression. We investigated whether blockade of the high-affinity interleukin (IL)-2 receptor effectively prevented T-cell alloreactivity in cardiac transplantation. Methods and Results. A study of a humanized monoclonal antibody against the high-affinity IL-2 receptor (daclizumab) was performed in 70 adult, cardiac-transplant recipients. Patients were stratified based on the degree of donor-recipient HLA-DR matches. Primary and secondary endpoints were incidence and frequency of high-grade allograft rejections, IL-2-dependent, T-cell outgrowth from biopsy sites as measured by lymphocyte growth assay, and production of anti-HLA antibodies. Treatment with daclizumab significantly prevented development of high-grade acute rejection in recipients with at least one donor HLA-DR locus match during the first 3 months posttransplantation; in this group 0 of 13 (0%) treated with daclizumab experienced at least one high-grade rejection versus 3 of 13 (23%) controls (P=0.05). In addition, 1 of 12 (9%) daclizumab-treated patients experienced one or more episodes of IL-2-dependent, T-cell outgrowth versus 5 of 12 (42%) patients in the untreated group (P=0.05). In contrast, daclizumab used at the same dose and schedule was not as effective in fully HLA-DR-mismatched recipients. After cessation of daclizumab, allograft rejection increased to levels seen in controls. Conclusions. IL-2-receptor blockade is effective for preventing alloreactivity and high-grade rejection in cardiac transplantation; however, its efficacy seemed to be influenced by the degree of donor-recipient, HLA-DR locus mismatching.

Background: Diabetes remains a relative contraindication to cardiac transplantation. Previous reports have described small numbers of diabetic patients without end-organ damage who have undergone successful cardiac transplantation. Methods: A retrospective analysis of diabetic patients transplanted and their outcome in a single large center from 1/1/95 to 12/31/99 was performed. Diabetes was defined as “medium risk” by the presence of any of the following parameters: duration of therapy >10 years; use of insulin; serum creatinine >2 mg/dl; urinary protein >300 mg per 24 hours; presence of peripheral vascular disease (ankle:brachial ratio

BACKGROUND: Using a rat (Lewis-Wistar Furth) abdominal heterotopic transplantation model, we reported previously that the expression of cyclooxygenase (COX)-2 is increased in parallel with that of nitric oxide synthase (NOS)-2 during cardiac allograft rejection. METHODS: To investigate effects of COX-2 inhibition in this model, allograft recipients were treated orally (PO) with 5 mg/kg per day of the tetra substituted furanone selective COX-2 inhibitor 5,5-dimethyl-3-(3 fluorophenyl)-4-(4 methylsulfonal) phenyl-2 (5H)-furanone (DFU) in 1% methyl cellulose solution. RESULTS: In the treated animals, allograft survival was increased from 6.3+/-0.5 to 12.6+/-2.6 days (P = .001). At days 3 and 5 posttransplantation, there were reductions in the extent of the inflammatory infiltrate, endovasculitis, myocardial edema, and cardiomyocyte damage in rejecting allografts. The mean numbers of apoptotic cardiomyocytes determined with the terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) technique were significantly reduced in DFU-treated grafts compared with untreated controls (P < 0.05). At day 3 posttransplantation, prostaglandin E2 synthesis by myocardial slices incubated with 100 microM bradykinin was reduced from 1,097+/-156 to 153+/-63 pg/mg of protein in the treated allografts (P < .005). At day 5, COX-2 protein and mRNA together with COX-2, NOS-2, and nitrotyrosine immunostaining in damaged cardiomyocytes were diminished in treated versus control grafts. CONCLUSION: The data indicate that the inhibition of COX-2 prolongs allograft survival and reduces myocardial damage and inflammation during acute cardiac allograft rejection.

Objective: The prognosis for patients with primary cardiac sarcoma is poor. Median survival is less than 10 months, especially when complete surgical excision is not feasible. Removal of all cardiopulmonary structures involved by tumor followed by orthotopic allotransplantation has been proposed to improve long-term survival. Methods: From 1996 through 1999, we performed combined heart and lung resection followed by en bloc heart and bilateral lung transplantation in 4 patients (2 men and 2 women): 2 with inoperable pulmonary arterial sarcoma and 2 with left atrial sarcoma extending into the pulmonary vein. Results: Median age at diagnosis was 39 years (range 37-45 years). All 4 patients were given chemotherapy before transplantation: doxorubicin and ifosfamide in 2 cases, and doxorubicin, ifosfamide, mesna, and dacarbazine in 2 cases. There were no operative deaths. Median survival after transplantation was 31 months (range 5-49 months). All patients had tumor recurrence: local recurrence in the chest (n = 1) and distant metastases in the brain (n = 2) and abdomen (n = 1). One patient remains alive 49 months after disease progression with cerebral metastasis as the only site of recurrence treated with whole-brain irradiation, resection, and stereotactic radiosurgery. Conclusions: Combined heart and lung transplantation is a technically feasible treatment for highly selected patients with localized advanced primary cardiac sarcomas. The high incidence of metastatic disease, however, limits its utility. J Thorac Cardiovasc Surg 2002;124:1145-8

The shortage of available donor hearts continues to limit cardiac transplantation. For this reason, strict criteria have limited the number of patients placed on the US waiting list to ≈6000 to 8000 per year. Because the number of available donor hearts has not increased beyond ≈2500 per year, the transplant waiting list mortality rate remains substantial. Suboptimal and variable utilization of donor hearts has compounded the problem in the United States. In 1999, the average donor yield from 55 US regions was 39%, ranging from 19% to 62%. This report provides the detailed cardiac recommendations from the conference on “Maximizing Use of Organs Recovered From the Cadaver Donor” held March 28 to 29, 2001, in Crystal City, Va. The specific objective of the report is to provide recommendations to improve the evaluation and successful utilization of potential cardiac donors. The report describes the accuracy of current techniques such as echocardiography in the assessment of donor heart function before recovery and the impact of these data on donor yield. The rationale for and specific details of a donor-management pathway that uses pulmonary artery catheterization and hormonal resuscitation are provided. Administrative recommendations such as enhanced communication strategies among transplant centers and organ-procurement organizations, financial incentives for organ recovery, and expansion of donor database fields for research are also described.

Background— Nitric oxide synthase-2 (NOS2) is expressed during acute cardiac allograft rejection in association with myocardial inflammation, contractile dysfunction, and death of cardiomyocytes by necrosis and apoptosis. Recently, allosteric inhibitors of NOS2 monomer dimerization that block NOS2 activity have been developed. Methods and Results— To investigate effects of selective NOS2 blockade, 15 mg/kg of BBS-1 or BBS-2 was administered twice daily subcutaneously to rats starting the day of heterotopic heart transplantation. Cardiac allograft survival was increased significantly, from 6.8 days in controls to 13.3 and to 14.2 days in NOS2-inhibited allografts. At day 5 after heart transplantation, synthesis of NOx was reduced by 53%. There were significantly fewer T lymphocytes and macrophages in the inflammatory infiltrate, as well as less edema and cardiomyocyte damage, and the International Society of Heart and Lung Transplantation score fell from 5 to 4 and 3.5. NOS2 and nitrotyrosine immunostaining and the mean numbers of apoptotic cells and of apoptotic cardiomyocytes were significantly diminished in the treated allografts. Conclusions— The data indicate that selective inhibition of NOS2 dimerization prolongs survival and reduces myocardial inflammation and cardiomyocyte damage in acute cardiac allograft rejection.

The shortage of available donor hearts continues to limit cardiac transplantation. For this reason, strict criteria have limited the number of patients placed on the US waiting list to approximately 6000 to 8000 per year. Because the number of available donor hearts has not increased beyond approximately 2500 per year, the transplant waiting list mortality rate remains substantial. Suboptimal and variable utilization of donor hearts has compounded the problem in the United States. In 1999, the average donor yield from 55 US regions was 39%, ranging from 19% to 62%. This report provides the detailed cardiac recommendations from the conference on "Maximizing Use of Organs Recovered From the Cadaver Donor" held March 28 to 29, 2001, in Crystal City, Va. The specific objective of the report is to provide recommendations to improve the evaluation and successful utilization of potential cardiac donors. The report describes the accuracy of current techniques such as echocardiography in the assessment of donor heart function before recovery and the impact of these data on donor yield. The rationale for and specific details of a donor-management pathway that uses pulmonary artery catheterization and hormonal resuscitation are provided. Administrative recommendations such as enhanced communication strategies among transplant centers and organ-procurement organizations, financial incentives for organ recovery, and expansion of donor database fields for research are also described.

Constantly changing practices in heart transplantation have improved posttransplant survival in patients with end-stage heart disease. The objective of this study was to evaluate long-term outcomes in different eras of immunosuppressive therapy after cardiac transplantation at a single center during a two-decade period.A retrospective review of 1,086 consecutive cardiac allograft recipients who underwent transplantation between 1977 to 1999 was performed. Patients were divided into four eras based on type of immunosuppressive therapy: era 1 = steroids, azathioprine (n = 26, February 1977 to March 1983), era II = steroids, cyclosporine (n = 43, April 1983 to April 1985), era III = cyclosporine, steroids, azathioprine (n = 752, April 1985 to December 1995), era IV = cyclosporine, steroids, mycophenolate mofetil (n = 315, January 1996 to October 1999).The actuarial survival of the entire cohort of 1,086 patients undergoing cardiac transplantation was 79%, 66%, and 49% at 1, 5, and 10 years, respectively. There were significant trends in recipient age and gender distribution among the four eras with increasing proportion of older age (60 years) and female recipients in eras III and IV (p = 0.001 and 0.02). Early mortality and long-term survival improved significantly over all eras (p0.001). Rejection as a cause of death decreased over time (era I, 24%; era II, 21%; era III, 15%; era IV, 9%; p = 0.02), whereas the contribution of transplant coronary artery disease as a cause of death remained unchanged.Cardiac transplantation provides satisfactory long-term survival for patients with end-stage heart failure. The improving outcomes in survival correlate with improved immunosuppressive therapy in each era. Although the reasons for improvement in survival over time are multifactorial, we believe that changes in immunosuppressive therapy have had a major impact on survival as evidenced by the decreasing number of deaths due to rejection.

Left ventricular remodeling is a major cause of progressive heart failure and death after myocardial infarction. Although neoangiogenesis within the infarcted tissue is an integral component of the remodeling process, the capillary network is unable to support the greater demands of the hypertrophied myocardium, resulting in progressive loss of viable tissue, infarct extension and fibrous replacement. Here we show that bone marrow from adult humans contains endothelial precursors with phenotypic and functional characteristics of embryonic hemangioblasts, and that these can be used to directly induce new blood vessel formation in the infarct-bed (vasculogenesis) and proliferation of preexisting vasculature (angiogenesis) after experimental myocardial infarction. The neoangiogenesis resulted in decreased apoptosis of hypertrophied myocytes in the peri-infarct region, long-term salvage and survival of viable myocardium, reduction in collagen deposition and sustained improvement in cardiac function. The use of cytokine-mobilized autologous human bone-marrow-derived angioblasts for revascularization of infarcted myocardium (alone or in conjunction with currently used therapies) has the potential to significantly reduce morbidity and mortality associated with left ventricular remodeling.

Alloantigen-activated T cells express the high-affinity interleukin-2 receptor. Specific blockade of this receptor with the human IgG1 monoclonal antibody daclizumab may prevent rejection of allografts after cardiac transplantation without inducing global immunosuppression.We randomly assigned 55 nonsensitized patients undergoing a first cardiac transplantation to receive either induction therapy with daclizumab (1.0 mg per kilogram of body weight), given intravenously within 24 hours after cardiac-transplantation surgery and every two weeks thereafter, for a total of five doses, or generalized immunosuppressive therapy. Concomitant immunosuppression was achieved in both groups with cyclosporine, mycophenolate mofetil, and prednisone. The primary end points were the incidence and severity of acute rejection, and the length of time to a first episode of biopsy-confirmed rejection.Of the 55 patients in the study, 28 were randomly assigned to receive daclizumab and 27 served as the control group. During induction therapy, the mean frequency of acute rejection episodes (defined as a histologic grade of 2 or higher according to the classification of the International Society of Heart and Lung Transplants) was 0.64 per patient in the control group and 0.19 per patient in the daclizumab group (P=0.02). Acute rejection developed in 17 of 27 patients in the control group (63 percent), as compared with 5 of 28 patients in the daclizumab group (18 percent; relative risk, 2.8; 95 percent confidence interval, 1.1 to 7.4; P=0.04). Throughout follow-up, there were nine patients with episodes of acute rejection of histologic grade 3 in the control group, as compared with two in the daclizumab group (P= 0.03), and the time to a first episode of rejection was significantly longer in the daclizumab group (P=0.04). There were no adverse reactions to daclizumab and no significant differences between the groups in the incidence of infection or cancer during follow-up.Induction therapy with daclizumab safely reduces the frequency and severity of cardiac-allograft rejection during the induction period.

Insertion of the inflow cannula of an implantable left ventricular assist device (LVAD) is a surgical challenge in patients who have previously undergone a Dor ventriculoplasty procedure. We report a 54-year-old man who had successful LVAD insertion 18 months after a Dor procedure. We also describe the strategy of LVAD insertion in such patients.

Cardiac transplantation is a limited option for end-stage heart failure because of the shortage of donor organs. Left-ventricular assist devices (LVADs) are currently under investigation as permanent therapy for end-stage heart failure, but long-term successful device implantation is limited because of a high rate of serious infections. To examine the relation between LVAD-related infection and host immunity, we investigated immune responses in LVAD recipients.We compared the rate of candidal infection in 78 patients with New York Heart Association class IV heart failure who received either an LVAD (n=40) or medical management (controls, n=38). Fluorochrome-labelled monoclonal antibodies were used in analyses of T-cell phenotype. Analysis of T-cell function included intradermal responses to recall antigens and proliferative responses after stimulation by phytohaemagglutinin, monoclonal antibodies to CD3, and mixed lymphocyte culture. We measured T-cell apoptosis in vivo by annexin V binding, and confirmed the result by assessment of DNA fragmentation. Activation-induced T-cell death was measured after T-cell stimulation with antibodies to CD3. All immunological tests were done at least 1 month after LVAD implantation. Between-group comparisons were by Kaplan-Meier actuarial analysis and Student's t test.By 3 months after implantation of LVAD, the risk of developing candidal infection was 28% in LVAD recipients, compared with 3% in controls (p=0.003). LVAD recipients had cutaneous anergy to recall antigens and lower (70%) T-cell proliferative responses than controls after activation via the T-cell receptor complex (p0.001). T cells from LVAD recipients had higher surface expression of CD95 (Fas) (p0.001) and a higher rate of spontaneous apoptosis (p0.001) than controls. Moreover, after stimulation with antibodies to CD3, CD4 T-cell death increased by 3.2-fold in LVAD recipients compared with only 1.2-fold in controls (p0.05).LVAD implantation results in an aberrant state of T-cell activation, heightened susceptibility of CD4 T cells to activation-induced cell death, progressive defects in cellular immunity, and increased risk of opportunistic infection.

Objective: To identify risk factors for survival after cardiac retransplantation and compare the survival after retransplantation with that after primary cardiac transplantation. Methods: A retrospective analysis of 952 patients undergoing cardiac transplantation for the treatment of end-stage heart disease at a single center between 1977 and October 1997. Of these, 43 patients (4.5%) underwent cardiac retransplantation for cardiac failure resulting from transplant-related coronary artery disease, rejection, and early graft failure. Results: No significant difference in actuarial patient survival was found by Kaplan-Meier analysis at 1, 2, and 5 years between patients undergoing primary transplantation and those undergoing retransplantation—76%, 71%, and 60% versus 66%, 66%, and 51%, respectively (P = .2). Multivariable analysis identified a shorter interval between transplants and an initial diagnosis of ischemic cardiomyopathy as significant risk factors for death after retransplantation (P = .04 and .03, respectively). Since 1993, when our criteria for patient selection for retransplantation were revised on the basis of earlier experience to exclude patients with allograft dysfunction as a result of primary graft failure and those with intractable acute rejection occurring less than 6 months after transplantation, the survival has been significantly better (

Background. Natural killer (NK) cells have been implicated in a process of delayed xenograft rejection occurring in pig-to-primate organ transplants. As tumor necrosis factor-α (TNF-α) induces expression of both adhesion receptors and major histocompatibility complex class I molecules on porcine endothelium, we investigated the effects of TNF-α on human NK cell adherence to and cytotoxicity of porcine aortic endothelial cell (PAEC) monolayers. Methods. Adherence of human NK cells was measured after PAEC treatment with increasing concentrations of TNF-α. Monoclonal antibodies (mAbs) against adhesion molecules on NK cells and PAEC were used in inhibition studies. Resting or TNF-α-treated PAEC were used as targets for NK lysis. Increasing titers of anti-swine leukocyte antigen (SLA) class I antibodies or pooled human immune globulin (IVIg) were used to reverse the effects of TNF-α on NK lysis. Results. NK cell adhesion to TNF-α-treated PAEC increased in a dose-dependent manner by a maximum of 44%, and was inhibited by mAbs against CD49d, CD11a, CD11b, CD18, and CD2, as well as porcine vascular cell adhesion molecules. In contrast, TNF-α treatment of PAEC reduced human NK lysis in a dose-dependent manner. Preincubation of TNF-α-treated PAEC with increasing concentrations of anti-SLA class I mAb increased NK lysis in a titer-dependent manner, and reversed the protective effect on human NK lysis by 77%. Treatment with IVIg, containing antibodies against an α-helical region of HLA class I molecules, had a similar effect. Conclusions. These results imply that SLA class I molecules can bind to inhibitory receptors on human NK cells, and that these interactions can be augmented by increasing the level of SLA class I molecule expression on porcine endothelium. Strategies that can increase porcine endothelial cell expression of either swine or human major histocompatibility complex class I molecules may reduce human NK activity against porcine xenografts.

Background. Monocyte binding to and activation by human endothelium requires a number of interactions, including those involving sialylated endothelial cell ligands. As porcine endothelial cell transfection with α(1,2)-fucosyltransferase has been shown to reduce terminal sialylation, we investigated whether high-level expression of α(1,2)-fucosyltransferase by porcine endothelium would reduce human monocyte adhesion and functional activation. Methods. Purified human monocytes were labeled with 51 Cr, and measured for adherence to human or porcine endothelial cell monolayers in the presence of either medium or monoclonal antibodies against monocyte lectins or sialylated endothelial cell ligands. Monocyte production of prostaglandin E2 (PGE2) and interleukin-1β (IL-1β) was measured by enzyme-linked immunosorbent assay, using supernatants collected from cultures performed between human monocytes and human or porcine endothelial cell monolayers. Finally, monocyte adhesion and activation were measured after culture with a porcine endothelial cell line transfected with α(1,2)-fucosyltransferase, expressing reduced surface expression of terminal Gal α(1,3)-Gal and sialic acid residues. Results. Human monocytes adhered by 50% higher levels to porcine endothelium than to human endothelium. This increased level of adherence was associated with augmented monocyte activation, as defined by 3.3-fold higher levels of PGE2 production and 7.3-fold higher levels of IL-1β production. Monoclonal antibodies against CD62L (L-selectin) on monocytes or CD15s (sialylated Lewis X) on porcine endothelium reduced mono-cyte adhesion by 38% and 52%, respectively. Porcine endothelial cell transfection with α(1,2)-fucosyltransferase reduced terminal sialic acid expression by 65%, monocyte adherence by 50%, and the production of PGE2 and IL-1β by 67% and 38%, respectively. Conclusions. Together, these results demonstrate that human monocytes use surface lectins to bind to sialylated carbohydrate structures on porcine endothelium, and indicate that reduction in porcine endothelial cell surface expression of terminally sialylated structures by high-level α(1,2)-fucosyltransferase activity reduces monocyte adherence and activation.

Background: Multiple stimuli converge in cardiopulmonary bypass to create a tremendous prothrombotic stimulus. The ideal anticoagulant for cardiopulmonary bypass should selectively target only the intravascular stimuli, thereby eliminating pathologic clotting in the bypass circuit while preserving hemostasis in the thoracic cavity. We propose the inhibition of factor IX as such a targeted anticoagulant strategy. Methods: We prepared an inhibitor of activated factor IX and applied it to a primate model of cardiopulmonary bypass to confirm the anticoagulant efficacy of activated factor IX in this setting and to assess more subtle markers of thrombin generation, macrophage procoagulant activity, and cellular tissue factor expression. Seven baboons that received activated factor IX (460 μg/kg) and 7 that received heparin (300 IU/kg) and protamine underwent cardiopulmonary bypass for 90 minutes and were followed after the operation for 3 hours. Results: Analysis of plasma factor IX activity demonstrated adequate inhibition (

The critical shortage of organ donors has greatly limited the number of clinical allotransplantations. This is particularly true for neonatal patients, for whom xenotransplantation could provide an alternative therapeutic option to allotransplantation. The role of neonatal infant immunity in xenotransplantation is not, however, clearly understood. We examined both the proliferative responses of human neonatal lymphocytes to pig aortic endothelial cells and serum levels of neonatal natural antipig xenoantibody. Neonatal human lymphocytes and serum were isolated from umbilical cord blood. Adult human lymphocytes and serum were used as controls. A one-way xenogeneic mixed lymphocyte–endothelial cell reaction was performed, and lymphocyte proliferation was measured by tritiated thymidine uptake. Neonatal human lymphocytes recognized and proliferated in response to pig aortic endothelial cells (mean 63,926 ± 26,054 counts per minute). The level of xenogeneic mixed lymphocyte–endothelial cell reaction of neonatal lymphocytes was significantly lower (p < 0.004) than that of adult human lymphocytes (mean 122,444 ± 33,132 counts per minute). An enzyme-linked immunosorbent assay was performed to determine the binding of natural immunoglobulin M and G antibodies to pig endothelial cells. Whole-cell enzyme-linked immunosorbent assay demonstrated neonatal human serum to contain very low binding levels of natural antipig immunoglobulin M xenoantibody compared with adult serum. Like adult serum, neonatal human serum contained natural antipig immunoglobulin G xenoantibody. Neonatal serum was not cytotoxic to pig endothelial cells, suggesting that immunoglobulin G was not the predominant xenoreactive antibody. To assess whether neonatal pig endothelial cells also expressed xenoantigens, adult and neonatal cultured pig endothelial cells were examined by enzyme-linked immunosorbent assay with adult human serum. Adult human natural immunoglobulin M xenoantibody recognized not only adult pig endothelial cell xenoantigens but also neonatal pig endothelial cell xenoantigens. The binding levels of adult natural antipig immunoglobulin M xenoantibodies to adult and neonatal pig endothelial cells were similar, suggesting that neonatal pig aortic endothelial cells express xenoantigens. The findings of low binding levels of cytotoxic antipig immunoglobulin M xenoantibody and low levels of lymphocyte xenoreactivity to pig endothelial cells in human neonates suggests that pig organs may eventually be a suitable source of xenografts for human neonates. (J T HORAC C ARDIOVASC S URG 1996;111:920-9)

The interaction of T cell costimulatory molecules with their ligands is required for optimal T cell activation. Interference with such interactions can induce antigen unresponsiveness and delay xeno- and allograft rejection. We have previously shown that LFA3TIP, a soluble human lymphocyte function-associated antigen (LFA)-3 construct, binds CD2 and inhibits responses of human T cells in vitro. This study reports the first use of a human fusion protein, LFA3TIP, to significantly prolong primate cardiac allograft survival. Based on our observations that LFA3TIP inhibits baboon allogeneic mixed lymphocyte reactions, we gave baboon recipients of heterotopic cardiac allografts injections of LFA3TIP, 3 mg/kg i.v., for 12 consecutive days, starting 2 days before transplantation. This regimen delayed graft rejection from an average of 10.6 +/- 2.3 days for human IgG-treated controls (n = 5) to an average of 18.0 +/- 5.3 days for LFA3TIP-injected animals (n = 7; P < or = 0.01). Grafts from LFA3TIP-treated animals showed markedly diminished coronary endothelialitis as compared with control animals. LFA3TIP reached peak serum levels of approximately 100 micrograms/ml after 7-9 injections and persisted in the 10-micrograms/ml range for 1 to 2 weeks after the final injection. Despite these blood levels, circulating antibodies to LFA3TIP were not detected in the serum. No renal or hepatic toxicity was noted. The possible mechanism by which LFA3TIP acts to inhibit graft rejection is discussed; success in prolonging graft survival when LFA3TIP is used as a single-agent therapy suggests great potential for this novel therapeutic agent.

SummaryTwenty-one cardiothoracic surgical patients have been treated with fibrin as a topical hemostatic/sealing agent, prepared from bovine fibrinogen clotted with bovine thrombin. Serum samples have been collected before treatment with fibrin and postoperatively between 1 and 9 days, 3 and 12 weeks, and 6 and 8 months. The titers of anti-bovine fibrinogen antibodies, measured by ELISA specific for immunoglobulins IgG or IgM, increased to maximal values after about 8 or 6 weeks, respectively. After 8 months, IgG titers were on average 20-fold lower than the mean maximal value, while IgM titers returned to the normal range. IgG was the predominant anti-bovine fibrinogen immunoglobulin as documented by ELISA, affinity chromatography and electrophoresis. Anti-bovine fibrinogen antibodies present in patients reacted readily with bovine fibrinogen, but did not cross-react with human fibrinogen as measured by ELISA or by immunoelectrophoresis. A significant amount of antibodies against bovine thrombin and factor V has been found, many cross-reacting with the human counterparts. No hemorrhagic or thrombotic complications, or clinically significant allergic reactions, occurred in any patient, in spite of antibody presence against some bovine and human coagulation factors. The treatment of patients with bovine fibrin, without induction of immunologic response against human fibrinogen, appeared to be an effective topical hemostatic/sealing measure.

Background. During cardiopulmonary bypass, global hypoperfusion of the brain has been shown to result in ischemic insult and subsequent neurologic injury. Furthermore, outcome after focal cerebral ischemia depends on collateral circulation, which is determined by the parameters of global perfusion. We therefore measured cerebral blood flow during independent manipulations of arterial blood pressure and pump flow rate to determine which of these hemodynamic parameters regulates cerebral perfusion during cardiopulmonary bypass. Methods. Seven anesthesized baboons were placed on cardiopulmonary bypass and cooled to 28°C. Pump flow rate and arterial blood pressure were altered in varied sequence to each of four conditions: (1) full flow (2.23 ± 0.06 L·min −1 ·m −2 , mean ± standard deviation) at high pressure (61 ± 2 mm Hg), (2) full flow (2.23 ± 0.06 L·min −1 ·m −2 ) at low pressure (24 ± 3 mm Hg), (3) low flow (0.75 L ·min −1 ·m −2 ) at high pressure (62 ± 2 mm Hg), and (4) low flow (0.75 L ·min −1 ·m −2 at low pressure (23 ± 3 mm Hg). During each of these hemodynamic conditions cerebral blood flow was measured by washout of intracarotid xenon 133 . Results. Cerebral blood flow was greater at high blood pressure than at low pressure during cardiopulmonary bypass both at low flow (34 ± 8.3 versus 14.1 ± 3.7 mL·min −1 ·100 g −1 ) and full flow (27.6 ± 9.9 versus 16.8 ± 3.7 mL·min −1 ·100 g −1 ) ( p Conclusions. These results indicate that cerebral blood flow during moderately hypothermic cardiopulmonary bypass is regulated by arterial blood pressure and not pump flow rate.

Discordant xenotransplantation represents an attractive alternative to allotransplantation in light of the shortage of donor organs currently available for cardiac allotransplantation. Unfortunately, discordant xenotransplantation is still limited by hyper-acute rejection, a process thought to be mediated by natural anti-xenodonor antibody. Based on data that cytotoxic natural xenoantibodies are IgM in nature, we postulated that natural xenoantibodies may be absent from newborn serum. Baboon sera were collected from infant baboons. Pooled adult baboon sera were used as controls. A whole cell ELISA was performed to determine the binding of xenoantibodies to pig aortic endothelial cells and pig lymphocytes. The cytotoxicity of both adult and newborn baboon sera to pig aortic endothelial cells was measured by a MTT (3-(4,5-dimethyl-thiazoyl-2-y) 2,5 diphenyl-tetrazolium bromide) assay. Newborn baboon sera demonstrated very low levels of binding of natural IgM xenoantibodies to pig endothelial cells and lymphocytes, whereas natural IgM xenoantibodies from adult baboon sera bound significantly to both pig aortic endothelial cells and lymphocytes. IgG natural antibodies in both adult and newborn sera bound to pig endothelial cells and pig lymphocytes. The MTT assay demonstrated high levels of cytotoxicity to pig endothelial cells from adult baboon sera and very low levels of cytotoxicity from newborn baboon sera. In this study, newborn baboon sera were demonstrated to be free of natural IgM xenoantibodies to pig endothelial cells and lymphocytes. Although natural anti-pig IgG antibodies were present in newborn sera, newborn baboon sera lack cytotoxicity to pig target cells. These findings suggest that IgM is the more important xenoantibody and that hyperacute rejection of discordant cardiac xenografts may be avoidable in the newborn.

The shortage of organ donors for transplantation is more pronounced for the lung than for any other solid organ. To address this problem, we evaluated the feasibility of pulmonary xenotransplantation. Preliminary investigations demonstrated that orthotopically placed pig lungs in cynomologous monkey recipients could be engrafted up to 9 hr after reperfusion without evidence of hyperacute rejection. In this study, the rejection reaction of pig lungs transplanted orthotopically into baboons (n = 6) was further investigated by ELISA and immunohistochemistry. Four baboon recipients were killed at 24 hr and 2 recipients were killed at 72 hr after transplantation. Pulmonary arterial flow measurements demonstrated flow to the grafts, and systemic arterial and xenograft pulmonary venous blood gas analysis suggested function of the donor lungs during the course of engraftment. Serum levels of baboon anti-pig endothelial cell xenoantibody were normal and decreased minimally over time. Immunohistochemical staining of biopsies demonstrated trace IgG and IgM along graft endothelium 2 hr after reperfusion. At 8 hr, biopsy samples showed no immunoglobulin bound to endothelial cells. Staining for complement was negative. Fibrin and platelets were detected along xenograft endothelium. Despite these findings, the lung xenografts appeared injured and clinically rejected. During the first 8 hr after reperfusion, the grafts were hyperemic and subsequently became focally ecchymotic. Chest x-rays showed progressive pulmonary congestion. These findings suggest that the lung may be relatively resistant to antibody-mediated hyperacute rejection and efforts are being directed toward identifying the mechanism of the observed xenograft lung injury.

The shortage of organs for transplantation is especially severe for the critically ill newborn infant, for whom donors of the appropriate size are particularly scarce. One way to overcome this problem is to use animals in lieu of humans as organ donors. The major limitation to using animals for this purpose is the susceptibility of animal organs to hyperacute rejection, a violent rejection reaction thought to be mediated by antidonor antibody and complement. To evaluate the potential application of xenotransplantation to newborns, we tested neonatal humans and neonatal baboons and found that neither population expressed significant levels of xenoreactive anti-pig antibodies. We transplanted heterotopically hearts from newborn pigs into unmanipulated newborn baboons (n = 4). There was no evidence of hyperacute rejection in any of the grafts; the animals were killed with functioning grafts at 15, 81, 82, and 82 hr. This outcome contrasts with that of newborn pig-to-mature baboon and mature pig-to-mature baboon cardiac xenografts, which were rejected within 1 hr of transplantation. The histology of pig graft biopsies from the newborn recipients was normal. Immunohistochemistry revealed only traces of IgM, C3, C4, and the membrane attack complex along graft endothelium. Fibrin deposition along endothelial surfaces was observed early after transplantation and became more extensive with time; in the absence of endothelial bound antibody or complement, this change may represent preservation injury. This study suggests that due to low levels of natural antibody, the newborn infant may permit prolonged xenograft survival.

We reviewed the impact of multiple donor characteristics on recipient mortality by univariate and multivariate analyses in a cohort of heart donors from 1995 to 1999. A sub-cohort of donors was also selected who met "marginal" criteria, and the early and late survival of these patients was then compared. Surrogates of donor size (donor weight, donor body mass index [BMI], BMI mismatch >20%), under-resuscitation (hematocrit, 24-hour fluid intake) and age >56 years were significantly associated with peri-operative mortality in the univariate analysis; in the multivariate analysis, only average donor heart rate at procurement ( p = .001), donor hematocrit ( p = .02) and donor weight ( p = .05) were significantly associated. Few donor characteristics actually impact significantly on recipient outcome, and thus recipient characteristics may figure more prominently than those of the donor toward the risk of death after transplantation.

Hypothermia is known to provide neuroprotection from focal ischemia. However, lethal cardiovascular complications resulting from total body cooling have greatly restricted hypothermia as a therapy for stroke. This study determined whether selective cerebral cooling induced after reversible cerebral artery occlusion would decrease the infarct volume.Under general anesthesia, 8 baboons were subjected to 1-hour simultaneous occlusion of the left internal carotid artery and anterior cerebral arteries by transorbital surgical approach. Four animals were treated with selective cerebral hypothermia to 25°C, initiated 2.5 hours after placement of cerebral artery clips. Selective cerebral hypothermia was achieved, after heparinization, by continuous withdrawal of femoral arterial blood into an extracorporeal closed-circuit pump system, cooling by water bath and perfusion into the right internal carotid artery. Pump flow was adjusted to maintain right internal carotid artery pressure near systemic blood pressure. Cerebral cortical temperature was maintained below 27°C for 12 hours, whereas systemic temperature was preserved near normal by convective air mattresses and warm water blankets. Four control animals were maintained at 36°C. Blood pressure, pH, and blood gases were maintained at normal values for both groups. Forty-eight to 72 hours after cerebral artery occlusion, magnetic resonance imaging brain scans were obtained and infarct volume measured.Normothermic baboons had infarction of 35.4±4.4% (mean±SD) of the left cerebral hemisphere compared with 0.5±1% for baboons treated with cerebral hypothermia (P0.01). In brain-cooled animals, esophageal temperature was maintained greater than 34°C, despite cerebral temperature less than 27°C.Selective brain cooling initiated 2.5 hours after onset of focal ischemia resulted in marked reduction in infarct volume, without cardiovascular derangement.