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There are limited data regarding the surgical management of primary pulmonary artery sarcomas (PPAS) because of their rarity and complicated diagnostic history. The objective of this study was to analyze our institution’s long-term surgical management outcomes for PPAS in the absence of a care pathway. From May 1997 to June 2013, 8 patients (mean age 60.6 ± 11.8 years; range, 40-73 years; 5 women and 3 men) underwent surgical intervention for PPAS at our institution. The most common computed tomography finding was a luminal filling defect obstructing the pulmonary artery (PA), without evidence of extraluminal extension. Three patients underwent debulking/pulmonary endarterectomy alone and 5 patients underwent a more radical resection with PA patch angioplasty, PA resection and reconstruction, pulmonary valve replacement, and unilateral pneumonectomy. The mean postoperative survival in this series was 3.8 ± 3.6 years (range, 1-11.9 years), with 2 radical surgical resection patients alive at 4.9 and 11.9 years, respectively. For those patients with incomplete resection, 3-dimensional (3D) models were created to demonstrate the advantage of a preoperative guide for a more complete resection and what it would entail. Six patients had local recurrences with mean disease-free interval of 14 ± 10.9 months (range, 2 months-2.5 years), and 2 patients with re-resections had an overall postoperative survival of 2.8 and 11.9 years, respectively. In our small cohort of PPAS, patients treated with radical surgical resection had better survival. The small number of PPAS cases in this series makes proving this association unlikely but warrants consideration.

Bioprosthetic leaflets made from animal tissues are used in the majority of surgical and transcatheter cardiac valve replacements. This study develops a new surgical bioprosthesis, using porcine pericardial leaflets. Porcine pericardium was obtained from genetically engineered pigs with a mutation in the GGTA-1 gene (GTKO) and fixed in 0.6% glutaraldehyde, and used to develop a new surgical valve design. The valves underwent in vitro hydrodynamic test in a pulse duplicator and high-cycled accelerated wear testing and were evaluated for acute haemodynamics and thrombogenicity in a juvenile sheep implant study for 48 h. The porcine surgical pericardial heart valves (pSPHVs) exhibited excellent hydrodynamics and reached 200 million cycles of in vitro durability, with no observable damage. Juvenile sheep implants demonstrated normal valve function with no acute thrombogenic response for either material. The pSPHV incorporates a minimalistic construction method using a tissue-to-tissue design to cover the stent. This new design is a proof of concept alternative to the use of bovine pericardium and synthetic fabric in surgical bioprosthetic heart valves.

OBJECTIVES Surgical strategies to treat drug refractory left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy include septal myectomy (SM) and, less frequently, mitral valve (MV) repair or replacement. The primary aim of this study was to report the surgical technique and management outcomes in a consecutive group of patients with variable phenotypes of hypertrophic cardiomyopathy in a broad national specialist practice. METHODS A total of 203 consecutive patients, 132 men (mean age 48.6 ± 14.6 years) underwent surgery for the management of LVOTO. Surgical approaches included SM (n = 159), SM with MV repair (n = 25), SM with MV replacement (n = 9) and MV replacement alone (n = 10). Specific surgical approaches were performed based on the underlying mechanism of obstruction. Eleven (5.4%) patients had previous alcohol septal ablation for the management of LVOTO. Concomitant non-mitral cardiac procedures were carried out in 22 (10.8%) patients. RESULTS Operative survival rate was 99.0% with 2 deaths within 30 days. The mean bypass time was 92.9 ± 47.8 min, with a mean length of hospital stay of 10.5 ± 7.8 days. Surgical complications included 3 ventricular septal defects requiring repair (1.5%), 1 Gerbode defect surgically repaired, 2 aortic valve repairs (1.0%), 2 transient ischaemic attacks (1.0%) and 4 strokes (2.0%). Thirty-nine (19.2%) patients had perioperative new-onset atrial fibrillation and 8 (3.9%) patients had unexpected atrioventricular block requiring a permanent pacemaker. Mean resting left ventricular outflow tract gradient improved from 70.6 ± 40.3 mmHg preoperatively to 11.0 ± 10.5 mmHg at 1 year postoperatively (P

Aims Surgical intervention is used to treat dynamic left ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy. This study assesses the effect of different surgical strategies on long-term mortality and morbidity. Methods and results In total, 347 patients underwent surgical intervention for LVOTO (1988-2015). Group A (n = 272) underwent septal myectomy; Group B (n = 33), septal myectomy and mitral valve (MV) repair; Group C (n = 22), myectomy and MV replacement; and Group D (n = 20), MV replacement alone. Median follow-up was 5.2 years (interquartile range 1.9-7.9). The mean resting LVOT gradient improved post-operatively from 71.9 ± 39.6 mmHg to 13.4 ± 18.5 mmHg (P 1 New York Heart Association (NYHA) class; 58.9% of patients undergoing MV replacement alone did not improve their NYHA class. There were 5 perioperative deaths and 20 late deaths (>30 days). Survival rates at 1, 5 and 10 years respectively were 98.4, 96.9, 91.9% in Group A; 97.0, 92.4, 61.6% in Group B; 100.0, 100.0, 55.6% in Group C; and 94.7, 85.3, 85.3% in Group D (log-rank, P 30 days) complications included atrial fibrillation (29.6%), transient ischaemic attack/stroke (2.4%) and heart failure hospitalisation (3.2%). There were 16 repeat surgical interventions at 3.0 years. Conclusion Septal myectomy is a safe procedure resulting in symptomatic improvement in the majority of patients. The annual incidence of non-fatal disease-related complications after surgical treatment of LVOTO is relatively high. Patients who underwent MV replacements had poorer outcomes with less symptomatic benefit in spite of a similar reduction in LVOT gradients.

Significant progress in understanding and overcoming cardiac xenograft rejection using a clinically relevant large animal pig-to-baboon model has accelerated in recent years. This advancement is based on improved immune suppression, which attained more effective regulation of B lymphocytes and possibly newer donor genetics. These improvements have enhanced heterotopic cardiac xenograft survival from a few weeks to over 2 years, achieved intrathoracic heterotopic cardiac xenograft survival of 50 days and orthotopic survival of 57 days. This encouraging progress has rekindled interest in xenotransplantation research and refocused efforts on preclinical orthotopic cardiac xenotransplantation.

Background This report studies the early and medium-term clinical and echocardiographic outcomes of the Alfieri edge-to-edge mitral valve repair, as adjunctive therapy, to prevent and treat systolic anterior motion (SAM) at the time of septal myectomy (SM) for left ventricular outflow tract obstruction in hypertrophic cardiomyopathy. Methods From 2009-2015, 11 consecutive patients had a trans-atrial Alfieri repair, to prevent (n = 7) or treat (n = 4) SAM at the time of SM. Results No patients were lost to follow-up. There were no perioperative or late deaths. Pre-bypass, the mean left ventricular outflow tract gradient, measured directly by simultaneous needle insertion, was 40.7 ± 19.9 mmHg at rest and 115.8 ± 30.4 mmHg on provocation with Isoproterenol, which reduced after SM and Alfieri repair and discontinuation of bypass, to a mean gradient of 8.3 ± 9.8 mmHg at rest and 25.8 ± 9.2 mmHg on provocation. One patient who required mitral valve replacement on day 4, was hospitalized at 2.7 years with heart failure requiring diuresis and remains well at 6 years. One patient developed postoperative atrial fibrillation. There were no other early or late complications. At a median follow-up of 6.6 years (international quartile range 1.2-7.4), clinical and echocardiographic data demonstrated maintained improvement in mean New York Heart Association class from 2.6 ± 0.9 preoperatively to 1.7 ± 0.4 and reduction in mean grade of mitral regurgitation from 2.7 ± 0.8 preoperatively to 0.7 ± 0.6. Conclusions The Alfieri repair, as adjunctive therapy, for the prevention or treatment of SAM at the time of SM demonstrates satisfactory early and medium-term clinical and echocardiographic outcomes supporting the ongoing utility of this approach.

We report the management of an acquired Gerbode defect, from the left ventricle to the coronary sinus, following mechanical mitral valve replacement. Following a failed percutaneous closure, surgical patch closure of the defect was performed.

Objectives Human subjects and Old World primates have high levels of antibody to galactose-α-1,3 galactose β-1,4-N-acetylglucosamine (α-Gal). Commercially available bioprosthetic heart valves of porcine and bovine origin retain the Gal antigen despite current processing techniques. Gal-deficient pigs eliminate this xenoantigen. This study tests whether binding of human anti-Gal antibody effects calcification of wild-type and Gal-deficient glutaraldehyde-fixed porcine pericardium by using a standard subcutaneous implant model. Methods Expression of α-Gal was characterized by lectin Griffonia simplicifolia –IB4 staining. Glutaraldehyde-fixed pericardial disks from Gal-positive and Gal-deficient pigs were implanted into 12-day-old Wistar rats and 1.5-kg rabbits with and without prelabeling with affinity-purified human anti-Gal antibody. Calcification of the implants was determined after 3 weeks by using inductively coupled plasma spectroscopy. Results The α-Gal antigen was detected in wild-type but not Gal-deficient porcine pericardium. Wild-type disks prelabeled with human anti-Gal antibody exhibited significantly greater calcification compared with that seen in antibody-free wild-type samples (mean ± standard error of the mean: 111 ± 8.4 and 74 ± 9.6 mg/g, respectively; P = .01). In the presence of anti-Gal antibody, a significantly greater level of calcification was detected in wild-type compared with GTKO porcine pericardium (111 ± 8.4 and 55 ± 11.8 mg/g, respectively; P = .005). Calcification of Gal-deficient pericardium was not affected by the presence of anti-Gal antibody (51 ± 9.1 and 55 ± 11.8 mg/g). Conclusions In this model anti-Gal antibody accelerates calcification of wild-type but not Gal-deficient glutaraldehyde-fixed pericardium. This study suggests that preformed anti-Gal antibody present in all patients might contribute to calcification of currently used bioprosthetic heart valves. Gal-deficient pigs might become the preferred source for new, potentially calcium-resistant bioprosthetic heart valves.

Background Cardiac allograft vasculopathy (CAV) is primarily immune-mediated. We investigated the role of cellular rejection in CAV development. Methods The study comprised 252 cardiac transplant recipients (mean age, 49.02 ± 17.05 years; mean follow-up, 7.61 ± 4.49 years). Total rejection score (TRS) based on the 2004 International Society of Heart and Lung Transplantation R grading system (0R = 0, 1R=1, 2R=2, 3R=3) and any rejection score (ARS; calculated as 0R=0, 1R=1, 2R=1; 3R=1, or the number of rejections of any grade) were normalized for the total number of biopsy specimens. CAV was defined as coronary stenosis of 40% or more and/or distal pruning of secondary side branches. Thirty-two patients had undergone 3-dimensional intravascular ultrasound (IVUS) at baseline and with virtual histology (VH) IVUS at 24 months. Results In univariate analysis, 6-month TRS (hazard ratio [HR], 1.9; 95% confidence interval [CI], 0.99–3.90, p = 0.05) and ARS (HR, 2.22; 95% CI, 1.01–4.95; p = 0.047) were associated with increased risk of CAV. In multivariate analysis, 6-month TRS (HR, 2.84; 95% CI, 1.44–6.91, p = 0.02) was significantly associated with increased risk of CAV onset. The 12- and 24-month rejection scores were not risk factors for the onset of CAV. By Kaplan-Meier analysis, 6-month TRS exceeding 0.3 was associated with a significantly shorter time to CAV onset ( p = 0.018). There was direct correlation ( r = 0.44, p = 0.012) between TRS at 6 months and the percentage of necrotic core demonstrated by VH-IVUS at 24 months. Conclusion Recurrent cellular rejection has a cumulative effect on the onset of CAV. The mechanism may be due to increased inflammation resulting in increased plaque burden suggesting a relationship between the immune basis of cellular rejection and CAV.

Objective To examine the incidence, tumor burden, and risk factors for nonmelanoma and other skin cancer types in this heart transplant cohort. Design Retrospective review of patient medical records. Setting Tertiary care center. Patients All heart transplant recipients at Mayo Clinic from 1988 to 2006. Main Outcome Measures Cumulative incidence of skin cancer and tumor burden, with Cox proportional hazards regression models used to evaluate risk factors for posttransplant primary and secondary nonmelanoma skin cancer. Results In total, 312 heart transplant patients had 1395 new skin cancers in 2097 person-years (mean, 0.43 per year per patient) with a range of 0 to 306 for squamous cell carcinoma (SCC) and 0 to 17 for basal cell carcinoma (BCC). The cumulative incidence rates of any skin cancer were 20.4%, 37.5%, and 46.4% at 5, 10, and 15 years after heart transplant, respectively. Cumulative incidence of SCC after the first BCC was 98.1% within 7 years. Multivariate analysis showed that posttransplant nonskin cancer, increased age, and heart failure etiologic factors other than idiopathic disease were associated with increased risk of SCC. Posttransplant herpes simplex viral infection, increased age, and use of mycophenolate mofetil for immunosuppression were associated with increased risk of BCC. Conclusions With prolonged survival, many heart transplant patients have numerous skin cancers. Vigilant sun protection practices, skin cancer education, and regular skin examination are appropriate interventions in these high-risk patients.

ObjectiveImproved durability of bioprostheses has led some surgeons to recommend biologic rather than mechanical prostheses for patients younger than 65 years. We compared late results of contemporary bioprostheses and bileaflet mechanical prostheses in patients who underwent aortic valve replacement between 50 and 70 years old.MethodsIn this retrospective study, patients received either St Jude bileaflet valves or Carpentier–Edwards bioprostheses. Operations were performed between January 1991 and December 2000, and groups were matched one-to-one according to age, sex, need for coronary artery bypass grafting, and valve size.ResultsFour hundred forty patients were matched, and follow-up was 92% complete, with median durations of 9.1 years for patients who received mechanical valves and 6.2 years for patients who received bioprostheses. The 5- and 10-year unadjusted survivals were 87% and 68% for mechanical valves and 72% and 50% for bioprostheses, respectively (P < .01). Freedoms from reoperation at 10 years were 98% for mechanical valves and 91% for bioprostheses (P = .06). Rates of late stroke or other embolic events and of endocarditis were similar between groups. Hemorrhagic complications necessitating hospitalization occurred in 15% of patients with mechanical valves and 7% of patients with bioprostheses (P = .01). Notably, 19% of patients with bioprostheses were receiving warfarin sodium at last follow-up. After adjustment for unmatched variables, including diabetes, renal failure, lung disease, New York Heart Association functional class, ejection fraction, and stroke, the use of a mechanical valve was protective against late mortality (hazard ratio 0.46, P < .01).ConclusionIn this study, patients aged 50 to 70 years who underwent aortic valve replacement with mechanical valves had a survival advantage relative to matched patients who received bioprostheses. These findings question recommendations of bioprostheses for younger patients and suggest that a randomized trial may be warranted.

Introduction Endomyocardial biopsy is the standard means of establishing cardiac allograft rejection diagnosis. The efficacy of this procedure in xenotransplantation has not been determined. In this study we compare the histology of right ventricular endomyocardial biopsy specimens with the corresponding full cross sections of explanted right ventricle (RV). We also compare RV with the related left ventricle (LV) cross sections. Methods Heterotopic CD46 pig-to-baboon cardiac xenotransplants (n = 64) were studied. RV endomyocardial biopsy specimens were taken at cardiac explant by using a standard bioptome (n = 24) or by sharp dissection (n = 40). Hematoxylin and eosin stained sections of RV and LV cross-section and RV endomyocardial biopsy specimens were compared in a blinded fashion. Characteristics of delayed xenograft rejection and a global assessment of ischemia were scored from 0 to 4 according to the percentage of myocardium involved (0, 0%; 1, 1%–25%; 2, 26%–50%; 3, 51%–75%; and 4, 76%–100%). Results Median graft survival was 30 days (range, 3–137 days). Linear regression analysis of histology scores demonstrated that specimens from both bioptome and sharp dissection equally represented the histology of the RV cross section. Global ischemic injury was strongly correlated between RV and RV endomyocardial biopsy ( R 2 = 0.84) and between RV and LV cross sections ( R 2 = 0.84). Individual characteristics of delayed xenograft rejection showed no significant variation between RV and RV endomyocardial biopsy or between RV and LV ( p Conclusions These results indicate that delayed xenograft rejection is a widespread process involving both right and left ventricles similarly. This study shows that histologic assessment of RV endomyocardial biopsy specimens is an effective method for the monitoring of delayed xenograft rejection after cardiac xenotransplantation.

Objective Although radiofrequency ablation is increasingly used to create the atrial lesions of the Cox maze procedure, its effectiveness in ablating atrial fibrillation compared with the standard cut-and-sew method is not known. We compare the freedom from atrial fibrillation in patients undergoing both methods with identical lesion sets. Methods Radiofrequency ablation was used to create full Cox maze lesions in 56 patients between January 2002 and February 2005; these patients were matched with those who underwent the standard cut-and-sew method. Matched variables were gender (33 male, 23 female, both), age (67.5 vs 67.2 years), New York Heart Association class (mean 2.28 vs 1.96), atrial fibrillation type (37 paroxysmal, 19 continuous, both), and concomitant mitral valve surgery (37 in both). Hypertension, preoperative left atrial size, and preoperative duration of atrial fibrillation were similar between groups. Results When compared with matched controls, fewer patients undergoing radiofrequency ablation were free from atrial fibrillation at dismissal (63% vs 88%; P = .0039) and at last follow-up (62% vs 92%; P = .016). According to logistic regression for matched pairs, patients undergoing radiofrequency ablation were 4.5 times more likely to be in atrial fibrillation at dismissal (95% confidence intervals [CI], 1.8, 10.9) and 5 times more likely to be in atrial fibrillation at follow-up (95% CI, 1.4, 17.3). No other covariate was associated with atrial fibrillation status at hospital dismissal or follow-up. Conclusion Creating Cox maze lesions with radiofrequency ablation is associated with less freedom from atrial fibrillation both early and late postoperatively. Because transmurality can be assured, the standard cut-and-sew Cox maze procedure remains the gold standard for the surgical treatment of atrial fibrillation.

OBJECTIVE: Infection is a major cause of mortality in the first year following single lung transplantation and is a distinct risk factor for the development of obliterative bronchiolitis. However, little is known about changes in pulmonary vascular activity in the setting of infection, which might affect and limit function of the graft. Therefore, the aim of this study was to determine how acute infection altered pulmonary arterial reactivity in single lung allografts. Such information could help to develop better diagnostic and therapeutic targets to improve outcome when grafts become infected. METHODS: Following single lung transplantation, dogs were immunosuppressed with methylprednisolone acetate, cyclosporine and azathioprine. On postoperative day 5, infection was induced in one group of dogs by endobronchial inoculation of antibiotic resistant Eschericia coli (infection group, n=5); in the second group, the same amount of culture media without bacteria was flushed into the bronchus (control group, n=4). All animals were medicated under the same drug protocol. On postoperative day 8, lungs were removed, reviewed for histological assessment, pulmonary arteries were isolated, cut into rings and suspended for pharmacological characterization in organ chambers. RESULTS: With acute infections, contractions to phenylephrine and angiotensin-1, but not endothelin-1, were reduced in pulmonary arteries with but not without endothelium. Inhibition of nitric oxide synthase with N(G)-monomethyl-L-arginine, monoacetate salt (L-NMMA) restored these contractions. Endothelium-dependent relaxations to adenosine diphosphate and calcium ionophore, which stimulate release of endothelium-derived nitric oxide by a receptor and non-receptor mediated process, respectively, were not different between groups. Relaxations to nitric oxide also were not different between groups. CONCLUSION: These results suggest that acute infection selectively reduces contractions of pulmonary arteries in part through receptor-mediated release of nitric oxide from the endothelium. Inhibiting nitric oxide during episodes of acute infection may help to improve graft perfusion during episodes of acute infection.

Genetic engineering of donor pigs to eliminate expression of the dominant xenogeneic antigen galactose α1,3 galactose (Gal) has created a sea change in the immunobiology of xenograft rejection. Antibody mediated xenograft rejection of GGTA-1 α-galactosyltransferase (GTKO) deficient organs is now directed to a combination of non-Gal pig protein and carbohydrate antigens. Glycan analysis of GTKO tissues identified no new neo-antigens but detected high levels of N-acetylneuraminic acid (Neu5Gc) modified glycoproteins and glycolipids. Humans produce anti-Neu5Gc antibody and in very limited clinical studies sometimes show an induced anti-Neu5Gc antibody response after challenge with pig tissue. The pathogenicity of anti-Neu5Gc antibody in xenotransplantation is not clear however as non-human transplant models, critical for modelling anti-Gal immunity, do not produce anti-Neu5Gc antibody. Antibody induced after xenotransplantation in non-human primates is directed to an array of pig endothelial cells proteins and to a glycan produced by the pig B4GALNT2 gene. We anticipate that immune suppression will significantly affect the T-cell dependent and independent specificity of an induced antibody response and that donor pigs deficient in synthesis of multiple xenogeneic glycans will be important to future studies.

Background As a step towards clinical cardiac xenotransplantation, our experimental heterotopic intrathoracic xenotransplantation model offers a beating and ejecting donor heart while retaining the recipient′s native organ as a backup in case of graft failure. Clinically applicable immunosuppressive regimens (IS) were investigated first, then treatments known to be effective in hypersensitized patients or those with recalcitrant rejection reactions. Methods Consecutive experiments were carried out between 2009 and 2013. Twenty-one genetically modified pigs (GGTA1-knockout/hCD46/± thrombomodulin, in one case HLA-E instead) were used as donors. In all experiments, two cycles of immunoabsorption reduced preformed antibodies. Recipient baboons were divided into two groups according to IS regimen: In group one (n = 10), pre-treatment started either one (anti-CD20) or four weeks (anti-CD20 plus the proteasome inhibitor bortezomib) prior to transplantation. The extended conventional (as for allotransplantation) immunosuppressive maintenance regimen included anti-thymocyte globuline, tacrolimus, mycophenolate mofetil, methylprednisolone and weekly anti-CD20. In group two (n = 11), myeloablative pre-treatment as in multiple myeloma patients (long and short regimens) was added to extended conventional IS; postoperative total thoracic and abdominal lymphoid irradiation (TLI; single dose of 600 cGY) was used to further reduce antibody-producing cells. Results In the perioperative course, the surgical technique was safely applied: 19 baboons were weaned off extracorporeal circulation and 17 extubated. Nine animals were lost in the early postoperative course due to causes unrelated to surgical technique or IS regimen. Excluding these early failures, median graft survival times of group 1 and 2 were 18.5 (12–50) days and 16 (7–35) days. Necropsy examination of group 1 donor organs revealed hypertrophy of the left ventricular wall in the six longer-lasting grafts; myocardial histology confirmed pre-clinical suspicion of humoral rejection, which was not inhibited by the extended conventional IS including intensified treatments, and signs of thrombotic microangiopathy. Grafts of group 2 presented with only mild-to-moderate features of humoral rejection and thrombotic microangiopathy, except in one case of delayed rejection on day 17. The other experiments in this group were terminated because of untreatable pulmonary oedema, recurring ventricular fibrillation, Aspergillus sepsis, as well as a combination of a large donor organ and late toxic side effects due to TLI. Conclusions Longer-term results were difficult to achieve in this model due to the IS regimens used. However, we conclude that heterotopic intrathoracic heart transplantation may be an option for clinical xenotransplantation.

OBJECTIVE To analyze the effect of adjuvant perfusion techniques of the distal aorta on the outcome of traumatic thoracic aortic transections. PATIENTS AND METHODS From 1973 to 2004, 72 patients (mean age, 39 years) with thoracic aortic transections arrived alive at the emergency department. Nineteen patients arrived in extremis and underwent emergency operations, 42 patients were stable and underwent diagnostic evaluation before surgery (4 patients experienced aortic rupture during evaluation), and 11 patients presented more than 24 hours after the accident. Sixteen patients died before aortic repair could be performed. Operative repair was possible in 53 patients (46 stable and 7 in extremis). Interposition graft was performed in 47 patients, and primary repair was performed in 6 patients. Morbidity, mortality, and paraplegia rate were analyzed. RESULTS Patients in extremis had a mortality rate of 84% (16 of 19), stable patients had a mortality rate of 11% (4 of 38), patients who experienced rupture during evaluation had a mortality rate of 100% (4 of 4), and patients who underwent delayed operation had a mortality rate of 0% (0 of 11). The paraplegia rate with and without adjuvant distal aortic perfusion techniques was 2% (1 of 41 patients) and 33% (4 of 12 patients), respectively ( P =.007). Mortality and paraplegia rates were 4% and 4% for partial bypass (n=24), 42% and 33% for the clamp and sew technique (n=12), 0% and 0% for Gott shunt (n=10), and 29% and 0% for full cardiopulmonary bypass (n=7), respectively. CONCLUSIONS Although thoracic aortic transections remain a highly lethal injury, hemodynamically stable patients have a low operative mortality. Spinal cord injury is decreased by the use of adjuvant perfusion techniques that maintain distal aortic perfusion during cross-clamping of the aorta.

Atrial rhythm disturbances, in particular atrial fibrillation (AF) and flutter (AFL), are common in the denervated transplanted heart. However, there is a relative paucity of data in the prevalence, mechanism of arrhythmia, and long-term significance.(1) Determine the prevalence of AF and AFL in heart transplant patients, (2) define the echo/Doppler features associated with arrhythmia, and (3) evaluate the impact of arrhythmia on long-term survival.All patients who received an orthotopic heart transplant at the Mayo Clinic, Rochester, Minnesota, between 1988 and 2000 were included. Analysis of serial electrocardiograms and Holter monitor records provided evidence of AF or AFL development. Variables including general patient demographics, histology-proven rejection numbers and grades, results of serial coronary angiography, endomyocardial biopsy specimens, and echocardiographic studies performed at 6 weeks and 3 years after transplant were obtained to determine variables predictive of arrhythmia development.There were 167 heart transplant recipients, of which 16 (9.5%) developed AF and another 25 (15.0%) developed AFL over 6.5 +/- 3.4 years. Patients who developed AF or AFL had lower left ventricular (LV) ejection fractions (56.6% +/- 1.6% vs 62.5% +/- 1.5%, p0.05), higher LV end-systolic dimensions (LVESD) (33.6 +/- 1.12 mm vs 29.7 +/- 0.97 mm, p0.01), higher right atrial volume indexes (43.2 +/- 12.3 ml vs 35 +/- 5.3 ml, p0.03), lower mitral deceleration time (145 +/- 8 msec vs 160 +/- 12 msec, p0.05), and lower late mitral annulus tissue a' velocities (0.06 +/- 0.005 cm/sec vs 0.08 +/- 0.01 cm/sec, p0.02) compared with an age- and gender-matched Sinus Rhythm Group. Grade 3 rejection was a time-dependent covariate predictor of AFL risk (hazard ratio [HR], 2.95; 95% confidence interval [CI], 1.3-6.6, p0.008) but not AF (HR, 2.264; 95% CI, 0.72-7.1; p = 0.10). Thirty-nine of 167 patients died: 13 in the arrhythmia group and 26 in the normal sinus rhythm group. Development of atrial dysrhythmia adversely affected the outcome in the first 5 years (p0.001) compared with normal sinus rhythm. Predictors of long-term mortality included AF/AFL (HR, 2.88; 95% CI, 1.38-5.96; p0.004), age at transplant (HR, 1.04; 95% CI, 1.00-1.07, p0.03), coronary artery disease (HR, 2.655; 95% CI, 1.25-5.64; p = 0.01), pre-transplant cardiac amyloidosis (HR, 5.02; 95% CI 2.37-10.62; p0.001), right atrial volume index (HR, 1.03; 95% CI, 1.00-10.7; p = 0.03), mitral deceleration time160 msec (p0.01), and LVESD30 mm (p0.04).Development of AF/AFL post-heart transplantation is not uncommon and is associated with decreased long-term survival. Cumulative effects of repeated moderate-to-severe (grade 3 or more) rejections that result in increased cardiac fibrosis are associated with the development of AFL, but not AF. Similarly advanced restrictive diastolic dysfunction caused by fibrosis from repeated moderate-to-severe (grade 3 or more) rejections was predominant in the patients with arrhythmia and was a marker of poor long-term outcome.

Background Cardiac allograft vasculopathy (CAV) is considered a major cause of morbidity and mortality in transplant recipients and may reflect immune-mediated endothelial injury in response to the donor heart. Elevated troponin levels in the donor serum might provide a marker for this phenomenon; therefore, we evaluated the relationship of donor troponin levels to the development of CAV. Methods A retrospective analysis of troponin levels was undertaken from cardiac donor patients, and transplant recipients were monitored for the development of vasculopathy by angiography (N = 171). Results Angiographically significant CAV developed in 6% of transplantation patients and troponin levels were inversely related to the severity of CAV. Conclusions Elevated donor troponin levels are not associated with the development of CAV but rather with a significantly reduced long-term risk of developing CAV, suggesting a possible protective effect of donor released protein.

Background Cardiac papillary fibroelastoma is a rare benign tumor that can cause thromboembolism. We have found no large surgical series describing its treatment and outcome. Methods A retrospective review of all patients treated surgically for this tumor from 1985 to 2002. Results There were 88 patients with a mean age of 62 ± 16 years. Sixty-two (71%) were male. Cardiac papillary fibroelastoma was a primary indication for surgery in 47 (group 1, 53%) and an incidental finding in 41 (group 2, 47%). The common clinical symptoms were neurologic (group 1) and cardiac (group 2). Cardiac valves were predominantly involved (77%); the aortic valve was the most affected (52%). Other common sites were the left ventricular outflow tract (18%) and anterior mitral leaflet (11%). All heart valves were involved in one patient. Seventy-three patients (83%) had shave excision and 8 (9%) excision with valve repair. Of 5 (6%) valve replacements, 2 were for concurrent degenerative valve disease. Concomitant procedures included repair or replacement of another valve (32 %), CABG (28%), and septal myectomy (19%). Surgical mortality occurred in 1 patient (2.1%) in group 1 who had concomitant lung resection for bronchiolitis obliterans. There was no tumor recurrence, and no tumor-related late morbidity or mortality at a mean follow-up of 3 years. Conclusions Cardiac papillary fibroelastoma has a propensity to affect the anatomically contiguous structures of the aortic valve, left ventricular outflow tract, and anterior mitral leaflet. Surgical treatment by simple shave excision is low risk and can achieve good results.

Background The process by which cardiac myocytes die during xenograft rejection is incompletely understood. The presence of cardiac myocyte apoptosis in discordant xenotransplant models has been noted, yet no investigators have examined whether a relationship between myocyte apoptosis and rejection severity exists. Thus, we chose to further investigate this observation. Methods Eight explanted pig-to-baboon cardiac grafts with varying severities of rejection, as determined by hematoxylin and eosin histology, were examined for apoptosis by transmission electron microscopy (TEM) and TUNEL (terminal deoxynucleotide transferase-mediated digoxigenin-dUTP nick-end labeling) immunohistochemistry. In addition, Western blot analysis for the cleavage of the apoptosis regulatory proteins pro-caspase 8 and 3 was performed. Results Transmission electron microscopy revealed that a severely rejected graft displayed widespread condensation of nuclear chromatin, which is a characteristic morphologic feature of apoptosis. TUNEL staining verified this observation and allowed for the quantification of myocyte apoptosis in each graft. Subsequent linear regression analysis of the extent of myocyte apoptosis and rejection severity revealed a direct correlation ( R 2 = 0.757, p = 0.005). In addition, Western blot analysis demonstrated that myocyte apoptosis involves the cleavage of pro-caspase 8 and 3. Conclusions Myocyte death in rejecting pig-to-baboon cardiac xenografts occurs through an apoptotic pathway and directly correlates with the severity of graft rejection. Further studies aimed at elucidating the apoptotic stimulus are therefore warranted. Moreover, our data suggest that antiapoptotic strategies may be of benefit in the treatment of xenograft rejection.

Background The purpose of this study was to evaluate outcomes of mitral and tricuspid valve repair after mediastinal radiation therapy. Methods From 1976 to 2001, 22 patients (mean age 61 ± 14 years) underwent mitral (n = 14), tricuspid (n = 6), or both (n = 2) valve repairs 15 ± 9 years after mediastinal radiation therapy. Concomitant procedures included coronary artery bypass graft, 11 patients; valve replacement, 6 patients (4 aortic, 3 mitral, 1 tricuspid, and 1 pulmonary); and pericardiectomy, 4 patients. Results Total follow-up was 82.5 patient-years (mean 3.7 ± 3.3 years). Early mortality was 3 patients. There were 7 late deaths, 4 of which were of cardiovascular origin. Of the 19 early survivors, 2 required subsequent valve replacements, and 1 required cardiac transplantation 3.4 ± 2.8 years after valve repair. One patient died after reoperation. In 4 patients who did not undergo reoperation, echocardiographic examinations showed progressive deterioration of their repaired valve function. Overall survival, freedom from cardiac death, and freedom from valve reoperation or cardiac transplantation at 5 years for early survivors was 66%, 85%, and 88%, respectively. New York Heart Association functional class at follow-up was I or II in 8 of the 12 late survivors. Conclusions Functional status was good in two-thirds of late survivors. However, severe dysfunction of the repaired valve developed in 32% of early survivors and 16% required further surgery. Valve repair is technically feasible in selected patients after mediastinal radiation therapy; however, the limited durability of repairs after mediastinal radiation in this series suggests that valve replacement might be preferable.

Background Advances in tissue prosthetic valve design and manufacturing have stimulated renewed interest in the use of biological valves in younger patients. This approach, however, risks reoperation. We therefore reviewed our recent experience with repeat mitral valve replacement to better define its contemporary risks. Methods Using a computerized database, we identified and compared 106 patients undergoing repeat mitral valve replacement with 562 control patients undergoing primary mitral valve replacement between January 1993 and December 2000 at our institution. Results There were no significant differences between repeat and primary surgery groups with respect to age (mean 66 ± 12 vs 64 ± 13 years), gender distribution (women 65% vs 64%), preoperative functional class, ejection fraction, or active endocarditis (6.6% vs 3.4%). The indication for reoperation in the repeat group was structural dysfunction in 49 patients (46%), paravalvular leak in 21 patients (20%), nonstructural dysfunction in 11 patients (10%), and progression of other native valve disease in 8 patients (8%). Prior prostheses were mechanical in 46 patients (43%). Mean time to reoperation was 11.5 ± 7.1 years. There were 5 deaths out of 106 patients in the repeat group (4.7%) and there were 23 deaths out of 562 patients in the control group (4.1%) ( p = NS). Multivariate analysis identified prior myocardial infarction ( p = 0.014, odds ratio 2.9) and nonelective surgical status ( p = 0.004, odds ratio 2.3) as significant predictors of operative mortality. Conclusions The risk of repeat mitral valve replacement was low suggesting that there should be less reluctance to recommend patients choose a bioprosthesis over a mechanical prosthesis. Given the expected durability of current designs, bioprosthetic use may be explored in younger patients without subjecting those individuals to excessive risk.

BACKGROUND AND AIMS: The combination of CTLA-4Ig with sirolimus can promote indefinite survival in allograft models for which CTLA-4Ig monotherapy is ineffective. We sought to determine whether a limited course of CTLA-4Ig and sirolimus would alter survival of rat orthotopic single-lung transplantations. METHODS: Left lungs of Brown Norway rats were transplanted into four groups of Lewis recipients (n=6 per group): group 1, no treatment; group 2, mCTLA-4Ig (250 microg/day for 4 days); group 3, sirolimus (3 mg/kg per day for 14 days); group 4, combined therapy with sirolimus and mCTLA-4Ig. Graft survival was determined by daily radiologic examination. Histologic grading of rejection and immunohistochemical staining for T and B lymphocytes were carried out at the time of radiologic graft loss. RESULTS: Rejection of lung allografts in group 1 occurred at a median of 6.5 days. Neither sirolimus nor mCTLA-4Ig monotherapy resulted in significant prolongation of graft survival (median 9.5 and 8.0 days, respectively). Graft survival in group 4 was significantly prolonged compared with all other groups (median 29.5 days), and a significant reduction in histologic grade of rejection was observed following combination therapy compared with all other groups. Infiltration by CD8+ve T cells at the time of rejection was proportionately greater than CD4+ve T-cell infiltration for groups 1, 2, and 3 but not for the combined-therapy group. CONCLUSIONS: A brief course of combined mCTLA-4Ig and sirolimus prolongs graft survival, reduces severity of rejection, and attenuates CD8+ve T-cell infiltration of fully major histocompatibility complex mismatched lung allografts.

The exercise capacity of cardiac transplant recipients is reduced compared with normal controls. However, clinical variables predictive of post-transplant exercise capacity have not been well defined. The objective of the present study was to identify clinical features predictive of post-transplant exercise capacity.Ninety-five cardiac transplant recipients underwent cardiopulmonary testing at 1 year after transplant. The exercise parameters were compared with both pre-transplant values and normal subjects. The relationships between exercise parameters and clinical characteristics were analyzed.Mean peak oxygen consumption (VO(2)) and exercise test duration at 1-year post-transplant improved significantly from 16.4 to 19.9 ml/kg/min and 5.5 to 7.6 minutes, respectively (p0.001), but were significantly lower than for normal controls (peak VO(2) 34.0 ml/kg/min; exercise duration 11.2 minutes; p0.001). Age- and gender-adjusted VO(2) was 54% of predicted. Pre-operative body weight correlated strongly with post-transplant weight (r = 0.80, p0.001). Significant recipient predictors of 1-year post-transplant peak VO(2) identified by multivariate regression analysis were age, male gender, body mass index, exercise peak heart rate and duration of post-operative intensive care. Donor variables did not contribute significantly to post-transplant peak VO(2).Peak VO(2) improved after cardiac transplantation but remained significantly impaired compared with normal subjects. In estimating the impact of cardiac transplantation on exercise capacity the most important pre-transplant factors to consider are age, gender and height and weight (or, alternatively, body mass index).

Radiation-induced heart disease is an increasingly recognized late sequela of mediastinal radiation therapy for malignant neoplasms. We report four cases of heart transplantation for end-stage heart failure induced by mediastinal radiation therapy. Short-term and intermediate-term results are excellent with all four patients currently surviving a mean of 48 months after transplantation. Neither a second malignancy nor recurrence of the primary malignancy has been observed to date. The early results of heart transplantation for end-stage, radiation-induced heart disease are encouraging.

Objective To review the outcome of cardiac transplantation undertaken in patients with congenital heart defects. Material and Methods Between November 1991 and March 1998 at our institution, cardiac transplantation was performed in 16 patients with congenital heart disease (age range,3 to 57 years; mean, 26.1). Preoperative diagnoses included univentricular heart (N = 4); complete transposition of the great arteries (N = 3); Ebstein's anomaly (N = 2); tetralogy of Fallot (N = 2); levotransposition (N = 2); dextrocardia, corrected transposition, ventricular and atrial septal defects, and pulmonary stenosis (N = 1); double-outlet right ventricle (N = 1); and hypertrophic obstructive cardiomyopathy (N = 1). All patients had undergone from one to five previous palliative operations. Results Four patients required permanent pacemaker implantation during the first month postoperatively because of bradycardia; more than 2 years later, another patient required a permanent pacemaker because of sick sinus syndrome. In addition, one patient had an automatic implantable cardioverter-detibrillator. Three patients required reconstruction of cardiovascular structures with use of prosthetic material (Teflon patches or donor tissue) at the time of cardiac transplantation. Actuarial 1-, 2-, and 5-year survival was 86.2 ±9.1 %. During the first year after transplantation, two deaths occurred-one at 41 days of putative vascular rejection and the second at 60 days of severe cellular rejection. All other patients are alive and functionally rehabilitated; the mean follow-up period has been 26.1 months (range, 2 to 89.6). Conclusion Cardiac transplantation for patients with congenital heart disease can be accomplished with a low perioperative mortality and an excellent medium-term survival despite the challenges presented by the technical difficulties during invasive diagnostic procedures and at operation and the need for adherence to long-term multiple-drug therapy in this patient population.

OBJECTIVE: The transfer of recombinant genes to donor organs may allow for novel therapeutic approaches to the challenges of acute and chronic rejection. Adenoviral vectors are capable of efficient gene transfer, but use of these vectors during donor organ preservation may be less efficient due to the low temperature. This study was designed to examine the effect of temperature on the efficiency of adenovirus-mediated gene transfer. METHODS: Gene transfer to human endothelial cells, porcine vascular smooth muscle cells and cultured rat thoracic aortas was examined. Incubation with an adenoviral vector encoding for E. coli beta-galactosidase was performed for 1 h at three different temperatures: 4 degrees C, 10 degrees C and 37 degrees C. Transgene expression was assessed by histochemical staining for beta-galactosidase in transduced cells and by evaluation of beta-galactosidase activity in organ cultures. RESULTS: Both in human endothelial cells and vascular smooth muscle cells the percentage of positively staining cells following transduction at 37 degrees C was significantly greater than at 4 degrees C and at 10 degrees C (30.55 +/- 7.26% vs. 14.29 +/- 3.79% and 12.43 +/- 2.47%, respectively for endothelial cells, P < 0.01 vs. 4 degrees C and 10 degrees C; and 28.25 +/- 4.52% vs. 17.91 +/- 3.76% and 16.63 +/- 3.92%, respectively for smooth muscle cells, P < 0.05 vs. 4 degrees C, P < 0.01 vs. 10 degrees C). Beta-galactosidase activity was significantly greater in aortas transduced at 37 degrees C than in vessels transduced at 4 degrees C and 10 degrees C (289,700 +/- 113,300 vs. 149,600 +/- 54,390 and 108,800 +/- 23,140 relative chemiluminesce units/mg of total protein, respectively; P < 0.05 vs. 4 degrees C, P < 0.001 vs. 10 degrees C). CONCLUSIONS: The present study demonstrates that the efficiency of adenovirus-mediated gene transfer is significantly reduced at lower temperatures. The need for cold preservation of donor organs may render efficient adenovirus-mediated gene transfer more difficult in the transplantation setting.

Objective: Shortage of donor organs for children has led to the use of living related adult lung lobar transplants. It is not known how these lobes or the recipient remaining lung grow after such transplants. The purpose of the present study was to assess lung growth in rat lungs up to 6 months after adult lobe transplantation into a juvenile recipient. Methods: Right cardiac lung lobes from adult male Lewis rats were transplanted into the left hemithorax of juvenile (6-week-old) male Lewis rats after left pneumonectomy. Animals with appropriate controls were put to death 14 days and 6 months after transplantation. The lungs were fixed inflated and studied by means of quantitative morphometric techniques. Results: By 6 months after transplantation both the recipient right lung and the transplanted cardiac lobe were significantly larger than normal ( p = 0.005; p = 0.001). In the recipient right lung this increase was due to an increase in the number of alveoli ( p = 0.004) and in the transplanted cardiac lobe to an increase in size of the alveoli ( p = 0.008). Conclusions: An adult lobe transplanted into a young recipient is still viable and has normal architecture after 6 months, and growth of the recipients' own lung continues. The outlook for comparable transplants in children is promising, although the human condition can be complicated by rejection, infection, and treatment strategies. (J Thorac Cardiovasc Surg 1998;115:644-51)

BACKGROUND: The current success of cardiac transplantation is in part attributable to the development of effective immunosuppressive agents such as cyclosporine. However, concern remains regarding the potential for cyclosporine-induced nephrotoxicity. Animal studies and early reports of renal protective effects of pentoxifylline in bone marrow transplant recipients prompted a randomized trial in cardiac transplant recipients. METHODS: Twenty-nine patients were randomized to receive pentoxifylline 400 mg p.o. t.i.d. or matching placebo for 1 year after cardiac transplantation. Renal function was assessed preoperatively and at 1, 6, and 12 months postoperatively. Glomerular filtration rate and renal plasma flow were measured with iothalamate and para-aminohippurate, respectively. Serum creatinine was also measured. Ambulatory blood pressure monitoring after withdrawal of antihypertensives for 3 days was performed 12 months postoperatively. RESULTS: Twenty-seven patients completed the study. Glomerular filtration rate rose between 1 and 6 months after transplantation, presumably due to the reduction in goal cyclosporine level in that period, and then fell modestly between 6 and 12 months, presumably due to ongoing nephrotoxic effects of cyclosporine. No difference in glomerular filtration rate or creatinine was seen between pentoxifylline and placebo groups at any interval. Renal plasma flow increased modestly between baseline and 6 months in the pentoxifylline group, but not in the placebo group, and then fell between 6 and 12 months. Serum creatinine increased between baseline and 6 months in both groups, apparently due to increased body weight. Results of 18-hr ambulatory blood pressure monitoring obtained 1 year after transplantation was not different between groups. CONCLUSIONS: Renal function declines only modestly in the first year after cardiac transplantation. Pentoxifylline did not attenuate this process and had no effect on blood pressure. The modest decline in renal function may be related to current immunosuppressive strategies.

This study compares the effect of lung preservation using flush perfusion of Euro-Collins or University of Wisconsin solution on the pulmonary vascular function of endothelium-dependent and endothelium-independent relaxations.Rings of canine intrapulmonary arteries were studied after 6 hours of cold ischemia in Euro-Collins or University of Wisconsin preservation solution. Endothelium-dependent and endothelium-independent relaxations were induced in organ chamber experiments. To also study pulmonary resistance vessels, endothelium-dependent relaxations were induced in in vitro perfused intact rabbit lungs.In the organ chamber experiments, a moderate but significant (p0.05) reduction in endothelium-dependent relaxations were found in the perfused and stored vessels. In perfused rabbit lungs, a decrease in the endothelial response occurred immediately after perfusion with Euro-Collins solution. However, a recovery and overshooting response was found after preservation with either solution and 6 hours of cold ischemia. A significant increase in the sensitivity of smooth muscle cells to nitric oxide was shown in both preparations.Both crystalloid perfusion fluids cause a decrease in endothelial function during the perfusion procedure. In contrast, endothelial function is well preserved during the ischemic time. University of Wisconsin solution induced a higher sensitivity of the vascular smooth muscle to the endothelium-derived relaxing factor nitric oxide. A reduction in pulmonary vascular resistance after University of Wisconsin preservation may be of importance in subsequent clinical lung transplantation.

The use of paracorporeal mechanical biventricular support devices either as a bridge to transplantation or while awaiting recovery of the failing heart has been well described in the literature. The majority of these reports detail conditions specific to the adult population. We describe use of the Thoratec ventricular assist device (Thoratec Corp, Pleasanton, CA) in the smallest known cardiomyopathy patient to date to be successfully supported with an emergent biventricular device before subsequent cardiac transplantation. The operative technique, pump settings, and modifications utilized to optimize peripheral perfusion are detailed.

Circulating leukocytes activated during rejection of organ allografts could potentially have generalized effects on systemic blood vessels of the transplant recipient. Experiments were designed, therefore, to determine the function of the endothelium and smooth muscle of arteries from nontransplanted organs in dogs who received single lung transplants. Dogs underwent single lung allotransplantation and were immunosuppressed for 5 days. Immunosuppression was then withheld for 3 days, allowing rejection to occur. Dogs were studied at this time (rejecting) or following treatment for rejection for an additional 6-8 days (treated). Arteries from unoperated, untreated dogs also were studied to provide baseline responses of healthy tissue. Rings cut from left circumflex coronary, nonoperated native pulmonary, and renal arteries were suspended in organ chambers for measurement of isometric force. Endothelium-dependent relaxations to the calcium ionophore A23187 were not affected by rejection in any of the arteries. Contractions to angiotensin I were reduced significantly only in native pulmonary arteries. Contractions to KCI and endothelin-1 increased in renal arteries with endothelium during rejection. These contractions in renal arteries were reduced following treatment of rejection. None of the responses of the coronary arteries were affected significantly by rejection of the lung allograft. These results demonstrate that contractions of arteries in the transplant recipient's native organs are altered during rejection of lung allografts. The effects are organ specific, may include production of endothelium-derived contractile factors in renal arteries, and can be partially reversed by treatment of rejection.

Experiments were designed to determine whether or not acute rejection of allotransplanted lungs altered endothelin-content and receptors in recipient heart and kidneys. Five groups of dogs were studied: 1) unoperated, non-immunosuppressed; 2) unoperated, immunosuppressed; 3) single lung autotransplanted, non-immunosuppressed; 4) nonrejecting single lung allotransplanted (allotransplant, immunosuppressed), and 5) rejecting single lung allotransplanted (allotransplant, rejecting). Operated animals were sacrificed eight days after the surgical intervention. Immunosuppression began the day of surgery and continued for five days. At this time, immunosuppression was either maintained in some animals (allotransplanted, immunosuppressed) or discontinued so that rejection would occur (allotransplanted, rejecting). Unoperated, immunosuppressed animals were maintained on the same drug schedule as the allotransplanted, rejecting animals. Serum levels of endothelin-1 were comparable among groups. However, tissue-conte...

Ischemia of the donor airway remains a significant cause of morbidity after single-lung transplantation; serious manifestations may occur early (anastomotic dehiscence) or late (stricture). Direct, immediate revascularization of the donor bronchial arteries, using the recipient internal thoracic artery, was performed in 10 consecutive recipients of single-lung transplants for whom we procured the organs. Mean recipient age was 52.6 years (range, 43 to 59 years); 6 were male and 4 female. Recipient diagnoses were emphysema (6), obliterative bronchiolitis (2), pulmonary fibrosis (1), and primary pulmonary hypertension (1). Bronchial artery revascularization initially prolonged the ischemic time by only 15 to 20 minutes; this improved with experience. There was one early death and two late deaths in the series. Internal thoracic arteriography was performed 7 to 10 days postoperatively in all 9 surviving patients. There was excellent perfusion of the donor bronchial arteries in 7 of these 9 patients. Bronchoscopy was performed when clinically indicated. No patient had early or late airway healing complications at a median follow-up of 13 months (range, 6 to 16 months). We conclude that direct, immediate bronchial artery revascularization is feasible on a routine basis for single-lung transplantation, and airway healing has been excellent.

The effects of pulmonary denervation and rejection on contractions of bronchial smooth muscle and epithelial modulation of these contractions were studied in dogs after denervation in right lung autotransplantation (n = 6) and acute rejection after right lung allotransplantation (n = 8). Immunosuppression was withdrawn from the latter group after 5 days; rejection developed after 3 additional days. A significant (p < 0.05) increase in mean peak airway pressure occurred with rejection of allotransplanted lungs. Rings cut from third-order bronchi of transplanted and contralateral unoperated (native) lungs in each animal were suspended in organ chambers for the measurement of isometric force. In some rings, the epithelium was removed mechanically. Acetylcholine (cholinergic neurotransmitter), serotonin (platelet-product), histamine (mast cell product), and endothelin-1 (endothelium-derived contracting factor) caused concentration-dependent contractions in all rings. In bronchi from native lungs, rings with epithelium contracted less than those without epithelium. This difference was lost after autotransplantation. The smooth muscle and epithelium were affected differently by autotransplantation. Contractions of rings without epithelium decreased in response to acetylcholine and endothelin-1, whereas contractions of rings with epithelium increased in response to histamine and 5-hydroxytryptamine (p < 0.05). During acute rejection, contractions were the same as those after autotransplantation. Bronchial content of endothelin increased fourfold with rejection. Relaxations to isoproterenol and prostaglandin E2 were similar in both groups. In conclusion, denervation reduced the ability of the smooth muscle to contract. The degree of acute pulmonary rejection seen in this study did not further affect bronchial contractions. Modulation of contractions by the bronchial epithelium was lost with both denervation and rejection.

To determine factors that influence survival and recovery of ventricular function in patients undergoing aortic valve replacement in the current surgical era, baseline risk factors related to outcome were analyzed in 1,012 consecutive patients undergoing aortic valve replacement between 1983 and 1990. Forty-two percent of patients underwent concomitant coronary bypass. Observed survival probabilities (expressed as 30-day/5-year) were 0.97/0.81 overall, 0.99/0.89 for patients aged less than 70 years, and 0.95/0.74 for patients aged 70 years or greater. Advanced age (p < 0.0001), decreased ejection fraction (p < 0.0001), extent of coronary disease (p < 0.006), smaller prosthetic valve (p < 0.03), and advanced New York Heart Association class (p < 0.04) were incremental risk factors for mortality. In patients with preoperative ventricular dysfunction (ejection fraction < or = 0.45), ejection fraction measured 1.4 years after aortic valve replacement improved in 72% and the mean increment in ejection fraction was 0.175 (95% confidence interval, 0.154 to 0.195). The increment in ejection fraction was greater in female patients than in male patients (p < 0.02) and greater in patients without than with coronary disease (p < 0.02). Female sex (p < 0.02) and lesser extent of coronary disease (p < 0.05) were independent predictors of change in ejection fraction. In all patients, early improvement in ejection fraction conveyed an independent subsequent survival benefit (p < 0.0001). The results of aortic valve replacement in the current era are excellent, and the majority of patients with ventricular dysfunction demonstrate significant improvement. Early improvement in ejection fraction, influenced by coexistent coronary artery disease and sex-associated factors, importantly affects subsequent survival.

Chronic pulmonary disease is associated with varying degrees of cardiac dysfunction. Because of the potentially predominant effect of severe lung disease on right ventricular (RV) size and function, a reliable method to assess RV mechanics before and after lung transplantation may provide information of long-term significance and/or prognosis. Conventional invasive and non-invasive imaging methods have a number of limitations in evaluating RV function. Ultrafast computed tomographic (ultrafast CT) scanning has been shown to provide quantitative assessment of RV and left ventricular (LV) function in individuals with and without cardiac disease. Twenty-two patients presenting during evaluation for possible lung transplantation with end-stage pulmonary disease formed the basis of this study. There were 14 patients with chronic obstructive pulmonary disease and 8 with pulmonary fibrosis. Conventional transthoracic echocardiography and ultrafast CT were used for the assessment of RV and LV function. All patients had invasive assessment of right-sided hemodynamics and pulmonary function studies performed within 7-10 days of cardiac imaging. A qualitative assessment of RV size or function was possible in all but two patients by echocardiogram, but in 45%, the echocardiographic examination was described as suboptimal. In contrast, a quantitative assessment of ventricular volumes and systolic function was obtained in all patients by ultrafast CT. Pulmonary function parameters or hemodynamic measurements obtained during cardiac catheterization did not correlate with any assessment of RV function. We concluded that (1) ultrafast CT provides measurement of the RV and LV cavity dimension and systolic function; (2) invasive right-sided hemodynamics or pulmonary function studies do not predict RV function; and (3) echocardiography does not uniformly provide assessment of RV function in patients with chronic pulmonary disease.

Transbronchial biopsy has become the procedure of choice for the diagnosis of acute lung rejection after transplantation, but the sensitivity of the technique in this setting remains unknown. In this study, 14 mongrel dogs underwent left lung transplantation, after which triple-drug immunosuppression was given for 5 days and then all immunosuppression was stopped. All animals had clear chest radiographs at this time. Transbronchial biopsy was performed in nine lung regions (two to six pieces of lung tissue were obtained per region, with a mean of 4.3 pieces per region) before the animals were killed 2 to 4 days later, at which time varying degrees of rejection had occurred. Rejection was graded histologically on a scale of 0 to 3 (0 = no rejection, 1 = mild rejection, 2 = moderate rejection, 3 = severe rejection) in each piece of lung tissue obtained at transbronchial biopsy. After the dogs were put to death, the true state of lung rejection was determined by histologic examination of the entire lung. We calculated the sensitivity of transbronchial biopsy with 95% confidence intervals. Five pieces of lung tissue were needed to yield a sensitivity of 92% (82%, 100%) to identify mild rejection in the entire lung with transbronchial biopsy. Three pieces of lung tissue were needed to yield a sensitivity of 92% (84%, 100%) to identify the presence of moderate to severe rejection in the entire lung (that is, rejection that requires pulse therapy) on transbronchial biopsy. These results indicate that three to five pieces of lung tissue that are suitable for diagnostic purposes obtained at transbronchial biopsy are adequate for the diagnosis of acute pulmonary rejection after lung transplantation.

Little is known regarding changes in reactivity of the vasculature of transplanted solid organs. Experiments were designed to differentiate the effects of denervation and rejection on the function of the endothelium and smooth muscle of pulmonary arteries in transplanted lungs of the dog. Single lungs were transplanted as autografts to study the effects of denervation or as allografts to study the additional effects of rejection. Immunosuppression was stopped in animals receiving allografts 5 days after operation, and rejection was allowed to proceed for an average of 3 days. Animals receiving autografts were studied after the same time period. There were no differences in concentrations of circulating leukocytes, platelets, or lymphocytes between the two groups. Circulating concentrations of angiotensin-converting enzyme were significantly reduced during rejection; concentrations of endothelin were unchanged. Rings of pulmonary arteries with and without endothelium were suspended for the measurement of isometric force in organ chambers. Contractions to angiotensin I and endothelin were less in rejecting than in autotransplanted arteries, whereas those to 5-hydroxytryptamine were enhanced. Contractions to norepinephrine were comparable in both autograft and rejecting allograft arteries. Relaxations to isoproterenol were greater in the autograft than in the rejecting autografted arteries; the opposite was observed for relaxations to histamine. Endothelium-dependent relaxations to adenosine diphosphate and bradykinin but not to calcium ionophore A23187 were reduced with rejection; relaxations to nitric oxide were unchanged. These results suggest that transplantation per se affects vascular reactivity. However, there are selective dysfunctions of receptor-operated mechanisms in arteries that are associated with rejection and that are distinct from denervation. Further, serum concentrations of angiotensin-converting enzyme may be an indicator of rejection of transplanted lungs.

Although glutaraldehyde fixation is known to reduce immunogenicity and degeneration of heart valve bioprostheses, some degree of immunogenicity persists, which may trigger calcification. The aims of this study were to: (1) define the role of alpha-1,3-galactosyltransferase (alpha-Gal) antigen in valve calcification by comparing alpha-Gal-positive and alpha-Gal-deficient (GT-KO) pig pericardium; and (2) elucidate the role of human anti-Gal antibodies in the process of calcification and to determine the potential influence of different tissue-fixation techniques.Glutaraldehyde-treated pericardium from alpha-Gal-positive and GT-KO pigs, with or without pre-labeling with human anti-Gal antibodies, were implanted in rats during 1 month.In glutaraldehyde-fixed pericardium, calcification levels were significantly lower in GT-KO pig pericardium (132.8 +/- 5.8 microg/mg) as compared with alpha-Gal-positive pig pericardium (155.7 +/- 7.1 microg/mg) (p0.015). In glutaraldehyde-fixed pig pericardium followed by a mix of formaldehyde, ethanol and Tween 80 (FET), the calcification levels were lower in GT-KO pig pericardium (0.35 +/- 0.1 microg/mg) as compared with alpha-Gal-positive pig pericardium (4.6 +/- 4.2 microg/mg). In glutaraldehyde-fixed pig pericardium + FET pre-incubated with human anti-Gal antibodies, calcification levels were significantly greater in alpha-Gal-positive pig pericardium (43.8 +/- 8.5 microg/mg) as compared with GT-KO pig pericardium (5.7 +/- 2.9 microg/mg) (p0.0001).This study demonstrates the role of alpha-Gal antigen and human alpha-Gal antibodies in the calcification process of valvular bioprostheses. It is suggested that GT-KO pig pericardium could be beneficial as a new source of material for heart valve bioprostheses.

BACKGROUND: Simultaneous combined orthotopic heart and liver transplantation (CHLTx) remains a lifesaving procedure for the patients suffering from coincident end-stage heart and liver disease and several metabolic disorders. We analyze the long-term outcome of the patients undergoing CHLTx. METHODS: Between January 1992 and May 2007, 15 CHLTx were attempted at the Mayo Clinic including two combined heart, liver, and kidney transplantations and one combined heart, lung, and liver transplantations. Pretransplant cardiac diagnoses were familial amyloidosis (11), hemochromatosis (1), restrictive cardiomyopathy and cardiac cirrhosis (1), previously operated congenital heart disease and cardiac cirrhosis (1), and primary pulmonary hypertension with primary biliary cirrhosis (1). RESULTS: Heart and liver transplantation were performed as a single combined procedure in 13 (93%) hemodynamically stable patients, and there was no perioperative mortality. Survival rates for the CHLTx recipients at 1 year, 5 years, and 10 years were 100%, 75%, and 60%, respectively, and did not differ from survival after isolated heart transplantation (93%, 83%, and 65%, respectively, P=0.39). Freedom from cardiac allograft rejection (ISHLT > or =grade 2) for CHLTx was 83% at 1 month, did not change with time, and was lower than after isolated heart transplantation (P=0.02). At the mean follow-up of 61.6+/-53.6 months, normal left ventricular ejection fraction and good liver allograft function were demonstrated. Three patients developed end-stage renal failure secondary to calcineurin nephrotoxicity. CONCLUSION: Simultaneous heart and liver transplantation is feasible and achieved excellent results for selected patients.