The Journal of Heart and Lung Transplantation - Articles in Press

Construct validity of the definition of primary graft dysfunction after lung transplantation - Corrected Proof

2010-07-23

Background: This study tested the discriminant validity of International Society for Heart and Lung Transplantation (ISHLT) primary graft dysfunction (PGD) grades with lung injury biomarker profiles and survival.Methods: The study samples consisted of a multicenter prospective cohort study for the biomarker analysis and a cohort study of 450 patients for the mortality analyses. PGD was defined according to ISHLT consensus at 24, 48, and 72 hours after transplantation. We compared the changes in plasma markers of acute lung injury between PGD grades using longitudinal data models. To test predictive validity, we compared differences in the 30-day mortality and long-term survival according to PGD grade.Results: PGD Grade 3 demonstrated greater differences between plasma intercellular adhesion molecule 1 (ICAM-1), protein C, and plasminogen activator inhibitor type 1 (PAI-1) levels than did PGD Grades 0 to 2 at 24, 48, and 72 hours after lung transplantation (p < 0.05 for each). Grade 3 had the highest 30-day (test for trend p < 0.001) and overall mortality (log rank p < 0.001), with PGD Grades 1 and 2 demonstrating intermediate risks of mortality. The ability to discriminate both 30-day and overall mortality improved as the time of grading moved away from the time of transplantation (test for trend p < 0.001).Conclusions: The ISHLT grading system has good discriminant validity, based on plasma markers of lung injury and mortality. Grade 3 PGD was associated with the most severely altered plasma biomarker profile and the worst outcomes, regardless of the time point of grading. PGD grade at 48 and 72 hours discriminated mortality better than PGD grade at 24 hours.

Low potassium dextran is superior to University of Wisconsin solution in high-risk lung transplant recipients - Corrected Proof

2010-07-15

Background: The ideal solution for recovery of donor lungs remains unknown. Low potassium dextran (LPD) solution is most common, but University of Wisconsin (UW) solution is also used. The United Network for Organ Sharing (UNOS) database allows assessment of preservation solutions in a large cohort of lung transplant (LTx) patients.Methods: We retrospectively reviewed the UNOS data set for adult primary LTx patients (2005–2008) whose donor lungs were recovered with UW or LPD solution. Patients were stratified by UW vs LPD, and secondarily grouped by quartiles of the lung allocation score (LAS) to examine high-risk recipients. Kaplan-Meier (KM) short-term mortality (30 days, 90 days, 1 year) and rejection in the first year were examined for intervals with adequate follow-up. Cox proportional hazard regression using 11 variables examined all cause 1-year mortality.Results: Of 4,455 patients, 4,161 (93.4%) received LPD lungs and 294 (6.6%) received UW lungs, and 1,105 patients (24.8%) died during the study. There was no mortality difference based on flush solution with all patients examined together. However, patients in the upper 2 LAS quartiles (Q3: 37.8–45.4, Q4: > 45.4) receiving LPD lungs had greater 1-year survival of 81.5% vs 73.5% (p = 0.02). On multivariable analysis, flush with UW solution resulted in an increased risk of 1-year mortality (hazard ratio, 1.77. 95% confidence interval, 1.21–2.58; p = 0.003) vs LPD. Preservation solution did not affect rejection rates in the year after LTx. KM modeling demonstrated the effect of flush solution on survival (p = 0.02).Conclusions: This study is the largest modern cohort to evaluate the effect of donor lung flush solutions on survival in adult LTx. UW solution increases the risk of 1-year mortality in high-risk LTx recipients.

Prevalence of de novo aortic insufficiency during long-term support with left ventricular assist devices - Corrected Proof

2010-07-12

Background: Left ventricular assist devices (LVADs) are increasingly used as long-term therapy for end-stage heart failure patients. We compared the prevalence of aortic insufficiency (AI) after HeartMate II (HMII) vs HeartMate XVE (HMI) support and assessed the role of aortic root diameter and aortic valve opening in the development of AI.Method: Pre-operative and post-operative echocardiograms of 93 HMI and 73 HMII patients who received implants at our center between January 2004 and September 2009 were retrospectively reviewed. After excluding patients with prior or concurrent surgical manipulation of the aortic valve, with baseline AI, or without baseline echoes, 67 HMI and 63 HMII patients were studied. AI was deemed significant if mild to moderate or greater. Pathology reports were reviewed for 77 patients who underwent heart transplant.Results: AI developed in 4 of 67 HMI (6.0%) and in 9 of 63 HMII patients (14.3%). The median times to AI development were 48 days for HMI patients and 90 days for HMII patients. For patients who remained on device support at 6 and 12 months, freedom from AI was 94.5% and 88.9% in HMI patients and 83.6% and 75.2% in HMII patients (log rank p = 0.194). Aortic root diameters, as determined by echocardiography for the patients with AI, trended to be larger at baseline (3.43 ± 0.43 vs 3.15 ± 0.40; p = 0.067) and follow-up (3.58 ± 0.54 vs 3.29 ± 0.50; p = 0.130) compared with those who did not have AI. Aortic root circumferences were assessed directly by a pathologist in those patients who underwent transplant and were significantly larger in HMII patients who had developed AI compared with those patients who did not (8.44 ± 0.89 vs 7.36 ± 1.02 cm; p = 0.034). Lastly, AI was more common in patients whose aortic valve did not open (11 of 26 vs 1 of 14; p = 0.03).Conclusion: Aortic insufficiency occurs frequently in patients who receive continuous-flow support with a HMII LVAD, and may be associated with aortic root diameter enlargement and aortic valve opening. These findings warrant a more thorough preoperative patient evaluation and additional studies to investigate the factors, that may be associated with AI development.Heart Lung Transplant 2010;XX:xxx–xxx

Long-term azithromycin therapy for bronchiolitis obliterans syndrome: Divide and conquer? - Corrected Proof

2010-07-12

Background: Azithromycin may reverse or halt the decline of pulmonary function (FEV1) in bronchiolitis obliterans syndrome (BOS). In this study we investigated the effects of long-term azithromycin treatment in lung transplant recipients with BOS.Methods: A retrospective, observational, cohort study was performed on 107 patients with BOS (Stages 0p/1/2/3, n = 23/62/20/2), who were treated with azithromycin for 3.1 ± 1.9 years. Patients were evaluated 6.3 ± 3.8 years after transplantation and assessed for evolution of FEV1, bronchoalveolar lavage neutrophilia and overall survival after initiation of azithromycin. Survival curves were analyzed using the log-rank test. Cox proportional hazard survival regression analysis was performed to estimate hazard ratios of clinical variables predicting outcome.Results: FEV1 increased ≥10% after 3 to 6 months of treatment in 40% of patients, of whom 33% later redeveloped BOS. FEV1 further declined in 78% and stabilized in 22% of the remaining non-responders. Pre-treatment neutrophilia was higher in responders: 29.3% (9.3% to 69.7%) vs 11.5% (2.9% to 43.8%) (p = 0.025), in whom it significantly decreased to 4.2% (1.8% to 17.6%) (p = 0.041) after 3 to 6 months of azithromycin. Responders demonstrated better survival compared with non-responders (p = 0.050), with 6 and 21 patients, respectively, dying during follow-up (p = 0.027). Multivariate analysis identified initial azithromycin response and earlier post-transplant initiation of azithromycin to be protective for both BOS progression/relapse (hazard ratio [HR] = 0.12 [95% confidence interval 0.05 to 0.28], p < 0.0001; and HR = 0.98 [95% confidence interval 0.97 to 0.98], p < 0.0001, respectively) and retransplantation/death during follow-up (HR 0.10 [95% confidence interval 0.02 to 0.48], p = 0.004; and HR 0.96 [95% confidence interval 0.95 to 0.98], p < 0.0001, respectively).Conclusions: Long-term azithromycin benefits pulmonary function and survival in BOS, particularly in patients with increased lavage neutrophilia.

Right ventricular reserve and outcome after continuous-flow left ventricular assist device implantation - Corrected Proof

2010-07-12

Continuous-flow left ventricular assist devices (LVAD) are now used as alternatives to orthotopic heart transplantation (OHT) for end-stage heart failure. However, right ventricular (RV) dysfunction is common in these patients, inducing a high rate (15% to 44%) of RV failure (RVF) after LVAD implantation. Previous studies demonstrated the link between preoperative RV systolic dysfunction and postoperative RVF in cardiogenic shock. However, prediction of RVF after LVAD implantation remains elusive, especially in patients with RV systolic dysfunction.

Mechanical circulatory support in patients with heart failure secondary to transposition of the great arteries - Corrected Proof

2010-07-12

Advances in palliation of congenital heart disease have resulted in improved survival to adulthood. Many of these patients ultimately develop end-stage heart failure requiring left ventricular assist device implantation (LVAD). However, morphologic differences in the systemic ventricle of these patients require careful attention to cannula placement. We report on the evolution of our surgical technique for implanting LVADs in 3 patients with transposition of the great arteries and congenitally corrected transposition of the great arteries. Applying standard LV cannulation techniques to the systemic ventricle led us too anteriorly in our first patient, creating obstruction by the moderator band. Subsequent use of epicardial and transesophageal echocardiography allowed for intraoperative localization of the intracardiac muscular structures to identify the optimal cannulation site. The acute angle of the inflow cannula on the DeBakey LVAD (MicroMed Technology, Houston, TX) required flipping the device 180°. The HeartMate II device (Thoratec, Pleasanton, CA) could be shifted towards the midline. One patient underwent successful transplant and 2 are home waiting for a donor organ. We conclude from our experience that LVAD surgery can be safely performed in patients with congenital heart disease when implanted under echocardiographic guidance.

Erythropoietin inhibits post-ischemic leukocyte adhesion but does not affect rejection in murine cardiac allografts - Corrected Proof

2010-07-12

Background: This study was aimed to assess the pleiotropic effects of non-hematopoietic doses of erythropoietin (Epo) on post-ischemic microcirculatory dysfunction and inflammation in murine cardiac allografts.Methods: Epo was given intraperitoneally 2 hours prior to explantation (Epo-donor) or 2 hours prior to the onset of reperfusion (Epo-recipient). Controls were not treated. Intravital fluorescence microscopy (IVM) was used to assess post-ischemic coronary microcirculatory dysfunction.Results: IVM exhibited decreasing capillary blood flow velocities and functional capillary densities (FCD) in controls. Capillary diameters and venular blood flow characteristics showed no significant changes over time. Epo-treatment had no effect on coronary microhemodynamics. Post-ischemic inflammation was characterized by augmented macromolecular leakage. Microvascular permeability decreased in the Epo-donor group (p < 0.05). Leukocyte rolling in coronary post-capillary venules decreased during reperfusion from 64 ± 16 to 19 ± 16 cells/min/mm, whereas firm adhesion increased from 333 ± 135 to 479 ± 154 cells/mm2 in controls. Capillary leukocyte plugging remained stationary over time with approximately 4 to 6 cells/HPF. Firm adhesion was inhibited in the Epo-recipient group, resulting in 84 ± 34 cells/mm2 at 6 hours of reperfusion (p < 0.05). Capillary leukocyte plugging was also reduced in the Epo-recipient group (p < 0.05). Epo exerted no effect on leukocyte rolling. Histology revealed significant myocardial edema formation in allografts, without any alteration by Epo treatment. Immunohistochemistry indicated the involvement of resident cardiac mast cells. Allograft rejection was not affected by Epo treatment.Conclusions: We demonstrate that non-hematopoietic treatment with Epo inhibits acute post-ischemic myocardial leukocyte sequestration, without affecting microcirculatory dysfunction and allograft rejection.

Impact of fixed pulmonary hypertension on post–heart transplant outcomes in bridge-to-transplant patients - Corrected Proof

2010-07-12

Background: Fixed pulmonary hypertension (FPH) is considered a contraindication to cardiac transplantation. Ventricular assist device (VAD) therapy through prolonged left ventricular unloading may reverse FPH. Our aim was to assess post-transplant outcomes and survival in patients with and without FPH undergoing VAD implantation as bridge to transplant.Methods: Fifty-four patients received an intracorporeal left VAD (LVAD) as a bridge to transplant from 2000 to 2008 at two institutions (Rigshospitalet, Denmark, and the Toronto General Hospital, Canada). Twenty-two (41%) patients had fixed FPH (defined as pulmonary vascular resistance [PVR] >3 Wood units and resistant to pulmonary vasodilators) prior to VAD implant (FPH group) and were compared with 32 patients without FPH (NoFPH group). Baseline characteristics, pre- and post-transplant pulmonary pressures, incidence of complications and post-transplant survival were analyzed.Results: Baseline characteristics were similar except that patients in the FPH group were older (46 ± 11 years vs 39 ± 13 years in the NoFPH group, p < 0.05). The mean pre-VAD PVR was 4.3 ± 1.7 Wood units in the FPH group and 1.7 ± 0.5 Wood units in the NoFPH group (p < 0.001). Pulmonary pressures were higher in the FPH group immediately prior to VAD implant, but they were comparable immediately pre-transplant and during the first year post-transplant. The incidence of post-transplant RV failure was not significantly different between groups. Post-transplant survival was similar between groups.Conclusions: VAD therapy successfully decreases pulmonary hypertension, even in patients with “fixed” FPH, allowing candidacy for heart transplantation. Among bridge-to-transplant candidates, the presence of FPH does not reduce post-transplant survival.

Social milestones after heart transplantation - Corrected Proof

Bryan D. Piotrowski, Eric S. Armbrecht, Paul J. Hauptman — 2010-07-12

An extensive literature on morbidity and mortality after heart transplantation currently exists, yet the opportunity to reach social milestones has not been emphasized. We describe the case of a patient transplanted for peripartum cardiomyopathy who survived long enough to witness the birth of a grandchild.

Outcomes of pediatric heart transplant recipients transitioned to adult care: An exploratory study - Corrected Proof

2010-07-12

Previous reports of pediatric kidney and liver transplant recipients transitioned to adult care centers have noted substantial graft loss and medical non-adherence in the first years after transition. To our knowledge, the effect of transition to adult care on outcomes in pediatric heart transplantation has not been studied. We compared the outcomes of our pediatric heart transplant recipients after their transition to an adult transplant program with their expected outcomes as transplant recipients as young adults in an adult heart transplant center or if they had remained in a pediatric environment. We hypothesized the observed outcomes in this transitioned group would be worse than either of their expected outcomes in a solely pediatric or adult environment.

Treatment of the brain-dead lung donor with aprotinin and nitric oxide - Corrected Proof

Vassilios S. Avlonitis, Christopher H. Wigfield, John A. Kirby, John H. Dark — 2010-07-08

Background: It has been previously shown that donor treatment with aprotinin or inhaled nitric oxide reduces reperfusion injury after lung transplantation in animals. These studies used living donors with normal lungs. However, the main source of lungs for transplantation is brain-dead donors. Brain death causes systemic inflammatory response and lung injury, rendering the organ susceptible to reperfusion injury after transplantation. We hypothesized that treatment with aprotinin or inhaled nitric oxide after brain death would improve the donor inflammatory response and reduce lung reperfusion injury after transplantation.Methods: Brain death was induced in 24 rats by intracranial balloon inflation. Subsequently, the animals received intravenous aprotinin (n = 8), inhaled nitric oxide (n = 7), or no treatment (n = 9) for 5 hours. The lungs were retrieved and reperfused for 2 hours using recipient rats.Results: After brain death, oxygenation deteriorated earlier and significantly more in rats that received treatment, especially with nitric oxide. Treatment did not reduce the donor systemic inflammatory response as assessed by serum levels of proinflammatory cytokines. Oxygenation, airway pressure, pulmonary vascular resistance, lung water index and bronchoalveolar lavage cytokine levels were similar after reperfusion ofgrafts from all three groups of donors.Conclusions: Donor treatment with aprotinin or inhaled nitric oxide does not improve lungs that have been injured by brain death.

Characterization of immune responses to cardiac self-antigens myosin and vimentin in human cardiac allograft recipients with antibody-mediated rejection and cardiac allograft vasculopathy - Corrected Proof

2010-07-08

Background: Herein we study the role of donor-specific antibodies (DSA) to mismatched human leukocyte antigen (HLA) and antibodies (Abs) to the cardiac self-antigens myosin (MYO) and vimentin (VIM) in the pathogenesis of acute antibody-mediated rejection (AMR) in the early post-transplant period (EP, <12 months) and cardiac allograft vasculopathy (CAV) in the late post-transplant period (LP, >12 months) after heart transplantation (HTx).Methods: One hundred forty-eight HTx recipients (65 in EP, 83 in LP) were enrolled in the study. Development of DSA was determined by Luminex. Circulating Abs against MYO and VIM in sera were measured using enzyme-linked immunoassay (ELISA). Frequency of CD4+ T-helper cells (CD4+ Th) secreting interferon (IFN)-γ, interleukin (IL)-17, IL-10 or IL-5 specific to either MYO or VIM were analyzed in vitro using ELISpot assays.Results: AMR patients were more likely DSA positive (AMR−: 15%; AMR+: 70%; p = 0.03) and demonstrated increased Abs to MYO (AMR−: 144 ± 115 μg/ml; AMR+: 285 ± 70 μg/ml; p = 0.033) and VIM (AMR−: 37 ± 19 μg/ml; AMR+: 103 ± 43 μg/ml; p = 0.014). AMR patients demonstrated increased IL-5 CD4+ Th cells specific to MYO (5.2 ± 0.9 fold, p = 0.003) and VIM (7.3 ± 2.9-fold, p = 0.004) and decreased IL-10 CD4+ Th cells specific to MYO (2.2 ± 0.4-fold, p = 0.009) and VIM (1.7 ± 0.2-fold, p = 0.03). CAV patients were more likely DSA positive (CAV−: 25%; CAV+: 79%; p = 0.03) and demonstrated increased Abs to MYO (CAV−: 191 ± 120 μg/ml; CAV+: 550 ± 98 μg/ml; p = 0.025) and VIM (CAV−: 55 ± 25 μg/ml; CAV+: 255 ± 49 μg/ml; p = 0.001). CAV patients demonstrated increased IL-17 CD4+ Th cells specific to MYO (10.5 ± 7.3-fold, p = 0.002) and VIM (7.0 ± 3.9-fold, p = 0.003).Conclusions: The presence of DSA in AMR and CAV is significantly associated with development of Abs to MYO and VIM in post-HTx patients. Induction of high CD4+ Th cells specific to cardiac self-antigens that secrete predominantly IL-5 and IL-17 plays a significant role in the development of Abs to self-antigens leading to AMR and CAV, respectively.

Combined heart–kidney transplant after CardioWest total artificial heart bridge - Corrected Proof

Adam J. Hansen, Jack G. Copeland — 2010-07-08

Combined, single-donor, heart and kidney transplant (HKTx) recipients have survival rates comparable with those after heart transplantation alone. Although HKTx provides superior outcomes in patients with dual-organ failure, appropriate single-donor organ pairs are very scarce. Mechanical circulatory support thus seems an attractive option as a bridge to HKTx. We report the case of an adult with end-stage cardiomyopathy and renal failure who was successfully bridged to combined, single-donor HKTx with a total artificial heart. Infectious complications associated with the CardioWest cavity were encountered prior to transplantation. The patient recovered and was discharged 14 days after transplantation. At 4 months post-transplantation, the patient required single-vessel coronary stenting for a high-grade stenosis. At 1 year, he has had no further complications and has excellent function of both transplanted organs. Despite limited availability of same donor organ pairs, patients with combined cardiac and renal failure can be bridged effectively to transplant with the CardioWest total artificial heart.

Cytomegalovirus disease among donor-positive/recipient-negative lung transplant recipients in the era of valganciclovir prophylaxis - Corrected Proof

2010-07-05

Background: Valganciclovir prophylaxis is advocated for lung transplant recipients, but its efficacy is unknown.Methods: Retrospective review was done of 109 donor-positive/recipient-negative lung transplant patients who received alemtuzumab induction and valganciclovir for cytomegalovirus prophylaxis.Results: Median duration of follow-up after transplant was 27 months. Valganciclovir dose reductions (< 900 mg/day or renal-equivalent) were required for 18 patients (17%) due to toxicity, most commonly for neutropenia (n = 15) or gastrointestinal symptoms (n = 2). Of the 109 patients, 34 (31%) had no CMV infections, 45 (41%) had asymptomatic viremia, and 30 (27%) had CMV disease. CMV disease developed off prophylaxis in 10 patients (18%) at a median of 8.7 months after transplant and 2 months after valganciclovir discontinuation. Breakthrough disease occurred during prophylaxis in 10 patients (9%) at a median of 6.7 months. Patients with asymptomatic viremia or no CMV infection received prophylaxis for median 8.6 and 8.7 months, respectively. Risk factors for CMV disease by univariate analysis were increased age (p = 0.01), single-lung transplant (p = 0.03), chronic obstructive pulmonary disease (p = 0.05), reduced-dose valganciclovir (p = 0.001), and less than 6 months of prophylaxis (p = 0.005). By multivariate analysis, advanced age (p = 0.01) and reduced-dose valganciclovir (p = 0.0006) were independent risk factors for CMV disease. CMV disease developed in 4 patients (4%) due to ganciclovir-resistant viruses. CMV-attributable mortality was 5% (5 of 109), including 100% (4 of 4) with ganciclovir-resistant disease.Conclusions: Valganciclovir prophylaxis among donor-positive/recipient-negative lung transplant recipients delayed but did not eliminate CMV disease or CMV-related deaths and was limited by toxicity and ganciclovir-resistance. Our experience suggests that valganciclovir at reduced-doses or for less than 6 months is sub-optimal in preventing CMV disease.

Concentric left ventricular hypertrophy as assessed by cardiac magnetic resonance imaging and risk of death in cardiac transplant recipients - Corrected Proof

2010-07-05

Background: Although risk factors for left ventricular (LV) hypertrophy in the native heart are well known, as is its association with increased risk of adverse outcomes, such information is poorly defined in heart transplant (HTx) recipients. We determined whether increased LV mass and concentricity (mass/volume) were associated with death in patients after HTx.Methods: Between May 2003 and May 2006, 140 HTx recipients underwent cardiac magnetic resonance imaging (MRI). Clinical characteristics associated with increased LV mass were determined. Cox proportional hazard models were constructed to assess the relationship of LV mass and concentricity with death.Results: MRIs were acquired a median of 6.0 years after transplant. The top quartile of indexed LV mass and concentricity were 35.8 g/m2.7 or higher and 1.5 g/ml or higher, respectively. History of rejection (odds ratio [OR], 5.9; 95% confidence interval [CI], 2.1–16.4; p < 0.01), diabetes (OR, 3.3; 95% CI, 1.3–8.2; p = 0.01), and post-transplant year of MRI acquisition (OR, 1.2; 95% CI, 1.1–1.4; p < 0.01) were associated with the top quartile of LV mass in multivariable models. LV mass and concentricity were independently associated with cardiovascular death (hazard risk [HR], 1.11 per g/m;2.7 HR, 10.1 per g/ml, p ≤ 0.01, respectively). LV concentricity was independently associated with all-cause mortality (HR, 4.4 per g/ml, p < 0.01).Conclusion: A history of rejection and diabetes are associated with increased LV mass. Increased LV mass, particularly of a concentric phenotype, is an independent risk factor for cardiovascular and all-cause mortality after HTx.

Comparison of wait times and mortality for idiopathic pulmonary fibrosis patients listed for single or bilateral lung transplantation - Corrected Proof

2010-07-05

Background: Lung transplantation is the one form of solid-organ transplantation in which there is the option for patients to receive one or two organs. Idiopathic pulmonary fibrosis (IPF) candidates can be accommodated by either procedure but the decision about these two options remains controversial. Therefore, we sought to determine whether IPF patients listed for bilateral lung transplantation only had longer wait times and higher mortality on the waiting list than those listed for single lungs only. Patients with chronic obstructive pulmonary disease (COPD) were also analyzed as a comparison group.Methods: This study was a retrospective analysis of the Organ Procurement and Transplantation Network database of patients with IPF and COPD listed for lung transplantation between May 2005 and December 2007. An analysis of wait times and mortality in this era as well as the pre–lung allocation score (pre-LAS) era of 2002 to 2004 was performed.Results: Of the 1,339 patients with IPF listed for lung transplantation, 31.7% were listed for bilateral lung transplantation only, 41% for single-lung transplantation only and 27.3% for either procedure. Patients listed for the bilateral procedure only were at greater risk of dying on the transplant list (p < 0.003), and were less likely to receive a lung transplant (p < 0.012). No difference in outcomes was seen in the COPD patients. Comparatively, in the pre-LAS era, wait times and mortality on the list for IPF patients were significantly greater for all forms of transplantation.Conclusions: There has been a significant improvement in wait times and mortality for IPF patients since the inception of the LAS system. Nonetheless, despite the goal of transplant equity, IPF patients listed for bilateral lung transplantation might have a clinically meaningful increased risk of pre-transplant mortality. The choice of procedures therefore needs to be made with careful consideration of patients' survival both pre- and post-transplantation. Evaluation of transplant outcomes should not only be based on post-transplant survival, but should also account for the impact of the choice of procedure.

Prolonged allograft ischemic time is not associated with higher incidence of antibody-mediated rejection - Corrected Proof

2010-07-05

The exact mechanisms through which a prolongation of allograft ischemic time (IT) results in a decrease in allograft survival remain unknown. The histologic features of perioperative ischemic graft injury include contraction band necrosis, often with myocyte vacuolization, followed by mixed inflammatory infiltrate of neutrophils, lymphocytes, macrophages, and eosinophils. These histologic findings are similar to those observed during episodes of antibody-mediated rejection (AMR). Such observations have led to the hypothesis that ischemic graft injury may trigger, or predispose, heart transplant recipients to AMR. Our practice of routine screening of all myocardial biopsies (EMB) specimens obtained in the first 2 months after transplant for AMR allowed us to test this hypothesis in 245 adult patients who received an allograft in our program between 1993 and 2002.

Relationship between obesity and resting energy expenditure in systolic heart failure - Corrected Proof

Bimal Padaliya, Keith D. Aaronson, Audrey H. Wu — 2010-07-01

Although obesity has been associated with lower resting energy expenditure, it is not well established how this relationship is influenced by the presence of heart failure (HF). The effect of obesity on resting metabolic rate may contribute to improved outcomes of obese patients with HF, a metabolically demanding disease. In this study, we examined the association between resting oxygen uptake (Vo2) and body mass index (BMI) in patients with systolic HF.

Increased Th17 rather than Th1 alloimmune response is associated with cardiac allograft vasculopathy after hypothermic preservation in the rat - Corrected Proof

2010-06-30

Background: Preservation injury decreases patient survival and promotes the development of cardiac allograft vasculopathy. We investigated the sequential effects of hypothermic preservation on ischemia-reperfusion injury (IRI), subsequent innate immune activation, and adaptive immune response in rat cardiac allografts.Methods: Allografts were transplanted from fully major histocompatibility complex-mismatched Dark Agouti to Wistar Furth rats without pre-operative hypothermia or after 4 hours of hypothermic preservation. Recipients received cyclosporine A immunosuppression. The allografts were recovered at 6 hours (n = 6, 7), 24 hours (n = 6), 10 days (n = 5), and 8 weeks (n = 5). Immunohistochemical, histologic, and reverse-transcription polymerase chain reaction analysis was performed.Results: In IRI, significantly increased messenger RNA (mRNA) levels for Toll-like receptor 4, hyaluronan synthases (HAS)1-2 (p = 0.03), high-mobility group box 1 (p = 0.05), CD80/83 (p = 0.01, p = 0.048), and the cytokines tumor necrosis factor-α (p = 0.004), interferon-γ (p = 0.012), and interleukin (IL)-6 (p = 0.019) were seen in allografts subjected to hypothermic preservation. During established alloimmune response, allografts subjected to hypothermic preservation expressed prominent infiltration of CD4+ T cells (p = 0.043) and dendritic cells (p = 0.029) and significantly up-regulated mRNA levels of CD80 (p = 0.036), chemokine (C-C motif) ligand 21 (p = 0.008), C-C chemokine receptor type 7 (p = 0.003), vascular endothelial growth factor-C (p = 0.016), and vascular endothelial growth factor receptor-3 (p = 0.02). These allografts also showed prominent mRNA upregulation of Foxp3 (p = 0.014), IL-17 (p = 0.038), and IL-23 (p = 0.043). Preservation significantly increased the incidence and intensity of allograft arteriosclerosis (p < 0.05) and cardiac fibrosis (p = 0.003) at 8 weeks.Conclusion: Our results demonstrate that preservation injury induced a cascade leading to an innate immune response that modulated the adaptive immune response towards Th17 rather than Th1 T-cell response in rat cardiac allografts and ultimately enhanced cardiac fibrosis and arterial occlusion. Our results also suggest that this immune response was not regulated by the calcineurin inhibitor cyclosporine A.

Myeloperoxidase and carbonyl proteins: Promising markers for non-invasive monitoring of graft rejection after heart transplantation - Corrected Proof

2010-06-30

Background: After heart transplantation (HTx), endomyocardial biopsy (EMB) is currently the standard method to diagnose acute graft rejection. A non-invasive marker of rejection would be desirable as an alternative or to permit more selective use of the costly and invasive EMB.Methods: In this retrospective study, outcomes of routinely taken EMBs were used to select 28 patients after HTx EMB Grade 0R (8 patients), 1R (9 patients) or 2R (11 patients). For these patients, myeloperoxidase (MPO) and carbonyl proteins (CP) in serum were measured using enzyme-linked immunoassay (ELISA).Results: MPO and CP levels in post-HTx patients with Grade 2R rejection were significantly (MPO: p < 0.01; CP: p < 0.001) elevated at the time of rejection compared with levels 1 month earlier. MPO and CP levels predicted Grade 2R rejection and the best cut-off point was 237.5 μg/l for MPO and 222.5 pmol/mg for CP, respectively. Clinically most important was the marked increase (doubling of basic values within 1 month) of MPO and CP levels in cases of Grade 2R rejection in post-HTx patients.Conclusions: MPO and CP seem to be appropriate parameters to monitor rejection events non-invasively and to minimize the application of EMBs after HTx.

Voriconazole exposure and geographic location are independent risk factors for squamous cell carcinoma of the skin among lung transplant recipients - Corrected Proof

2010-06-30

Background: Skin cancer, in particular squamous cell carcinoma (SCC), is the most common malignancy after solid-organ transplantation. SCC has been reported in immunosuppressed patients receiving voriconazole, but the agent has not been shown to be a risk factor. Universal voriconazole prophylaxis and alemtuzumab induction are standard in our lung transplant program.Methods: We performed a retrospective, case–control study (matched 1:3) among lung transplant recipients at our center from 2003 to 2008.Results: SCC was diagnosed in 3.1% (17 of 543) of patients at a median follow-up of 36 months. Median time to development of SCC was 19 months post-transplant. Risk factors for SCC by univariate analysis included older age (p = 0.02), residence in locations with high levels of sun exposure (p = 0.0001), single-lung transplant (p = 0.02) and duration (p = 0.03) and cumulative dose (p = 0.03) of voriconazole. Duration of voriconazole (hazard ratio [HR] = 2.1; p = 0.04) and residence in locations with high sun exposure (HR = 3.8; p = 0.0004) were independent risk factors by multivariate analysis. SCC lesions were located on the head and neck in 94% of cases, and 53% had multiple lesions. All patients were treated with surgery. At least one independent lesion developed subsequently in 47% of patients. Local spread and distant metastases each occurred in 7% of cases. There were no deaths among the cases.Conclusions: Voriconazole exposure is a risk factor for SCC after lung transplantation, particularly among older patients living in areas with high sun exposure. Voriconazole should be used cautiously in these patients.

Early adverse events as predictors of 1-year mortality during mechanical circulatory support - Corrected Proof

2010-06-28

Background: Ventricular assist devices (VADs) provide effective treatment for end-stage heart failure; however, most patients experience ≥1 major adverse events (AEs) while on VAD support. Although early, non-fatal AEs may increase the risk of later death during VAD support, this relationship has not been established. Therefore, we sought to determine the impact on 1-year mortality of AEs occurring during the first 60 days of VAD support.Methods: A retrospective analysis was performed using prospectively collected data from a single-site database for patients aged ≥18 years receiving left ventricular or biventricular support during 1996 to 2008 and who survived >60 days on VAD support. Fourteen major classes of AEs occurring during this 60-day period were examined. One-year survival rates of patients with and without each major AE were compared.Results: The study included 163 patients (80% men; mean age, 49.5 years), of whom 87% were European American, 72% had left ventricular support, and 83% were bridge to transplant. The occurrence of renal failure, respiratory failure, bleeding events, and reoperations during the first 60 days after implantation significantly increased the risk of 1-year mortality. After controlling for gender, age, VAD type, and intention to treat, renal failure was the only major AE significantly associated with later mortality (hazard ratio, 2.96; p = .023).Conclusions: Specific AEs, including renal failure, respiratory and bleeding events, and reoperations, significantly decrease longer-term survival. Renal failure conferred a 3-fold increased risk of 1-year mortality. Peri-operative management should focus on strategies to mitigate risk for renal failure in order to maximize later outcomes.

Balancing rejection and infection with respect to age, race and gender: Clues acquired from 17 years of cardiac transplantation data - Corrected Proof

2010-06-28

Background: Donor and recipient risk factors for rejection and infection have been well characterized. The contribution of demographic factors, especially age at the time of transplantation to morbidity and mortality due to rejection and infection, is much less well understood.Methods: Using parametric hazard analysis and multivariate risk-factor equations for infection and rejection events, we quantitatively determined the relationship of fundamental demographic variables (age, race and gender) to infection and rejection. These analyses were conducted with respect to date of transplant and age at the time of transplantation. The patient group consisted of all primary heart transplants performed at the University of Alabama at Birmingham during the years 1990 to 2007 (n = 526).Results: Risk factors for rejection within 12 months post-transplantation were date of transplant (p < 0.0001) and age at the time of transplantation (young adults 10 to 30 years of age, p < 0.0001). Risk factors for infection were date of transplant (p < 0.0001) and age at the time of transplantation (young children and older adults, p < 0.0001). There were three immunosuppressive eras in 1990 to 2007. Notably, although the proportion of patients experiencing rejection and infection events decreased during each successive immunosuppressive era, the relative relationship of infection to rejection, as well as age at the time of transplantation, remained similar into the most recent era. The maximal frequency of rejection events and rejection death occurred among patients transplanted at ages 10 to 30 years. Conversely, the frequency of infection events was minimal within the same group. In the oldest and youngest patients receiving transplants, infection was the predominant cause of death and rates of rejection events decreased.Conclusions: These data show that evolving immunosuppressive strategies have successfully reduced rejection and infection frequencies, and those patients transplanted at 30 to 60 years of age have the lowest frequency of rejection/infection events. However, individuals transplanted at younger or older ages, especially non-white recipients in the 10- to 30-year age group, experience significantly more infection or rejection. Therefore, programs should increase the level of surveillance in these patients and consider modification of immunosuppressive regimens in order to lower the frequency of infection and rejection events.

What they say versus what we see: “hidden” distress and impaired quality of life in heart transplant recipients - Corrected Proof

2010-06-28

BAckground: Quality of life (QoL) studies in heart transplant recipients generally rely on quantifiable self-report questionnaires and have shown that approximately 20% of patients undergo distress and poor QoL not clearly related to medical variables.Methods: Building on existing qualitative research, we used a phenomenologically informed audiovisual method to explore the nature of “distress” in heart transplant recipients. Focused open-ended interviews were conducted in non-clinical settings with 27 medically stable heart transplant recipients (70% male, mean age 53 ± 13 years, range 18 to 72 years; mean time since transplant 4.1 ± 2.4 years). Interviews were audio/videotaped and transcribed verbatim. A qualitative software program (NVIVO8) was used to code interview transcripts and videotaped bodily gestures and “expressive artifacts” as well as vocal tone and volume.Results: Distress was displayed by 88% of patients during the interview, and 52% displayed a profound disjunct between the words they used to describe their quality of life (e.g., “wonderful”) and their embodied expressions of the same (e.g., protective body posturing, distressed facial expression). Most also expressed significant distress when discussing issues such as the donor and their “gift of life,” as well as a disrupted sense of bodily integrity and identity that they felt could only be appreciated by fellow heart recipients.Conclusions: Increased awareness of this distress and disruption related to bodily integrity and identity after heart transplant may allow transplant professionals and researchers to see beyond “words” to more effectively reduce distress and improve quality of life.

Impact of previous cardiovascular disease on the outcome of lung transplantation - Corrected Proof

2010-06-28

Background: The impact of previous cardiovascular disease on the outcome of lung transplantation may be important but remains unstudied.Methods: Cardiovascular risk factors, echocardiography, right heart catheterization, isotopic ventriculography and vascular ultrasonography data were obtained from 258 adults who underwent lung transplantation at our center between 1988 and 2007. The effect of these parameters on survival and cardiovascular disease after transplantation was determined using the Cox model.Results: By multivariate analysis, diabetes (hazard ratio [HR]: 2.4), atrial fibrillation (HR: 3.51), elevated systolic pulmonary artery pressure (HR: 1.23 per 10 mm Hg) and low cardiac index (HR: 1.47 per-liters/min/m2) before transplantation were associated with a higher risk of death after transplantation. Heart failure (2.08 cases per 100 patient-years) and atherothrombosis (2.5 cases per 100 patient-years) were frequent after lung transplantation. A history of atherothrombosis (HR: 12.98) and diabetes (HR: 5.8) before transplantation were associated with a higher risk of atherothrombosis after transplantation. Major cardiovascular events led to death in 11 patients. Diabetes (HR: 62.5) and a low cardiac index (HR: 6.8 per-liters/min/m2) were associated with a higher risk of death from cardiovascular causes.Conclusions: Diabetes and a history of atrial fibrillation before lung transplantation were associated with excess mortality after transplantation. Diabetes was also associated with a major increase in the risk of atherothrombosis and death from cardiovascular causes. Lung transplant recipients may be considered at high risk for cardiovascular disease.

Long-term outcomes in pulmonary arterial hypertension in the first-line epoprostenol or first-line bosentan era - Corrected Proof

2010-06-28

Background: The aim of this study was to describe the long-term outcomes in idiopathic pulmonary arterial hypertension (IPAH) treated with first-line bosentan or intravenous (IV) epoprostenol, and additional therapy as needed.Methods: In a single-center, retrospective, longitudinal cohort, data on right heart catheterization, 6-minute walk distance (6MWD), disease progression and mortality were collected. Outcomes were assessed in first-line bosentan and first-line epoprostenol patients. To reduce selection bias due to differences between groups, two independent analyses were performed. First, a comparison was made of World Health Organization (WHO) Functional Class (FC) III patients. Second, to control for disease severity, a matched-pairs analysis was performed, with matching according to baseline cardiac output and exercise capacity and irrespective of FC at baseline.Results: Thirty-seven IPAH patients initiated first-line bosentan treatment and 37 first-line IV epoprostenol. Twenty-nine of the bosentan patients and 16 of the IV epoprostenol patients were in WHO FC III; demographic profiles were similar, although hemodynamic measurements and 6MWD suggested more severe disease in the IV epoprostenol group at treatment initiation. At 1 and 3 years, median change in 6MWD for patients initiating bosentan was +54 m (95% confidence interval: −3 to 76) and +71 m (−123 to 116), respectively, and +92 m (17 to 128) and +142 m (−6 to 242) for those on IV epoprostenol. Absence of disease progression of WHO FC III at 1 and 3 years was 72% and 45% with bosentan and 75% and 44% with IV epoprostenol, respectively. Survival at 1 and 3 years was 93% and 89% with bosentan and 94% and 75% with IV epoprostenol, respectively. Results were confirmed in matched-pairs analysis of 16 bosentan and 16 IV epoprostenol patients with similar disease severity.Conclusions: First-line epoprostenol treatment may lead to greater improvement in exercise capacity than first-line bosentan. However, these greater exercise improvements did not translate into longer time to disease progression or survival.

Comparison of bronchiolitis obliterans syndrome to other forms of chronic lung allograft dysfunction after lung transplantation - Corrected Proof

2010-06-28

Background: The radiographic presence of allograft infiltrates is atypical of bronchiolitis obliterans (BO) and inconsistent with the definition of bronchiolitis obliterans requires that restrictive processes are ruled out. The natural history of these other forms of chronic allograft dysfunction has not been well characterized. We examined the prognostic significance of radiographic and spirometric restrictive processes in comparison to BOS among lung transplant recipients.Methods: We performed a retrospective review of lung transplant recipients with chronic lung allograft dysfunction (CLAD) as defined by spirometry. Subgroups based on the presence or absence of persistent radiographic abnormalities were labeled as non-specific (CLAD-NS) and CLAD due to BOS (CLAD-BOS), respectively. The CLAD-BOS group was further divided into obstructive (OBOS) and restrictive (RBOS) phenotypes based on spirometry. Groups were compared with respect to survival and decline in forced expiratory volume in 1 second (FEV1).Results: Among 241 lung transplant recipients, 96 (40%) were identified as having CLAD, of whom 62 (65%) had CLAD-BOS and 34 (35%) CLAD-NS. No difference between groups was identified with respect to post-CLAD survival or decline in FEV1. CLAD-BOS subgroups included 35 (56%) patients with OBOS and 27 (44%) with RBOS. There was no difference in these subgroups with respect to survival or subsequent FEV1 decline.Conclusions: Patients with CLAD and persistent radiographic infiltrates have a similar prognosis to BOS patients but may still represent a clinically distinct phenotype. BOS patients frequently exhibited a restrictive pattern on spirometry, which also did not offer further prognostic information, but could still represent a unique disease phenotype.

Cardiomyocyte-targeted HIF-1α gene therapy inhibits cardiomyocyte apoptosis and cardiac allograft vasculopathy in the rat - Corrected Proof

2010-06-28

Background: Hypoxia-inducible factor-1 (HIF-1), a key transcription factor in hypoxia, affects a wide range of adaptive cell functions. We examined the kinetics of endogenous HIF-1α during acute and chronic rejection, and the effect of exogenous HIF-1α in chronically rejecting rat cardiac allografts.Methods: Heterotopic cardiac transplantations were performed between major MHC-mismatched Dark Agouti and Wistar–Furth rats. Cyclosporine A (CsA) was used to prevent acute rejection in the chronic rejection model. The effect of HIF-1α overexpression was investigated by adeno-assocated virus 2 (AAV2)-mediated gene transfer of a constitutively stabilized form of mouse HIF-1α (AAV-HIF-1α). The analysis of allografts was based on histology, immunohistochemistry and quantitative reverse transcript–polymerase chain reaction (RT-PCR).Results: Acute and chronic rejection significantly induced HIF-1α mRNA in rat cardiac allografts when compared with syngeneic controls. Immunohistochemistry localized significantly increased HIF-1α immunoreactivity to vascular smooth muscle cells, vascular endothelial cells, post-capillary venules and graft-infiltrating mononuclear inflammatory cells of the allograft, whereas expression in cardiomyocytes remained unchanged. Regression analysis revealed a linear correlation between the progression of cardiac allograft vasculopathy (CAV) and HIF-1α immunoreactivity in post-capillary venules and graft-infiltrating mononuclear inflammatory cells in chronically rejecting rat cardiac allografts. AAV-HIF-1α enhanced cardiomyocyte HIF-1α production and significantly reduced cardiomyocyte apoptosis and the development of CAV in chronically rejecting rat cardiac allografts.Conclusions: We found that acute and chronic rejection increased HIF-1α mRNA and protein levels in rat cardiac allografts. On the other hand, cardiomyocyte-targeted HIF-1α gene transfer inhibited cardiomyocyte apoptosis and the development of CAV, suggesting a novel therapeutic strategy for HIF-1α in cardiac allografts.

Third sequential bilateral lung transplant - Corrected Proof

Farhan Zafar, George B. Mallory, David L.S. Morales — 2010-06-28

In the growing field of pediatric lung transplantation (LTx), an increasing number of patients are presenting for re-LTx. This report describes an elective third-time sequential bilateral LTx from the United States.

Initial clinical experience with a novel left ventricular assist device with a magnetically levitated rotor in a multi-institutional trial - Corrected Proof

2010-06-21

Background: Third-generation rotary blood pumps have magnetically levitated rotors that eliminate mechanical wear over the years. Together with their potential for miniaturization, these pumps seem suitable for long-term support of patients with a wide range of body surface areas (BSA). Recently, the novel HVAD pump (HeartWare Inc, Framingham, MA), a miniaturized centrifugal pump with a hydrodynamic, magnetically levitated rotor, became ready for clinical application.Methods: In a multi-institutional trial in Europe and Australia, 23 patients (mean age, 47.9 ± 12 years) in end-stage heart failure were enrolled in 5 centers. The primary end point of the bridge-to-transplant study was survival to heart transplant or survival to 180 days on the device, whichever occurred first. Follow-up data at 1 year are presented. The small size of the device allows for intrapericardial placement of the pump.Results: Implant procedures were generally fast and uneventful. Mean duration of support was 167 ± 143 days (range, 13–425 days), and mean blood flow provided by the pump was 6.1 ± 1.1 liters/min. At the 180-day end point, 2 patients had undergone successful transplant at 157 and 175 days, 2 patients died while on the device, and 19 patients continued pump support for more than 180 days. Actuarial survival after 6 months was 91% and was 86% at the 1-year follow-up.Conclusions: The design of the HVAD pump enables a quick and less invasive implantation. The results to date demonstrate satisfactory long-term survival with excellent quality of life in this cohort of 23 patients of the initial multi-institutional Conformité Européene (CE) mark trial.

Predictive value of the Seattle Heart Failure Model in patients undergoing left ventricular assist device placement - Corrected Proof

2010-06-17

Background: Left ventricular assist devices (LVADs) are increasingly used in advanced heart failure patients. Despite proven efficacy, optimal timing of LVAD implantation is not well defined.Methods: Patients receiving an LVAD were prospectively recorded. Laboratory and clinical data were extracted and used to calculate the predicted survival with medical therapy using the Seattle Heart Failure Model (SHFM). This was compared with observed survival, hospital length of stay and timeliness of discharge.Results: We identified 104 patients. Survival with an LVAD vs SHFM predicted survival was 69% vs 11% at 1 year, corresponding to a hazard ratio of 0.17 (p < 0.0001). SHFM-estimated 1-year survival with medical therapy increased from 4% in 1997 to 2004 to 25% in 2007–2008 (p < 0.0001). Subgroup analysis of higher vs lower risk LVAD patients showed observed 1-year survival of 83% vs 57% (p = 0.04). The lower risk group had a shorter length of stay (46 vs 75 days, p = 0.03), along with higher rates of discharge prior to transplant (88% vs 61%, p = 0.01) and discharge within 60 days of LVAD placement (77% vs 52%, p = 0.03).Conclusions: The SHFM allows prediction of important features of a patient's hospital course post-operatively, including length of stay and 1-year survival. Given evidence of improved survival and shorter hospital stay in lower risk patients, earlier LVAD placement based on a prediction model like the SHFM should be considered in advanced heart failure patients. The SHFM may have utility as a virtual control arm for single-arm LVAD trials.

The impact of recipient body mass index on survival after lung transplantation - Corrected Proof

2010-06-17

Background: Lung transplant (LTx) candidates are frequently over or underweight. Few studies have examined recipient weight and outcomes after LTx. The United Network for Organ Sharing (UNOS) database provides an opportunity to examine outcomes related to body mass index (BMI) in a large cohort of LTx patients.Methods: The UNOS data set was retrospectively reviewed for 11,411 adult primary LTx patients (1998 to 2008). Patients were stratified by recipient BMI (kg/m2): less than 18.5 (underweight), 18.5 to 24.9 (normal), 25.0 to 29.9 (overweight), more than 30 (obese). All-cause mortality was examined with Cox proportional hazard regression incorporating 15 variables. Survival was modeled using the Kaplan-Meier method.Results: Of 11,411 recipients, 1,355 (11.9%) were underweight, 4,998 (43.8%) were normal weight, 3,662 (62.1%) were overweight, and 1,396 (12.2%) were obese. During the study, 4,959 patients (43.5%) died. Mortality was significantly different between the strata, with incremental increases in death for each BMI category above or below normal. On multivariable analysis, BMI strata predicted death compared with normal weight. Risk of death was increased in recipients who were underweight (hazard ratio [HR], 1.14; 95% confidence interval [CI], 1.03–1.26; p = 0.01), overweight (HR, 1.06; 95% CI, 0.99–1.14; p = 0.1), and obese (HR, 1.16; 95% CI, 1.04–1.28; p = 0.005). Kaplan-Meier modeling showed a significant effect of BMI on survival; however, this effect was no longer significant when first-year deaths were excluded.Conclusions: Mortality is higher in underweight, overweight, and obese LTx patients than in normal-weight controls. However, this effect appears to be governed by survival in the first year after LTx.

Anti-human leukocyte antigen antibodies and preemptive antibody-directed therapy after lung transplantation - Corrected Proof

2010-06-17

Background: Because the development of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSA) after lung transplantation has been associated with acute and chronic rejection, we implemented a clinical protocol to screen all transplant recipients for DSA and preemptively treat those who developed DSA with rituximab and intravenous immune globulin (IVIG), or IVIG alone.Methods: We conducted a prospective observational study of this protocol and used the LABScreen Single Antigen assay to detect DSA after transplantation. We compared the incidence of acute rejection, lymphocytic bronchiolitis, and bronchiolitis obliterans syndrome (BOS) between those who developed DSA and those who did not using Cox proportional hazards models. We used the Kaplan-Meier method to compare freedom from BOS and survival between those who had persistent DSA and those who had successful depletion of DSA.Results: Among 116 recipients screened, DSA developed in 65 during the study period. Those who developed DSA and received antibody-directed therapy had a similar incidence of acute rejection, lymphocytic bronchiolitis, and BOS as those who did not develop DSA. Furthermore, recipients who had successful depletion of DSA had greater freedom from BOS and better survival than those who had persistent DSA. Finally, those treated for DSA had a similar incidence of infectious complications as those who did not develop DSA.Conclusions: The development of DSA is surprisingly common after lung transplantation. Antibody-directed therapy may reduce the risk of rejection associated with DSA, but a randomized controlled trial is necessary to critically evaluate the efficacy of this treatment protocol.

Pandemic influenza (H1N1): Impact on lung transplant recipients and candidates - Corrected Proof

2010-06-17

Background: The year 2009 was notable for the outbreak of a novel strain of influenza A (H1N1). We report the outcomes of H1N1 infection in a large cohort of lung transplant (LTx) recipients and candidates.Methods: This was a retrospective review of 22 suspected cases of H1N1 influenza screened using real-time polymerase chain reaction from nasal secretions. There were 15 confirmed cases (10 LTx recipients, 5 LTx candidates).Results: All patients were treated with oseltamivir at the time of the first clinical assessment. In the LTx recipients group, 7 of the 10 confirmed cases were treated at home with oseltamivir alone. Three patients were admitted with complications (2 pneumonia, 1 acute rejection). Two patients required mechanical ventilation. Two patients had prolonged viral shedding. No deaths occurred among the LTx recipients. In the 5 LTx candidates with confirmed H1N1, 2 deaths occurred from pneumonia and acute respiratory distress syndrome.Conclusions: Influenza H1N1 had a significant complication rate amongst LTx recipients and a high mortality rate amongst LTx candidates.

Retrospective review of Japanese patients undergoing heart transplantation in Japan compared with those undergoing transplantation in the United States - Corrected Proof

Noboru Oda, Tomoko S. Kato, Kazuo Komamura, Jignesh Patel, Jon A. Kobashigawa — 2010-06-11

Domestic legal issues have severely limited the number of transplants in Japan. Pediatric patients have been excluded from receiving heart transplantation (HTx) because tests to establish brain death were prohibited on young donors under the Organ Transplant Law established in Japan in 1997. Even for adult patients, HTx opportunity was very limited, and the mean waiting period occasionally reached 4 years. Therefore, not only pediatric but also adult patients had gone abroad from Japan for transplant surgery under such circumstances.

Is stress cardiomyopathy the underlying cause of ventricular dysfunction associated with brain death? - Corrected Proof

2010-06-07

Most deaths in the first 30 days after cardiac transplantation are due to failure of the donor heart, often with the clinical picture of right ventricular failure. Indeed, there is a significant reduction in contractility of the human donor heart and loss of contractile reserve before and soon after transplantation. This myocardial insult appears in association with brain death in the donor and follows a “catecholamine storm” associated with a rapidly rising intracranial pressure. Microscopy of the myocardium in organ donors shows a picture typical of catecholamine-induced injury and similar to changes found in endomyocardial specimens of stress cardiomyopathy (catecholamine-induced cardiomyopathy, or Takotsubo cardiomyopathy). There are 3 common features between stress cardiomyopathy and the heart of a brain-dead donor: exposure of the heart to unusually high catecholamine levels, ventricular dysfunction, and prompt recovery.Stress cardiomyopathy is a temporary myocardial dysfunction that has been described after sub-arachnoid hemorrhage, traumatic head injury, pheochromocytoma, acute emotional distress, exogenous administration of catecholamines, and non-related surgery. Given the common features of this catecholamine-mediated myocardial insult, we ask if brain-dead donor heart dysfunction is an extreme variant of stress cardiomyopathy? And, if so is it, like stress cardiomyopathy, reversible? Can we therefore expect recovery of the dysfunctional donor heart over time, thereby permitting increased use of hearts offered for transplantation?

Systemic and exhaled cytokine and chemokine pofiles are associated with the development of bronchiolitis obliterans syndrome - Corrected Proof

2010-06-07

Background: The mechanisms that lead to the fibrotic obliteration in bronchiolitis obliterans syndrome (BOS) may involve the interactions between T-helper (Th)1 and Th2 cytokines. The aim of this study is to determine the Th1 and Th2 cytokine and chemokine profiles in serum and exhaled breath condensate (EBC) in lung transplant recipients and to assess their usefulness as biomarkers to predict the development of BOS.Methods: Serum and EBC from 10 patients with BOS (BOSpos) and 10 patients without BOS (BOSneg), matched for clinical and demographic variables, were analyzed with a multiplex immunoassay to measure a panel of 27 cytokines and chemokines.Results: The pro-inflammatory cytokines in serum were elevated in lung transplant recipients compared with controls. BOSpos patients had significantly lower concentrations of interleukin (IL)-4, IL-13, and vascular endothelial growth factor (VEGF) compared with BOSneg patients. The concentration of IL-5, however, was significantly higher in BOSpos patients. Levels of IL-4 and IL-5 were hardly detectable in EBC. IL-13 and VEGF, both decreased in serum in BOSpos patients, were also decreased in EBC in BOSpos patients compared with BOSneg patients. Longitudinal analysis of cytokines and chemokines in serum and EBC from the time of lung transplantation onwards did not reveal significant trends in cytokines and chemokines that preceded the diagnosis of BOS.Conclusions: Levels of pro-inflammatory cytokines were increased in lung transplant recipients compared with controls. From the moment of transplantation onwards, there is a different pattern of Th2 cytokines in serum in BOSpos patients than in BOSneg patients.

Supratherapeutic anticoagulation from low-molecular-weight heparin in lung transplant recipients - Corrected Proof

2010-06-07

Background: Venous thromboembolism (VTE) is common after lung transplantation. Enoxaparin is an approved therapy for VTE and anti-factor Xa level can be used to monitor enoxaparin activity. Some studies have demonstrated elevated anti-factor Xa levels are associated with an increased risk of hemorrhage. Having identified a high incidence of supratherapeutic anti-factor Xa levels in lung transplant recipients, we aimed to elucidate the relationship between enoxaparin dose and anti-factor Xa level in this patient population.Methods: We identified post–lung transplantation patients with VTE receiving therapeutic enoxaparin who had anti-factor Xa level measured. Standard enoxaparin dosing was defined as 0.9 to 1.1 mg/kg. After identifying a high incidence of supratherapeutic anti-factor Xa levels, we implemented “non-standard” dosing of 0.8 mg/kg. Multivariate linear regression analysis was used to examine the association between enoxaparin dose and anti-factor Xa level; age, body mass index (BMI) and creatinine clearance were included as covariates.Results: In the cohort, 18 patients received standard and 8 patients received non-standard enoxaparin dosing. Twelve of 18 patients (67%; 95% confidence interval [CI]: 43% to 91%) receiving standard dosing had supratherapeutic anti-factor Xa levels vs 0 of 8 patients (0%; 95% CI: 0% to 37%) receiving lower non-standard dosing (p = 0.002). Anti-factor Xa levels were significantly different between the two groups; the mean anti-factor Xa level was 1.3 IU/ml (95% CI: 1.06 to 1.53) in the standard group vs 0.79 IU/ml (95% CI: 0.67 to 0.91) in the non-standard group (p = 0.008). After controlling for covariates, for each 0.1-mg/kg increase in enoxaparin, the mean anti-factor Xa level increased by 0.18 IU/ml (95% CI: 0.05 to 0.31; p = 0.011; model r2 = 0.53).Conclusions: Standard dosing of enoxaparin in lung transplant recipients is associated with a high incidence of supratherapeutic anti-Xa levels. Further study will be required to correlate this finding with risk of hemorrhage.

Transfusion-related acute lung injury (TRALI) in graft by blood donor antibodies against host leukocytes - Corrected Proof

2010-06-07

It is unknown the extent to which transfusion-related acute lung injury (TRALI) contributes to primary graft dysfunction (PGD), the leading cause of death after lung transplantation. In this case of suspected transfusion-associated acute bilateral graft injury in a 61-year-old idiopathic pulmonary fibrosis patient, recipient sera from before and after transplantation/transfusion, as well as the sera of 22 of the 24 implicated blood donors, were individually screened by Luminex bead assay for the presence of human leukocyte antigen (HLA) antibodies, with recipient and lung donor HLA typing to explore for cognate relationships. A red-cell-unit donor-source anti-Cw6 antibody, cognate with the HLA type of the recipient, was identified. This is the second reported case of TRALI in the setting of lung transplantation, and the first to show an associated interaction between donor antibodies (in a low-plasma volume product) with recipient leukocytes (rather than graft antigens); therefore, it should be considered in the differential diagnosis of PGD.

Epoprostenol-associated pneumonitis: Diagnostic use of a T-cell proliferation assay - Corrected Proof

2010-06-07

We describe a case of severe drug-induced interstitial pneumonitis in a woman with idiopathic pulmonary arterial hypertension receiving epoprostenol confirmed by a drug T-cell proliferation assay. Proliferation assays were completed in our patient and in a healthy control. Isolated T cells were incubated with CD3-depleted peripheral blood mononuclear cells and then stimulated to proliferate with H-thymidine in the presence of epoprostenol, other prostanoid analogs, and controls. A significant (p < 0.001) T-cell proliferation response occurred in our patient in the presence of epoprostenol alone. There was a trend towards an increased T-cell response to treprostinil but this was statistically insignificant. There was no significant T-cell response to the diluent alone, normal saline, iloprost, or alprostadil. There was no significant proliferation to any drug in the healthy control. Hence, a drug T-cell proliferation assay confirmed that epoprostenol can rarely incite a profound inflammatory response in the pulmonary interstitium.

New prioritization of heart transplant candidates on mechanical circulatory support in an era of severe donor shortage - Corrected Proof

Takeshi Komoda, Thorsten Drews, Roland Hetzer, Hans B. Lehmkuhl — 2010-06-07

Background: Nearly all patients receiving heart transplantation (HTx) in Germany are now those listed in urgent status. In this study we review urgency-based allocation policy for HTx candidates with ventricular assist devices (VADs).Methods: We retrospectively studied 345 adult candidates for de novo HTx. Group U (n = 160) comprised patients primarily listed in urgent status without VAD. Group VAD-45 (n = 167) comprised patients with intended bridging to HTx who survived >45 days after VAD implantation (after initial drop in survival rates). Among these patients, those who died of stroke or were awarded urgent status due to difficulties of coagulation management (thrombus formation, thromboembolism and bleeding) in the first year after VAD implantation were assigned to Group COAG (n = 36), and those who died or were awarded urgent status due to device-related infection in the same period were assigned to Group INF (n = 31). Actuarial survival rates were studied in each group.Results: Survival rates during support in Group VAD-45 were comparable to those during urgent status in Group U. Bridge-to-transplant rate was 63.9% in Group COAG and 58.1% in Group INF. The post-transplant 3-year survival rate of 85.3% in Group COAG was significantly higher than that in Group INF (46.8%, p < 0.01) and Group U (62.4%, p < 0.05).Conclusions: Patients who have a VAD for >45 days should be awarded some priority for urgent HTx, which is currently prohibited in Germany. Patients listed in urgent status due to difficulties of coagulation management should be prioritized over those listed for device-related infection to make effective use of limited resources.

Tension pneumoperitoneum as the sole presentation of an intraoperative bronchial rupture - Corrected Proof

Edward Gologorsky, Angela Gologorsky, Kenneth Stahl, Dao M. Nguyen, Si M. Pham — 2010-05-31

TThoracic etiology of pneumoperitoneum is rare, usually associated with pneumothorax and pneumomediastinum. Uniquely, in the presented patient, the tension pneumoperitoneum was a sole manifestation of an intraoperative bronchial disruption. Consent for this presentation was obtained.

Characterization of a cardiac mass using a systematic multimodality imaging approach - Corrected Proof

2010-05-31

This report highlighted a multimodality imaging approach for the characterization of cardiac masses. Initial identification of a left ventricle mass was made with 2D transthoracic echocardiogram (TTE). Real-time 3D TTE added further anatomic localization and indicated that the mass was attached to the posterior mitral valve leaflet/annulus complex, not to ventricular myocardium. Tissue characterization was performed with cardiac magnetic resonance (CMR) to refine the differential diagnosis to that of a myxoma. Unique features included a large myxoma originating from the ventricular side of the mitral valve, CMR for tissue characterization and cardiac auto-transplantation with complete ex vivo tumor resection, and implantation of a mechanical mitral valve prosthesis. .

Clinical management of continuous-flow left ventricular assist devices in advanced heart failure - Corrected Proof

Keith M. Swetz, Monica R. Freeman, Paul S. Mueller, Soon J. Park — 2010-05-31

Slaughter and colleagues are to be congratulated for their significant contributions, including their article “Clinical management of continuous-flow left ventricular assist devices in advanced heart failure.” It is a comprehensive and authoritative guide to the intraoperative and post-operative management of patients receiving left ventricular assist devices (LVADs). The authors discuss device management, diagnosis, and management of post-operative complications, and troubleshooting mechanical emergencies. Furthermore, they present an excellent review of risk factors and characteristics that will assist clinicians with patient selection. This “how-to” guide compliments the recently reported findings of the HeartMate II Clinical Investigators, which showed significantly improved survival free from stroke and device failure at 2 years with continuous-flow devices compared with older pulsatile-flow devices.

Speckle-tracking 2-dimensional strain echocardiography: A new noninvasive imaging tool to evaluate acute rejection in cardiac transplantation - Corrected Proof

2010-05-21

Background: There remains no reliable non-invasive method to detect cardiac transplant rejection. Recently, speckle-tracking 2-dimensional strain echocardiography (2DSE) was shown to be sensitive in the early detection of myocardial dysfunction in various models of cardiomyopathy. We aim to determine if 2DSE-derived functional indices can detect cardiac transplant rejection.Methods: Heterotopic rat cardiac transplantation was performed in histocompatible isografts or histoincompatible allografts. Histologic rejection scores were determined. Short-axis, mid-left ventricular (LV) echocardiography was performed on Day 6 after transplantation. Conventional measures of function were measured, (including LV fractional shortening and ejection fraction) as well as 2DSE parameters.Results: Despite class IIIB rejection in allografts and no rejection in isografts, there was no difference between isografts vs allografts in fractional shortening (15% ± 3% vs 12% ± 3%) or ejection fraction (36% ± 5% vs 26% ± 6%; both not significant). In contrast, 2DSE revealed decreases between isografts and allografts in global radial strain (12.6% ± 5.6% vs 1.1% ± 0.2%, p < 0.05), peak radial systolic strain rate (3.10 ± 0.74/s vs 0.54 ± 0.13/s, p < 0.001), and peak circumferential systolic strain rate (–1.99 ± 0.55 vs –0.43 ± 0.11/s; p < 0.01).Conclusions: Systolic strain imaging using 2DSE differentiates myocardial function between experimental cardiac transplant rejection in allografts and non-rejection in isografts. Therefore, 2DSE may be useful in early non-invasive detection of transplant rejection.