The Journal of Heart and Lung Transplantation - Articles in Press

Does vitamin D really impact survival after lung transplantation? - Corrected Proof

Stijn E. Verleden, Geert M. Verleden, Bart M. Vanaudenaerde — 2012-05-17

We read with great interest the article by Lowery et al reporting that 25-hydroxyvitamin D (25-OHD) deficiency occurs in lung transplant patients with various important clinical implications, the major being a greater mortality in the group deficient in vitamin D. Because we recently published a similar cross-sectional study and are also conducting a randomized placebo-controlled trial with vitamin D supplementation in lung transplant patients, we still have some unresolved questions.

Heart transplant recipient selection issues: Limited assets, infinite possibilities - Corrected Proof

Sharon Ann Hunt — 2012-05-10

“Innocent heart sentenced to life in Cheney.” The press and pundits have had a heyday discussing the recent heart transplant of former U.S. Vice President Dick Cheney. The jibes have included comments, such as Jon Stewart's above, relevant to Mr Cheney's political history and activities, but also have raised issues regarding the allocation of the scarce societal resource of donor hearts to the elderly.

Use of height and a novel echocardiographic measurement to improve size-matching for pediatric heart transplantation - Corrected Proof

2012-05-07

Background: A major limitation of pediatric heart transplantation is scarcity of pediatric donor organs, leading to longer waiting times and higher waiting list mortality. Current practice is to match potential pediatric recipients with donors by weight; however, we hypothesize height to be a better predictor of heart size as estimated by left ventricular end-diastolic diameter (LVEDd), as well as a novel measurement from the superior vena cava–right atrium junction to inferior vena cava–right atrium junction (SVC-IVC distance). Our ultimate objective is to present a more effective means of size-matching for pediatric heart transplantation. Methods: Measurements of LVEDd and SVC-IVC distance were taken from 254 normal echocardiograms performed on individuals aged 7 days to 22 years, and correlated with demographic variables, including height, weight, and body surface area. Simulations were conducted using echocardiographic measurements and size parameters of past recipients with hypothetic donors to demonstrate practicality. Results: There was a linear relationship between height and SVC-IVC distance (R2 = 0.904) and LVEDd (R2 = 0.889), whereas the relationships with weight were logarithmic (SVC-IVC distance, R2 = 0.855; LVEDd, R2 = 0.880), and the relationships with body surface area were polynomial (SVC-IVC distance, R2 = 0.880; LVEDd, R2 = 0.884). Three simulations demonstrate improvements in efficiency of the size-matching process. Conclusions: The use of height and a novel SVC-IVC distance measurement to evaluate heart size in potential pediatric heart transplant recipients and donors may allow for broadening of the donor pool and creation of a more efficient and accurate size-matching process. The prospective evaluation of these novel methods with respect to clinical outcomes is necessary.

Tacrolimus and cyclosporine have differential effects on the risk of development of bronchiolitis obliterans syndrome: Results of a prospective, randomized international trial in lung transplantation - Corrected Proof

2012-05-04

Background: Chronic lung allograft dysfunction, which manifests as bronchiolitis obliterans syndrome (BOS), is recognized as the primary cause of morbidity and mortality after lung transplantation. In this study we assessed the efficacy and safety of two de novo immunosuppression protocols to prevent BOS. Methods: Our study approach was a multicenter, prospective, randomized (1:1) open-label superiority investigation of de novo tacrolimus vs cyclosporine, with both study arms given mycophenolate mofetil and prednisolone after lung transplantation. Cytolytic induction therapy was not employed. Patients were stratified at entry for cystic fibrosis. Primary outcome was incidence of BOS 3 years after transplant (intention-to-treat analysis). Secondary outcomes were survival and incidence of acute rejection, infection and other adverse events. Results: Group demographic data were well matched: 110 of 124 tacrolimus vs 74 of 125 cyclosporine patients were treated per protocol (p < 0.01 by chi-square test). Cumulative incidence of BOS Grade ≥1 at 3 years was 11.6% (tacrolimus) vs 21.3% (cyclosporine) (cumulative incidence curves, p = 0.037 by Gray's test, pooled over strata). Univariate proportional sub-distribution hazards regression confirmed cyclosporine as a risk for BOS (HR 1.97, 95% CI 1.04 to 3.77, p = 0.039). Three-year cumulative incidence of acute rejection was 67.4% (tacrolimus) vs 74.9% (cyclosporine) (p = 0.118 by Gray's test). One- and 3-year survival rates were 84.6% and 78.7% (tacrolimus) vs 88.6% and 82.8% (cyclosporine) (p = 0.382 by log-rank test). Cumulative infection rates were similar (p = 0.91), but there was a trend toward new-onset renal failure with tacrolimus (p = 0.09). Conclusions: Compared with cyclosporine, de novo tacrolimus use was found to be associated with a significantly reduced risk for BOS Grade ≥1 at 3 years despite a similar rate of acute rejection. However, no survival advantage was detected.

High incidence of unexpected defibrillation coil retention during orthotopic heart transplantation - Corrected Proof

Pal Abraham, Kadir Caliskan, Tamas Szili-Torok — 2012-05-04

Implantation of a cardioverter-defibrillator (ICD) is a reasonable choice for non-hospitalized patients awaiting orthotopic heart transplantation (OHTx) to prevent arrhythmic death. Malfunction or failure of ICD leads can occur by several mechanisms, and some of them may be attributed to lead design. Surgical removal of the entire ICD system is part of the OHTx procedure and is usually accomplished without complications.

Cyclosporine immunosuppression does not prevent the production of donor-specific antibody capable of mediating allograft vasculopathy - Corrected Proof

Alison J. Gareau, Bjorn Nashan, Gregory M. Hirsch, Timothy D.G. Lee — 2012-05-04

Background: Late cardiac graft rejection, primarily mediated by allograft vasculopathy (AV), remains a major limitation to cardiac transplantation, even in the face of significant calcineurin inhibitor (CNI) immunosuppression. The role played by alloantibody in AV is unclear. Evidence that CNI immunosuppression suppresses CD4+ T-cell function would suggest that antibody production and effector function would be severely limited in CNI-treated patients. In this study we examine the capacity of CNI-treated animals to develop effective alloantibody that can mediate AV. Methods: Wild-type (WT) B6 mice were alloimmunized using donor splenocytes or a fully major histocompatibility complex-mismatched allogeneic abdominal aortic graft in the presence of CNI immunosuppression (30 or 50 mg/kg/day cyclosporine A). Anti-serum was harvested and tested using complement-dependent in vitro cytotoxicity assays. Anti-serum was passively transferred to immunodeficient RAG1−/− recipients of allogeneic grafts. C4d deposition was quantified in the allografts from WT recipients. Results: CNI immunosuppression did not prevent the development of alloantibody in response to either immunization method (p < 0.05). Passive transfer of anti-serum generated AV lesions in immunodeficient graft recipients and mediated complement-dependent destruction of donor cells (p < 0.05). C4d deposition was localized to the media of grafts of CNI treated animals. Conclusions: CNI therapy does not prevent the production of alloantibody with the capacity to mediate AV. C4d deposition in the media suggests a role for medial smooth muscle cell loss in antibody-mediated AV lesion development in our model.

Outcomes of cardiac transplantation in septuagenarians - Corrected Proof

2012-05-04

Background: Cardiac transplantation in many centers is programmatically limited to patients aged younger than 70 years. We investigated the trends and outcomes for cardiac transplantation in recipients aged 70 years and older in the United States. Methods: De-identified data were provided by United Network of Organ Sharing. Transplant recipients were grouped by age 60–69 years and 70 years and older. Univariate comparisons were performed using Student's t-test or the Pearson chi-square test. Survival was estimated using the Kaplan-Meier technique and compared with the log-rank test. Cox regression was used to determine predictors of death after transplant. Statistical significance was assigned to p < 0.05. Results: Between January 1, 1998, and June 15, 2010, 5,807 sexagenarians and 332 septuagenarians received allografts. The septuagenarian cohort had more men, less diabetes, was less likely to have a ventricular assist device, and more likely to be status II. Donors for septuagenarians were older and died more frequently from intracranial hemorrhage. Median unadjusted survival was 9.8 years for sexagenarians vs 8.5 years for septuagenarians (p = 0.003). There was no difference in the incidence of cerebrovascular accident, length of stay, or pacemaker need between groups. Septuagenarians were less likely to be treated for rejection the first year (p = 0.001). Age was a multivariate predictor of death (hazard ratio, 1.289; 95% confidence interval, 1.039–1.6; p = 0.021). Conclusions: Selected septuagenarians with advanced heart failure can derive great benefit from cardiac transplantation, although survival is inferior to that of an immediately younger sexagenarian cohort. Most of the mortality risk is seen in the first year after transplantation. A reduced incidence of rejection was observed and warrants further study.

Biopsy-diagnosed antibody-mediated rejection based on the proposed International Society for Heart and Lung Transplantation working formulation is associated with adverse cardiovascular outcomes after pediatric heart transplant - Corrected Proof

2012-05-03

Background: There is greater awareness of the pathologic features and clinical implications of antibody-mediated rejection (AMR) after heart transplantation (HT). Yet, compared with adults, the lack of routine surveillance for AMR has limited the growth of evidence in the pediatric population. Herein, we compared outcomes of pediatric HT recipients with and without AMR. Methods: All recipients ≤18 years of age with at least 1 endomyocardial biopsy (EMB) between 1988 and 2009 were included in this study. Assessment for AMR was routine. AMR severity was assigned retrospectively using the proposed 2011 ISHLT grading schema for pathologic AMR (pAMR). Outcome comparisons were made between patients with histologic and immunopathologic evidence for AMR (pAMR 2), those with severe AMR (pAMR 3), and those without evidence of AMR (pAMR 0) or without both histologic and immunopathologic findings (pAMR 1). Results: Among 1,406 EMBs, pAMR 2 or higher was present in 258 (18%), occurring in 45 of 76 (59%) patients. Of the 17 episodes of pAMR 3 in 9 patients, 6 (35%) were sub-clinical. Mortality was not different between groups. Patients with at least 1 pAMR 3 episode had lower freedom from cardiovascular (CV) mortality or cardiac allograft vasculopathy within 5 years of HT than those without pAMR 3 (45% vs 91%, p < 0.001). Conclusions: Biopsy findings of AMR (pAMR 2 or higher) are common after pediatric HT. Like cellular rejection, biopsy grading of AMR seems important to delineate those at risk of adverse events. Our results suggest that pAMR 3 is associated with worse CV outcomes. Widespread surveillance for pAMR with a uniform grading system is an important next step to further validate these findings in the pediatric HT population.

Level of awareness of personnel in hospital services related to the donation process: A Spanish and Latin American multicenter study - Corrected Proof

2012-05-03

Background: Services related to the donation and transplantation process are fundamental for developing solid organ transplantation and procuring organs from deceased donors. This study was conducted to analyze the attitude toward deceased organ donation among hospital personnel working in donation- and transplantation-related services in hospitals in Spain and Latin America. Methods: Nine hospital centers within the “International Donor Collaborative Project” were selected (Spain, Mexico, Cuba, and Costa Rica). A random employee sample was taken and stratified according to the type of service and job category in transplant-related hospital services. Results: Of the 925 employees surveyed, 78% were in favor of donation. By job category, attitude was more favorable among physicians (89%; p < 0.001). By type of service, attitude was more positive among personnel in transplant patient follow-up units (87%; p = 0.018). By country, the Cubans were most in favor (91%), followed by the Mexicans (81%), the Costa Ricans (77%), and the Spanish (70%; p < 0.001). Other factors were age (p < 0.001), sex (p = 0.005), considering the possibility of needing a transplant (p = 0.002), understanding the concept of brain death (p < 0.001), being in favor of living donation (p < 0.001), having discussed the subject of donation and transplantation within the family and the partner (p < 0.001), carrying out pro-social activities (p = 0.002), and concern about mutilation after donation (p = 0.002). Conclusions: Transplant-related personnel had a favorable attitude toward deceased donation, although it was not as positive as we would expect, especially among non-physicians. This attitude needs to be improved because of the negative effect that can result in organ donation. There were pronounced differences between countries, and the discordance between attitude and actual deceased donation rates in each country is notable.

Characteristics and survival of patients with chemotherapy-induced cardiomyopathy undergoing heart transplantation - Corrected Proof

2012-05-03

Background: New anti-neoplastic drugs have improved survival of cancer patients but have also been associated with chemotherapy-induced cardiomyopathy (CCMP), ultimately requiring orthotopic heart transplantation (OHT). We conducted this study to describe the clinical characteristics and outcomes of patients with CCMP treated with OHT and compare them with outcomes of patients with other forms of non-ischemic cardiomyopathy (NICMP). Methods: We retrospectively identified 232 CCMP patients and 8,890 NICMP patients from the International Society of Heart and Lung Transplantation Registry who underwent OHT between January 2000 and December 2008. Survival rates were calculated using the Kaplan-Meier method. Categoric characteristics and outcomes groups were compared using the χ2 and Fisher exact test. Comparisons for continuous variables were made using Wilcoxon–Mann-Whitney test. Multivariable analyses of predictors of survival were performed using Cox proportional hazard regression analysis. Results: Short-term and long-term post-transplant survival of the 232 CCMP patients was similar to the 8,890 NICMP patients (p = 0.19). Survival (95% confidence interval) at 1, 3, and 5 years was, respectively, 86% (0.81–0.91), 79% (0.76–0.87), and 71% 0.73–0.85) in the CCMP patients and 87% (0.86–0.88), 81% (0.82–0.84), and 74% (0.80–0.81) in the NICMP patients (p = 0.19). Compared with NICMP patients, CCMP patients had higher rates of post-OHT infection (22% vs 14%, p = 004) and malignancies (5% vs 2%, p = 0.006), but neither affected survival. There was only 1 malignancy recurrence in the CCMP patients and no differences in post-OHT death due to malignancies between the groups. Importantly, CCMP patients were twice as likely as NICMP patients to require right ventricular assist devices before OHT (5.6% vs 2.3%, p = 0.0021). Conclusions: Patients with CCMP selected for OHT are younger, have less comorbidity, and are more likely to require biventricular mechanical support pre-OHT than other NICMP patients who receive allografts. Despite the higher incidence of malignancy and infection in CCMP patients who have received a heart transplant, their survival is comparable to those who receive allografts for other cardiomyopathies.

Pilot investigation of a novel testing strategy for bleeding in ventricular assist device recipients - Corrected Proof

2012-04-27

Purpose: A universal loss of von Willebrand factor (vWF) high-molecular-weight multimers (HMWM) has been demonstrated in continuous-flow left ventricular assist device (HeartMate II) recipients. However, no reliable clinical or laboratory predictors for an increased bleeding tendency in this patient population have been identified. This study evaluated the ability of a new automated latex particle-enhanced immunoturbidimetric vWF activity assay (ALPEIVA) to predict non-surgical bleeding risk in HeartMate II recipients. Methods: As part of a prospective multicenter trial, pre-surgical, 7-day, and 30-day post-implantation blood samples were collected from 24 patients. ALPEIVA-assessed vWF activities were compared among patients with and without non-surgical bleeding complications after HeartMate II implantation. Additional laboratory testing included factor VIII activity (FVIII:C), vWF antigen (vWFAg), vWF ristocetin cofactor activity (vWF:RCo), and vWF multimer analysis. Results: All 24 patients had HMWM losses after HeartMate II implantation. Five patients (20%) developed non-surgical bleeding complications between 14 days and 6 months after HeartMate II implantation. Among various laboratory variables, only mean ALPEIVA/vWFAg ratios (referred to as the “bleeding ratio”) were significantly lower in patients with clinically relevant bleeding (mean, 0.70 ± 0.06) compared with patients without bleeding (mean, 0.78 ± 0.09; p = 0.02) when measured at 30 days. Conclusions: The post-surgical bleeding ratio could potentially predict non-surgical bleeding risk and guide anti-platelet and anti-coagulation strategies in HeartMate II recipients.

Prioritizing sensitized heart transplant candidates: A sensitive affair - Corrected Proof

Abdallah G. Kfoury, Jon A. Kobashigawa — 2012-04-27

The fundamental guiding principle behind strategies for donor organ use is equitable distribution that prioritizes such a limited resource to the sickest suitable candidates first. As simple and intuitive of an aspiration this may be, the quest for the ideal gaming-proof organ allocation system continues. At the heart of this unmet pursuit often is the failure to reach a collective agreement on defining criteria for the truly sickest patient at imminent risk of death, the one most in need of a donated organ. Even then, the process of formulating a universally acceptable organ provision scheme is tedious and challenging.

Plexiform vasculopathy of severe pulmonary arterial hypertension and microRNA expression - Corrected Proof

2012-04-26

Background: Recent studies have revealed that microRNAs (miRNAs) play a key role in the control of angiogenesis and vascular remodeling. Specific miRNAs in plexiform vasculopathy of severe pulmonary arterial hypertension (PAH) in humans have not yet been investigated. Methods: We analyzed expression of miR-143/145 (vascular smooth muscle–specific), miR-126 (endothelial-specific) and related mRNAs in plexiform (PLs) and concentric lesions (CLs), which had been laser-microdissected from specimens of formalin-fixed, paraffin-embedded, explanted lungs of PAH patients (n = 12) and unaffected controls (n = 8). Samples were analyzed by real-time polymerase chain reaction, and protein expression was determined by immunohistochemistry. Results: Expression levels of miR-143/145 and its target proteins (e.g., myocardin, smooth muscle myosin heavy chain) were found to be significantly higher in CLs than in PLs, whereas miR-126 and VEGF-A were significantly up-regulated in PLs when compared with CLs, indicating a more prominent angiogenic phenotype of PL. This correlates with a down-regulation of miR-204 as well as an up-regulation of miR-21 in PLs, which in turn corresponds to enhanced cell proliferation. Conclusions: Our findings show that morphologic changes of plexiform vasculopathy in the end-stage PAH lung are reflected by alterations at the miRNA level.

The effect of β-2 adrenoreceptor agonist inhalation on lungs donated after cardiac death in a canine lung transplantation model - Corrected Proof

2012-04-26

Background: It is a matter of great importance in a donation after cardiac death to attenuate ischemia–reperfusion injury (IRI) related to the inevitable warm ischemic time. Methods: Donor dogs were rendered cardiac-dead and left at room temperature. The dogs were allocated into 2 groups: the β-2 group (n = 5) received an aerosolized β-2 adrenoreceptor agonist (procaterol, 350 μg) and ventilation with 100% oxygen for 60 minutes starting at 240 minutes after cardiac arrest, and the control group (n = 6) received an aerosolized control solvent with the ventilation. Lungs were recovered 300 minutes after cardiac arrest. Recipient dogs underwent left single-lung transplantation to evaluate the functions of the left transplanted lung for 240 minutes after the reperfusion. Results: Oxygenation and dynamic compliance were significantly higher in the β-2 group than in the control group. The β-2 group revealed significantly higher levels of cyclic adenosine monophosphate and high-energy phosphates in the donor lung after the inhalation than before it. Histologic findings revealed that the β-2 group had less edema and fewer inflammatory cells. Conclusion: Our results suggest that β-2 adrenoreceptor agonist inhalation during the pre-procurement period may ameliorate IRI.

Less urgent (UNOS 1B and 2) listings in pediatric heart transplantation: A vanishing breed - Corrected Proof

William T. Mahle, Steven A. Webber, Wida S. Cherikh, Leah B. Edwards — 2012-04-20

The allocation of organs for pediatric heart transplantation in the United Network for Organ Sharing (UNOS) scheme only utilizes 3 risk categories, 1A, 1B and 2. Status 1B criteria include support with moderate-dose inotropic medications or growth failure related to the heart condition. Status 2 candidates do not meet 1A or 1B criteria and usually are not hospitalized. Concerns have been raised that trends in the present allocation process result in a top-heavy waiting list with a high proportion of candidates listed a 1A, which may assign organs on the basis of time on the list rather than candidate risk of death.

Seroconversion and avidity maturation of cytomegalovirus-specific IgG in D+/R− lung transplant patients receiving different prophylactic anti-viral regimens - Corrected Proof

2012-04-20

Cytomegalovirus (CMV)-seronegative recipients (R−) of CMV-positive donor lungs (D+) are at high risk of developing CMV disease and therefore receive prophylactic (val-) ganciclovir for at least 3 months after lung transplantation (LuTx). As shown recently, prolonging anti-viral prophylaxis may even improve the clinical outcome. Primary CMV infections in D+R− patients tend to be severe because there is lack of cellular immunity, but possibly also because of delayed humoral immune responses when compared with immunocompetent individuals. So far, no data are available on how humoral immune responses develop in lung transplant recipients (LTRs) with primary CMV infection and whether this is influenced by the duration of anti-viral prophylaxis. The aim of this study was therefore to analyze in D+R− LTRs the development and avidity maturation of CMV-specific antibodies and their association with the duration of anti-viral prophylaxis.

Changes in serial B-type natriuretic peptide level independently predict cardiac allograft rejection - Corrected Proof

2012-04-16

Background: Despite positive associations with rejection, the clinical value of B-type natriuretic peptide (BNP) monitoring in heart transplant recipients has not been established. We sought to determine the predictive value of changes in serial BNP level for identifying patients with acute allograft rejection. Methods: BNP, hemodynamics and biopsies were obtained for 205 transplant recipients who underwent a total of 4,007 endomyocardial biopsy procedures. Samples analyzed were collected ≥180 days post-transplant, without evidence of rejection on the immediately preceding biopsy. Using a repeated-measures multivariate model, we assessed the association of change in BNP with Grade ≥3A (2R) rejection. We also determined predictive values of various cut-off thresholds of change in serial BNP levels to predict Grade ≥3A rejection. Results: There were 47 episodes of Grade ≥3A rejection among the 1,350 samples analyzed. Median change in serial BNP (ΔBNP) for those with Grade ≥3A rejection was 20 pg/ml (IQR −26 to 169 pg/ml) and among those with Grade <3A rejection was −4 pg/ml (IQR −34 to 22 pg/ml, p = 0.003). On multivariate analysis, ΔBNP remained the most potent independent predictor of Grade ≥3A rejection (p = 0.001). ΔBNP >100 pg/ml predicted increased risk of Grade ≥3A rejection (OR = 5.3, p < 0.001) with high specificity (93.3%) and positive predictive value (13.0%) and excellent negative predictive value (97.3%). Conclusions: Change in serial BNP level is an independent predictor of cardiac allograft rejection. With wide availability, rapid turnaround, low cost, favorable positive predictive value and excellent negative predictive value, serial BNP monitoring has several advantages for non-invasive monitoring of heart transplant recipients for acute cardiac allograft rejection.

Acquired premature ventricular ectopy after cardiac transplantation - Corrected Proof

Duy Thai Nguyen, Russell Heath, Amrut Ambardekar, William Sauer — 2012-04-16

Our case involves a 51-year-old woman who had undergone cardiac transplantation. The patient had a history of non-ischemic dilated cardiomyopathy and had biatrial anastomosis 15 years earlier. She presented with palpitations and was found to have 42,111 premature ventricular contractions (PVCs) in 24 hours, accounting for 50% of her heart beats despite beta-blocker treatment. Echocardiography revealed a left ventricular ejection fraction (LVEF) of 45%. After ruling out transplant rejection with a biopsy and coronary vasculopathy with an angiogram, she was referred for electrophysiologic study and ablation.

Connective tissue growth factor (CTGF/CCN2): A protagonist in cardiac allograft vasculopathy development? - Corrected Proof

Malena P. Pantou, Athanasios Manginas, Peter A. Alivizatos, Dimitrios Degiannis — 2012-04-16

Background: Connective tissue growth factor (CTGF) has been reported to be upregulated in experimental models of chronic cardiac allograft rejection. We investigated the contribution of CTGF to the development of cardiac allograft vasculopathy (CAV), a surrogate marker for chronic rejection. Methods: This prospective study included 72 adult heart allograft recipients. Genotyping of the rs6918698 polymorphism was performed by sequence-specific primer polymerase chain reaction (PCR). CTGF protein levels were measured in serum. CTGF messenger RNA (mRNA) from myocardial biopsy specimens was quantified by quantitative real-time PCR. Results: Recipient genotype was associated with the development of CAV (p = 0.014) and the carriers of the C allele (CC and CG genotype) were high-risk recipients for the development of CAV (odds ratio, 3.30; 95% confidence interval, 1.12–9.74; p = 0.044). Serum CTGF protein levels could not be associated with the presence of the C allele but were significantly lower in the patients that had developed CAV (p = 0.038). This was attributed to the addition of everolimus to their immunosuppression scheme. Myocardial relative CTGF mRNA expression was estimated to be approximately twice as much in the CAV patients than in the patients without CAV (p = 0.013). Conclusions: The important role of CTGF during the development of CAV in heart transplantation was supported by the association of CAV with the recipient CTGF-945 CC/CG genotypes. The CAV patients, who were all receiving everolimus treatment, displayed elevated myocardial CTGF mRNA transcription levels, while everolimus has been observed to reduce serum CTGF protein levels.

High cumulative dose exposure to voriconazole is associated with cutaneous squamous cell carcinoma in lung transplant recipients - Corrected Proof

2012-04-09

Background: Lung transplant recipients (LTR) have an increased risk of cutaneous squamous cell carcinoma (SCC) due to immunosuppressive therapy. Voriconazole, which is associated with phototoxic side effects in some patients, may be an additional risk factor for SCC in this population. Methods: To test whether voriconazole is a risk factor for developing SCC in LTR, we evaluated cumulative exposure to voriconazole in 327 adults who underwent lung transplantation at one center between 1991 and 2010. Voriconazole exposure was assessed as a time-varying covariate. We used survival analysis methods to assess the risk of developing SCC over time. Results: Exposure to voriconazole was associated with a 2.6-fold increased risk for SCC. This phenomenon was dose-dependent: the risk for SCC increased by 5.6% with each 60-day exposure at a standard dose of 200 mg twice daily. At 5 years after transplant, voriconazole conferred an absolute risk increase for SCC of 28%. Conclusions: These results suggest that caution should be taken when using voriconazole in LTR because this drug increases the already high risk for SCC in this population.

Use of a donor heart with pre-transplant percutaneous patent foramen ovale closure - Corrected Proof

Victor Bautista-Hernandez, Maria C. Iglesias, Francisco Portela — 2012-04-06

We describe the case of an 8-year-old boy with hypoplastic left heart syndrome who had undergone palliative Stages I and II. His clinical course was complicated by significant neo-aortic valve regurgitation and progressively impaired ventricular function. He was not considered suitable for Fontan completion and was listed for heart transplantation (weight 25 kg). The organ donor was a 33-year-old woman (weight 45 kg) who had brain death consequent to a cerebrovascular accident (CVA). Two years earlier, a CVA in the donor prompted the diagnosis of a patent foramen ovale (PFO) and an occluder was successfully implanted using supportive anti-coagulation.

Long-term treatment, tolerability, and survival with sub-cutaneous treprostinil for severe pulmonary hypertension - Corrected Proof

2012-04-05

Background: Randomized controlled trials have resulted in improved outcomes in pulmonary arterial hypertension; however, they are biased by stringent inclusion criteria, pre-specified patient sub-sets, and study durations. In addition, common practice is to start oral therapies ahead of the more potent and titratable prostanoid therapies, despite advanced disease states at diagnosis. The objectives of our prospective registry were to evaluate long-term effects on functional class, 6-minute walking distance, hemodynamics, and survival, and also long-term tolerability of first-line sub-cutaneous treprostinil, a prostacyclin analog, in patients with severe pulmonary hypertension. Methods: Data were collected from patients with functional class III/IV pre-capillary pulmonary hypertension (Dana Point groups 1 and 4; mean right arterial pressure ≥ 10 mmHg, and/or cardiac index ≤ 2.2 liters/min/m2). Treprostinil dose adjustments were driven by clinical symptoms and side effects. Results: The study included 111 patients (1999 to 2010). Of these, 13 (12%) stopped treatment prematurely because of drug side effects, 11 (9.9%) underwent double lung transplantation, and 49 (44.1%) died of any cause (41 on treatment, 8 after early drug discontinuation). Overall survival rates at 1, 5, and 9 years were 84%, 53%, and 33%. In patients who were able to tolerate treatment > 6 months, survival rates were 57% at 9 years. Conclusion: First-line treatment of severe pre-capillary pulmonary hypertension with sub-cutaneous treprostinil is safe and efficacious over many years. If up-titration beyond 6 months is tolerated, effective doses are reached and outcomes are good.

Non-cameral coronary artery fistulae after pediatric cardiac transplantation: A multicenter study - Corrected Proof

2012-03-26

Background: Cameral coronary artery fistulae (C-CAFs) are common after heart transplantation (HTx) and typically drain into the right ventricle. The development of CAFs to non-cameral structures after HTx has not been systematically investigated. We studied the incidence, anatomic distribution, and natural history of non-cameral CAFs (NC-CAFs) in a multicenter pediatric population. Methods: Medical records from pediatric HTx patients at 2 centers from January 1, 1999, to August 31, 2009 were reviewed. A classification system for CAF size was developed, and serial angiograms were evaluated for CAF presence, size, and anatomy. Risk factors and outcomes were determined. Results: Identified were 100 patients with a median age at HTx of 8.7 years. Median follow-up was 4.2 years. NC-CAFs occurred in 52 patients, C-CAFs in 20, with both types noted in 11. NC-CAFs originated from coronary arteries and drained predominantly into ipsilateral recipient pulmonary vasculature. Multiple NC-CAFs occurred in 19 patients (19%) for a total of 77 fistulae in 52 patients. Fistulae were classified as small (56%), moderate (36%), and large (8%). NC-CAFs were present at the first post-HTx angiogram in 95% of cases (median 1 year after HTx). Longer donor ischemic time was associated with the development (p = 0.043) and size (p = 0.05) of NC-CAFs. NC-CAFs were not associated with rejection, death, re-transplantation, or coronary revascularization, and none required intervention. Conclusions: Fistulae from donor coronary arteries to recipient pulmonary vasculature develop frequently and early after pediatric HTx. These correlate with graft ischemic time, but are not associated with early graft loss or death.

Highly sensitized patients in cardiac transplantation: Early outcomes from the Canadian Prioritized Organ Sharing Program - Corrected Proof

Sharon Chih, Heather J. Ross, Michael A. McDonald, Debra L. Isaac — 2012-03-23

Cardiac transplantation in a human leukocyte antigen (HLA)-sensitized patient poses significant challenges. HLA sensitization increases waiting time to transplantation as well as the risk of post-transplant rejection, graft loss and cardiac allograft vasculopathy. Registry data show a >10% panel-reactive antibody (PRA) in 12% of patients wait-listed for heart transplant and in 9% of heart transplant recipients. Desensitization strategies have shown only varied success with no large multicenter and/or randomized, controlled trials to support this approach.

Gastrointestinal bleeding with the HeartMate II left ventricular assist device - Corrected Proof

2012-03-16

Background: Continuous flow left ventricular assist devices (CF-LVADs) have yielded improved outcomes compared with pulsatile flow devices for patients on long-term support. However, significant rates of gastrointestinal bleeding (GIB) have been observed during CF-LVAD support. Methods: From March 2006 through March 2011, 86 patients with chronic heart failure underwent implantation of a CF-LVAD (HeartMate II; Thoratec Corp., Pleasanton, CA). Records were reviewed to determine the prevalence of post-implant GIB, location of the bleeding site and associated morbidity and mortality. Uni- and multivariate analyses were conducted to identify independent predictors of GIB. Results: GIB occurred in 19 patients (22.1%) with a duration of support that ranged from 5 to 456 days. Sources of GIB included small bowel and rectum in 6 patients each, large bowel in 2 patients and stomach in 1 patient. No definite source was identified in 4 patients. There were no deaths referable to GIB. Recurrent GIB occurred in 4 patients. History of a GIB prior to LVAD implant was the only variable significantly different between patients with and without post-implant GIB (21.1% vs 10.4%, p = 0.016), and was the only independent predictor of GIB (OR = 2.24, 95% CI 2.121 to 2.435, p = 0.004). Conclusions: Gastrointestinal bleeding is a frequent source of morbidity for patients on HeartMate II LVAD support but does not significantly impact survival. As implantation of CF-LVADs with non-pulsatile flow gains popularity for both bridge-to-transplant and destination therapy, a better understanding of the pathophysiology of GIB in these patients will be needed for minimizing this complication.

Left ventricular dilation and functional impairment assessed by gated SPECT are indicators of cardiac allograft vasculopathy in heart transplant recipients - Corrected Proof

2012-03-16

Background: Coronary angiography (CA) is the standard method for diagnosis of cardiac allograft vasculopathy (CAV). Little is known about the value of measuring left ventricular function over time, which can be derived from gated myocardial perfusion single-photon emission computed tomography (SPECT). We evaluated the potential of measuring myocardial perfusion and left ventricular function with gated SPECT, as compared with CA, to detect CAV in the follow-up of heart transplantation. Methods: One hundred sixty-one heart transplant recipients (137 men, 24 women, age 50.7 ± 12.2 years) were followed-up for 4.2 ± 2.0 years by annual routine gated perfusion SPECT and consecutive CA. Myocardial perfusion was quantified by summed stress, rest and difference scores (SSS, SRS and SDS, respectively). Left ventricular function (ESV, EDV and LVEF) was derived from gated SPECT. Both were compared with angiographically defined stages of CAV. Results: ESV/EDV derived from gated SPECT increased from 61 ± 25 ml/169 ± 39 ml in patients with no CAV over 74 ± 38 ml/188 ± 55 ml in patients with moderate CAV to 153 ± 75 ml/278 ± 86 ml in patients with severe CAV (p < 0.01 and p < 0.001), whereas LVEF decreased from 64 ± 10% over 62 ± 11% to 47 ± 13% in patients with severe CAV (p < 0.001). Perfusion quantified by SRS and SSS increased from 1.2 ± 1.5/1.9 ± 2.3 over 1.9 ± 1.4/2.8 ± 2.0 to 6.5 ± 5.1/7.7 ± 5.8 in patients with severe CAV (p < 0.01). Overall, for the prediction of severe CAV, accuracy was found to be higher for gated SPECT functional analysis as compared with perfusion analysis. Conclusions: Impaired left ventricular function, as assessed by gated SPECT, correlated significantly with CAV. Thus, for this purpose, gated SPECT offers higher sensitivity than analysis of perfusion while having a comparable specificity.

Effects of exercise training on exercise capacity and quality of life in patients with a left ventricular assist device: A preliminary randomized controlled trial - Corrected Proof

Kate Hayes, Angeline S. Leet, Scott J. Bradley, Anne E. Holland — 2012-03-16

Background: A paucity of studies has examined the effect of exercise training after left ventricular assist device (LVAD) implantation. Previous research has demonstrated that insertion of the LVAD alone improves exercise capacity and quality of life (QOL). This study investigated whether supervised exercise training results in a further improvement. Methods: This prospective, randomized controlled trial with concealed allocation, assessor blinding, and intention-to-treat analysis investigated the effect of exercise training on exercise capacity and QOL in 14 patients who underwent LVAD insertion as a bridge to heart transplantation. Exercise training consisted of 8 weeks of gym-based aerobic and strengthening exercises 3 times a week, with a progressive mobilization program, compared with the control group that completed mobilization alone. Exercise capacity was measured before and after the intervention using maximal cardiopulmonary exercise testing and 6-minute walk distance (6MWD). QOL was measured using the Short Form 36-item assessment. Results: No adverse events were reported. There was a trend toward greater improvement in peak oxygen consumption (Vo2), 6MWD, and QOL in the exercise group (n = 7) compared with the control group (n = 7); however, no significant between-group difference was detected for improvements in peak Vo2 [mean difference (exercise – control)] of 2.96 ml/kg/min (95% confidence interval, −1.04 to 6.97), 6MWD at 54 meters (−51 to 159 meters), and QOL scores over time (p > 0.05). Conclusion: Exercise training is feasible and safe in patients with a LVAD. Trends toward greater improvement in exercise capacity and QOL after exercise training warrant further investigation in a larger trial.

Non-cardiac surgery in patients on long-term left ventricular assist device support - Corrected Proof

2012-03-16

Background: An increasing number of patients on left ventricular assist device (LVAD) support are requiring non-cardiac surgical (NCS) procedures. We reviewed our experience with the management of patients on continuous flow (CF) LVAD support undergoing NCS. Methods: From March 2006 through March 2011, 86 patients with chronic heart failure underwent implantation of a HeartMate II (Thoratec Corp, Pleasanton, CA) LVAD. Clinical records of these patients were reviewed to identify patients who underwent NCS while on LVAD support, with a focus on peri-operative death, bleeding, thrombosis, and device malfunction, as well as management of pre-operative anti-coagulation. Results: While on CF-LVAD support, 20 patients underwent 25 NCSs, comprising 13 major and 12 minor procedures. Operations were performed electively in 22 and as emergencies in 3. No peri-operative deaths, thromboembolic complications, or device malfunctions occurred. The incidence of bleeding requiring transfusion of packed red blood cells was 36.0%, including 25% of patients undergoing minor NCSs and 46.2% undergoing major NCSs (p = 0.004). All bleeding complications occurred in patients on both warfarin and aspirin pre-operatively. The only significant differences between patients who did and did not require transfusion were pre-operative warfarin use and significantly higher pre-operative international normalized ratio in the transfused group (1.9 ± 0.4 vs 1.4 ± 0.3; p = 0.008). Conclusions: Non-cardiac operations can be performed safely in patients with CF-LVADs. It may possible to reduce peri-operative bleeding by lowering pre-operative anti-coagulation goals, especially before major surgery. However, additional analysis is required to determine if this can be performed safely.

Low vitamin D levels are associated with increased rejection and infections after lung transplantation - Corrected Proof

2012-03-05

Background: The prevalence of vitamin D deficiency in lung disease is greater than in the general population. Vitamin D deficiency may negatively affect immune and lung function. Accordingly, we hypothesized that lung transplant recipients with vitamin D deficiency are more susceptible to rejection and infections after transplantation. Methods: Transplant outcomes were reviewed in a retrospective cohort of 102 lung transplant recipients who had 25-hydroxyvitamin D [25(OH)D] levels drawn during the near-transplant period (100 days pre- or post-transplant). Results: In the near-transplant period, 80% of recipients were 25(OH)D-deficient and 20% were not 25(OH)D-deficient. Episodes of acute cellular rejection in the deficient group were more frequent than in the non-deficient group [mean 1.27 (0.99 to 1.55) vs 0.52 (0.12 to 0.93), p = 0.006]. The rejection rate in the deficient group was more than double that of the the non-deficient group [IRR 2.43 (1.30 to 4.52), p = 0.005]. Infectious episodes were also more frequent in the deficient group than in the non-deficient group [mean 4.01 (3.24 to 4.79) vs 2.71 (1.47 to 3.96), p = 0.04]. The mortality rate of recipients who remained 25(OH)D-deficient 1 year after transplant was almost 5-fold higher than in recipients who were not 25(OH)D-deficient [IRR 4.79 (1.06 to 21.63), p = 0.04]. Conclusions: Low serum 25(OH)D levels in lung transplant recipients were associated with increased incidence of acute rejection and infection. The mortality of recipients who remained deficient 1 year post-transplant was higher than that of recipients who maintained normal vitamin D levels at 1 year post-transplant.

Parameters of donor–recipient size mismatch and survival after bilateral lung transplantation - Corrected Proof

2011-10-31

Background: The purpose of this study was to investigate the relationship between donor–recipient height, gender and predicted estimates of total lung capacity (pTLC) mismatches and post-transplant survival.Methods: The lung transplant databases at three programs were reviewed. The pTLC ratios (donor pTLC/recipient pTLC) and height ratios (donor height/recipient height) were calculated retrospectively. Patients were grouped according to pTLC ratio ≤1.0 or >1.0 and height ratio ≤1.0 or >1.0, and according to gender (mis-)matching. A time-to-event analysis was performed for risk of death after transplantation conditional on 30-day survival using Kaplan–Meier survival and Cox proportional hazard models.Results: There were 211 adult bilateral lung transplant recipients who qualified for the analysis. Mean follow-up was comparable for all cohorts (range 2.21 to 3.85 years). In the univariate Cox proportional hazard models, a pTLC ratio >1.0 (HR 0.43, p = 0.002) and a height ratio >1.0 (HR 0.61, p = 0.03) were associated with better survival, and a female-donor-to-male-recipient gender mismatch (F-to-M) was associated with worse survival (HR 2.35, p = 0.01). In the multivariate Cox proportional hazard model accounting for F-to-M gender mismatch and height ratio >1.0, a pTLC ratio >1.0 remained associated with survival (HR 0.38, p = 0.015). However, accounting for a pTLC ratio >1.0, a height ratio of >1.0 and F-to-M mismatch were not associated with survival.Conclusions: A pTLC ratio >1.0 is associated with improved survival after bilateral lung transplantation. The pTLC ratio might better reflect allograft–thorax mismatch than the height ratio, as it also accounts for effects of gender on lung and thoracic volumes.

WITHDRAWN: Predictors of long-term survival in pulmonary hypertension treated with bosentan - Corrected Proof

2011-03-18

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