The Journal of Heart and Lung Transplantation

The dawn of the ISHLT Mechanical Assisted Circulatory Support (IMACS) Registry: Fulfilling our mission

James K. Kirklin, Mandeep R. Mehra — 2012-02-01

ISHLT Mission Statement: The International Society of Heart and Lung Transplantation is a multidisciplinary, professional organization dedicated to improving the care of patients with advanced heart or lung disease through transplantation, mechanical support, and innovative therapies via research, education, and advocacy.

The Fourth INTERMACS Annual Report: 4,000 implants and counting

2012-02-01

The Fourth Annual Report of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) summarizes and analyzes the first 5 years of patient and data collection. With more than 4,000 patients entered into the database, the evolution of pump technology, strategy at implant, and pre-implant patient profiles are chronicled. A risk factor analysis of the entire adult primary implant population is provided, and the recent composition of patient profiles is examined. Current actuarial survival with continuous-flow pumps exceeds 80% at 1 year and 70% at 2 years.

Use of sublingual tacrolimus in lung transplant recipients

2011-12-19

Background: In lung transplant recipients (LTRs), tacrolimus is often utilized as a core component of immunosuppressive regimens. Although tacrolimus can be delivered orally or intravenously, oral tacrolimus is associated with fewer adverse effects. Various reports have suggested that sublingual tacrolimus may be used as an alternative to oral tacrolimus; however, information regarding converting between routes is limited. We aimed to identify a dose conversion ratio between oral and sublingual tacrolimus in LTRs. Methods: We identified adult LTRs at the University of California, San Francisco, who transitioned between oral and sublingual tacrolimus between 2005 and 2010 (n = 34). For tacrolimus, we obtained steady-state blood concentrations and total daily doses before and after the route conversion. Blood concentrations divided by daily doses were calculated for each route. The conversion ratio was then defined as: (blood concentrationsublingual/daily dosesublingual)/(blood concentrationoral/daily doseoral). This ratio was tested in inpatient vs outpatient settings and in the presence of impaired gastric emptying. Adverse effects, including nephrotoxicity, hepatotoxicity and anaphylaxis, were evaluated. Results: The conversion ratio of sublingual to oral tacrolimus was 0.46 ± 0.20 (mean ± SD). The ratio was not associated with hospital setting (p = 0.82) or with impaired gastric emptying (p = 0.31). When comparing sublingual to oral tacrolimus administration, there were no differences in serum creatinine, liver function tests or anaphylaxis. Conclusions: Tacrolimus administered sublingually at approximately half of the oral dose achieves therapeutic blood concentrations and is safe in LTRs. Delivery via the sublingual route using this conversion ratio may aid clinicians in maintaining therapeutic tacrolimus blood concentrations while avoiding the need for intravenous administration.

Comparison of risk factors and outcomes for pediatric patients listed for heart transplantation after bidirectional Glenn and after Fontan: An analysis from the Pediatric Heart Transplant Study

2011-12-15

Background: Patients listed for transplant after the bidirectional Glenn (BDG) may have better outcomes than patients listed after Fontan. This study examined and compared outcomes after listing for BDG and Fontan patients. Methods: All patients listed for transplant after the BDG in the Pediatric Heart Transplant Study between January 1993 and December 2008 were evaluated. Comparisons were made with Fontan patients and with a matched cohort of congenital heart disease patients. Competing outcomes analysis and actuarial survival were evaluated for the study populations, including an examination of various risk factors. Results: Competing outcomes analysis for BDG and Fontan patients after listing were similar. There was no difference in actuarial survival after listing or transplant among the 3 cohorts. Mechanical ventilation, United Network of Organ Sharing status, and age were risk factors for death after listing in BDG and Fontan patients, but ventilation at the time of transplant was significant only for the Fontan patients. Mortality was increased in Fontan patients listed < 6 months after surgery compared with patients listed > 6 months after surgery, but no difference was observed in BDG patients. There was a trend toward improved survival after listing for both populations across 3 eras of the study, but this did not reach statistical significance. Conclusion: Outcomes after listing for BDG and Fontan patients are similar. Mechanical ventilation at the time of transplant remains a significant risk factor for death in the Fontan population, as does listing for transplant soon after the Fontan, suggesting that some patients may benefit from transplant instead of Fontan completion.

Decision tree for adjuvant right ventricular support in patients receiving a left ventricular assist device

2011-12-15

Background: Right ventricular (RV) failure is a significant complication after implantation of a left ventricular assist device (LVAD). It is therefore important to identify patients at risk a priori. However, prognostic models derived from multivariate analyses have had limited predictive power. Methods: This study retrospectively analyzed the records of 183 LVAD recipients between May 1996 and October 2009; of these, 27 later required a RVAD (RVAD+) and 156 remained on LVAD only (RVAD−) until transplant or death. A decision tree model was constructed to represent combinatorial non-linear relationships of the pre-operative data that are predictive of the need for RVAD support. Results: An optimal set of 8 pre-operative variables were identified: transpulmonary gradient, age, right atrial pressure, international normalized ratio, heart rate, white blood cell count, alanine aminotransferase, and the number of inotropic agents. The resultant decision tree, which consisted of 28 branches and 15 leaves, identified RVAD+ patients with 85% sensitivity, RVAD− patients with 83% specificity, and exhibited an area under the receiver operating characteristic curve of 0.87. Conclusions: The decision tree model developed in this study exhibited several advantages compared with existing risk scores. Quantitatively, it provided improved prognosis of RV support by encoding the non-linear, synergic interactions among pre-operative variables. Because of its intuitive structure, it more closely mimics clinical reasoning and therefore can be more readily interpreted. Further development with additional multicenter, longitudinal data may provide a valuable prognostic tool for triage of LVAD therapy and, potentially, improve outcomes.

Usefulness of first-line combination therapy with epoprostenol and bosentan in pulmonary arterial hypertension: An observational study

2011-12-05

Background: Recent guidelines have proposed first-line combination therapy as a potential strategy for the treatment of functional class IV pulmonary arterial hypertension (PAH). Methods: We analyzed efficacy and safety of upfront epoprostenol and bosentan combination therapy in consecutive patients with idiopathic, heritable, or anorexigen-associated PAH and compared outcomes with matched controls treated by epoprostenol monotherapy. Results: Data for 16 functional class III patients and 7 functional class IV patients were analyzed. Baseline 6-minute walk distance (6MWD) was 287 ± 133 meters, mean pulmonary artery pressure was 65 ± 12 mm Hg, cardiac index was 1.8 ± 0.3 L/min/m2, and pulmonary vascular resistance (PVR) was 1493 ± 398 dynes/sec/cm5. After 4 months, 6MWD and PVR significantly improved to 421 ± 100 meters and 784 ± 364 dynes/sec/cm5, respectively. These improvements were maintained long-term (30 ± 19 months). At 1, 2, 3, and 4 years, overall survival estimates were 100%, 94%, 94%, and 74%, and transplant-free survival estimates were 96%, 85%, 77%, and 60%, respectively. Compared with matched controls started on epoprostenol monotherapy, there was a trend to an improvement in overall survival (p = 0.07). Conclusions: Initial combination therapy with epoprostenol and bosentan in patients with severe PAH is associated with improvements in important outcomes such as functional class, exercise capacity, and hemodynamics. This combination strategy might also favorably affect overall and transplant-free survival.

Evaluation of valganciclovir pharmacokinetics in lung transplant recipients

Tyree H. Kiser, Douglas N. Fish, Martin R. Zamora — 2012-02-01

Background: Valganciclovir is commonly used for cytomegalovirus prevention after lung transplantation. The pharmacokinetic profile of valganciclovir in lung transplant patients has not been well described or linked to efficacy and safety. Methods: This prospective, randomized, crossover study determined the steady-state pharmacokinetic profile of 2 different doses of valganciclovir in lung transplant recipients and compared these profiles with intravenous ganciclovir. Results: Ten patients were evaluated. Patients were 56.8 ± 3.4 years old and had a mean creatinine clearance of 69 ± 9 ml/min. Oral bioavailability of ganciclovir after administration of valganciclovir was 59%, and mean half-life was 3.73 ± 1.15 hours. The maximal concentration after intravenous 5 mg/kg ganciclovir was significantly higher than after 450 mg valganciclovir (8.37 ± 3.03 mg/liter vs. 5.3 ± 2.09 mg/liter, respectively; p = 0.02) and similar to 900 mg valganciclovir (7.93 ± 3.97 mg/liter; p = 0.78). A higher area under the curve at 0–24 hours (AUC0–24) was found with 900 mg valganciclovir compared with intravenous 5 mg/kg/day ganciclovir (47.8 ± 19.7 vs 32.9 ± 10.8 mg · hour/liter, respectively; p = 0.049). The AUC0–24 for 450 mg valganciclovir twice daily was 45.5 ± 22.9 mg · hour/liter. Conclusion: Valganciclovir at 900 mg/day resulted in the equivalent of a mean daily dose of 7.7 mg/kg intravenous ganciclovir. Higher systemic ganciclovir exposures occurred after 900 mg/day valganciclovir compared with intravenous 5 mg/kg/day ganciclovir. Valganciclovir therapeutic drug monitoring may be warranted in select lung transplant patients to avoid increased toxicity.

Extremes of body mass index do not impact mid-term survival after continuous-flow left ventricular assist device implantation

2012-02-01

Background: Extremes of body mass index (BMI) are often considered contraindications to use of a left ventricular assist device (LVAD), but data regarding outcomes across the spectrum of BMI are limited. We sought to assess the association of BMI with survival and major morbidity after continuous-flow (CF) LVAD implantation. Methods: Patients (n = 896) enrolled in the HeartMate II LVAD bridge-to-transplantation and destination therapy trials were divided into 4 BMI groups: underweight (<18.5 kg/m2); normal (18.5 kg/m2 ≤ BMI < 30 kg/m2); obese (30 kg/m2 ≤ BMI < 35 kg/m2); and extremely obese (≥35 kg/m2). The association of BMI with survival was tested using Kaplan–Meier analysis and proportional hazards regression. Major adverse events were compared using Poisson's regression and chi-square tests. Results: At implantation, 48 (5%) patients were underweight, 596 (67%) normal weight, 164 (18%) obese and 88 (10%) extremely obese. BMI extremes were associated with differences in creatinine, albumin, age, central venous pressure and etiology. BMI was not associated with survival in the univariate analysis (p = 0.83) or in adjusted models (extremely obese: hazard ratio [HR] 1.29, p = 0.231; obese: HR 0.94, p = 0.723; underweight: HR 1.23, p = 0.452). Underweight patients were more likely to have bleeding events (p < 0.001), whereas extremely obese patients had higher rates of device-related infection (p = 0.041) and rehospitalization (p = 0.014). Conclusions: Overall survival in patients receiving CF LVAD is similar across BMI categories. Carefully selected patients at both extremes of BMI have good mid-term survival after LVAD and should be considered for LVAD implantation relative to overall risk profile.

ABO-incompatible heart transplantation: Analysis of the Pediatric Heart Transplant Study (PHTS) database

2012-02-01

Background: ABO incompatible (ABOi) heart transplantation is an accepted approach to increasing organ availability for young patients. Previous studies have suggested that early survival for ABOi transplants is similar to ABO compatible (ABOc) transplants. We analyzed the Pediatric Heart Transplant Study (PHTS) database from 1/96 to 12/08 to further assess this strategy. Methods: We analyzed the numbers of ABOi and ABOc done at the PHTS centers. We then compared the clinical characteristics, and short-term freedom from death, rejection and infection in the ABOi patients with the patients that had an ABOc heart transplant during the same period. All patients were less than or equal to 15 months of age at listing (the age of the oldest ABOi patient). We adjusted for co-variates shown to increase risk for mortality (age less than 1 month, extracorporeal membrane oxygenation (ECMO), ventilator, previous sternotomy, and congenital heart disease). Results: There were 931 total transplants done at 34 PHTS centers during the 12 year time period in patients ≤15 months of age. Of these, 502 transplants were performed at 20 PHTS centers that did at least one ABOi heart transplant. Eighty-five of the 502 (17%) were ABOi. At time of transplant, ABOi recipients compared with ABOc were more likely to be on a ventilator (49.4% vs 36.5%, p=0.025), and more often supported with ECMO (23.5% vs 13.4%, p=0.018). There was similar survival at 12 months (82% vs 84%, p=0.7). In risk adjusted analysis ABOi status was not associated with 1 year mortality (HR 0.85, 95% CI 0.45–1.6, p=0.61). The ABOi patients had greater freedom from rejection when compared with ABOc patients for all 34 centers (75% vs 62%, p=0.016), but the difference was not significant when limited only to the 20 centers doing ABOi transplants (75% vs 69%, p=0.4). The ABOi cohort had lower infection rates (23.5% vs 37.9%, p = 0.013). This difference remained after adjusting for center and other covariates. Conclusions: In center and risk adjusted analysis, young children who received an ABOi transplant had equivalent one-year survival and freedom from rejection compared with those who received an ABOc transplant. In spite of the favorable outcome for ABOi recipients, many centers appear to reserve ABOi transplantation for sicker patients. These data mandate reexamination of the current United Network for Organ Sharing (UNOS) policy that gives priority to ABOc over ABOi transplantation in the United States.

Peripartum cardiomyopathy: Post-transplant outcomes from the united network for organ sharing database

2012-02-01

Background: Nearly 25% of patients with peripartum cardiomyopathy (PPCM) will require cardiac transplantation. Whether post-transplant outcomes differ among patients with PPCM compared with other recipients remains unsettled. Methods: The United Network for Organ Sharing database was queried for cardiac transplants, comparing characteristics and outcomes for PPCM, other women, and all others. Results: Between 1987 and 2010, 42,406 patients (9,419 women and 32,987 men) received a heart transplant. Of these, 485 women who had PPCM as the indication were younger (p < 0.001), had higher sensitization (p < 0.001), required higher intensity of cardiovascular support pre-transplant (p = 0.026), and had higher listing status (p < 0.001). Those with PPCM had more post-transplant rejection during the index transplant hospitalization (p < 0.001) and during the first year (p = 0.003). Comparing PPCM with other women and all others, graft survival was inferior (p = 0.004 and p < 0.003, respectively) and age-adjusted survival was lower (p < 0.001 and p = 0.02, respectively). Conclusions: This large report shows outcomes of graft failure and death are inferior for recipients with PPCM, which may be partly explained by younger age, higher allosensitization, higher pre-transplant acuity, and increased rejection. More research is needed to determine management strategies to improve outcomes in PPCM heart transplant recipients.

Reconditioning of lungs donated after circulatory death with normothermic ex vivo lung perfusion

2012-02-01

Background: The use of donation-after-circulatory-death (DCD) donors for lung transplantation has come into practice. In this study we investigated whether DCD lungs can be resuscitated after warm ischemia with normothermic ex vivo lung perfusion (EVLP). Methods: Four hours after cardiac arrest, beagle dogs were divided into two groups (n = 6 each): those with static cold storage (SCS group) and those with normothermic EVLP (EVLP group), for 3.5 hours. Physiologic lung functions were evaluated during EVLP. In both groups, the left lungs were then transplanted and reperfused for 4 hours to evaluate post-transplant lung functions. Lung tissue adenosine triphosphate (ATP) levels were measured at given time-points. Results: Lung oxygenation was significantly improved with EVLP (p < 0.01), and lung oxygenation at the end of EVLP significantly reflected post-transplant lung oxygenation (r = 0.99, p < 0.01). Post-transplant lung oxygenation was significantly better in the EVLP group than in the SCS group (p < 0.05). Both dynamic pulmonary compliance and wet-to-dry lung weight ratio 4 hours after transplantation were also significantly better in the EVLP group than in the SCS group (p < 0.05). Microthrombi in the donor lungs before transplantation were microscopically detected more often in the SCS group. The lung tissue ATP levels 4 hours after transplantation were significantly higher in the EVLP group compared with the SCS group (p = 0.03). Conclusions: Normothermic ex vivo lung perfusion could resuscitate DCD lungs injured by warm ischemia, and may ameliorate ischemia–reperfusion injury.

Effect of simvastatin on development of obliterative airway disease: An experimental study

2012-02-01

Background: Obliterative bronchiolitis after lung transplantation is characterized by airway inflammation leading to obliteration of small airways. Statins are known to have lipid-independent immunomodulatory properties. We investigated the effect of simvastatin treatment on innate and adaptive immune responses and the development of obliterative airway disease (OAD). Methods: In fully MHC-mismatched rat tracheal allograft recipients, we used simvastatin at different doses (0.1 to 20 mg/kg/day orally) to assess its effect on OAD development. No immunosuppressive treatment was administered. Histologic, immunohistochemical and real-time RT-PCR analyses were performed 3, 10 and 30 days after transplantation. Results: Simvastatin treatment with doses ranging from 0.5 to 20 mg/kg/day significantly enhanced early epithelial recovery and reduced the development of OAD. No dose response was observed. Simvastatin treatment markedly reduced IL-23 mRNA and lymphocyte chemokine CCL20 production, and the infiltration of CD4+ and CD8+ T cells into allografts already at 3 days. At 10 days, simvastatin significantly attenuated the production of pro-inflammatory cytokines, IL-1β, TNF-α, MCP-1 and IP-10, and Th17-polarizing cytokines, IL-6 and IL-17e, and inhibited allograft infiltration by inflammatory cells. The protective effects of simvastatin on inflammation and OAD were partially mediated through nitric oxide synthase. Conclusions: Simvastatin treatment inhibited adaptive T-cell alloimmune activation as depicted by reduced expression of lymphocyte chemokine and pro-inflammatory cytokine mRNA and reduced allograft infiltration by inflammatory cells. Importantly, simvastatin inhibits the development of OAD and this effect is partially mediated by increased nitric oxide activity. These results suggest a role for simvastatin in the prevention of obliterative bronchiolitis.

Construction of vascularized cardiac tissue from genetically modified mouse embryonic stem cells

2012-02-01

Background: The aim of myocardial tissue engineering is to repair or regenerate damaged myocardium with engineered cardiac tissue constructed by a combination of cells and scaffolds in vitro. However, this strategy has been hampered by the lack of cardiomyocytes and the significant cell death after transplantation in vivo. Methods: In this study we explored the feasibility of in vitro construction of vascularized cardiac muscle using genetically modified mouse embryonic stem cells (ESCs) transfected by pMHC-neo/SV40-hygro. A stirred bioreactor was used to facilitate the formation of a large number of ESC-derived cardiomyocytes, which were then mixed with human umbilical vein endothelial cells (HUVECs) and mouse embryonic fibroblasts (MEFs) in a liquid collagen scaffold to construct highly vascularized cardiac tissue in vitro. Results: The resulting tissue constructs were transplanted into dorsal subcutaneous sites of nude mice. Tumor formation was not detected in all samples and vascularized cardiac tissue could survive after transplantation. Vascularization of the implanted cardiac muscle was significantly enhanced by the addition of HUVECs and MEFs, which resulted in a thicker myocardium. The combination of genetically modified ESCs and stirred bioreactor cultivation not only benefited the large-scale production of pure ESC-derived cardiomyocytes, but also effectively controlled the potential risk of undifferentiated ESCs. Conclusions: Using liquid collagen as scaffold, the enriched cardiomyocytes derived from genetically modified ESCs mixed with HUVECs and MEFs in 3-dimensional culture resulted in highly vascularized cardiac tissues.

Searching for novel molecular targets of chronic rejection in an orthotopic experimental lung transplantation model

2012-02-01

Background: Chronic rejection (CR) is the main reason for the limited survival rates among lung transplant (LT) recipients. There remains no effective treatment for CR. The aim of this study was to identify new molecular mechanisms involved in CR by using DNA microarray analysis. Methods: We performed 10 left LTs using the microsurgical cuff technique in inbred Sprague-Dawley rats. Lung isograft samples were obtained 3 months after surgery. We analyzed histologic, apoptotic and gene expression changes by DNA microarray and quantitative PCR analysis. Results: Histologic analyses confirmed signs of CR in all lungs and positive labeling for apoptotic and anti-apoptotic markers. A total of 702 genes were regulated in the CR lungs: 317 genes were upregulated and 385 were downregulated. Significant changes for about 30 biologic processes, including regulation of the cytoskeleton, and 15 signaling pathways, such as adherens junctions, were observed. We found significantly increased mRNA expression of the Cldn5, Epas1, Tgfb1, Vegf, Selp1, Hsp27 and Igf1 genes. Conclusions: This is the first experimental study performed in an orthotopic model of LT using DNA microarray analysis. The individual genes, biologic process and pathways identified may represent novel targets that could be manipulated and contribute to the development of treatments capable of providing protection from CR.

Altered progenitor cell and cytokine profiles in bronchiolitis obliterans syndrome

2012-02-01

Background: Bone marrow–derived progenitor cells may play a key role in both lung repair and in fibrogenesis. The contribution of CD45+collagen-1+ fibrocytes to fibrosis has been documented elsewhere and recently identified epithelial-like progenitor cells marked by Clara cell secretory protein (CCSP+) may be protective after lung injury. Interplay between these populations has not yet been studied in bronchiolitis obliterans syndrome (BOS) post–lung transplant. Methods: In a cross-sectional design, blood samples were analyzed for CCSP+ cells and CD45+collagen-1+ fibrocytes by flow cytometry. Plasma cytokines were analyzed by multiplex array. Results: A higher proportion of circulating fibrocytes was measured in patients with BOS Grade ≥1 than in those with BOS Grade 0(p). In parallel, a lower proportion of CCSP+ cells was found in BOS ≥1 patients compared with BOS 0(p) and non-transplant controls, resulting in an altered cell ratio between the groups. A higher ratio of CD45+collagen-1+ to CCSP+ cells was associated with greater airflow limitation based on FEV1 and FEV1/FVC ratio. No relationship between cell profiles and time post-transplant was found. Plasma analysis showed an increase in key stem cell and inflammatory cytokines in both groups post-transplant, whereas stromal-derived factor-1 and vascular endothelial growth factor were increased in cases of BOS ≥1 specifically. Plasma stromal-derived factor-1 levels also correlated with fibrocytes post-transplant. Conclusions: Overall, altered progenitor cell profiles were found in patients who developed advanced BOS, which may be mediated by alterations in circulating cytokines. Ultimately, measurement of progenitor cell profiles may lead to further insight into the pathogenesis of airflow obstruction after lung transplantation.

Combined heart and liver transplantation in an adult with familial heterozygous hypercholesterolemia and severe ischemic cardiomyopathy

Snehal R. Patel, David D'alessandro, Jooyoung J. Shin — 2012-02-01

Familial hypercholesterolemia (FH) is an autosomal-dominant disorder caused by mutations in the low-density lipoprotein (LDL) receptor. The clinical manifestations of FH include severe atherosclerosis and premature heart disease. Liver transplantation restores defective LDL receptors and has been used for long-term treatment in homozygous FH.

Editorial Board

2012-02-01

The Journal of Heart and Lung Transplantation

The dawn of the ISHLT Mechanical Assisted Circulatory Support (IMACS) Registry: Fulfilling our mission

The Fourth INTERMACS Annual Report: 4,000 implants and counting

Use of sublingual tacrolimus in lung transplant recipients

Comparison of risk factors and outcomes for pediatric patients listed for heart transplantation after bidirectional Glenn and after Fontan: An analysis from the Pediatric Heart Transplant Study

Decision tree for adjuvant right ventricular support in patients receiving a left ventricular assist device

Usefulness of first-line combination therapy with epoprostenol and bosentan in pulmonary arterial hypertension: An observational study

Evaluation of valganciclovir pharmacokinetics in lung transplant recipients

Extremes of body mass index do not impact mid-term survival after continuous-flow left ventricular assist device implantation

ABO-incompatible heart transplantation: Analysis of the Pediatric Heart Transplant Study (PHTS) database

Peripartum cardiomyopathy: Post-transplant outcomes from the united network for organ sharing database

Reconditioning of lungs donated after circulatory death with normothermic ex vivo lung perfusion

Effect of simvastatin on development of obliterative airway disease: An experimental study

Construction of vascularized cardiac tissue from genetically modified mouse embryonic stem cells

Searching for novel molecular targets of chronic rejection in an orthotopic experimental lung transplantation model

Altered progenitor cell and cytokine profiles in bronchiolitis obliterans syndrome

Combined heart and liver transplantation in an adult with familial heterozygous hypercholesterolemia and severe ischemic cardiomyopathy

Editorial Board

Contents