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  • Circulating NEDD9 is Increased in Pulmonary Arterial Hypertension: A Multicenter, Retrospective Analysis
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-12-31
    Andriy O. Samokhin; Steven Hsu; Paul B. Yu; Aaron B. Waxman; George A. Alba; Bradley M. Wertheim; C. Danielle Hopkins; Frederick Bowman; Richard N. Channick; Ivana Nikolic; Mariana Faria-Urbina; Paul M. Hassoun; Jane A. Leopold; Ryan J. Tedford; Corey E. Ventetuolo; Peter J. Leary; Bradley A. Maron
    更新日期:2019-12-31
  • ULTRASTRUCTURAL CHANGES IN PULMONARY ALLOGRAFTS WITH ANTIBODY MEDIATED REJECTION
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-12-06
    Mariam P Alexander, Andrew Bentall, Patrice C. Abell Aleff, Manish Gandhi, John P. Scott, Anja C. Roden

    Background Antibody mediated rejection (AMR) is an important cause of lung allograft loss in some patients. Challenges with current diagnostic criteria limit timely detection. Ultrastructural studies (US) of endothelium allow early detection of AMR in kidney allografts. This study aimed to define the ultrastructural changes of the endothelium in lung allografts in the setting of AMR and determine its specificity for AMR. Methods US were performed on lung allograft biopsies of twelve patients using glutaraldehyde fixed or paraffin embedded material (PEM). AMR had been classified according to International Society of Heart and Lung Transplant (ISHLT) 2016 consensus report criteria. Endothelial changes (swelling (ES), vacuolization (EV), surface irregularity, detachment, neutrophil margination (NM)) and basement membrane changes were graded semi quantitatively using electron microscopy (EM). Grades were compared between AMR, Acute cellular rejection (ACR) and non-transplant controls. Results Significant differences were found between AMR and ACR biopsies, particularly in ES (p=0.006), EV (p=0.023.) and NM (p=0.038). Using a combined score of all categories of assessment, the Total EM score was significantly higher in AMR (p=0.007) and provided excellent sensitivity and specificity with a receiver operator characteristic curve of 1.0. C4d did not correlate with EM changes associated with AMR. The use of PEM samples did not significantly affect analysis compared to glutaraldehyde fixed tissue, although ES was reduced in the former. Conclusions Endothelial structural analysis using EM can facilitate improved diagnostic accuracy of AMR and needs to be validated in larger cohorts, but also allows retrospective studies to be performed.

    更新日期:2019-12-06
  • Increased sensitivity to ischemic interval of donor hearts with diminished left ventricular function
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-12-05
    Allison B. Davila, Wendy Shih, Liset N. Stoletniy, Tim P. Martens, Leonard L. Bailey, Anees J. Razzouk, David G. Rabkin

    Background Previous studies have demonstrated that carefully selected donor hearts (DH) with poor left ventricular ejection fraction (EF) may be transplanted with long-term survival equivalent to hearts with normal function. The purpose of this study is to facilitate their selection. Methods Using the UNOS database, we reviewed all adult heart transplants between January 2000 and March 2016. Regression models were developed to estimate hazard ratios (HR) with 95% confidence intervals of post-transplant 1-year mortality and failure of EF to recover at one year for DH with (EF) ≥ 50%, EF 40-49.9% and EF 30-30.9%. Results 31,979 DH were transplanted during the study period. Compared to DH with LVEF ≥50%, DH with reduced EF were younger and had slightly lower body mass index. There were no differences in the mechanism of death between groups, and no differences in recipient characteristics except for a higher incidence of African American recipients of EF 40-49.9% hearts. Of the variables analyzed only a one-hour increase in ischemia time had different HRs for one-year mortality between groups with increasing hazard as EF diminished. It was also the only variable that predicted failure of recovery of normal EF and that was in the lowest EF group. Conclusions The impact of DH traits associated with adverse outcomes after heart transplantation that we studied are similar between DH with EF<50% and those ≥50%, however limiting ischemic time may be even more important for DH with diminished LV function particularly at the low end of the EF spectrum.

    更新日期:2019-12-05
  • Longitudinal Impact of Temporary Mechanical Circulatory Support on Durable Ventricular Assist Device Outcomes: An IMACS Registry Propensity Matched Analysis
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-12-05
    Jaime A. Hernandez-Montfort, Rongbing Xie, Van-Khue Ton, Bart Meyns, Takeshi Nakatani, Masanobu Yanase, Steve Shaw, Stephen Pettit, Ivan Netuka, James Kirklin, Daniel J. Goldstein, Jennifer Cowger

    Background Patients with advanced heart failure and cardiogenic shock (CS) often require temporary circulatory support (TCS) as a bridge to durable ventricular assist devices (dVAD). We aim to characterize longitudinal outcomes of patients with and without CS. Methods Between 2013 and 2017, 13,813 adult patients classified as Intermacs profiles 1-3 with CF-LVADs or BiVADs were registered into IMACS. Patients were sub-grouped according to support type (ECMO, IABP, other-TCS). Other-TCS included all other surgical and percutaneous TCS devices. Estimated survival was compared based on need for preoperative TCS and by Profile. Results Preoperative TCS was used in 5632 (41%). Of these, ECMO in 1138 (20%), IABP in 3901 (69%), and other-TCS in 595 (11%). Patients requiring ECMO had greater needs for biventricular support after dVAD (22% ECMO, 5% IABP, 7% Other-TCS, p< 0.001) with longer post-implant intensive care stays (ECMO 24 days (d), IABP 14 d, Other-TCS 12 d, p <0.001). Intermacs Profile 1-3 patients with pre-implant ECMO had the lowest longitudinal survival (82% at 1 month, 44% at 48 months) compared to IABP (93% at 1 month, 51% at 48 months), other-TCS (92% at 1 month, 52% at 48 months) and non-TCS (95% at 1 months, 55 % at 48 months) (p < 0.0001). Propensity score matching analysis of the pre-implant ECMO Intermacs Profile 1 group when compared to alternative pre-implant TCS strategies had an associated higher hazard impacting early phase survival vs. other-TCS (HR 1.80, p < 0.01) and IABP (HR 1.65, p< 0.01) . Conclusions In AHF with CS patients, the use of ECMO prior to dVAD was associated with lower longitudinal survival and increased utilization of bi-ventricular support compared to alternative TCS strategies. Research focused on longitudinal profiling in CS and pre-implant TCS is warranted to further understand these differences.

    更新日期:2019-12-05
  • FLOW-TARGETED PEDIATRIC EX-VIVO HEART PERFUSION in DONATION AFTER CIRCULATORY DEATH: A Porcine Model
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-12-05
    Junko Kobayashi, Shuhua Luo, Yohei Akazawa, Marlee Parker, Jian Wang, David Chiasson, Mark K. Friedberg, Christoph Haller, Osami Honjo

    Objectives The optimal blood flow and pressure to perfuse pediatric hearts donation after circulatory death (DCD) on the ex-vivo perfusion system has not been elucidated. This study sought to investigate the optimal perfusion strategy for pediatric DCD hearts by using a juvenile porcine model comparing pressure- vs. flow-targeted strategy. Methods The hearts of the juvenile DCD pigs were explanted and the coronary arteries were perfused for 2 hours by the ex-vivo heart perfusion system with two different perfusion strategies; pressure-targeted perfusion (target coronary perfusion pressure: 40mmHg, group A) and flow-targeted perfusion (target coronary perfusion flow: 10ml/kg/min, group B). The working model heart perfusion was used to assess systolic and diastolic myocardial performance. Results Body weight, warm and cold ischemic time, and ex-vivo perfusion time were comparable between the groups. In the working model, group B showed significantly preserved cardiac output (A: 70.5+/-15.3ml/kg/min vs. B: 113.8+/-15.0ml/kg/min, p<0.01), stroke volume (A: 0.4+/-0.1ml/kg vs. B: 0.7+/-0.1ml/kg, p<0.01), and ejection fraction (A: 18.8+/-5.9% vs. B: 35.0+/-10.6%, p<0.01). E/e’ and Tei index were also significantly preserved in group B. %gain of heart weight after ex-vivo (net increase of the heart weight/heart weight at baseline) was significantly smaller in group B (A: 20.0+/-5.3% vs. B: 11.6+/-5.0%, p<0.05). Troponin-I, myocardial hemorrhage, oxidative stress markers; myeloperoxidase and 8-hydroxy-2’-deoxyguanosine were also significantly lower after ex-vivo perfusion in group B (p<0.05). Conclusions The tightly-controlled flow-targeted myocardial perfusion strategy for DCD donor hearts achieved better myocardial performance by causing less myocardial edema and limiting myocardial reperfusion injury.

    更新日期:2019-12-05
  • Pulmonary vascular imaging characteristics after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-12-05
    Natalia J. Braams, Dieuwertje Ruigrok, Monique G.M. Schokker, Lina Padervinskiene, Frances S. de Man, J.T. Marcus, Rutger J. Lely, Marcel A.M. Beijk, Frederikus A. Klok, Menno V. Huisman, Esther J. Nossent, Anton Vonk Noordegraaf, Petr Symersky, Harm Jan Bogaard, Lilian J. Meijboom

    Background Between 16 and 51% of chronic thromboembolic pulmonary hypertension (CTEPH) patients will have residual pulmonary hypertension (PH) after pulmonary endarterectomy (PEA). Whether residual PH is related to remaining (sub-)segmental macrovascular lesions or to microvascular disease is unknown. New imaging techniques can provide detailed information about (sub-)segmental pulmonary arteries and parenchymal perfusion. The aim of this study was to describe the prevalence after PEA of remaining (sub-)segmental vascular lesions on ECG-gated CT pulmonary angiography (CTPA) and parenchymal hypoperfusion on MR and to relate these imaging abnormalities to the presence or absence of residual PH after PEA. Methods In a prospective cohort of operable CTEPH patients, hemodynamics, CTPA and lung perfusion MRI were performed before and 6 months after PEA. The percentage of (sub-)segmental vascular lesions was calculated on CTPA and parenchymal hypoperfusion on lung perfusion MRI. Results PEA led to significant improvements in hemodynamics and a reduction of imaging abnormalities. Residual PH was present in 45% of patients after PEA, while remaining (sub-)segmental vascular lesions and parenchymal hypoperfusion were present in respectively 20% and 21% of the pulmonary vasculature. Patients with and without residual PH after PEA had similar percentages of remaining (sub-)segmental vascular lesions (25±14% vs. 17±15%; p=0.16) and similar degrees of parenchymal hypoperfusion (20±7% vs. 19±6%; p=0.63). Conclusions After successful PEA, advanced imaging shows that around 20% of the pulmonary vasculature remains abnormal, independent of the presence of residual PH. This may suggest that microvascular disease, rather than residual macrovascular lesions, plays a prominent role in residual PH after PEA.

    更新日期:2019-12-05
  • Donor Fraction Cell-Free DNA and Rejection in Adult and Pediatric Heart Transplantation
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-11-29
    Marc E Richmond, Steven D Zangwill, Steven J Kindel, Shriprasad R Deshpande, Jacob N Schroder, David P Bichell, Kenneth R Knecht, William T Mahle, Mark A Wigger, Nunzio A Gaglianello, Elfriede Pahl, Pippa M Simpson, Mahua Dasgupta, Paula E North, Mats Hidestrand, Aoy Tomita-Mitchell, Michael E Mitchell

    Purpose Endomyocardial biopsy (EMB) is the current standard for rejection surveillance in heart transplant recipients. Quantification of donor-specific cell-free DNA (cfDNA) may be an appropriate biomarker for non-invasive rejection surveillance. A multi-center prospective blinded study (DNA-based Transplant Rejection Test, DTRT) investigated the value of donor fraction (DF), defined as the ratio of cfDNA specific to the transplanted organ to total amount of cfDNA present in a blood sample. Methods 241 heart transplant patients were recruited from seven centers. Age at transplant ranged from 8 days to 73 years, with 146 subjects <18 years and 95 ≥ 18 years. All patients were followed for at least one year, with blood samples drawn at routine and for-cause biopsies. 624 biopsy-paired samples were included for analysis via a commercially available cfDNA assay (myTAIHEART®, TAI Diagnostics, Inc). Blinded analysis of repeated measures compared outcomes using receiver operating characteristic (ROC) curves. All primary clinical endpoints were monitored at 100%. All analysis and conclusions were reviewed by both an independent external oversight committee and the NIH mandated DTRT steering committee. Results DF in ACR 1R/2R (n=15) was higher than ACR 0R (n=42) (p=0.02); DF in pAMR1 (n=8) and pAMR2 (n=12) (p=0.05) were higher than pAMR0 (n=466) (p=0.04 and p=0.05 respectively). By ROC analysis an optimal DF threshold was determined which ruled out the presence of either ACR or AMR. Conclusion Cell-free DNA donor fraction holds promise as a non-invasive diagnostic test to rule out acute rejection in both adult and pediatric heart transplant populations.

    更新日期:2019-11-30
  • ABNORMALITIES OF BRAIN IMAGING IN PATIENTS AFTER LEFT VENTRICULAR ASSIST DEVICE SUPPORT FOLLOWING EXPLANTATION
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-11-29
    Sho Murase, Shuhei Okazaki, Daiske Yoshioka, Kotaro Watanabe, Yasufumi Gon, Kenichi Todo, Tsutomu Sasaki, Manabu Sakaguchi, Yusuke Misumi, Koichi Toda, Yoshiki Sawa, Hideki Mochizuki

    Background The potential impact of long-term left ventricular assist device (LVAD) support on the brain remains unclear. This study aimed to investigate cerebral microvascular damage in patients after long-term LVAD implantation using magnetic resonance imaging (MRI). Methods We reviewed medical records of patients after continuous-flow LVAD implantation in our hospital from 2006 to 2016 who underwent brain MRI after LVAD explantation for either transplantation or recovery. Age- and sex-matched healthy controls and chronic heart failure (CHF) patients were collected from our pooled MRI database. The presence of cerebral microbleeds (CMBs) and cortical superficial siderosis and the severity of white matter hyperintensity (WMH) and cerebral atrophy were compared between prior LVAD patients and two control groups. Results This study included 49 prior LVAD patients, 49 healthy controls, and 45 CHF patients. CMBs and cortical superficial siderosis were detected in 98% (p < 0.001) and 31% (p < 0.001) of prior LVAD patients, respectively. The number of CMBs was higher in prior LVAD patients than in the two control groups. The severity of WMH was higher in prior LVAD patients than in healthy controls, but similar to that in CHF patients. Quantitative analyses of cerebral atrophy revealed a significantly higher bicaudate ratio and cella media index in prior LVAD patients than in the two control groups. Conclusions Patients after long-term LVAD support showed a higher prevalence of CMBs and cortical superficial siderosis and more severe cerebral atrophy than did controls. These findings may indicate cerebral microvascular damages in long-term LVAD support patients.

    更新日期:2019-11-29
  • PREGNANCY OUTCOMES IN WOMEN WITH CARDIOTHORACIC TRANSPLANTS: A SYSTEMATIC REVIEW AND META-ANALYSIS
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-11-28
    Sergio Acuna, Nusrat Zaffar, Susan Dong, Heather Ross, Rohan D'Souza

    Background Increasing numbers of women with thoracic transplants are planning and continuing pregnancies; however, pregnancy outcomes and risks to mother and baby have not been systematically assessed. Methods MEDLINE, EMBASE and Cochrane Central were searched from inception to January 2018 to identify studies reporting outcomes on three or more pregnancies following thoracic transplants. Pooled incidences were calculated using random-effect meta-analysis. Risk-of-bias was assessed using the Joanna Briggs Checklist for case series. Subgroup analysis was conducted based on transplanted organ. Results Of the 3658 records identified, 12 studies were included that reported on 385 pregnancies in 272 thoracic transplant recipients. Maternal complications included mortality [0.5% (0, 1.1%) during pregnancy and 15.4% (10.4, 20.3%) during follow-up which ranged between 3 and 7 years], graft rejection [7.4% (4.2, 10.5%)], hypertensive disorders of pregnancy [26.6% (13.7, 39.6%)] and caesarean deliveries [41.4% (33.4, 48.7%)]. Maternal mortality was more common in recipients of lung vs. heart transplants [41.4% (23.4, 59.3) vs. 10.8% (5.9, 15.8)]. Although 78.4% (69.8, 86.9%) of pregnancies resulted in live births, 51.2% (31, 71.3%) were born preterm and neonatal deaths occurred in 3.4% (1.3, 5.6%). Congenital anomalies affected 4.3% (1.8, 6.8%) newborns. Conclusions Although few maternal deaths occurred during pregnancy, in keeping with median survival data, delayed mortality for thoracic transplant recipients remains high. Despite high numbers of live births, these pregnancies continue to be at risk for hypertensive disorders, graft rejection, preterm birth and neonatal mortality. Prospectively-gathered data from international registries should supplement these findings to better inform clinical counselling and practice.

    更新日期:2019-11-28
  • Right heart failure with left ventricular assist device implantation in children: an analysis of the Pedimacs registry database
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-11-28
    Kathleen E. Simpson, James K. Kirklin, Ryan S. Cantor, Mary Mehegan, Jacqueline M. Lamour, Kristine J. Guleserian, David M. Peng, Elfriede Pahl

    Introduction Use of ventricular assist device (VAD) in children has increased, but decision of left VAD (LVAD) versus biventricular support remains a challenge. Children who undergo LVAD placement are at risk for right ventricular failure (RHF), but incidence has not been described. Methods Analysis was performed for patients <18 years old who underwent durable LVAD placement within the Pedimacs registry (9/19/2012 to 2/28/17), excluding single ventricle morphology and temporary devices. RHF was defined as need for RVAD or prolonged inotrope use between 1 week-1 month and 1-3 months. Endpoints included death, heart transplant (HT), and recovery. Results A total of 272 durable LVAD were placed of which 37 died on device over 24 month follow-up, primarily from multi-organ failure and neurologic dysfunction. RVAD occurred in 12 children at median 8.5 days, with 9 undergoing HT and 3 dying on device. In LVAD only patients, RHF was present in 111/207 (55%) between 1 week-1 month and 28/116 (25%) between 1-3 months. Younger age, smaller weight, Intermacs profile 1, chemical paralysis, and pulsatile flow VAD were associated with RHF. RHF was associated with increased risk of death on device at both >1 month (HR 3.2, 95%CI 1.4-7.7, p=0.007) and >3 month (HR 6.9, 95%CI2-23.1, p=0.002). Conclusions In children, RHF is common after durable LVAD implantation, but subsequent RVAD is relatively rare. RHF in children, as indicated by prolonged inotrope support, was associated with increased risk of death on device. Whether early RVAD support and higher waitlist status may improve outcome remains unknown.

    更新日期:2019-11-28
  • Reverse transcriptase multiplex ligation-dependent probe amplificatioN IN ENDOMYOCARDIAL BIOPSIES for the diagnosis of cardiac allograft rejection
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-11-26
    Nicolas Adam, Guillaume Coutance, Pierre-Julien Viailly, Fanny Drieux, Philippe Ruminy, Ahmad Abdel Sater, Claire Toquet, Philippe Rouvier, Arnaud François, Marie-Pierre Chenard, Eric Epailly, Romain Guillemain, Sabine Pattier, Arnaud Gay, Shaida Varnous, Jean-Luc Taupin, Marion Rabant, Alexandre Loupy, Jean Paul Duong Van Huyen

    Background Molecular biology has emerged as a potential companion to histology for the diagnosis of rejection after heart transplantation. Reverse transcriptase multiplex ligation-dependent probe amplification (RT-MLPA) is a technique of targeted gene expression analysis suitable for formalin-fixed paraffin-embedded (FFPE) biopsies. Our aim was to assess RT-MLPA for the diagnosis of allograft rejection in heart transplantation. Methods We performed a cross-sectional, case-control, multicenter study. After selection of a 14-transcript panel (endothelial burden, Natural-Killer cells, interferon-γ pathway, effector T-cells and antigen presentation), RT-MLPA was applied to 183 FFPE endomyocardial biopsies (EMB), randomized into a training (n=113) and a validation (n=70) series. A two-step class prediction analysis was developed (Linear prediction score - LPS1: rejection versus non-rejection; LPS2: antibody-mediated rejection -AMR- versus acute cellular rejection -ACR). A study of the agreement between pathology and RT-MLPA was performed. Results Overall, 48 ACR, 82 AMR, five mixed-rejection, and 48 non-rejection EMBs were analyzed. Three molecular clusters were delineated by unsupervised hierarchical analysis (molecular non-rejection, ACR and AMR). AMR was characterized by high expression of CCL4, GNLY, FCGR3, CXCL11 and ACR by high expression of CCL18 and ADAMdec. RT-MLPA and histopathology agreed in the final diagnosis in 82.2%, 67.7%, and 76.8% of the EMB in the test, validation and overall cohort, respectively. Disagreement cases were more common in the case of histological low-grade rejection and early post-transplant EMB. Conclusion RT-MLPA is a suitable technique for targeted gene expression analysis on FFPE EMB with a good overall agreement with the histological diagnosis of heart allograft rejection.

    更新日期:2019-11-27
  • Outcomes Based on Blood Pressure in Patients on Continuous Flow LVAD Support: An INTERMACS analysis
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-11-26
    J. Cowger, P. Shah, F. Pagani, G. Grafton, J. Stulak, T. Chamogeorgakis, D. Lanfear, H. Nemeh, S. Pinney

    Background An optimal blood pressure (BP) range to mitigate morbidity and mortality on left ventricular assist device (LVAD) support has not been clearly defined. Methods Average Doppler opening pressure, mean arterial pressure (MAP), and/or systolic blood pressure (SBP) were calculated in operative survivors (n=16155) of LVAD support in INTERMACS. BP distributions were used to group patients: low (BP <25th percentile), normal (25-75th percentile), high (75th-95th) and very high (>95th percentile). Associations between BP and adverse events were evaluated using Cox Regression (Hazard ratio (HR), 95% confidence interval). Results The median MAP, Doppler, and SBPs (mmHg) during CFLVAD support were 84 [77, 90], 85 [80, 92], and 99 [90,107] mmHg. BP had a bimodal risk association with survival. At 3 years, survival was 58±1.8% in those with low MAPs (≤75 mmHg) vs. 70±0.9%, 71±1.5%, and 63±3.0% in the those with normal, high, or very high average MAPs. Patients with chronically low MAPs (≤75 mmHg), Dopplers (≤80 mmHg) and SBPs (<90 mmHg) had 35-42% higher adjusted hazards of death than patients with normal or high BPs (p≤0.0001). Patients with MAPs >100 mmHg, Dopplers ≥105 mmHg, and SBPs ≥120 mmHg had 17-20% higher adjusted hazards of death than those with normal pressures (p<0.05). In patients on axial flow LVADs, elevated SBP (HR 1.08 [1.04-1.13] per 10 mmHg increase) but not MAP correlated with increased incident stroke. Conclusions In INTERMACS, BP extremes during LVAD support increase the risk for adverse events, supporting a MAP goal >75 mmHg and <90 mmHg. Hypotension conferred the highest risk for mortality. Excessive BP control should be avoided, and Doppler opening pressure should not be assumed to represent MAP in all patients.

    更新日期:2019-11-27
  • T follicular helper and memory cell responses and the mTOR pathway in murine heart transplantation
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-11-26
    Aini Xie, Hui Yan, Jinfei Fu, Adam He, Xiang Xiao, Xian C. Li, Wenhao Chen

    BACKGROUND Mammalian target of rapamycin (mTOR) inhibitors are valuable immunosuppressants in clinical transplantation, but mTOR regulation of allogeneic T cell responses is not fully understood. Here, we investigated the effects of T cell-specific mTOR deletion on allogeneic T cell responses and heart transplant survival. METHODS Wild type C57BL/6, Mtorfl/flCd4-Cre, Stat3fl/flCd4-Cre, and Mtorfl/flStat3fl/flCd4-Cre mice were transplanted with BALB/c heart allografts, with or without BALB/c skin-sensitization. Graft survival and histology, as well as T cell frequencies and phenotypes, were evaluated after transplantation. RESULTS In the absence of donor skin-sensitization, long-term heart allograft survival was achieved in Mtorfl/flCd4-Cre recipients, which was associated with significantly decreased frequencies of CD62L–CD44+ effector T cells and BCL-6+CXCR5+ T follicular helper (Tfh) cells in the periphery. Long-term heart allograft survival was also achieved in donor skin-sensitized Mtorfl/flStat3fl/flCd4-Cre mice, whereas heart allograft survival was prolonged in donor skin-sensitized Mtorfl/flCd4-Cre and Stat3fl/flCd4-Cre mice. CONCLUSIONS mTOR is required for Tfh cell response in murine heart transplantation. T cell-specific deletion of both mTOR and Stat3 abrogates memory response to heart transplants. These findings help us to better understand the molecular mechanisms underlying T cell immunity to transplanted organs.

    更新日期:2019-11-27
  • Induction Type and Outcomes for Kidney Graft and Patient Survival in Recipients with Prior Lung Transplantation in the United States
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-11-25
    Samy Riad, Umesh Goswami, Scott Jackson, Marshall Hertz, Arthur Matas

    Background Induction immunosuppression regimens for kidney transplant in lung transplant recipients vary widely. We studied the impact of induction types for kidney-after-lung transplant recipients. Methods Using the SRTR database between 1994 and 2015, we studied outcomes of patients and kidney grafts for 330 kidney-after-lung transplant recipients for whom induction before kidney transplant included depletional (n=115), non-depletional (n=170) or no induction (steroids only) (n=45). We studied risk factors for recipient and graft survival using Cox proportional hazards model adjusted for kidney and lung induction, kidney donor type, dialysis status, recipient and donor ages, time from lung to kidney transplant, cause of lung disease, bilateral vs. single lung transplant, diabetes and HLA mismatches before kidney transplant, with transplant center as a random effect. Results There was no difference between groups in patient survival or death-censored kidney allograft survival. The one-year kidney acute rejection rates were 15.5 %, 7.14 % and 0% in depletional, non-depletional and no induction groups, respectively. In the Cox model for patient survival, living kidney donor recipients and bilateral lung transplant recipients were favorable predictors. For death-censored graft survival, kidney induction type did not predict graft survival. Results did not change when models only included recipients on tacrolimus and mycophenolate based maintenance. Conclusion Type of kidney induction did not influence patient or kidney graft survival following kidney transplant for those with previous lung transplants. No induction may be the preferred choice for kidney-after-lung transplant due to the lack of benefits of biologic induction in this large cohort.

    更新日期:2019-11-26
  • USE OF CT-SCAN SCORE AND VOLUME MEASURES TO EARLY IDENTIFY RESTRICTIVE ALLOGRAFT SYNDROME IN SINGLE-LUNG TRANSPLANT RECIPIENTS
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-11-25
    Q Philippot, MP Debray, René Bun, J Frija-Masson, V Bunel, L Morer, A Roux, C Picard, G Jebrak, G Dauriat, Y Castier, A Cazes, H Mal, JL Taupin, C Couffignal, O Brugière

    Background Restrictive allograft syndrome (RAS) after lung transplantation (LTx) is associated with the poorer graft survival in patients with chronic lung allograft dysfunction (CLAD). Nevertheless, its diagnostic criteria remain not well defined after single-LTx (SLTx). Hence, we studied an SLTx cohort with CLAD to investigate the utility of both CT-score/volume measures and functional spirometric criteria for early identifying RAS in this population. Methods We included 51 SLTx patients (17 RAS, 17 bronchiolitis obliterans syndrome [BOS], 17 stable condition). Criteria for RAS diagnosis in SLTx included FVC<80% baseline (BL) or FEV1<80%BL with FEV1/FVC ratiounchanged or >0.7 and persistent CT-scan-lung opacities. We defined 4 time points (T): T-baseline, T-onset (first CT-scan-opacities), T-follow-up, and T-last. Results In RAS patients, spirometric criteria for RAS at T-onset were reached in only 47% (FVC decline <80%BL [29%] or FEV1<80%BL/ratiounch or >0.7 [41%]), whereas at the same T-onset date, graft CT-score was increased to 5 [4-6] versus 1 [0-2] at baseline (p<0.001) (CT-score ≥2 at T-onset in 100% and ΔCT-score ≥2 in 74% of RAS patients), and median CT-scan graft-volume decreased to 1722 ml (vs 1796 ml at T-baseline, p=0.003) (decreased CT-graft-volume<90%BL in 50% of patients). In contrast, in BOS patients, CT-score/volume were unchanged at T-onset versus T-baseline (p=0.8,p=0.68, respectively). Conclusion Our results suggest that the use of a simple CT-score and to a lesser extent CT-volume measures might allow for early identification and/or prediction of RAS in SLTx rather than functional criteria.

    更新日期:2019-11-26
  • Donation after circulatory death in lung transplantation—five-year follow-up from ISHLT Registry
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-11-21
    Dirk Van Raemdonck, Shaf Keshavjee, Bronwyn Levvey, Wida S. Cherikh, Greg Snell, Michiel Erasmus, André Simon, Allan R. Glanville, Stephen Clark, Frank D'Ovidio, Pedro Catarino, Kenneth McCurry, Marshall I. Hertz, Rajamiyer Venkateswaran, Peter Hopkins, Ilhan Inci, Rajat Walia, Daniel Kreisel, Marcelo Cypel

    Background This study aimed to examine intermediate-term outcomes of lung transplantation (LTx) recipients from donors after circulatory death (DCD). Methods We examined the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry data for patients transplanted between January 2003 and June 2017 at 22 centers in North America, Europe, and Australia participating in the DCD Registry. The distribution of continuous variables was summarized as median and interquartile range (IQR) values. Wilcoxon rank sum test was used to compare distribution of continuous variables and chi-square or Fisher's exact test for categorical variables. Kaplan-Meier survival rates after LTx from January 2003 to June 2016 were compared between DCD-III (Maastricht category III withdrawal of life-sustaining therapy [WLST]) only and donors after brain death (DBD) using the log-rank test. Risk factors for 5-year mortality were investigated using Cox multivariate proportional-hazards model. Results The study cohort included 11,516 lung transplants, of which 1,090 (9.5%) were DCD lung transplants with complete data. DCD-III comprised 94.1% of the DCD cohort. Among the participating centers, the proportion of DCD-LTx performed each year increased from 0.6% in 2003 to 13.5% in 2016. DCD donor management included extubation in 91%, intravenous heparin in 53% and pre-transplant normothermic ex vivo donor lung perfusion in 15%. The median time interval from WLST to cardiac arrest was 15 minutes (IQR: 11-22 minutes) and to cold flush 32 minutes (IQR: 26-41minutes). Compared with DBD, donor age was higher in DCD-III donors (46 years [IQR: 34-55] vs 40 years [IQR: 24-52]), bilateral LTx was performed more often (88.3% vs 76.6%), and more recipients had chronic obstructive pulmonary disease and emphysema as their transplant indication. Five-year survival rates were comparable (63% vs 61%, p = 0.72). In multivariable analysis, recipient and donor ages, indication diagnosis, procedure type (single vs bilateral and double LTx), and transplant era (2003-2009 vs 2010-2016) were independently associated with survival (p < 0.001), but donor type was not (DCD-III vs DBD; hazard ratio, 1.04 [0.90-1.19], p = 0.61). Conclusion This ISHLT DCD Registry report with 5-year follow-up demonstrated similar favorable long-term survival in DCD-III and DBD lung donor recipients at 22 experienced centers globally. These data indicate that more extensive use of DCD-LTx would increase donor organ availability and may reduce waiting list mortality.

    更新日期:2019-11-22
  • PLASMA CD5L AND NON-INVASIVE DIAGNOSIS OF ACUTE HEART REJECTION
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-11-21
    Estefanía Tarazón, Nerea Corbacho-Alonso, María G. Barderas, Carolina Gil-Cayuela, María García Manzanares, Sandra Feijóo-Badín, Francisca Lago, José Ramón González-Juanatey, Luis Martínez-Dolz, Manuel Portolés, Esther Roselló-Lletí

    Background Acute rejection is one of the most important direct contributors of mortality after heart transplantation. Advances in the development of novel non-invasive approaches for the early identification of allograft rejection are necessary. We conducted a non-targeted proteome characterization focused on identifying multiple plasmatic protein differences to evaluate their diagnostic accuracy for rejection episodes. Methods We included consecutive plasma samples from transplant recipients undergoing routine endomyocardial biopsies. A LC-MS/MS analysis using isobaric tags (TMT 10-plex) was performed and concentrations of CD5L were validated using a specific sandwich enzyme-linked immunosorbent assay. Results A total of 17 altered proteins were identified as potential markers for detecting heart transplant rejection, most involved in inflammation and immunity. CD5L, apoptosis inhibitor expressed by macrophages, showed the best results in the proteomic analysis (n=30). We confirm this finding in a larger patient cohort (n=218), obtaining a great diagnostic capacity for clinically relevant rejection (≥Grade 2R AUC=0.892, p<0.0001) and preserving the accuracy at mild rejection (Grade 1R AUC=0.774, p<0.0001). CD5L was a strong independent predictor, with an odds ratio of 14.74 (p<0.0001), for the presence of rejection. Conclusions Episodes of acute cardiac allograft rejection are related to significant changes in a key inhibitor of apoptosis in macrophages, CD5L. Because of its precision to detect acute cellular rejection, even at mild grade, we propose CD5L as a potential candidate to be included in the studies of molecule combination panel assays. This finding could contribute to improving the diagnostic and preventive methods for the surveillance of cardiac transplanted patients.

    更新日期:2019-11-21
  • Validating TSAM Predictions for Impact of Broader Geographic Sharing of Donor Lungs on Transplant Waitlist Outcomes
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-11-21
    Carli J. Lehr, Melissa Skeans, Maryam Valapour

    Background The thoracic simulated allocation model (TSAM) is used by the Scientific Registry of Transplant Recipients (SRTR) to predict the relative effect of organ allocation policy changes. A new lung allocation policy changing the first unit of allocation from donation service area to 250 nautical miles took effect on November 24, 2017. We studied TSAM's ability to correctly predict trends caused by changes in allocation policy. Methods We compared the population characteristics from the TSAM cohort, 6386 lung transplant candidates from 2009-2011, with the observed cohort of 7601 candidates from the year prior to the policy change on November 24, 2017, and the year after. Simulations were run 10 times. Waitlist mortality and transplant rates were calculated and compared with observed mortality and transplant rates in the years before and after the policy change. Results TSAM correctly predicted no change in overall waitlist mortality or transplant rates with the policy change. Observed waitlist mortality values were higher, as were transplant rates, due to increased organ donation and population change. TSAM predicted increased transplant rates for diagnosis group D (idiopathic pulmonary fibrosis), decreased rates for group A (chronic obstructive pulmonary disease), and increased rates for candidates with lung allocation score ≥ 50, but these changes did not occur in the waitlist and transplant populations after the policy change. Conclusions TSAM correctly predicted the relative trends caused by a change in allocation policy but smaller sub-group predictions were not seen.

    更新日期:2019-11-21
  • Influence of azithromycin and allograft rejection on the post-lung transplant microbiota
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-11-21
    Christopher D Spence, Bart Vanaudenaerde, Gísli G Einarsson, John Mcdonough, Andrew J Lee, Elinor Johnston, Geert M Verleden, J Stuart Elborn, Lieven J Dupont, Anke Van Herck, Deirdre F Gilpin, Robin Vos, Michael M Tunney, Stijn E Verleden

    Background Alterations in the lung microbiota may drive disease development and progression in patients with chronic respiratory diseases. Following lung transplantation (LTx), azithromycin is used to both treat and prevent chronic lung allograft dysfunction (CLAD). The objective of this study was to determine the association between azithromycin use, CLAD, acute rejection, airway inflammation and bacterial microbiota composition and structure after LTx. Methods Bronchoalveolar lavage (BAL) samples (n=219) from 69 LTx recipients (azithromycin, n=32; placebo, n=37) from a previously conducted randomized placebo-controlled trial with azithromycin were analysed. Samples were collected at discharge, 1 and 2 years following randomization and at CLAD diagnosis. Bacterial microbial community composition and structure was determined using 16S rRNA gene sequencing and associated with clinically important variables. Results At discharge and following 1 and 2 years of azithromycin therapy, no clear differences in microbial community composition or overall diversity were observed. Moreover, no changes in microbiota composition were observed in CLAD phenotypes. However, acute rejection was associated with a reduction in community diversity (p = 0.0009). Significant correlations were observed between microbiota composition, overall diversity and levels of inflammatory cytokines in BAL, particularly CXCL8. Conclusions Chronic azithromycin usage did not disturb the bacterial microbiota. However, acute rejection episodes were associated with bacterial dysbiosis.

    更新日期:2019-11-21
  • Quality of Life and Treatment Preference for VAD therapy in Ambulatory Advanced Heart Failure: A Report from the REVIVAL Study
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-11-20
    Josef Stehlik, Maria Mountis, Donald Haas, Maryse Palardy, Amrut V. Ambardekar, Jerry D. Estep, Gregory Ewald, Stuart D. Russell, Shawn Robinson, Ulrich Jorde, Wendy C. Taddei-Peters, Neal Jeffries, Blair Richards, Shokoufeh Khalatbari, Catherine Spino, J. Timothy Baldwin, Douglas Mann, Garrick C. Stewart, Keith D. Aaronson

    Introduction The Registry Evaluation of Vital Information for VADs in Ambulatory Life (REVIVAL) study is a prospective multicenter cohort of 400 ambulatory patients with advanced chronic systolic heart failure (HF). The aim of REVIVAL is to better understand disease trajectory and optimal timing of advanced HF therapies. We examined patient health-related quality of life (HRQOL) data collected at enrollment, and their association with patient treatment preferences for ventricular assist device (VAD) placement. Methods Baseline assessment of HRQOL included Kansas City Cardiomyopathy Questionnaire (KCCQ) and EuroQol EQ-5D-3L Visual Analog Scale (VAS), along with patient self-assessment of remaining life (PSARL). Descriptive statistics were used to present baseline HRQOL data and Spearman correlation test to assess the association between KCCQ, VAS and VAD treatment preference with patient clinical characteristics of interest. Results The median age was 60 years, 75% were male, and the median left ventricular ejection fraction was 20%. The median [25th percentile, 75th percentile], baseline KCCQ summary score was 64 [48,78], VAS score 65 [50,75] and PSARL 7 years [5,10]. There were statistically significant associations of baseline KCCQ and VAS with NYHA Class and INTERMACS profile (p<0.005 for all comparisons). Baseline KCCQ and VAS revealed a modest association with PSARL (correlation=0.45 and 0.35, respectively; p<0.001), and many patients were overly optimistic about their expected survival. VAD treatment preference was associated with KCCQ scores (P<0.031), but the absolute differences were small. VAD treatment preference was independent of other key clinical characteristics such as subject age, VAS and PSARL. Conclusion We found lack of strong association of HRQOL and patient preference for VAD therapy. Better understanding of patients’ perceptions of their illness and how this relates to HRQOL outcomes, clinician risk assessment, and patient decision-making is needed. This may in turn allow better guidance toward available HF therapies in this vulnerable population.

    更新日期:2019-11-21
  • Structured review of post-cardiotomy extracorporeal membrane oxygenation: Part 2—pediatric patients
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-07-17
    Roberto Lorusso, Giuseppe Maria Raffa, Mariusz Kowalewski, Khalid Alenizy, Niels Sluijpers, Maged Makhoul, Daniel Brodie, Mike McMullan, I-Wen Wang, Paolo Meani, Graeme MacLaren, Heidi Dalton, Ryan Barbaro, Xaotong Hou, Nicholas Cavarocchi, Yih-Sharng Chen, Ravi Thiagarajan, Peta Alexander, Glenn Whitman

    Veno-arterial extracorporeal membrane oxygenation (ECMO) is established therapy for short-term circulatory support for children with life-treating cardiorespiratory dysfunction. In children with congenital heart disease (CHD), ECMO is commonly used to support patients with post-cardiotomy shock or complications including intractable arrhythmias, cardiac arrest, and acute respiratory failure. Cannulation configurations include central, when the right atrium and aorta are utilized in patients with recent sternotomy, or peripheral, when cannulation of the neck or femoral vessels are used in non-operative patients. ECMO can be used to support any form of cardiac disease, including univentricular palliated circulation. Although veno-arterial ECMO is commonly used to support children with CHD, veno-venous ECMO has been used in selected patients with hypoxemia or ventilatory failure in the presence of good cardiac function. ECMO use and outcomes in the CHD population are mainly informed by single-center studies and reports from collated registry data. Significant knowledge gaps remain, including optimal patient selection, timing of ECMO deployment, duration of support, anti-coagulation, complications, and the impact of these factors on short- and long-term outcomes. This report, therefore, aims to present a comprehensive overview of the available literature informing patient selection, ECMO management, and in-hospital and early post-discharge outcomes in pediatric patients treated with ECMO for post-cardiotomy cardiorespiratory failure.

    更新日期:2019-11-18
  • Mesenchymal stromal cell therapy during ex vivo lung perfusion ameliorates ischemia-reperfusion injury in lung transplantation
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-07-26
    Daisuke Nakajima, Yui Watanabe, Akihiro Ohsumi, Mauricio Pipkin, Manyin Chen, Pierre Mordant, Takashi Kanou, Tomohito Saito, Ryan Lam, Rafael Coutinho, Lindsay Caldarone, Stephen Juvet, Tereza Martinu, Rohin K. Iyer, John E. Davies, David M. Hwang, Thomas K. Waddell, Marcelo Cypel, Shaf Keshavjee

    BACKGROUND The application of mesenchymal stromal cell (MSC)–based therapy during ex vivo lung perfusion (EVLP) could repair injured donor lungs before transplantation. The aim of this study was to determine the efficacy of MSC therapy performed during EVLP on ischemia-reperfusion injury using a pig lung transplant model. METHODS Following 24 hours of cold storage, pig lungs were randomly assigned to 2 groups (n = 6 each), the control group without MSC vs the MSC group, where 5 × 106 cells/kg MSCs were delivered through the pulmonary artery during EVLP. After 12 hours of EVLP, followed by a 1-hour second cold preservation period, the left lung was transplanted and reperfused for 4 hours. RESULTS EVLP perfusate hepatocyte growth factor (HGF) level at 12 hours was significantly elevated in the MSC group compared with the control and was associated with a significant decrease in cell death markers, cleaved caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling–positive cells, in the MSC group. The MSC group showed significantly lower interleukin (IL)-18 and interferon gamma levels and a significantly higher IL-4 level in lung tissue at 12 hours of EVLP than the control group. After transplantation, the MSC group showed a significant increase in lung tissue HGF level compared with the control group, associated with a significantly reduced lung tissue wet-to-dry weight ratio. Lung tissue tumor necrosis factor-α level and pathological acute lung injury score were significantly lower in the MSC group than the control group. CONCLUSIONS The administration of MSCs ameliorated ischemic injury in donor lungs during EVLP and attenuated the subsequent ischemia-reperfusion injury after transplantation.

    更新日期:2019-11-18
  • An aging population of patients with cystic fibrosis undergoes lung transplantation: An analysis of the ISHLT Thoracic Transplant Registry
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-07-04
    Christian Benden, Samuel B. Goldfarb, Josef Stehlik

    BACKGROUND Since lung transplantation became a viable option for cystic fibrosis (CF) lung disease, adult transplant recipients with CF have superior survival than all the other major diagnostic indications. However, among adults, recipients with CF have a younger age at transplant than other transplant recipients. Over time, the frequency and proportion of lung transplants for CF has increased for adults compared with children. Using a large international transplant registry, we investigated time trends in numbers of transplants, age at transplant, and post-transplant survival and cause of death for recipients with CF. METHODS We conducted a retrospective cohort study of primary lung-alone deceased-donor transplants with a primary diagnostic indication of CF reported to the International Society for Heart and Lung Transplantation Thoracic Transplant Registry from January 2005 through December 2014. We assessed outcomes through December 31, 2015. The study defined the pediatric group as age <18 years at transplant and the adult as ≥18 years at transplant. We assessed time trends (Era I 2005–2009, Era II 2010–2014) in age and compared post-transplant outcomes of age sub-groups with Kruskal–Wallis or chi-square tests. Kaplan–Meier survival analysis estimated the incidence of survival, censoring for loss to follow-up, end of study, and retransplant. In addition, we compared outcomes in age groups and transplant eras with the log-rank test. RESULTS Of the 5,613 transplanted recipients with CF, the pediatric group comprised 10.9% and the adult group comprised 89.1%. Of the adults, 73.3% were aged 18 to 39 years and 15.9% were ≥40 years old. During Era I, 2,508 of transplant recipients had CF, whereas 3,105 recipients had CF in Era II (p < 0.001). Comparing Era I with Era II, recipient mean age increased from 28.4 years to 29.5 years (p < 0.001) and the proportion of pediatric CF recipients dropped from 12.4% to 9.6% (p < 0.001), whereas the proportion with age ≥40 years increased from 14.2% to 17.2% (p < 0.001). Mean donor age was significantly lower in children than in recipients aged 18 to 39 years and ≥40 years (17.0 vs 37.0 vs 41.0 years, p < 0.001). Pediatric CF transplant recipients had lower survival in the first 3 years post-transplant than adults (p < 0.0001). Chronic graft failure caused most pediatric deaths, whereas infection was the leading cause of death in adult recipients. CONCLUSION As survival of patients with CF has improved in recent decades, the mean age of lung transplant recipients with CF has increased. Currently, an increasing number of adults undergoes lung transplant for this indication. Adult CF transplant recipients continue to have better survival than pediatric recipients, and among adults, older adults have had better survival than younger adults.

    更新日期:2019-11-18
  • DIFFERENCES IN HEALTH-RELATED QUALITY OF LIFE BY IMPLANT STRATEGY: ANALYSES FROM INTERMACS
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-11-06
    Connie White-Williams, Pariya L. Fazeli, James K. Kirklin, Salpy V. Pamboukian, Kathleen L. Grady

    Background Mid-term change in health-related quality of life (HRQOL) by left ventricular assist device (LVAD) implant strategy is unknown. The purpose of this study was to examine HRQOL by pre-operative implant strategy from before to 2 years after surgery. Methods Adult patients in the Interagency Registry for Mechanically Assisted Circulatory Support were stratified into three groups based on pre-implant device strategy: destination therapy (DT) (n=2901), bridge to transplant (BTT) (n=2209), and bridge to candidacy (BTC) (n=3076). HRQOL data were collected before and 2 years after surgery using the generic EQ-5D-3L survey and heart failure-specific KCCQ-12. Statistical analyses included chi square tests, analysis of variance, paired t-tests, and general linear random effects models. Results Between 04/01/08 and 06/30/13, 4422 patients and 1660 patients (majority males and ≥ 50 years) who received primary continuous flow LVADs completed baseline EQ-5D-3L and KCCQ-12 questionnaires, respectively, while 1615 and 1408 patients completed EQ-5D-3L and KCCQ-12 questionnaires at 2 years, respectively. While paired t-tests and general linear random effects models showed that both heart failure-specific and generic HRQOL improved for all groups across time (p-values <0.05), some differences in HRQOL were found by implant strategy at baseline and 2 years, with a pattern favoring better functioning for BTT patients. The BTT group reported significantly higher overall HRQOL pre-implant using the KCCQ-12 (BTT=37.09, BTC=33.57, DT=33.56) and at 2 years using the EQ-5D-3L (BTT=75.18, BTC=72.27, DT=70.87) (p-values <0.05), although these differences were not clinically important differences. Differences in HRQOL domains were also found. Conclusions Using generic and heart failure-specific instruments, overall HRQOL generally improved from before to 2 years after MCS implant regardless of implant strategy, although important domain-specific differences by group were identified.

    更新日期:2019-11-06
  • Reduced Flow ex vivo Lung Perfusion to Rehabilitate Donation After Cardiac Death Lungs
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-09-18
    Jared P. Beller, Matthew R. Byler, Dustin T. Money, William Z. Chancellor, Aimee Zhang, Yunge Zhou, Mark H. Stoler, Adishesh K. Narahari, Alexander Shannon, J Hunter Mehaffey, Curtis G. Tribble, Victor E. Laubach, Irving L. Kron, Mark E. Roeser

    Background Current ex vivo lung perfusion (EVLP) protocols aim to achieve perfusion flows of 40% of cardiac output or more. We hypothesized that a lower target flow rate during EVLP would improve graft function and decrease inflammation of donation after circulatory death (DCD) lungs. Methods A porcine DCD and EVLP model was utilized. Two groups (n=4/group) of DCD lungs were randomized to target EVLP flows of 40% (High Flow) or 20% (Low Flow) predicted cardiac output based on 100mL/min/kg. At the completion of 4 hours of normothermic EVLP using Steen solution, left lung transplantation was performed, and lungs were monitored during 4 hours of reperfusion. Results After transplant, left lung-specific pulmonary vein PO2 was significantly higher in the Low Flow group at 3 and 4 hours of reperfusion (3-hour: 496.0±87.7 vs. 252.7±166.0 mmHg, p=0.017; 4-hour: 429.7±93.6 vs. 231.5±178 mmHg, p=0.048). Compliance was significantly improved at 1 hour of reperfusion (20.8±9.4 vs. 10.2±3.5 ml/cm H2O, p=0.022) and throughout all subsequent time points in the Low Flow group. After reperfusion, lung wet-to-dry weight ratio (7.1±0.7 vs. 8.8±1.1, p=0.040) and IL-1β expression (927±300 vs. 2070±874 pg/ng protein, p=0.048) were significantly reduced in the Low Flow group. Conclusions EVLP of DCD lungs with low flow targets of 20% predicted cardiac output improves lung function, reduces edema and attenuates inflammation after transplant. Therefore, EVLP for lung rehabilitation should use reduced flow rates of 20% predicted cardiac output.

    更新日期:2019-09-19
  • PULMONARY ARTERIAL HYPERTENSION PATIENTS WITH AND WITHOUT CARDIOVASCULAR RISK FACTORS: RESULTS FROM THE AMBITION TRIAL
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-09-17
    Vallerie V. McLaughlin, Jean-Luc Vachiery, Ronald J. Oudiz, Stephan Rosenkranz, Nazzareno Galiè, Joan A. Barberà, Adaani E. Frost, Hossein-Ardeschir Ghofrani, Andrew J. Peacock, Gérald Simonneau, Lewis J. Rubin, Christiana Blair, Jonathan Langley, Marius M. Hoeper

    Background To compare patients with pulmonary arterial hypertension enrolled in the AMBITION trial with (excluded from the primary analysis set [ex-primary analysis set]) and without (primary analysis set) multiple risk factors for left ventricular diastolic dysfunction. Methods Treatment-naïve patients with pulmonary arterial hypertension were randomised to once-daily ambrisentan and tadalafil combination therapy, ambrisentan monotherapy, or tadalafil monotherapy. The primary endpoint was time from randomization to first adjudicated clinical failure event. Results Primary analysis set patients (n=500) versus ex-primary analysis set patients (n=105) were younger (mean, 54.4 versus 62.1 years) with greater baseline 6-minute walk distance (median, 363.7 versus 330.5 m) and fewer comorbidities (e.g., hypertension, diabetes). Treatment effects of initial combination therapy versus pooled monotherapy were directionally the same for both populations, albeit of a lower magnitude for ex-primary analysis set patients. Initial combination therapy reduced the risk of clinical failure versus pooled monotherapy in primary analysis set patients (hazard ratio, 0.50; 95% CI, 0.35–0.72), while the effect was less clear in ex-primary analysis set patients (hazard ratio, 0.70; 95% CI, 0.35–1.37). Overall, primary analysis set patients had fewer clinical failure events (25% versus 33%), higher rates of satisfactory clinical response (34% versus 24%), and lower rates of permanent study drug withdrawal due to adverse events (16% versus 31%) than ex-primary analysis set patients. Conclusions Efficacy of initial combination therapy versus pooled monotherapy was directionally similar for primary analysis set and ex-primary analysis set patients. However, ex-primary analysis set patients (with multiple risk factors for left ventricular diastolic dysfunction) experienced higher rates of clinical failure events and the response to combination therapy versus monotherapy was attenuated. Tolerability was better in primary analysis set than ex-primary analysis set patients. ClinicalTrials.gov identifier NCT01178073

    更新日期:2019-09-18
  • Registry Evaluation of Vital Information for VADs in Ambulatory Life (REVIVAL): Rationale, Design, Baseline Characteristics and Inclusion Criteria Performance
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-09-14
    Keith D Aaronson, Garrick C Stewart, Francis D Pagani, Lynne W Stevenson, Maryse Palardy, Dennis M McNamara, Donna M Mancini, Kathleen Grady, John Gorcsan, Robert Kormos, Neal Jeffries, Wendy C Taddei-Peters, Blair Richards, Shokoufeh Khalatbari, Cathie Spino, J Timothy Baldwin, Douglas L Mann

    Introduction Improved understanding of the clinical course of ambulatory advanced chronic systolic heart failure may improve the provision of appropriate care and is central to the design of clinical trials in this population. Methods Twenty-one implanting VAD centers enrolled 400 subjects in REVIVAL, a prospective, observational study in ambulatory, chronic advanced systolic heart failure (HF), designed to identify a cohort with an approximately 25% 1-year risk of the primary composite outcome of death, urgent transplant or durable MCS. Inclusion criteria utilized only information collected during routine clinical care. Exclusion criteria identified patients with contraindications to VAD. Study inclusion required at least 1 of 10 high-risk criteria derived from established hospitalization and non-hospitalization markers of increased mortality risk . We evaluated the test performance characteristics of the high-risk criteria. Results Data on 373 subjects evaluable for the primary composite outcome at the 1-year visit are presented. Baseline data were consistent with a less advanced cohort than MedaMACS or ROADMAP. Freedom from the primary composite outcome was 75.9%. Non-hospitalization inclusion criteria identified 89% of patients with events. Conclusions Using routinely obtained clinical information for enrollment, REVIVAL successfully recruited an ambulatory chronic systolic heart failure cohort with an approximately 25% annual risk of the primary composite outcome. Information from this registry will be relevant to the planning of future trials of earlier VAD use and of other interventions in this population.

    更新日期:2019-09-16
  • Extracorporeal Life Support Bridge for Pulmonary Hypertension: A High Volume Single Center Experience
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-09-12
    EB Rosenzweig, W Gannon, P Madahar, C Agerstrand, D Abrams, P Liou, D Brodie, M Bacchetta

    Background Application of extracorporeal life support (ECLS) for advanced pulmonary hypertension (PH) is evolving and may be deployed as a bridge to lung transplantation (BTT) or non-BTT bridge back to chronic PH clinical state as bridge to recovery (BTR) in the setting an acute PH trigger or through non-transplant surgery (BTNTS) or after lung transplantation (BPT). Methods We conducted a retrospective analysis of all adult patients with World Symposium on Pulmonary Hypertension (WSPH) group 1,3,4, or 5 PH, who received ECLS at Columbia University Medical Center/New York Presbyterian Hospital between 1/1/2010 and 8/18/2018. We describe patient characteristics, outcomes and our approach to medical and surgical management of these patients. Results There were 98 patients with significant PH in the cohort (54 female; median age 48 years (IQR 32-58)). Forty-four (45%) PH patients received ECLS as non-BTT with intent to recover back to their baseline functional state, optimize therapy, or support through a definitive surgery including (19 BTR, 17 BTNTS and 8 BPT) and 54 (55%) as BTT. In the overall cohort, 67 (68.4%) patients received venoarterial ECLS and 31 (31.6%) venovenous ECLS. Fifty-two of 83 (63%) patients were liberated from invasive mechanical ventilation and 85.2% of PH BTT patients ambulated while on ECLS. Management of PH medications was individualized often requiring titration with use of inhaled pulmonary vasodilators increased after cannulation in non-BTT. Overall 30-day survival was 73.5%, survival to ECLS decannulation was 66.3%, and survival to hospital discharge was 54.1%. All 8 BPT patients (100%) survived to hospital discharge, 64.7% of BTNTS patients survived to hospital discharge, and 59.3% (n=32) of BTT patients survived to lung transplantation. Early era use of VV-ECLS for BTT had worse survival to discharge then those initially configured with VA-ECLS, impacting the overall survival, and leading to limited use of VV ECLS in the current era to BPT, BTNTS, and select BTR cases. Conclusions ECLS instituted by a specialized, multidisciplinary team has a role in the management of advanced PH as BTT or as non-BTT (including BTR, BTNTS and BPT). Careful selection of ECLS cannulation configurations, patient-specific optimization of PH medical therapies, and avoidance of endotracheal intubation may be an effective strategy in managing these complex patients.

    更新日期:2019-09-12
  • Ambulatory Central Veno-Arterial Extracorporeal Membrane Oxygenation in Lung Transplant Candidates
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-09-11
    Peter Downey, William Ragalie, Vadim Gudzenko, Abbas Ardehali

    Veno-Arterial Extracorporeal Membrane Oxygenation (VA ECMO) has emerged as a fundamental tool in selected lung transplant candidates with respiratory and cardiac dysfunction as a bridge to transplantation. Central VA ECMO provides the most reliable route of oxygenation and circulatory support. We describe a technique of minimally invasive central VA ECMO that spares the sternum. This tunneled approach minimizes the risk of catheter–associated infections and allows the patient to be ambulatory.

    更新日期:2019-09-12
  • DRUG RESISTANT CMV INFECTION AFTER LUNG TRANSPLANTATION: INCIDENCE, CHARACTERISTICS AND CLINICAL OUTCOMES
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-09-10
    Elina Heliövaara, Shahid Husain, Tereza Martinu, Lianne G. Singer, Marcelo Cypel, Atul Humar, Shaf Keshavjee, Jussi Tikkanen

    Background Cytomegalovirus (CMV) infection and development of CMV drug resistance can cause significant morbidity and mortality in lung transplantation (LTX) patients. We investigated the incidence of CMV drug resistance in adult LTX patients and characterized this patient group and its outcomes. Methods We analyzed a single-center retrospective cohort of 735 patients who received LTX between January 2012 and October 2017. We assessed the incidences of CMV UL97 and UL54 genotyping for clinically suspected drug resistance and of confirmed drug resistance. Case-matched controls (3 control patients for each resistant patient) were identified by matching for CMV serologic status, development of CMV disease or significant viremia (≥3000 IU/ml), and transplantation date. Results The incidence of drug resistant CMV was 1.98% (11/556) in CMV donor and/or recipient positive patients and 4.7% (7/150) in donor positive/recipient negative patients. Altogether 27 patients were tested for drug resistance and 11 of strains were resistant, 8 sensitive, and 8 inconclusive. No differences in immunosuppression, acute rejection, or pre-transplant sensitization were seen between case-matched groups. The peak CMV viral load and mean duration of viremia were significantly higher in the resistant group (324000 vs. 117000 mean IU/mL; p=0.048 and 140 vs. 55 days; p<0.001, respectively). The resistant group had increased overall mortality after onset of viremia compared to controls (3-year mortality 70% vs. 30%; p=0.01). Conclusions Drug resistant CMV infection is rare but patients who develop it have decreased overall survival. Peak CMV viral load and duration of CMV viremia were associated with development of resistant CMV infection.

    更新日期:2019-09-11
  • Poor Outcomes in Carriers of the RNF213 Variant (p.Arg4810Lys) with Pulmonary Arterial Hypertension
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-09-02
    Takahiro Hiraide, Masaharu Kataoka, Hisato Suzuki, Yuki Aimi, Tomohiro Chiba, Sarasa Isobe, Yoshinori Katsumata, Shinichi Goto, Kohsuke Kanekura, Yoshitake Yamada, Hidenori Moriyama, Hiroki Kitakata, Jin Endo, Shinsuke Yuasa, Yasumichi Arai, Nobuyoshi Hirose, Toru Satoh, Yoji Hakamata, Keiichi Fukuda

    Background A variant of c.14429G>A (p.Arg4810Lys, rs112735431) in the ring finger protein 213 gene (RNF213; NM_001256071.2) has been recently identified as a risk allele for pulmonary arterial hypertension (PAH). PAH can be added as a new member of RNF213-associated vascular diseases, which include Moyamoya disease and peripheral pulmonary stenosis. Our aim was to identify the clinical features and outcomes of PAH patients with this variant. Methods Whole-exome sequencing was performed in 139 idiopathic (or possibly heritable) PAH patients. Results The RNF213 p.Arg4810Lys variant was identified in a heterozygous state in 11 patients (7.9%). Time-course changes in hemodynamics after combination therapy in the patients with the RNF213 p.Arg4810Lys variant were significantly poorer compared with those carrying the bone morphogenic protein receptor type 2 (BMPR2) mutation (n = 36) (comparison of changes in mean pulmonary arterial pressure, p = 0.007). The event-free rate of death or lung transplantation was significantly poorer in RNF213 p.Arg4810Lys variant carriers than in BMPR2 mutation carriers (5-year event-free rate since the introduction of prostaglandin I2 infusion, 0% vs. 93%, respectively; p < 0.001). Conclusions Idiopathic PAH patients with the RNF213 p.Arg4810Lys variant are associated with poor clinical outcomes even in recent times. Earlier consideration of lung transplantation might be required for RNF213 p.Arg4810Lys variant carriers developing PAH. Documentation of the RNF213 p.Arg4810Lys variant, as well as already known pathogenic genes, such as BMPR2, can provide clinically relevant information for therapeutic strategies, leading to a personalized approach for the treatment of PAH.

    更新日期:2019-09-03
  • A DONOR PaO2/FiO2 LESS THAN 300 MMHG DOES NOT DETERMINE GRAFT FUNCTION OR SURVIVAL AFTER LUNG TRANSPLANTATION
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-09-02
    Helen Whitford, Christina E. Kure, Aimee Henriksen, Jamie Hobson, Greg I. Snell, Bronwyn J. Levvey, Silvana F. Marasco, Julian H. Gooi, Adam Zimmet, Justin Negri, Adrian Pick, Mark Buckland, Trevor Williams, Glenn Westall, Miranda A. Paraskeva, Catherine Martin, David C. McGiffin

    Background A donor arterial PO2/FiO2 (P/F ratio) less than the 300 threshold would frequently result in either exclusion of the donor or placement of the lungs on ex-vivo lung perfusion (EVLP). The aim was to investigate the veracity of the P/F ratio threshold of 300 for donor lung acceptability. Methods In 93 brain dead lung donors, arterial blood gases were drawn in the intensive care unit (ICU) just prior to procurement and each of the four donor pulmonary veins in the operating room (OR). No donor lungs were rejected for transplantation based on the last ICU or OR P/F ratio and EVLP was not used. Recipients were followed up 6 and 12 months following transplantation. Results There were 93 recipients of bilateral lung transplantation. An arterial P/F ratio of less than 300 was largely driven by a low P/F ratio in the lower lobes. There were no differences between recipients receiving donor lungs where the ICU P/F ratio was less than 300 compared to greater than or equal to 300 in time to extubation, grade of primary graft dysfunction, pulmonary function at 6 and 12 months, and 12-month survival. Conclusions From this study: 1. If a donor P/F threshold of 300 was adhered to, 36% would have been rejected. 2. The donor P/F ratio threshold of 300 is excessively conservative and results in wastage of donor lungs and the application of unnecessary EVLP.

    更新日期:2019-09-03
  • INTERMACS Profiles and Outcomes of Ambulatory Advanced Heart Failure Patients: A Report from the REVIVAL Registry
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-08-28
    Michelle M Kittleson, Palak Shah, Anuradha Lala, Rhondalyn C McLean, Salpy Pamboukian, Douglas A Horstmanshof, Jennifer Thibodeau, Keyur Shah, Jeffrey Teuteberg, Nisha A Gilotra, Wendy C Taddei-Peters, Thomas M Cascino, Blair Richards, Shokoufeh Khalatbari, Neal Jeffries, Lynne W Stevenson, Douglas Mann, Keith D Aaronson, Garrick C Stewart

    Introduction Ambulatory patients with advanced heart failure are often considered for advanced therapies, including durable mechanical circulatory support (MCS). The Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Profiles are a commonly used descriptor of disease severity in patients receiving MCS devices, but their role in defining the prognosis of ambulatory patients is less well-established, especially for Profiles 6 and 7. Methods REVIVAL is a prospective, observational study of 400 outpatients from 21 MCS/cardiac transplant centers. Eligible patients had NYHA class II-IV symptoms despite optimal medical and electrical therapies with a recent heart failure hospitalization, heart transplant listing, or evidence of high neurohormonal activation. Results The cohort included 33 (8%) INTERMACS Profile 4, 83 (21%) Profile 5, 155 (39%) Profile 6, and 129 (32%) Profile 7. Across INTERMACS Profiles, there were no differences in age, gender, ejection fraction, blood pressure, or use of guideline-directed medical therapy. A lower INTERMACS Profile was associated with more hospitalizations, greater frailty and more impaired functional capacity and quality of life. The composite endpoint of death, durable MCS, or urgent transplant at 12 months occurred in 39%, 27%, 24%, and 14% subjects with INTERMACS Profiles 4, 5, 6, and 7, respectively (p = 0.004). Conclusions Among ambulatory patients with advanced heart failure, a lower INTERMACS Profile was associated with a greater burden of heart failure across multiple dimensions and a higher composite risk of durable MCS, urgent transplant, or death. These Profiles may assist in risk assessment and triaging ambulatory patients to advanced therapies.

    更新日期:2019-08-28
  • Impact of Combined Heart and Lung Transplantation on Bronchiolitis Obliterans Syndrome, Cardiac Allograft Vasculopathy, and Long-Term Survival
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-08-27
    Takeshi Kitai, Toshihiro Okamoto, Chisato Miyakoshi, Hiromichi Niikawa, Paulino A. Alvarez, Chayakrit Krittanawong, Andrew Xanthopoulos, Kenneth R McCurry

    Background Evidence from animal studies and small case series suggests that primary graft dysfunction occurs less often following combined organ transplantation than following isolated organ transplantation. In this large-scale national registry study, we aimed to investigate whether survival as well as the rates of bronchiolitis obliterans syndrome (BOS) and coronary allograft vasculopathy (CAV) are affected by simultaneous heart and/or lung transplantation (HLTx). Methods Clinical data from the United Network of Organ Sharing (UNOS) database were retrospectively reviewed to identify transplant-naive patients who underwent heart and/or lung transplantation between 1987 and 2016. Comparisons were conducted for isolated vs combined organ transplant. Outcomes included all-cause mortality, as well as the incidences of BOS and CAV Results Of the 98,310 patients reviewed, 63,976, 1,189, and 33,145 had received isolated heart transplantation (iHTx), HLTx, and isolated lung transplantation (iLTx), respectively. In the early post-operative period, mortality rates were higher after HLTx than after iHTx or iLTx (on crude and propensity score-matched analyses). However, the adjusted hazard risk for mortality associated with HLTx was significantly lower relative to the iLTx-associated risk beyond 3 years postoperatively, and similar relative to the iHTx-associated risk beyond 7 years postoperatively. On both crude and adjusted analyses, the incidences of BOS and CAV were significantly lower after HLTx than after iHTx or iLTx (P<0.001 for all comparisons). Conclusions Combined (rather than single) organ transplantation may provide immunoprotective benefits enhancing long-term survival and attenuating the risk of BOS and CAV.

    更新日期:2019-08-27
  • Impact and Predictors of Positive Response to Desensitization in Pediatric Heart Transplant Candidates
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-08-25
    Jonathan J. Edwards, Naomi Seliktar, Rachel White, Steven D. Heron, Kimberly Lin, Joseph Rossano, Dimitri Monos, Deborah Sesok-Pizzini, Matthew J. O'Connor

    Background Desensitization, the process of reducing anti-human leukocyte antigen (HLA) antibodies in sensitized patients awaiting heart transplantation (HT), has unclear efficacy in pediatric HT candidates. Methods Pediatric HT candidates listed at our institution between 1/1/13 - 6/30/18 were retrospectively evaluated. Sensitization was defined as panel reactive antibody (cPRA) ≥ 10% with ≥ 1 strong positive antibody. Desensitization response was defined as ≥ 25% reduction in mean fluorescence intensity (MFI) for ≥ 90% of strong positive antibodies on follow up PRA testing prior to waitlist removal, HT, or death (data available for 13 patients). Results HT candidates were categorized as sensitized receiving desensitization therapy (“ST”, n = 14), sensitized not receiving therapy (“SNT”, n = 18), or non-sensitized (“NS”, n = 55). Desensitization response was seen in 8 (62%) of the ST upon repeat PRA testing, with ST responders receiving more doses of IVIG (8 vs. 2, p < 0.05). Anti-HLA class I antibodies were particularly resistant for non-responders (p = 1.9 × 10−4). The combination of homograft and ventricular assist device was more sensitizing than either alone (p = 3.1 × 10−4); however these sensitization risk factors did not impact desensitization response. ST was associated with higher likelihood of remaining listed and longer waitlist time without substantially impacting HT rate, waitlist mortality, or early post-HT outcomes. Conclusions Most ST patients had a favorable response to desensitization, with a dose-dependent response observed for IVIG. Anti-HLA class likely impacts ST response, while traditional sensitization risk factors had no impact on response.

    更新日期:2019-08-26
  • Outcomes of Heart Transplantation from Hepatitis C Virus Positive Donors
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-08-24
    Saima Aslam, Ily Yumul, Mark Mariski, Victor Pretorius, Eric Adler

    Background National data demonstrate that increasing opportunities exist for organ donation among hepatitis C virus (HCV) infected individuals. Methods We developed a clinical practice protocol for acceptance of HCV+ organs for HCV- patients that underwent heart transplantation (HT) and retrospectively reviewed outcomes at our institution. Inclusion criteria: All adult patients listed for HT. Exclusion criteria: Pre-existing human immunodeficiency virus or active hepatitis B viremia in the recipient/donor. Results We transplanted 21 patients from HCV+ donors; 19 were viremic donors and two non-viremic. Recipients included 18 patients who underwent HT alone and three patients that underwent combined heart-kidney transplants. There was no HCV transmission from non-viremic donors (n=2); all 19 recipients of viremic donors developed HCV infection (100% transmission). Median age of viremic donors was 34 years (IQR 30-46), and 84.2% were considered PHS increased risk. Induction immunosuppression consisted of antithymocyte globulin (7/21), basiliximab (7/21) or none (8/21). Maintenance immunosuppression was comprised of tacrolimus, mycophenolate mofetil and prednisone. Post-operative week two HCV viral load was not related to induction. DAA therapy for 12-week course consisted of glecaprevir/pibrentasvir (14/19, 74%), sofosbuvir/velpatasvir (2/19, 11%), elbasvir/grazoprevir (2/19, 11%) and ledipasvir/sofosbuvir (1/19, 5%). All patients on DAA therapy cleared viremia; sustained virological response rate at 12 weeks (SVR12) in 18 evaluable patients was 100%. Conclusions We report successful single-center experience utilizing HCV+ organs for HT into HCV- recipients. We believe that there is utility in using such organs in order to expand the current donor pool. Further long-term follow-up is needed.

    更新日期:2019-08-25
  • Mesenchymal stem cell-derived extracellular vesicles improve the molecular phenotype of isolated rat lungs during ischemia/reperfusion injury
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-08-24
    Caterina Lonati, Giulia Alessandra Bassani, Daniela Brambilla, Patrizia Leonardi, Andrea Carlin, Marco Maggioni, Alberto Zanella, Daniele Dondossola, Valentina Fonsato, Cristina Grange, Giovanni Camussi, Stefano Gatti

    BACKGROUND Lung ischemia/reperfusion (IR) injury contributes to development of severe complications in patients undergoing transplantation. Mesenchymal-stem-cells (MSCs)-derived Extracellular vesicles (EVs) exert beneficial actions comparable to those of MSCs without the risks of the cell-based strategy. The present research investigated EV-effects during IR injury in isolated rat lungs. METHODS An established model of 180 min-ex vivo lung perfusion (EVLP) was used. At 60 min EVs (N=5) or saline (N=5) were administered. Parallel experiments used labelled-EVs to determine EV biodistribution (N=4). Perfusate samples were collected to perform gas analysis and to assess concentration of nitric oxide, hyaluronan, inflammatory mediators, and leukocytes. Lung biopsies were taken at 180 min to evaluate hyaluronan, ATP, gene expression, and histology. RESULTS Compared to untreated lungs, EV-treated organs showed decreased vascular resistance and a rise of perfusate nitric oxide metabolites. EVs prevented the reduction in pulmonary ATP caused by IR. Increased medium-high-molecular-weight hyaluronan was detected in the perfusate and in the lung tissue of the IR+EV group. Significant differences in cell count on perfusate and tissue samples, together with induction of transcription and synthesis of chemokines, suggested EV-dependent modulation of leukocyte recruitment. EVs up-regulated genes involved in resolution of inflammation and oxidative stress. Biodistribution analysis showed that EVs were retained in the lung tissue and internalized within pulmonary cells. CONCLUSIONS This study shows multiple, novel EV influences on pulmonary energetics, tissue integrity, and gene expression during IR. The use of cell-free therapies during EVLP could constitute a valuable strategy for reconditioning and repair of injured lungs before transplantation.

    更新日期:2019-08-25
  • Increasing Heart Transplant Donor Pool by Liberalization of Size Matching
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-08-24
    Luise Holzhauser, Teruhiko Imamura, Nikhil Bassi, Takeo Fujino, Daisuke Nitta, Anthony J. Kanelidis, Nikhil Narang, Gene Kim, Jayant Raikhelkar, Catherine Murks, David Onsager, Tae Song, Takeyoshi Ota, Valluvan Jeevanandam, Gabriel Sayer, Nir Uriel

    Background The heart transplant (HT) guidelines recommendation to match recipient and donors within 30% of body weight lacks a strong evidence base and is not well established in patients bridged to transplant with left-ventricular-assist-devices (LVAD). In light of scarcity of donor hearts we investigated the effect of size-mismatch on hemodynamics, one-year survival and length of stay (LOS) following HT. Methods Single-center retrospective analysis of consecutive HT patients from 04/07 to 09/17. Recipients were divided into 3 cohorts based on Donor-to-Recipient-Weight Ratio (DRWR): (1) undersized (<0.7); (2) size-matched (0.7-1.3); (3) oversized (>1.3). Results 288 consecutive patients were identified (mean age 53±11 years, 76% male), 46 were undersized (0.61 ± 0.05), 210 size-matched (0.94 ± 0.16), and 32 oversized (1.65 ± 0.38). There was no significant difference in donor LVEDD between the three groups (p=0.11). D/R predicted heart mass (PHM) was lowest in the undersized group (0.92 ± 0.13). There were no significant differences in 1-year survival in the overall and LVAD cohort (p=0.65, 0.59, respectively). Neither donor LVEDD nor D/R PHM differed among survivors or non-survivors. LOS was longer in the undersized group than the size matched cohort (p=0.004). Among the groups undersized hearts had the highest filling pressures and lowest cardiac-index at 1 week (p=0.009, 0.017, and p=0.05, respectively). There were no clinically significant differences in hemodynamics at 1 or 6 months. Conclusion HT undersizing affects hemodynamics early but not later in the course and does not impact 1-year survival. Liberalization of size-matching may increase the HT donor-pool significantly.

    更新日期:2019-08-25
  • THE IMPACT OF UTILIZING HEPATITIS C VIRUS NUCLEIC ACID TEST-POSITIVE DONOR HEARTS ON HEART TRANSPLANT WAITLIST TIME AND TRANSPLANT RATE
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-08-14
    Yan K. Gernhofer, Michela Brambatti, Barry H. Greenberg, Eric Adler, Saima Aslam, Victor Pretorius

    BACKGROUND Previous studies suggest that direct-acting antivirals (DAAs) for treatment of hepatitis C virus (HCV) infection permits transplantation of HCV-viremic donor organs in uninfected recipients. This opportunity may expand donor pool. We assessed the impact of utilizing HCV nucleic acid test-positive (NAT+) donor hearts on heart transplant (HTx) waitlist time and transplant rate. METHODS We retrospectively analyzed 156 patients who were listed for HTx from October 2015 through October 2018. Patients were stratified into 2 periods centered on April 27, 2017, when the protocol to accept HCV NAT+ donor organs for transplantation in non-HCV-infected recipients began; Period 1 (October 27, 2015 to April 26, 2017) and Period 2 (April 27, 2017 to October 26, 2018). RESULTS In Period 1, 57 of the 71 patients on HTx waitlist were transplanted, whereas in Period 2, 57 of the 85 patients were transplanted. Median waitlist time to transplant decreased from 63.1 days in Period 1 to 34.1 days in Period 2 (p = 0.002). Transplant rate increased from 168.2 per 100 patient-years in Period 1 to 280.0 per 100 patient-years in Period 2 (incidence rate ratio [IRR] 2.0, 95% confidence interval [CI] 1.2—3.3; p = 0.006). Neither waitlist mortality rate, hospital stay post-transplantation, nor post-transplant mortality differed significantly between the time periods. Nineteen patients received HCV NAT+ donor hearts. Short-term post-transplant outcomes were similar between recipients who received HCV NAT+ and HCV NAT- donor hearts. CONCLUSIONS This single-center retrospective analysis suggests that utilization of HCV NAT+ donor hearts may result in reduced HTx waitlist time and increased transplant rate. Additionally, transplanting HCV NAT+ donor hearts in non-HCV-infected recipients, followed by DAAs, can provide acceptable short-term post-transplant outcomes.

    更新日期:2019-08-15
  • Structured review of post-cardiotomy extracorporeal membrane oxygenation: part 1 - Adult patients
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-08-10
    Roberto Lorusso, Giuseppe Maria Raffa, Khalid Alenizy, Niels Sluijpers, Maged Makhoul, Daniel Brodie, Mike McMullan, I-Wen Wang, Paolo Meani, Graeme MacLaren, Mariusz Kowalewski, Heidi Dalton, Ryan Barbaro, Xaotong Hou, Nicholas Cavarocchi, Yih-Sharng Chen, Ravi Thiagarajan, Peta Alexander, Glenn J.R. Whitman

    Cardiogenic shock, cardiac arrest, acute respiratory failure, or a combination of such events, are all potential complications after cardiac surgery which lead to high mortality. Use of extracorporeal temporary cardio-circulatory and respiratory support for progressive clinical deterioration can facilitate bridging the patient to recovery or to more durable support. Over the last decade, extracorporeal membrane oxygenation (ECMO) has emerged as the preferred temporary artificial support system in such circumstances. Many factors have contributed to widespread ECMO use, including the relative ease of implantation, effectiveness, versatility, low cost relative to alternative devices, and potential for full, not just partial circulatory support. While there have been numerous publications detailing the short and midterm outcomes of ECMO support, specific reports about post-cardiotomy ECMO (PC-ECMO), are limited, single-center experiences. Etiology of cardiorespiratory failure leading to ECMO implantation, associated ECMO complications, and overall patient outcomes may be unique to the PC-ECMO population. Despite the rise in PC-ECMO use over the past decade, short term survival has not improved. This report, therefore, aims to present a comprehensive overview of the literature with respect to the prevalence of ECMO use, patient characteristics, ECMO management, and in-hospital and early post-discharge patient outcomes for those treated for post-cardiotomy heart, lung, or heart-lung failure.

    更新日期:2019-08-10
  • FIRST REPORT OF A SUCCESSFUL PEDIATRIC HEART TRANSPLANTATION FROM DONATION AFTER CIRCULATORY DEATH WITH DISTANT PROCUREMENT USING NORMOTHERMIC REGIONAL PERFUSION AND COLD STORAGE
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-08-10
    Vincent Tchana-Sato, Didier Ledoux, Katrien Vandendriessche, Johan Van Cleemput, Gregory Hans, Arnaud Ancion, Bjorn Cools, Philippe Amabili, Olivier Detry, Paul Bernard Massion, Josee Monard, Marie-Hélène Delbouille, Bart Meyns, Jean Olivier Defraigne, Filip Rega

    Heart Transplantation (HT) from donation after circulatory death (DCD) is a promising alternative to expand the heart donor pool. Cold storage can be used in a strategy to successfully retrieve and transplant DCD hearts after reconditioning using normothermic regional perfusion for distant procurement. Herein, we present the first report of a pediatric DCD heart reconditioned with normothermic regional perfusion, preserved using only cold storage while being transported to a neighboring center, and then successfully transplanted after nearly 2 hours of cold static storage. If supported by an appropriate trial, this finding could obviate the need to use expensive perfusion devices for short inter-hospital distances for DCD heart transportation, and stimulate more centers across the world to embrace DCD HT.

    更新日期:2019-08-10
  • Adipose tissue quantification and primary graft dysfunction after lung transplantation: The Lung Transplant Body Composition study
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-08-10
    Michaela R. Anderson, Jayaram K. Udupa, Ethan Edwin, Joshua M. Diamond, Jonathan P. Singer, Jasleen Kukreja, Steven R Hays, John R Greenland, Anthony Ferrante, Matthew Lippel, Tatiana Blue, Amika McBurnie, Michelle Oyster, Laurel Kalman, Melanie Rushefski, Caiyun Wu, Gargi Pednekar, Wen Liu, David J. Lederer

    Background Obesity is associated with increased risk of primary graft dysfunction (PGD) after lung transplantation. The contributions of specific adipose tissue depots is unknown. Methods We performed a prospective cohort study of adult lung transplant recipients at four U.S. transplant centers. We measured cross-sectional areas of subcutaneous (SAT) and visceral adipose tissue (VAT) on chest and abdominal CT scans and indexed each measurement to height2. We used logistic regression to examine associations of adipose indices and adipose classes with grade 3 PGD at 48 or 72 hours, and Cox proportional hazards models to examine survival. We used latent class analyses to identify patterns of adipose distribution. We examined associations of adipose indices with plasma biomarkers of obesity and PGD. Results 262 and 117 subjects had available chest CT scans and underwent protocol abdominal CT scans, respectively. In adjusted models, greater abdominal SAT index was associated with an increased risk of PGD (OR 2.0, 95% CI 1.03 to 4.1, p=.04) but not with survival time. VAT indices were not associated with PGD risk or survival time. Greater abdominal SAT index correlated with greater pre- and post-transplant leptin (r=.60, p<0.001, and r=0.42, p<0.001), pre-transplant IL-1RA (r=.25, p=0.04), and post-transplant ICAM-1 (r=.25, p=0.04). We identified three latent patterns of adiposity. The class defined by high thoracic and abdominal SAT had the greatest risk of PGD. Conclusions Subcutaneous, but not visceral, adiposity is associated with increased risk of PGD after lung transplantation.

    更新日期:2019-08-10
  • Endothelin-1, cardiac morphology, and heart failure: The MESA Angiogenesis Study
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-08-10
    Peter J. Leary, Nancy S. Jenny, David A. Bluemke, Steven M. Kawut, Richard A. Kronmal, Joao A. Lima, Bradley A. Maron, David D. Ralph, Samuel G. Rayner, John J. Ryan, Zachary L. Steinberg, Karen D. Hinckley Stukovsky, Ryan J. Tedford

    Background Circulating levels of endothelin-1 (ET1) are elevated in heart failure and predict poor prognosis; however, it is not clear whether ET1 elevation is an adaptive response, maladaptive response, or an epiphenomenon of heart failure. In the current study, we evaluated relationships between ET1, cardiac morphology, and incident heart failure or cardiovascular death in participants with no evidence of clinical cardiovascular disease at the time ET1 was measured. Methods and Results ET1 was measured 1,361 participants in the Multi-Ethnic Study of Atherosclerosis Angiogenesis Sub-Study. As suggested by linear regression, participants with lower circulating ET1 levels tended to be older, non-white, more likely to have smoked heavily, and less likely to report intentional exercise. Participants with higher ET1 levels had smaller left ventricular end-diastolic volumes (8.9 mL smaller per log increase in ET1, 95% CI 17.1 to 0.7, p=0.03) with an increased left ventricular ejection fraction (2.8% per log increase in ET1, 95% CI 0.5 to 5.2%, p=0.02). As suggested by Cox Proportional Hazards estimates, participants with higher ET1 levels had a lower risk for the composite outcome of heart failure or cardiovascular death in models that were unadjusted or had limited adjustment (p=0.03 and 0.05 respectively). Lower risk for heart failure could not be clearly shown in a model including health behaviors. Conclusions These results suggest, but do not confirm that elevated levels of circulating ET1 are associated with a more favorable cardiac phenotype. The relationship between ET1 and outcomes was not fully independent of one or more covariates.

    更新日期:2019-08-10
  • LONG-TERM OUTCOME OF CARDIAC ALLOGRAFT VASCULOPATHY: IMPORTANCE OF THE ISHLT ANGIOGRAPHIC GRADING SCALE
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-08-10
    Jan M. Van Keer, Lucas N.L. Van Aelst, Filip Rega, Walter Droogne, Gabor Voros, Bart Meyns, Johan Vanhaecke, Marie-Paule Emonds, Stefan Janssens, Maarten Naesens, Johan Van Cleemput

    Background Cardiac allograft vasculopathy (CAV) is a major complication limiting long-term survival after heart transplantation (HTx). However, long-term outcome data of HTx recipients with detailed information on angiographic severity are scarce. Methods The study included 501 HTx recipients with angiographic follow-up up to 20 years post-transplant. All coronary angiograms were classified according to the International Society for Heart and Lung Transplantation (ISHLT) grading scale. Results CAV prevalence increased over time after transplantation, reaching 10% at 1 year, 44% at 10 years and 59% at 20 years. Older donor age (hazard ratio (HR) 1.38 per 10 years, 1.20–1.59, p<0.001), male donor gender (hazard ratio 1.86, 1.31–2.64, p<0.001), stroke as donor cause of death (HR 1.47, 1.04–2.09, p=0.03), recipient pretransplant hemodynamic instability (HR 1.79, 1.15–2.77, p=0.01), post-transplant smoking (HR 1.59, 1.06–2.39, p=0.03) and first-year treated rejection episodes (HR 1.49, 1.01–2.20, p=0.046) were independent risk factors for CAV. Baseline antimetabolite drug use (HR 0.57, 0.34–0.95, p=0.03) and more recent transplant date (HR 0.78 per 10 years, 0.62–0.99, p=0.04) were protective factors. Compared to patients without CAV, the hazard ratio for death or retransplantation was 1.22 (0.85–1.76, p=0.28) for CAV 1, 1.86 (1.08–3.22, p=0.03) for CAV 2 and 5.71 (3.64 – 8.94, p<0.001) for CAV 3. Conclusions CAV is highly prevalent in HTx recipients, and is explained by immunological and non-immunological factors. Higher ISHLT CAV grades are independently associated with worse graft survival.

    更新日期:2019-08-10
  • The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Twenty-second Pediatric Lung and Heart-Lung Transplantation Report—2019; Focus Theme: Donor and Recipient Size Match
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-08-08
    Don Hayes, Wida S. Cherikh, Daniel C. Chambers, Michael O. Harhay, Kiran K. Khush, Rebecca R. Lehman, Bruno Meiser, Joseph W. Rossano, Eileen Hsich, Luciano Potena, Aparna Sadavarte, Tajinder P. Singh, Andreas Zuckermann, Josef Stehlik

    The 22nd International Society for Heart and Lung Transplantation (ISHLT) Transplant Registry Report summarizes data from pediatric lung and combined heart-lung transplant recipients and their donors for transplants that occurred through June 30, 2018. This year's Report focuses on an overall theme of donor and recipient size match. In addition to reporting key data for pediatric lung and heart-lung transplant recipients, we report transplant types, historical trends, geographical associations, indications, donor and recipient characteristics, and transplant outcomes including rejection burden, bronchiolitis obliterans syndrome (BOS), and survival for transplant recipients associated with donor and recipient size match. The full Registry slide set available online (https://ishltregistries.org/registries/slides.asp) provides more detail, additional analyses, and other information not included in this printed Report.

    更新日期:2019-08-09
  • The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-Sixth Adult Lung and Heart–Lung Transplantation Report—2019; Focus Theme: Donor and Recipient Size Match
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-08-08
    Daniel C. Chambers, Wida S. Cherikh, Michael O. Harhay, Don Hayes, Eileen Hsich, Kiran Khush, Bruno Meiser, Luciano Potena, Joseph W. Rossano, Aparna Sadavarte, Tajinder P. Singh, Alice E. Toll, Andreas Zuckermann, Josef Stehlik

    This thirty-sixth adult lung and heart–lung transplant report summarizes data from 69,200 adult lung and 4,128 adult heart-lung transplants performed through June 30, 2018 and reported to the International Thoracic Organ Transplant Registry. With each year's report, we now provide more detailed analyses on a particular focus theme important to patient outcomes. Since 2013, these have been donor and recipient age; retransplantation; early graft failure; indication for transplant; allograft ischemic time; and multiorgan transplantation. Although widely accepted as critical to decision making at the time of receipt of an organ donor offer, there is surprisingly little literature outlining current practice and the impact of size (mis-)matching on outcomes. Hence this year's report focuses on an overall theme of donor and recipient size matching. In addition to reporting donor and recipient height and weight difference for all adult lung and heart-lung transplant recipients stratified by transplant type (bilateral or single) and indication, we report historical trends and associations between size match and survival. The Registry's online slide sets include results from additional analyses and complementary information not included in this publication (see https://ishltregistries.org/registries/slides.asp).

    更新日期:2019-08-09
  • Outcomes in Patients Undergoing Cardiac Re-Transplantation: A Propensity Matched Cohort Analysis of the UNOS Registry
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-07-08
    Robert JH Miller, Brian A Clarke, Jonathan G Howlett, Kiran K Khush, Jeffrey J Teuteberg, Francois Haddad
    更新日期:2019-07-09
  • Elevated pre-transplant left ventricular end-diastolic pressure increases primary graft dysfunction risk in double lung transplant recipients
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-02-18
    David Li, Justin Weinkauf, Alim Hirji, Ali Kapasi, Dale Lien, Jayan Nagendran, Daniel Kim, Justin Ezekowitz, Kieran Halloran

    BACKGROUND Primary graft dysfunction (PGD) represents ischemia‒reperfusion injury in the lung allograft, and elevated left ventricular end-diastolic pressure (LVEDP) may contribute to capillary leak. We tested whether pre-transplant LVEDP or pulmonary capillary wedge pressure (mPCWP) are related to PGD risk. We hypothesized that elevated LVEDP and mPCWP would increase PGD risk. METHODS We reviewed adult double lung transplant recipients at the University of Alberta Hospital from 2004 to 2016 with pre-transplant LVEDP measurements. The primary outcome was Grade 3 PGD at 48 to 72 hours post-transplant. We used regression analysis to assess the association between LVEDP and mPCWP with Grade 3 PGD risk, as well as agreement between these measurements. RESULTS Three hundred thirty double lung transplant recipients were included in the study, and 63 (19%) developed Grade 3 PGD at 48 or 72 hours. Mean LVEDP was 16 ± 7 mm Hg in the Grade 3 PGD group and 12 ± 5 mm Hg in the non-PGD group (p < 0.0001). LVEDP >15 mm Hg was associated with an adjusted odds ratio (OR) of 3.83 (95% confidence interval [CI] 1.90 to 7.73, p < 0.0001), whereas mPCWP >15 mm Hg showed similar findings (adjusted OR 4.25 [1.83 to 9.86], p = 0.0008). Correlation and agreement between LVEDP and mPCWP were fair. CONCLUSIONS Elevated pre-transplant LVEDP increases the risk of severe PGD after lung transplant, as does elevated mPCWP. These measurements appear to be complementary as markers of prospective PGD risk.

    更新日期:2019-07-07
  • Stroke and death risk in ventricular assist device patients varies by ISHLT infection category: An INTERMACS analysis
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-02-12
    Palak Shah, Sarah E. Birk, Lauren B. Cooper, Mitchell A. Psotka, James K. Kirklin, Scott D. Barnett, Shalika B. Katugaha, Sheila Phillips, Mary M. Looby, Francis D. Pagani, Jennifer A. Cowger

    BACKGROUND Ventricular assist device (VAD) patients often experience infections, which increase the risk of stroke and mortality. Using the definitions of the International Society for Heart and Lung Transplantation (ISHLT), we have characterized differences in clinical outcomes for categories of infection: VAD-specific (e.g., pump component related); VAD-related (e.g., bloodstream infection, BSI); and non-VAD infections (e.g., pneumonia). METHODS Querying of the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) identified 16,597 continuous-flow VAD recipients. Categories of infection were tested in multivariate models to determine the risk of stroke and death. RESULTS After implant, 7,046 patients (42%) developed an infection at a median of 69 (interquartile range 12 to 272) days. A majority were non-VAD infections (49%), followed by VAD-related (26%) and VAD-specific infections (25%). BSIs were the most common form of VAD-related infection (92%), and the majority (59%) had no associated infection, that is, idiopathic bacteremia. Internal pump component infections were rare (0.003 event per patient-year [EPPY]). Infected VAD patients had a higher prevalence of stroke compared to patients without an infection (18% vs 11%, p < 0.001). The lowest stroke rate occurred after a VAD-specific infection (0.11 EPPY) compared with VAD-related (0.17 EPPY) and non-VAD infections (0.15 EPPY, p < 0.001). Hemorrhagic strokes were more common than ischemic strokes in all infection groups and highest after a VAD-related infection (0.13 EPPY). One-year survival after an infection was 87% in VAD-specific infections, as compared with VAD-related (71%) and non-VAD infections (72%, p < 0.001). CONCLUSIONS The ISHLT categorization of VAD infections unveils notable differences in associated risk of stroke and mortality. A re-assessment of transplant prioritization for eligible infected VAD patients may be useful to increase transplant-related survival benefit.

    更新日期:2019-07-07
  • DireCt Lung Ultrasound Evaluation (CLUE): A novel technique for monitoring extravascular lung water in donor lungs
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-03-13
    Kamal S. Ayyat, Toshihiro Okamoto, Hiromichi Niikawa, Yoshifumi Itoda, Siddharth Dugar, Samir Q. Latifi, Daniel J. Lebovitz, Ajit Moghekar, Kenneth R. McCurry
    更新日期:2019-07-07
  • Differential effects of ischemia/reperfusion on endothelial function and contractility in donation after circulatory death
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-03-13
    Natalia Méndez-Carmona, Rahel K. Wyss, Maria Arnold, Anna Joachimbauer, Adrian Segiser, Georg M. Fiedler, Thierry P. Carrel, Hendrik T. Tevaearai Stahel, Sarah L. Longnus

    BACKGROUND Donation after circulatory death (DCD) could significantly improve cardiac graft availability. However, DCD hearts undergo potentially deleterious warm ischemia/reperfusion (I/R). As endothelial damage is a key factor in cardiac I/R injury, we aimed to investigate the tolerance of cardiac and endothelial function after various durations of warm ischemia to improve the timing and choice of cardioprotective therapies. METHODS Isolated, working rat hearts were perfused for 20 minutes aerobically, then underwent various periods of warm global ischemia and either 30 or 60 minutes of reperfusion. RESULTS Compared with non-ischemic hearts, recovery of left ventricular work (heart rate–developed pressure product) was significantly reduced at 60 minutes of reperfusion with ≥27 minutes of ischemia (p <0.05 for all), but was unchanged after 21 or 24 minutes of ischemia. Markers of cell death and edema significantly increased with ≥27-minute ischemia compared with non-ischemic hearts (p <0.05 for all). Endothelial-dependent vasodilation was significantly impaired compared with non-ischemic hearts with ≥24 minutes of ischemia, whereas endothelial-independent vasodilation was impaired with ≥27 minutes of ischemia (p <0.05 for all). Furthermore, with ≥24 minutes of ischemia, superoxide production by nitric oxide synthase and peroxynitrite levels were significantly increased compared with non-ischemic hearts, suggesting endothelial nitric oxide synthase (eNOS) uncoupling (p <0.05 for both). CONCLUSIONS The first signs of endothelial dysfunction after cardiac ischemia occur with less ischemia than cardiac functional alterations, and may result from increased eNOS uncoupling. Strategies aimed at improving eNOS coupling may thus help to optimize both endothelial and myocardial recovery, ultimately facilitating DCD heart transplantation.

    更新日期:2019-07-07
  • Short-term results with transcatheter aortic valve replacement for treatment of left ventricular assist device patients with symptomatic aortic insufficiency
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-03-11
    Amin Yehya, Vivek Rajagopal, Christopher Meduri, James Kauten, Morris Brown, Lynn Dean, Julie Webster, Arun Krishnamoorthy, Tara Hrobowski, David Dean

    BACKGROUND After 3years of continuous-flow left ventricular assist device (CF-LVAD) support, nearly a third of patients develop at least moderate aortic insufficiency (AI). Percutaneous occluder devices, surgical aortic valve replacement (SAVR), and urgent heart transplantation are available treatment options. Transcatheter aortic valve replacement (TAVR) has not been widely used for treating symptomatic AI in patients on LVAD support. METHODS Retrospective chart review and data analysis from October 2010 through August 2017 was performed. A total of 286 patients with end-stage heart failure (ESHF) were implanted with a durable CF-LVAD. Nine patients subsequently developed significant symptomatic AI, which was treated with TAVR. RESULTS All 9 patients had 1 TAVR procedure with resolution of AI and were discharged home. Procedural complications include valve migration warranting a second valve for stabilization, retroperitoneal and groin hematoma, and pseudoaneurysm requiring thrombin injection. A significant improvement of the New York Heart Association classification was noted from the time of implant to 6 months. Two patients had unplanned heart failure‒related hospitalizations within 6 months. At 6 months, 89% of patients were alive on LVAD support. CONCLUSIONS TAVR is a successful treatment modality for LVAD patients who develop symptomatic AI.

    更新日期:2019-07-07
  • Mechanical Ventilation and Extracorporeal Membrane Oxygenation as a Bridge to Lung Transplantation: Closing the Gap
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-07-04
    J.W. Awori Hayanga, Heather K. Hayanga, Sari D. Holmes, Yue Ren, Norihisa Shigemura, Vinay Badhwar, Ghulam Abbas

    BACKGROUND The purpose of this study was to examine outcomes and survival with mechanical ventilation (MV) and extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation (LT) using a national registry. METHODS The United Network for Organ Sharing database was analyzed for recipients in 2005-2017. Recipients were categorized into 3 groups based on pre-transplant bridging. Multivariable regression analyses examined effect of bridging on post-LT outcomes adjusting for clinical characteristics, including era (early=2005-2011, late=2012-2017) and center volume. RESULTS There were 21,576 LT recipients: no bridge (n=19,783), MV (n=1,129), and ECMO (n=664). Mean age was 54±15 years (41% female). Use of ECMO increased significantly in the late era (1% vs 5%, P<0.001). Compared to no bridge, MV and ECMO patients had greater odds for perioperative outcomes including ventilator support >48 hours, acute rejection, and dialysis. Patients with MV had reduced odds for ventilator support >48 hours (P=0.003), dialysis (P=0.003), postoperative ECMO (P=0.006), and greater odds for reintubation (P=0.005) compared to ECMO. Patients in both MV (HR=1.45, P<0.001) and ECMO (HR=1.48, P<0.001) groups had greater risk for 5-year mortality, but MV and ECMO groups did not differ (HR=0.98, P=0.817). Risk for mortality in the ECMO group decreased in the later era (HR=0.54, P=0.006). CONCLUSIONS ECMO as a bridge to LT has increased 271% while MV has decreased 38% over the past decade. Survival with ECMO has significantly improved and is now equivalent to survival in recipients bridged on MV. These results suggest gains in use, outcomes, and safety of ECMO in this patient cohort.

    更新日期:2019-07-05
  • Single Lung Transplantation in Patients With Severe Secondary Pulmonary Hypertension
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-07-04
    Basil S. Nasir, Michael S. Mulvihill, Yaron D Barac, Muath Bishawi, Morgan L. Cox, Dominick J. Megna, John C. Haney, Jacob A. Klapper, Mani A. Daneshmand, Matthew G. Hartwig

    Purpose The optimal transplant strategy for patients with end-stage lung disease complicated by secondary pulmonary hypertension (PH) is controversial. The aim of this study is to define the role of single lung transplantation in this population. Methods We performed a retrospective study of lung transplant recipients using the UNOS-OPTN STAR registry. Adult recipients that underwent isolated lung transplantation between May 2005 and June 2015 for end stage lung disease due to obstructive or restrictive etiologies were identified. Patients were stratified by mean pulmonary artery pressure (mPAP ≥ or < 40mmHg) and by treatment - single (SOLT) or bilateral (BOLT) orthotopic lung transplantation. The primary outcome measure was overall survival (OS), which was estimated using the Kaplan-Meier method and compared by the log-rank test. To adjust for donor and recipient confounders, Cox proportional hazards models were developed to estimate the adjusted hazard ratio (AHR) of mortality associated with elevated mPAP in SOLT and BOLT recipients. Results A total of 12,392 recipients met inclusion criteria. Of recipients undergoing SOLT, those with mPAP ≥ 40 were shown to have lower survival, with 5-year OS of 43.9% (95% CI 36.6-52.7) (P=0.007). Of recipients undergoing BOLT, OS was superior to SOLT, and no difference in 5-year OS between mPAP ≥ and < 40 was observed (P=0.15). In the adjusted analysis, mPAP ≥ 40 mm Hg was found to be an independent predictor for mortality in SOLT, but not BOLT recipients. This finding remained true on multivariable analysis. In patients undergoing SOLT, mPAP ≥ 40 was associated with an AHR for mortality of 1.31 (1.08 - 1.59, p = 0.07). In BOLT, mPAP was not associated with increased hazard (AHR 1.04, P=0.48). Conclusion There is a reduced survival when a patient with severe secondary PH undergoes SOLT. This increased mortality hazard is not seen in BOLT. It appears that a BOLT may negate the adverse effect that severe PH has on overall survival, and may be superior to SOLT in patients with mPAP over 40 mm Hg.

    更新日期:2019-07-04
  • HFSA/SAEM/ISHLT clinical expert consensus document on the emergency management of patients with ventricular assist devices
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-07-01
    Michael M. Givertz, Ersilia M. DeFilippis, Monica Colvin, Chad E. Darling, Tonya Elliott, Eman Hamad, Brian C. Hiestand, Jennifer L. Martindale, Sean P. Pinney, Keyur B. Shah, Juliane Vierecke, Mark Bonnell

    Mechanical circulatory support is now widely accepted as a viable long-term treatment option for patients with end-stage heart failure (HF). As the range of indications for the implantation of ventricular assist devices grows, so does the number of patients living in the community with durable support. Because of their underlying disease and comorbidities, in addition to the presence of mechanical support, these patients are at a high risk for medical urgencies and emergencies (Table 1). Thus, it is the responsibility of clinicians to understand the basics of their emergency care. This consensus document represents a collaborative effort by the Heart Failure Society of America, the Society for Academic Emergency Medicine, and the International Society for Heart and Lung Transplantation (ISHLT) to educate practicing clinicians about the emergency management of patients with ventricular assist devices. The target audience includes HF specialists and emergency medicine physicians, as well as general cardiologists and community-based providers.

    更新日期:2019-07-01
  • Utilization Rates and Clinical Outcomes of Hepatitis C Positive Donor Hearts in The Contemporary Era
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-06-28
    Shivank Madan, Snehal R. Patel, Kusha Rahgozar, Omar Saeed, Sandhya Murthy, Sasa Vukelic, Daniel B. Sims, Jooyoung Julia Shin, Daniel J. Goldstein, Ulrich P. Jorde

    Background Hepatitis C virus(HCV) donors should be categorized as HCV-viremic[Antibody(Ab) –or+/Nucleic Acid testing(NAT)+] or HCV Ab+ nonviremic(Ab+/NAT-). Whereas recipients of hearts from HCV-viremic donors will develop viremia but can likely be cured of HCV shortly after transplant with direct-acting antivirals (DAAs), recipients of hearts from HCV Ab+ nonviremic donors are highly unlikely to become viremic or require DAAs. Given this important difference in risk, we assessed the utilization trends and post heart-transplantation(HT) outcomes of HCV-naïve (Ab-/NAT-), HCV-viremic and HCV Ab+ nonviremic donor hearts. Methods 26,572 adult donors(≥18 years) with information on HCV Ab and NAT status were identified in United Network for Organ Sharing registry between August-2015 and June-2018 for utilization rates. Adult HT recipients of these donors were compared for primary graft failure(PGF) at 90 days and 1-year recipient survival. Results 96 HCV Ab+ nonviremic and 135 HCV-viremic adult donor hearts were transplanted during the study period. The utilization rates of both HCV Ab+ nonviremic (1.4% to 23.4%) and HCV-viremic (0.7% to 25.4%) donor hearts increased significantly approaching HCV-naïve rates (29.04%). There was no significant difference in rates of PGF and 1-year survival between recipients in the three donor HCV groups. We also used (1:3) propensity score matching and found similar 1-year survival in different donor HCV groups (HCV-naïve vs. HCV Ab+ nonviremic, p=0.59 and HCV-naïve vs. HCV-viremic, p=0.98). Conclusions Recipients of HCV-viremic and HCV Ab+ nonviremic donor hearts had equivalent risk of PGF and 1-year mortality compared to recipients of HCV-naïve donor hearts. While only HCV-viremic organs require DAAs, and although the risk of coronary artery vasculopathy after treated HCV infection has not been defined, the utilization rates of both HCV Ab+ nonviremic and HCV-viremic adult donor hearts have increased at an equal pace now approaching HCV-naïve rates.

    更新日期:2019-06-29
  • 2019 Updated Consensus Statement on the Diagnosis and Treatment of Pediatric Pulmonary Hypertension. The European Pediatric Pulmonary Vascular Disease Network (EPPVDN), endorsed by AEPC, ESPR and ISHLT
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-06-21
    Georg Hansmann, Martin Koestenberger, Tero-Pekka Alastalo, Christian Apitz, Eric A Austin, Damien Bonnet, Werner Budts, Michele D'Alto, Michael A Gatzoulis, Babar S Hasan, Rainer Kozlik-Feldmann, R Krishna Kumar, Astrid E Lammers, Heiner Latus, Ina Michel-Behnke, Oliver Miera, Nicholas W Morrell, Guido Pieles, Peter Zartner

    The European Pediatric PVD Network (EPPVDN) is a registered, non-profit organization that strives to define and develop effective, innovative diagnostic methods and treatment options in all forms of pediatric pulmonary hypertensive vascular disease, including pulmonary hypertension (PH) associated with bronchopulmonary dysplasia (BPD), PH associated with congenital heart disease (CHD), persistent PH of the newborn (PPHN), and related cardiac dysfunction. The executive writing group (EWG) members conducted searches of the PubMed/MEDLINE bibliographic database (1990-2018), held face-to-face and web-based meetings. Ten section task forces voted on the updated recommendations, based on the 2016 executive summary. Clinical trials, meta-analyses, guidelines, and other articles which include pediatric data were searched using the terms ´pulmonary hypertension´ and other keywords. Class of recommendation (COR) and level of evidence (LOE) were assigned based on ESC/AHA definitions and on pediatric data only, or on adult studies that included > 10% children, or on studies that enrolled adults with CHD. New definitions by the World Symposium on Pulmonary Hypertension 2018 were included. We generated ten tables with graded recommendations (COR/LOE). The topics include diagnosis/monitoring, genetics/biomarkers, cardiac catheterization, echocardiography, CMR/chest CT, associated forms of PH, ICU/lung transplantation, and treatment of pediatric PH. For the first time, a set of specific recommendations on the management of PH in middle and low income regions was developed. Taken together, these executive, up-to-date guidelines provide a specific, comprehensive, detailed but practical framework for the optimal clinical care of children and young adults with PH.

    更新日期:2019-06-24
  • CLINICAL OUTCOMES AND SURVIVAL FOLLOWING LUNG TRANSPLANTATION IN PATIENTS WITH LYMPHANGIOLEIOMYOMATOSIS
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-06-21
    Muhammad Umair Khawar, Dina Yazdani, Zheng Zhu, Roman Jandarov, Daniel F. Dilling, Nishant Gupta

    Background The primary aim of our study was to derive disease-specific outcomes following lung transplantation (LT) in patients with lymphangioleiomyomatosis (LAM). Methods We queried the Organ Procurement and Transplant Network database to identify LAM patients that have undergone LT in the United States. The overall survival was analyzed with Kaplan-Meier curves. Survival estimates between subgroups of interest were compared using the log rank method. Cox proportional hazard models were employed to determine the pre-transplant variables that impact post-LT survival. Results 138 women with LAM underwent LT at 31 centers between January 2003 and June 2017. The median age at listing and transplant was 44 (IQR: 36-51) and 45 (IQR: 38-52) years, respectively. The median time spent on LT waitlist was 257 (IQR: 85-616) days. Majority of the patients (109/134, 81%) received bilateral sequential LT. The median ischemic time was 4.9 (IQR: 4.1-6.1) hours. The actuarial Kaplan-Meier survival following LT for LAM patients at 1-, 5-, and 10-years was 94%, 73% and 56%, respectively. The post-LT survival was significantly better in LAM compared to other lung diseases (10-year survival 56% vs. 32%, p<0.01), and this advantage persisted after age and gender matched analysis (10-year survival 54% vs. 37%, p<0.01). Pre-transplant parameters such as presence of pulmonary hypertension, six-minute walk distance, age at transplant, ischemic time during transplant, or type of transplant (single vs. bilateral sequential LT) did not affect post-transplant survival. Conclusions The median survival after LT in LAM is 12 years, and is substantially better compared to other lung diseases.

    更新日期:2019-06-21
  • Consequences of donor-derived passengers (pathogens, cells, biological molecules and proteins) on clinical outcomes
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-06-20
    Gregory Snell, Steven Hiho, Bronwyn Levvey, Lucy Sullivan, Glen Westall

    It is recognized donor factors contribute to lung transplant outcomes. Recent observations and studies have started to elucidate potential mechanisms behind explaining these observations. This perspective piece summarizes evolving lung transplant literature on the subject, focussing on donor ‘passenger’ organisms, cells, hormones and proteins transferred to the recipient. Many extrinsic and intrinsic donor features or properties have important consequences for subsequent allograft function in the recipient. Potentially, a better understanding of these features may provide useful novel therapeutic targets to enhance allograft outcomes.

    更新日期:2019-06-21
  • EARLY OUTCOMES FOR LOW RISK PEDIATRIC HEART TRANSPLANT RECIPIENTS AND STEROID AVOIDANCE: A MULTICENTER COHORT STUDY (CLINICAL TRIALS IN ORGAN TRANSPLANTATION IN CHILDREN - CTOTC-04)
    J. Heart Lung Transplant. (IF 8.578) Pub Date : 2019-06-20
    Jacqueline M. Lamour, Kristen L. Mason, Daphne T. Hsu, Brian Feingold, Elizabeth D. Blume, Charles E. Canter, Anne I. Dipchand, Robert E. Shaddy, William T. Mahle, Warren A. Zuckerman, Carol Bentlejewski, Brian D. Armstrong, Yvonne Morrison, Helena Diop, David N. Iklé, Jonah Odim, Adriana Zeevi, Steven A. Webber

    Background Immunosuppression strategies have changed over time in pediatric heart transplantation (PHT). Thus, comorbidity profiles may have evolved. CTOTC-04 is a multicenter, prospective, cohort study assessing the impact of pre-transplant sensitization on outcomes after PHT. This sub study reports one year outcomes among recipients without pre-transplant donor-specific antibodies (DSA). Methods We recruited consecutive candidates (<21 years) at 8 centers. Sensitization status was determined by a core laboratory. Immunosuppression was standardized: thymoglobulin induction with tacrolimus/mycophenolate mofetil maintenance. Steroids were not used beyond 1 week. Rejection surveillance was by serial biopsy. Results There were 240 transplants. Subjects for this sub-study (n=186) were non-sensitized (n=108) or had no DSA (n=78). Median age was 6 years, 48.4% male, and 38.2% had congenital heart disease. Patient survival was 94.5% (95% CI: 90.1-97.0). Freedom from any type of rejection was 67.5%. Risk factors for rejection were older age at transplant and presence of non-DSA pre-transplant. Freedom from infection requiring hospitalization/intravenous antimicrobials was 75.4%. Freedom from rehospitalization was 40.3%. New onset diabetes mellitus and post-transplant lymphoproliferative disorder (PTLD) occurred in 1.6% and 1.1% of subjects respectively. There was no decline in renal function over the first year. Corticosteroids were used in 14.5% at 1 year. Conclusions PHT recipients without DSA at transplant, and managed with a steroid avoidance regimen, have excellent short-term survival and low risk of first year diabetes mellitus, and PTLD. Rehospitalization remains common. These contemporary observations allow for improved caregiver/patient counseling and provide the necessary outcomes data to help design future randomized controlled trials.

    更新日期:2019-06-20
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