Journal: J Heart Lung Transplant

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Abstract

Structured review of post-cardiotomy extracorporeal membrane oxygenation: Part 2-pediatric patients.

Lorusso R, Raffa GM, Kowalewski M, Alenizy K, ... Boeken U, Whitman G

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.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Oct 2019; 38:1144-1161
Lorusso R, Raffa GM, Kowalewski M, Alenizy K, ... Boeken U, Whitman G
J Heart Lung Transplant: 30 Oct 2019; 38:1144-1161 | PMID: 31421976
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Abstract

Extracorporeal life support bridge for pulmonary hypertension: A high-volume single-center experience.

Rosenzweig EB, Gannon WD, Madahar P, Agerstrand C, ... Brodie D, Bacchetta M
Background
Application of extracorporeal life support (ECLS) for advanced pulmonary hypertension (PH) is evolving and may be deployed as a bridge to transplantation (BTT) or in one of several non-BTT uses, such as bridge to recovery (BTR) to the chronic PH clinical state in the setting of an acute PH trigger, bridge through non-transplant surgery (BTNTS), or bridge post-transplantation (BPT).
Methods
We conducted a retrospective analysis of all adult patients with World Symposium on Pulmonary Hypertension Group 1, 3, 4, or 5 PH who received ECLS at Columbia University Medical Center/New York Presbyterian Hospital between January 1, 2010 and August 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 [interquartile range, 32-58]). Of these, 44 (45%) patients with PH 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%) patients received ECLS as BTT. In the overall cohort, 67 (68.4%) patients received venoarterial ECLS and 31 (31.6%) received venovenous (VV) ECLS. Out of 83 patients, 52 (63%) were liberated from invasive mechanical ventilation, and 85.2% of BTT patients with PH 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 32 (59.3%) BTT patients survived to lung transplantation. Early-era use of VV-ECLS for BTT had worse survival to discharge than those initially configured with venoarterial ECLS, impacting the overall survival and leading to limited use of VV-ECLS in the current era for 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 effective strategies in managing these complex patients.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 11 Sep 2019; epub ahead of print
Rosenzweig EB, Gannon WD, Madahar P, Agerstrand C, ... Brodie D, Bacchetta M
J Heart Lung Transplant: 11 Sep 2019; epub ahead of print | PMID: 31582284
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Abstract

The impact of using hepatitis c virus nucleic acid test-positive donor hearts on heart transplant waitlist time and transplant rate.

Gernhofer YK, Brambatti M, Greenberg BH, Adler E, Aslam S, Pretorius V
Background
Previous studies suggest that direct-acting anti-virals (DAAs) for the treatment of hepatitis C virus (HCV) infection permits the transplantation of HCV-viremic donor organs in uninfected recipients. This opportunity may expand the donor pool. We assessed the impact of using 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 the HTx waitlist were transplanted, whereas in Period 2, 57 of the 85 patients were transplanted. The median waitlist time to transplant decreased from 63.1 days in Period 1 to 34.1 days in Period 2 (p = 0.002). The 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 2.0, 95% CI 1.2-3.3; p = 0.006). Waitlist mortality rate, hospital stay post-transplantation, and post-transplant mortality did not differ significantly between the time periods. Nineteen patients received HCV NAT+ donor hearts. The short-term post-transplant outcomes were similar between the recipients who received HCV NAT+ and HCV NAT- donor hearts.
Conclusions
This single-center retrospective analysis suggests that the use of HCV NAT+ donor hearts may result in a reduced HTx waitlist time and an increased transplant rate. In addition, transplanting HCV NAT+ donor hearts into non-HCV-infected recipients, followed by DAAs, can provide acceptable short-term post-transplant outcomes.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Oct 2019; 38:1178-1188
Gernhofer YK, Brambatti M, Greenberg BH, Adler E, Aslam S, Pretorius V
J Heart Lung Transplant: 30 Oct 2019; 38:1178-1188 | PMID: 31492607
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Abstract

Increasing heart transplant donor pool by liberalization of size matching.

Holzhauser L, Imamura T, Bassi N, Fujino T, ... Sayer G, Uriel N
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 the 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 April 2007 to September 2017. 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 left ventricular end diastolic diameter (LVEDD) between the 3 groups (p = 0.11). The donor/recipient (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 and 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). The undersized group had hearts with the highest filling pressures and lowest cardiac index at 1 week among the remaining groups (p = 0.009, 0.017, and p = 0.05, respectively). There were no clinically significant differences in hemodynamics at 1 or 6 months.
Conclusions
HT undersizing affects hemodynamics early but not later in the course and does not impact 1-year survival. The liberalization of size matching may increase the HT donor pool significantly.

Copyright © 2019. Published by Elsevier Inc.

J Heart Lung Transplant: 30 Oct 2019; 38:1197-1205
Holzhauser L, Imamura T, Bassi N, Fujino T, ... Sayer G, Uriel N
J Heart Lung Transplant: 30 Oct 2019; 38:1197-1205 | PMID: 31672219
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Abstract

Mesenchymal stromal cell therapy during ex vivo lung perfusion ameliorates ischemia-reperfusion injury in lung transplantation.

Nakajima D, Watanabe Y, Ohsumi A, Pipkin M, ... Liu M, Keshavjee S
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 × 10 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.

Copyright © 2019. Published by Elsevier Inc.

J Heart Lung Transplant: 30 Oct 2019; 38:1214-1223
Nakajima D, Watanabe Y, Ohsumi A, Pipkin M, ... Liu M, Keshavjee S
J Heart Lung Transplant: 30 Oct 2019; 38:1214-1223 | PMID: 31474491
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Abstract

Impact and predictors of positive response to desensitization in pediatric heart transplant candidates.

Edwards JJ, Seliktar N, White R, Heron SD, ... Sesok-Pizzini D, O\'Connor MJ
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 January 1, 2013 and June 30, 2018 were retrospectively evaluated. Sensitization was defined as the calculated panel reactive antibody (cPRA) ≥ 10% with ≥ 1 a strong positive antibody. The desensitization response was defined as a ≥ 25% reduction in the mean fluorescence intensity (MFI) for ≥ 90% of the strong positive antibodies on follow-up panel reactive antibody (PRA) testing before waitlist removal, HT, or death (data available for 13 patients).
Results
The HT candidates were categorized as sensitized receiving desensitization therapy (ST, n = 14), sensitized not receiving therapy (SNT, n = 18), or non-sensitized (n = 55). A desensitization response was observed in 8 (62%) of the ST upon repeat PRA testing, with the ST responders receiving more doses of intravenous immunoglobulin (IVIG) (8 vs 2, p < 0.05). The anti-HLA class I antibodies were particularly resistant for non-responders (p = 1.9 × 10). The combination of homograft and ventricular assist device was more sensitizing than either alone (p = 3.1 × 10). However, these sensitization risk factors did not impact the desensitization response. The ST was associated with a higher likelihood of remaining listed and a longer waitlist time without substantially impacting the 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. The anti-HLA class likely impacts the ST response, whereas traditional sensitization risk factors had no impact on the response.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Oct 2019; 38:1206-1213
Edwards JJ, Seliktar N, White R, Heron SD, ... Sesok-Pizzini D, O'Connor MJ
J Heart Lung Transplant: 30 Oct 2019; 38:1206-1213 | PMID: 31672220
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Abstract

Impact of combined heart and lung transplantation on bronchiolitis obliterans syndrome, cardiac allograft vasculopathy, and long-term survival.

Kitai T, Okamoto T, Miyakoshi C, Niikawa H, ... Xanthopoulos A, McCurry KR
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 and 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 database were retrospectively reviewed to identify transplant-naive patients who had undergone heart and/or lung transplantation between 1987 and 2016. The comparisons were conducted for isolated vs combined organ transplant. The outcomes included all-cause mortality, as well as the incidence of BOS and CAV Results: Of the 98,310 patients reviewed, 63,976, 1,189, and 33,145 had received isolated heart transplantation (iHTx) (65%), HLTx (1%), and isolated lung transplantation (iLTx) (34%), respectively. In the early post-operative period, the 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 incidence of BOS and CAV was 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.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Oct 2019; 38:1170-1177
Kitai T, Okamoto T, Miyakoshi C, Niikawa H, ... Xanthopoulos A, McCurry KR
J Heart Lung Transplant: 30 Oct 2019; 38:1170-1177 | PMID: 31672218
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Abstract

Long-term outcome of cardiac allograft vasculopathy: Importance of the International Society for Heart and Lung Transplantation angiographic grading scale.

Van Keer JM, Van Aelst LNL, Rega F, Droogne W, ... Naesens M, Van Cleemput J
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 sex (HR 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 pre-transplant 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 anti-metabolite 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 with patients without CAV, the HR 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 immunologic and non-immunologic factors. Higher ISHLT CAV grades are independently associated with worse graft survival.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Oct 2019; 38:1189-1196
Van Keer JM, Van Aelst LNL, Rega F, Droogne W, ... Naesens M, Van Cleemput J
J Heart Lung Transplant: 30 Oct 2019; 38:1189-1196 | PMID: 31543298
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Abstract

Structured review of post-cardiotomy extracorporeal membrane oxygenation: part 1-Adult patients.

Lorusso R, Raffa GM, Alenizy K, Sluijpers N, ... Boeken U, Whitman GJR

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.

Copyright © 2019 International Society for Heart and Lung Transplantation. All rights reserved.

J Heart Lung Transplant: 30 Oct 2019; 38:1125-1143
Lorusso R, Raffa GM, Alenizy K, Sluijpers N, ... Boeken U, Whitman GJR
J Heart Lung Transplant: 30 Oct 2019; 38:1125-1143 | PMID: 31522913
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Abstract

An aging population of patients with cystic fibrosis undergoes lung transplantation: An analysis of the ISHLT Thoracic Transplant Registry.

Benden C, Goldfarb SB, Stehlik J
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.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Oct 2019; 38:1162-1169
Benden C, Goldfarb SB, Stehlik J
J Heart Lung Transplant: 30 Oct 2019; 38:1162-1169 | PMID: 31353276
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Abstract

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.

Hansmann G, Koestenberger M, Alastalo TP, Apitz C, ... Weber SC, Zartner P

The European Pediatric Pulmonary Vascular Disease Network 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, PH associated with congenital heart disease (CHD), persistent PH of the newborn, and related cardiac dysfunction. The executive writing group members conducted searches of the PubMed/MEDLINE bibliographic database (1990-2018) and 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 that include pediatric data were searched using the term \"pulmonary hypertension\" and other keywords. Class of recommendation (COR) and level of evidence (LOE) were assigned based on European Society of Cardiology/American Heart Association definitions and on pediatric data only, or on adult studies that included >10% children or studies that enrolled adults with CHD. New definitions by the World Symposium on Pulmonary Hypertension 2018 were included. We generated 10 tables with graded recommendations (COR/LOE). The topics include diagnosis/monitoring, genetics/biomarkers, cardiac catheterization, echocardiography, cardiac magnetic resonance/chest computed tomography, associated forms of PH, intensive care unit/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.

Copyright © 2019. Published by Elsevier Inc.

J Heart Lung Transplant: 30 Aug 2019; 38:879-901
Hansmann G, Koestenberger M, Alastalo TP, Apitz C, ... Weber SC, Zartner P
J Heart Lung Transplant: 30 Aug 2019; 38:879-901 | PMID: 31495407
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Abstract

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).

Lamour JM, Mason KL, Hsu DT, Feingold B, ... Webber SA,
Background
Immunosuppression strategies have changed over time in pediatric heart transplantation. Thus, comorbidity profiles may have evolved. Clinical Trials in Organ Transplantation in Children-04 is a multicenter, prospective, cohort study assessing the impact of pre-transplant sensitization on outcomes after pediatric heart transplantation. This sub-study reports 1-year outcomes among recipients without pre-transplant donor-specific antibodies (DSAs).
Methods
We recruited consecutive candidates (<21 years) at 8 centers. Sensitization status was determined by a core laboratory. Immunosuppression was standardized as follows: Thymoglobulin induction with tacrolimus and/or 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 DSAs (n = 78). Median age was 6 years, 48.4% were male, and 38.2% had congenital heart disease. Patient survival was 94.5% (95% confidence interval, 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-DSAs pre-transplant. Freedom from infection requiring hospitalization/intravenous anti-microbials 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
Pediatric heart transplantation recipients without DSAs at transplant and managed with a steroid avoidance regimen have excellent short-term survival and a low risk of first-year diabetes mellitus and PTLD. Rehospitalization remains common. These contemporary observations allow for improved caregiver and/or patient counseling and provide the necessary outcomes data to help design future randomized controlled trials.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Aug 2019; 38:972-981
Lamour JM, Mason KL, Hsu DT, Feingold B, ... Webber SA,
J Heart Lung Transplant: 30 Aug 2019; 38:972-981 | PMID: 31324444
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Abstract

Clinical outcomes and survival following lung transplantation in patients with lymphangioleiomyomatosis.

Khawar MU, Yazdani D, Zhu Z, Jandarov R, Dilling DF, Gupta N
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
One hundred and thirty-eight 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 the LT waitlist was 257 (IQR: 85-616) days. The 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 than in 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 the 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 than in other lung diseases.

Published by Elsevier Inc.

J Heart Lung Transplant: 30 Aug 2019; 38:949-955
Khawar MU, Yazdani D, Zhu Z, Jandarov R, Dilling DF, Gupta N
J Heart Lung Transplant: 30 Aug 2019; 38:949-955 | PMID: 31303421
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Impact:
Abstract

Single lung transplantation in patients with severe secondary pulmonary hypertension.

Nasir BS, Mulvihill MS, Barac YD, Bishawi M, ... Daneshmand MA, Hartwig MG
Background
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 Organ Procurement and Transplantation Network/United Network for Organ Sharing Standard Transplant Analysis and Research registry. Adult recipients that underwent isolated lung transplantation between May 2005 and June 2015 for end-stage lung disease because of obstructive or restrictive etiologies were identified. Patients were stratified by mean pulmonary artery pressure ([mPAP] ≥ or < 40 mm Hg) 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 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% confidence interval 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 adjusted hazard ratio for mortality of 1.31 (1.08-1.59, p = 0.07). In BOLT, mPAP was not associated with increased hazard (adjusted hazard ratio 1.04, p = 0.48).
Conclusions
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 OS, and may be superior to SOLT in patients with mPAP over 40 mm Hg.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Aug 2019; 38:939-948
Nasir BS, Mulvihill MS, Barac YD, Bishawi M, ... Daneshmand MA, Hartwig MG
J Heart Lung Transplant: 30 Aug 2019; 38:939-948 | PMID: 31495410
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Impact:
Abstract

Controlled donation after circulatory death (DCD) donors: A focus on the utilization of pediatric donors and outcomes after lung transplantation.

Snell G, Levvey B, Paraskeva M, Whitford H, ... McGiffin D, Westall G
Background
Access to timely suitably size-matched quality organs remains a challenge for pediatric (pLTx) and adult (aLTx) lung transplantation. The outcomes of donation after circulatory death (DCD) donor lungs from pediatric or adult donors are rarely reported.
Methods
This report describes the controlled DCD and pLTx activity (≤ age 18 years) and outcomes since 2006 when DCD LTx started at our center at the Alfred Hospital.
Results
Forty pLTx have been performed since 2006, 9 utilizing DCD and 31 donation after brain death (DBD) donors. A total of 22 pLTX have been conducted since 2012 (when DCD pLTx started); 9 DCD LTx (median age 15 years), including 4 pediatric DCD donors (mean age 8 years) and 5 adult (including 2 cutdown bilobar) DCD LTx donors (mean age 43 years). The other 13 pLTx utilized DBD donors - 8 pediatric (mean age 9 years) and 5 adult (including 2 cutdown bilobar) DBD LTx donors (mean age 44 years). One hundred percent survived 1 year, and 7 of 9 DCD pLTx (78%) are alive (median of 1,316 days), with one Chronic Lung Allograft Dysfunction (CLAD) death at 531 days and one renal failure death at 1,813 days. Three waiting list pediatric deaths occurred at 166 and 320 days. Since 2006, 77 pediatric donors have been used for LTx. Fifteen of these were DCD donors (median age 16 years), 11 of 15 have been used for aLTx (73%). Ten of 11 aLTx are alive at a median 1,992 days (91%) with 1 death at Day 2,444 from CLAD.
Conclusions
Controlled DCD provide a significant and quality donor lung pool to increase LTx opportunities for pediatric patients (and adults) with terminal lung disease.

Copyright © 2019 International Society for Heart and Lung Transplantation. All rights reserved.

J Heart Lung Transplant: 29 Sep 2019; 38:1089-1096
Snell G, Levvey B, Paraskeva M, Whitford H, ... McGiffin D, Westall G
J Heart Lung Transplant: 29 Sep 2019; 38:1089-1096 | PMID: 31301968
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Impact:
Abstract

Outcomes in patients undergoing cardiac retransplantation: A propensity matched cohort analysis of the UNOS Registry.

Miller RJH, Clarke BA, Howlett JG, Khush KK, Teuteberg JJ, Haddad F
Background
Cardiac retransplantation accounts for approximately 3% of cardiac transplantation and is considered a risk factor for increased mortality. However, factors inherent to retransplantation including previous sternotomy, sensitization, and renal dysfunction may account for the increased mortality. We assessed whether retransplantation was associated with all-cause mortality after adjusting for such patient risk factors.
Methods
We conducted a retrospective cohort study of adult and pediatric patients enrolled in the United Network for Organ Sharing database. We identified patients undergoing cardiac retransplantation based on transplant listing diagnosis and history of previous transplant. We used propensity-score matching to identify a matched cohort undergoing initial heart transplantation.
Results
In total, 62,112 heart transplant recipients were identified, with a mean age 46.6 ± 19.1 years. Of these, 2,202 (3.4%) underwent late cardiac retransplantation (>1 year after initial transplant and not for acute rejection). Compared with a matched group of patients undergoing initial heart transplantation, patients undergoing late retransplantation had comparable rates of all-cause mortality at 1 year (13.6% vs 13.8%, p = 0.733). In addition, overall mortality was not significantly different after matching (unadjusted hazard ratio [HR] 1.08, p = 0.084). In contrast, patients undergoing retransplantation within 1 year of initial transplant or for acute rejection remained at increased risk of mortality post-transplant after similar matching (unadjusted HR 1.79, p < 0.001).
Conclusions
After matching for comorbidities, late retransplantation in the adult population was not associated with an increase in all-cause mortality. Our findings highlight the importance of assessing indication acuity and comorbid conditions when considering retransplant candidacy.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2019; 38:1067-1074
Miller RJH, Clarke BA, Howlett JG, Khush KK, Teuteberg JJ, Haddad F
J Heart Lung Transplant: 29 Sep 2019; 38:1067-1074 | PMID: 31378576
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Impact:
Abstract

Drug-resistant cytomegalovirus infection after lung transplantation: Incidence, characteristics, and clinical outcomes.

Heliövaara E, Husain S, Martinu T, Singer LG, ... Keshavjee S, Tikkanen J
Background
Cytomegalovirus (CMV) infection and development of CMV drug resistance can cause significant morbidity and mortality in patients with lung transplantation (LTX). We investigated the incidence of CMV drug resistance in adult patients with LTX 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 confirmed drug resistance. Case-matched controls (3 control patients for each resistant patient) were identified by matching for CMV serological status, development of CMV disease or significant viremia (≥3,000 IU/ml), and transplantation date.
Results
The incidence of drug-resistant CMV was 1.98% (11/556) in donor and/or recipient CMV-positive patients and 4.7% (7/150) in donor-positive/recipient-negative patients. Altogether, 27 patients were tested for drug resistance, and 11 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 (324,000 vs. 117,000 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 with 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.

Copyright © 2019 International Society for Heart and Lung Transplantation. All rights reserved.

J Heart Lung Transplant: 09 Sep 2019; epub ahead of print
Heliövaara E, Husain S, Martinu T, Singer LG, ... Keshavjee S, Tikkanen J
J Heart Lung Transplant: 09 Sep 2019; epub ahead of print | PMID: 31570289
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Impact:
Abstract

First report of a successful pediatric heart transplantation from donation after circulatory death with distant procurement using normothermic regional perfusion and cold storage.

Tchana-Sato V, Ledoux D, Vandendriessche K, Van Cleemput J, ... Defraigne JO, Rega F

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 interhospital distances for DCD heart transportation and stimulate more centers across the world to embrace DCD HT.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2019; 38:1112-1115
Tchana-Sato V, Ledoux D, Vandendriessche K, Van Cleemput J, ... Defraigne JO, Rega F
J Heart Lung Transplant: 29 Sep 2019; 38:1112-1115 | PMID: 31548033
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Impact:
Abstract

Mechanical ventilation and extracorporeal membrane oxygenation as a bridge to lung transplantation: Closing the gap.

Hayanga JWA, Hayanga HK, Holmes SD, Ren Y, ... Badhwar V, Abbas G
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 the period 2005 to 2017. Recipients were categorized into 3 groups based on pre-transplant bridging. Multivariable regression analyses examined the 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 with no bridge, patients with MV and ECMO had greater odds for peri-operative 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), post-operative ECMO (p = 0.006), and greater odds for reintubation (p = 0.005) compared with ECMO. Patients in both MV (hazard raio [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.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2019; 38:1104-1111
Hayanga JWA, Hayanga HK, Holmes SD, Ren Y, ... Badhwar V, Abbas G
J Heart Lung Transplant: 29 Sep 2019; 38:1104-1111 | PMID: 31443999
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Impact:
Abstract

The carnitine-butyrobetaine-TMAO pathway after cardiac transplant: Impact on cardiac allograft vasculopathy and acute rejection.

Trøseid M, Mayerhofer CCK, Broch K, Arora S, ... Aukrust P, Ueland T
Background
Alterations in the partly microbiota-dependent carnitine-γ-butyrobetaine (γBB)-trimethylamine N-oxide (TMAO) pathway have been linked to the progression of heart failure and atherosclerotic disease. We evaluated if circulating γBB, TMAO, and their common precursors carnitine and trimethyllysine (TML) were dysregulated after heart transplantation and associated with development of cardiac allograft vasculopathy (CAV) and acute rejection.
Methods
We measured these metabolites in plasma from heart transplant recipients with everolimus-based (n = 32) and standard cyclosporine-based immunosuppression (n = 30) at different time-points and accompanied by assessment of CAV by intravascular ultrasound.
Results
Baseline levels of carnitine, TMAO, and TML were elevated in heart transplant recipients compared with controls, and TML remained elevated throughout the observation period. The microbiota-dependent metabolite γBB increased steadily during 3 years of follow-up, with a similar decrease in its endogenous precursor TML. The increase in γBB and the change in TML were associated with a change in total atheroma volume from baseline to 3 years. Increases in γBB and carnitine levels from baseline to 1 year were associated with an increased frequency of acute rejection within the first year after heart transplant.
Conclusions
Our study reveals alterations of the carnitine-γBB-TMAO pathway after heart transplant, with increasing levels of γBB being associated with acute rejection and increase in total atheroma volume during 3 years of follow-up. Future studies should clarify whether interactions between dietary factors, immunosuppressive drugs, and the gut microbiota could influence acute rejection and CAV development to delineate mechanisms and potential novel treatment targets.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2019; 38:1097-1103
Trøseid M, Mayerhofer CCK, Broch K, Arora S, ... Aukrust P, Ueland T
J Heart Lung Transplant: 29 Sep 2019; 38:1097-1103 | PMID: 31301965
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Impact:
Abstract

Exercise cardiovascular magnetic resonance imaging allows differentiation of low-risk pulmonary arterial hypertension.

Göransson C, Vejlstrup N, Carlsen J
Background
Patients with pulmonary arterial hypertension (PAH) have a decreased ability to compensate for demands on increased cardiac output, such as during exercise. In this study we aimed to differentiate cardiac exercise responses in patients with PAH, stratified according to known measurements of disease severity.
Methods
Right and left ventricular end-diastolic volume and end-systolic volume, stroke volume (SV), and cardiac output were measured in 20 patients with PAH and a lower risk of mortality with 6-month intervals using cardiovascular magnetic resonance (CMR) imaging during rest and during ergometer exercise (totaling 44 scans). Exercise measurements were compared with resting cardiac conditions and clinical assessment using mixed model statistics.
Results
SV response during exercise was associated with disease severity. World Health Organization functional class (WHO FC) I and right ventricular end-diastolic volume (RVEDV) <221 ml were associated with increased SV during exercise (WHO FC I: 7% increase in SV; p < 0.001). In contrast, WHO FC II was associated with an 8% decrease in SV (p = 0.02), and SV response declined progressively with right ventricular dilation (7-ml decrease in SV per 100-ml increase in RVEDV; p < 0.001).
Conclusions
Assessment of right ventricular function with CMR during exercise stratifies patients currently perceived as having a low risk of mortality into different degrees of right ventricular inotropic reserve. Reduced SV during exercise is a plausible factor to increased risk of decompensation, possibly warranting targeted therapy intensification to restore right ventricular functional reserve.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 May 2019; 38:627-635
Göransson C, Vejlstrup N, Carlsen J
J Heart Lung Transplant: 30 May 2019; 38:627-635 | PMID: 30733157
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Impact:
Abstract

Heart or lung transplant outcomes in HIV-infected recipients.

Koval CE, Farr M, Krisl J, Haidar G, ... Grossi P, Huprikar S
Background
Limited published data exist on outcomes related to heart and/or lung transplantation in human immunodeficiency virus (HIV)-infected individuals.
Methods
We conducted a multicenter retrospective study of heart and lung transplantation in HIV-infected patients and describe key transplant- and HIV-related outcomes.
Results
We identified 29 HIV-infected thoracic transplant recipients (21 heart, 7 lung, and 1 heart and/or lung) across 14 transplant centers from 2000 through 2016. Compared with an International Society for Heart and Lung Transplantation registry cohort, we demonstrated similar 1-, 3-, and 5-year patient and allograft survivals for each organ type with a median follow up of 1,064 (range, 184-3,745) days for heart and 1,540 (range, 116-3,206) days for lung recipients. At 1 year, significant rejection rates were high (62%) for heart transplant recipients (HTRs). Risk factors for rejection were inconclusive, likely because of small numbers, but may be related to cautious early immunosuppression and infrequent use of induction therapy. Pulmonary bacterial infections were high (86%) for lung transplant recipients (LTRs). Median CD4 counts changed from baseline to 1 year from 399 to 411 cells/µl for HTRs and 638 to 280 cells/µl for LTRs. Acquired immunodeficiency syndrome-related events, including infections and malignancies, were rare. Rates of severe renal dysfunction suggest a need to modify nephrotoxic anti-retrovirals and/or immunosuppressants.
Conclusions
HIV-infected HTRs and LTRs have similar survival rates to their HIV-uninfected counterparts. Although optimal immunosuppression is not defined, it should be at least as aggressive as that for HIV-uninfected recipients. Such data may help pave the way for the use of hearts and lungs from HIV-infected donors in HIV-infected recipients through HIV Organ Policy Equity Act protocols.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 24 Sep 2019; epub ahead of print
Koval CE, Farr M, Krisl J, Haidar G, ... Grossi P, Huprikar S
J Heart Lung Transplant: 24 Sep 2019; epub ahead of print | PMID: 31636044
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Impact:
Abstract

Log files analysis and evaluation of circadian patterns for the early diagnosis of pump thrombosis with a centrifugal continuous-flow left ventricular assist device.

Consolo F, Esposti F, Gustar A, De Bonis M, Pappalardo F
Background
No clinical standardized methods exist to identify the early stage of the development of pump thrombosis in the setting of HVAD (Medtronic Inc., USA) implantation. We aimed at developing a clinically relevant tool to evaluate HVAD operation during long-term support and at identifying a new reliable marker for the early diagnosis of pump thrombosis reflecting altered patient-pump physiological interplay.
Methods
We developed a novel algorithm based on time-frequency analysis of the HVAD log files allowing the detection of the intrinsic circadian rhythmicity of the pump power consumption. With this tool, we retrospectively evaluated (1) post-operative restoration of circadian rhythm (n = 14 patients), (2) long-term stability of circadian rhythmicity in patients with no reported adverse events (n = 12), and (3) alteration of circadian fluctuations in patients who suffered from pump thrombosis (n = 19).
Results
We demonstrate (1) progressive development of circadian rhythm following post-operative recovery (93% of the patients, 23 ± 15 days after implantation), (2) long-term stability of circadian rhythmicity in patients with no thrombotic complications (92% of the patients; 962 (445-1447) days of support), and (3) severe instability and loss of circadian fluctuations before the thrombotic event (89% of the patients, 12 ± 6 days ahead of the clinical manifestation of overt pump thrombosis). Furthermore, we provide the first clinical evidence of recovery of circadian rhythmicity following non-surgical resolution of pump thrombosis.
Conclusions
Time-frequency analysis of the HVAD log files provides a new tool for the early diagnosis of pump thrombosis. Loss of circadian rhythmicity might trigger medical evaluation, improving the results of medical management of pump thrombosis, and decreasing the need for pump exchange.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2019; 38:1077-1086
Consolo F, Esposti F, Gustar A, De Bonis M, Pappalardo F
J Heart Lung Transplant: 29 Sep 2019; 38:1077-1086 | PMID: 31103382
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Impact:
Abstract

The pleural mesothelium and transforming growth factor-β pathways in restrictive allograft syndrome: A pre-clinical investigation.

Sacreas A, von der Thüsen JH, van den Bosch TPP, Weynand B, ... Vos R, Verleden SE
Background
Chronic lung allograft dysfunction (CLAD) hampers long-term survival after lung transplantation. Common fibrosis-related mechanisms in idiopathic pulmonary fibrosis and CLAD instigated the consideration of investigating the differential regulation of pleural mesothelium and transforming growth factor-β (TGF-β) in restrictive allograft syndrome (RAS).
Methods
TGF-β was assessed in bronchoalveolar lavage (BAL) fluid using enzyme-linked immunoassay and via immune staining of explant biopsies. To assess the role of the pleura, explanted bronchiolitis obliterans syndrome (BOS) and RAS lungs were compared using computed tomography scans, calretinin stainings, Western blot, and quantititative real-time PCR. Last, a pleural mesothelial cell line was used to assess mesothelial-to-mesenchymal transition and its inhibition.
Results
TGF-β was increased in BAL of RAS patients (p = 0.035), and was present in the (sub)pleural area of biopsies. Explanted RAS lungs demonstrated an increased volume fraction of pleura (p = 0.0004), a higher proportion of calretinin-positive stainings (p = 0.0032), and decreased E-cadherin (p = 0.019) and increased α-smooth muscle actin (p = 0.0089) mRNA expression and protein levels in isolated pleural tissue. Moreover, TGF-β stimulation of pleural mesothelial cells led to a phenotypical switch to mesenchymal cells, accompanied with an increased migratory capacity. Interleukin-1α was able to accentuate TGF-β‒induced mesothelial-to-mesenchymal transition. None of the tested drugs could inhibit mesothelial-to-mesenchymal transition at the used concentrations.
Conclusions
Our results support an interplay between TGF-β and the pleural mesothelium in the pathophysiology of RAS.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Apr 2019; 38:570-579
Sacreas A, von der Thüsen JH, van den Bosch TPP, Weynand B, ... Vos R, Verleden SE
J Heart Lung Transplant: 29 Apr 2019; 38:570-579 | PMID: 30819647
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Impact:
Abstract

Molecular assessment of rejection and injury in lung transplant biopsies.

Halloran KM, Parkes MD, Chang J, Timofte IL, ... Klepetko W, Halloran PF
Background
Improved understanding of lung transplant disease states is essential because failure rates are high, often due to chronic lung allograft dysfunction. However, histologic assessment of lung transplant transbronchial biopsies (TBBs) is difficult and often uninterpretable even with 10 pieces.
Methods
We prospectively studied whether microarray assessment of single TBB pieces could identify disease states and reduce the amount of tissue required for diagnosis. By following strategies successful for heart transplants, we used expression of rejection-associated transcripts (annotated in kidney transplant biopsies) in unsupervised machine learning to identify disease states.
Results
All 242 single-piece TBBs produced reliable transcript measurements. Paired TBB pieces available from 12 patients showed significant similarity but also showed some sampling variance. Alveolar content, as estimated by surfactant transcript expression, was a source of sampling variance. To offset sampling variation, for analysis, we selected 152 single-piece TBBs with high surfactant transcripts. Unsupervised archetypal analysis identified 4 idealized phenotypes (archetypes) and scored biopsies for their similarity to each: normal; T-cell‒mediated rejection (TCMR; T-cell transcripts); antibody-mediated rejection (ABMR)-like (endothelial transcripts); and injury (macrophage transcripts). Molecular TCMR correlated with histologic TCMR. The relationship of molecular scores to histologic ABMR could not be assessed because of the paucity of ABMR in this population.
Conclusions
Molecular assessment of single-piece TBBs can be used to classify lung transplant biopsies and correlated with rejection histology. Two or 3 pieces for each TBB will probably be needed to offset sampling variance.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Apr 2019; 38:504-513
Halloran KM, Parkes MD, Chang J, Timofte IL, ... Klepetko W, Halloran PF
J Heart Lung Transplant: 29 Apr 2019; 38:504-513 | PMID: 30773443
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Impact:
Abstract

Outcomes in cystic fibrosis lung transplant recipients infected with organisms labeled as pan-resistant: An ISHLT Registry‒based analysis.

Lay C, Law N, Holm AM, Benden C, Aslam S
Background
The presence of pan-resistant organisms in patients with cystic fibrosis (CF) potentially impacts mortality after lung transplant (LT). In this study we aimed to study LT mortality in CF patients with and without pan-resistant infection.
Methods
The International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry was used to identify adults with CF, first-time, bilateral LT from 1991 to 2015. Extracted data included demographics, clinical characteristics, post-transplant outcomes, and mortality (infection-related, overall). Multivariate binary logistic regression models were created with 90-day and 1-year mortality as primary outcomes.
Results
Among 3,256 LT recipients with CF, 697 were labeled as having pan-resistant infection, the others were included as controls (n = 2,649). Pre-transplant, those labeled as pan-resistant were more likely to require ventilator support, have an infection requiring intravenous antibiotics, and have had ≥2 pneumonia episodes within 1 year. Ninety-day and 1-year mortality was similar between groups, but infection-related mortality at 90days (3.3% vs 1.88%, p = 0.01) and 1 year (6.6% vs 4.6%, p < 0.001) was higher in those labeled as pan-resistant. In multivariate analysis, presence of organisms labeled as pan-resistant was not associated with 90-day (odds ratio [OR] 1.5, 95% confidence interval [CI] 0.93 to 2.42, p = 0.09) or 1-year mortality (OR 1.32, 95% CI 0.95 to 1.83, p = 0.097).
Conclusions
CF patients with pre-transplant infection from organisms labeled as pan-resistant had similar 90-day and 1-year mortality as those without. Despite increased infection-related mortality in these patients, it was not predictive of mortality in multivariate analysis. The higher occurrence of post-transplant infections in these patients warrants diligent follow-up. A multicenter cohort study will be required to validate the findings of our study.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Apr 2019; 38:545-552
Lay C, Law N, Holm AM, Benden C, Aslam S
J Heart Lung Transplant: 29 Apr 2019; 38:545-552 | PMID: 30733155
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Impact:
Abstract

Implantation of a fully magnetically levitated left ventricular assist device using a sternal-sparing surgical technique.

Gosev I, Wood K, Ayers B, Barrus B, ... McNitt S, Prasad S
Background
Left ventricular assist devices (LVADs) have improved outcomes for selected patients with advanced heart failure, but alternative optimal surgical techniques remain to be defined. We aim to describe our initial experience in using a sternal-sparing (SS) technique for implantation of a magnetically levitated LVAD, the HeartMate 3 (HM3) pump.
Methods
This retrospective, single-center study included consecutive patients implanted with the HM3 LVAD between September 2015 and September 2018. Patients were compared based on surgical approach: SS or traditional sternotomy (TS). The primary outcome was overall survival at 6 months. Secondary outcomes included peri-operative complications, blood product utilization, and hospital readmissions.
Results
Of 105 patients implanted with the HM3 LVAD, 41 (39%) were implanted via SS and 64 (61%) via TS approach. There were no intraoperative conversions. The SS patients were younger; otherwise, all other characteristics were similar between cohorts. The SS cohort demonstrated a significantly lower incidence of severe right ventricular failure (7% vs 28%, p = 0.012), fewer blood-product transfusions (41% vs 86%, p < 0.001), and shorter index hospital length of stay (15.5 vs 21 days, p = 0.018). Six-month survival was 93% for the SS cohort.
Conclusions
In this single-center observational study, we have demonstrated that the SS approach may be a safe and effective surgical technique for implantation of the HM3 LVAD in well-selected patients. The potential benefits compared with TS require further inquiry.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 24 Sep 2019; epub ahead of print
Gosev I, Wood K, Ayers B, Barrus B, ... McNitt S, Prasad S
J Heart Lung Transplant: 24 Sep 2019; epub ahead of print | PMID: 31636043
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Impact:
Abstract

Patients with pulmonary arterial hypertension with and without cardiovascular risk factors: Results from the AMBITION trial.

McLaughlin VV, Vachiery JL, Oudiz RJ, Rosenkranz S, ... Hoeper MM,
Background
The purpose of this study was 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-naive patients with pulmonary arterial hypertension were randomized to once-daily ambrisentan and tadalafil combination therapy, ambrisentan monotherapy, or tadalafil monotherapy. The primary end point was time from randomization to first adjudicated clinical failure event.
Results
Primary analysis set patients (n = 500), compared with ex-primary analysis set patients (n = 105), were younger (mean, 54.4 vs 62.1 years) with greater baseline 6-minute walk distance (median, 363.7 vs 330.5 meters) and fewer comorbidities (e.g., hypertension and diabetes). Treatment effects of initial combination therapy vs 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 compared with pooled monotherapy in primary analysis set patients (hazard ratio, 0.50; 95% confidence interval, 0.35-0.72), whereas the effect was less clear in ex-primary analysis set patients (hazard ratio, 0.70; 95% confidence interval, 0.35-1.37). Overall, primary analysis set patients had fewer clinical failure events (25% vs 33%), higher rates of satisfactory clinical response (34% vs 24%), and lower rates of permanent study drug withdrawal due to adverse events (16% vs 31%) than ex-primary analysis set patients.
Conclusions
Efficacy of initial combination therapy vs 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 vs monotherapy was attenuated. Tolerability was better in primary analysis set than ex-primary analysis set patients.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 16 Sep 2019; epub ahead of print
McLaughlin VV, Vachiery JL, Oudiz RJ, Rosenkranz S, ... Hoeper MM,
J Heart Lung Transplant: 16 Sep 2019; epub ahead of print | PMID: 31648845
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Abstract

Utilization rates and clinical outcomes of hepatitis C positive donor hearts in the contemporary era.

Madan S, Patel SR, Rahgozar K, Saeed O, ... Goldstein DJ, Jorde UP
Background
Hepatitis C virus (HCV) donors should be categorized as HCV-viremic (antibody [Ab] negative or positive/Nucleic Acid testing [NAT] positive) or HCV Abnonviremic (Ab/NAT). Whereas recipients of hearts from HCV-viremic donors will develop viremia but can 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 outcomes of HCV-naive (Ab/NAT), HCV-viremic, and HCV Ab nonviremic donor hearts.
Methods
A total of 26,572 adult donors (≥18 years) with information on HCV Ab and NAT status were identified in the United Network for Organ Sharing registry between August 2015 and June 2018 for utilization rates. Adult heart transplant recipients of these donors were compared for primary graft failure (PGF) at 90 days and 1-year recipient survival.
Results
A total of 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%-23.4%) and HCV-viremic (0.7%-25.4%) donor hearts increased significantly approaching HCV-naive rates (29.04%). There was no significant difference in rates of PGF and 1-year survival between recipients in the 3 donor HCV groups. We also used (1:3) propensity score matching and found similar 1-year survival in different donor HCV groups (HCV-naive vs HCV Ab nonviremic, p = 0.59, and HCV-naive 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 with recipients of HCV-naive donor hearts. Although only HCV-viremic organs require DAAs and 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-naive rates.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Aug 2019; 38:907-917
Madan S, Patel SR, Rahgozar K, Saeed O, ... Goldstein DJ, Jorde UP
J Heart Lung Transplant: 30 Aug 2019; 38:907-917 | PMID: 31495408
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Abstract

Implications of declining donor offers with increased risk of disease transmission on waiting list survival in lung transplantation.

Cox ML, Mulvihill MS, Choi AY, Bishawi M, ... Wolfe CR, Hartwig M
Background
Donors with characteristics that may increase the likelihood of disease transmission with transplantation are noted as increased risk via Public Health Service criteria. This study aimed to establish the implications of declining an increased-risk donor (IRD) organ offer in lung transplantation.
Methods
Adult candidates waitlisted for isolated lung transplantation in the United States using the Organ Procurement and Transplantation Network /United Network of Organ Sharing registry from 2007 to 2017 were identified. Individual match run files identified candidate recipients who matched to an IRD offer. Competing-risks analysis ascertained the likelihood of survival to transplantation. A stratified Cox model and restricted mean survival times estimated the survival benefit associated with the acceptance of an IRD organ.
Results
A total of 6,963 candidates met inclusion criteria, and 1,473 (21.2%) accepted an IRD offer. Candidates who accepted an IRD offer were older, more likely to be male, and had a higher lung allocation score at the time of listing (all p < 0.05). At 1 year after an IRD offer decline, 70.5% of candidates underwent a lung transplant, 13.8% died or decompensated, and 14.9% were still awaiting transplant. Compared with those who declined, candidates who accepted the IRD offer had significantly improved cumulative mortality at 1 year (14.1% vs 23.9%, p < 0.001) and 5 years (48.4% vs 53.8%, p < 0.001).
Conclusions
IRD organ declination is associated with a decreased rate of lung transplantation and worse survival. Overall post-transplant survival rates for those who survive to transplantation are equivalent.

Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 27 Feb 2019; 38:295-305
Cox ML, Mulvihill MS, Choi AY, Bishawi M, ... Wolfe CR, Hartwig M
J Heart Lung Transplant: 27 Feb 2019; 38:295-305 | PMID: 30773195
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Abstract

Usefulness of gene expression profiling of bronchoalveolar lavage cells in acute lung allograft rejection.

Weigt SS, Wang X, Palchevskiy V, Li X, ... Palmer S, Belperio JA
Background
Chronic lung allograft dysfunction (CLAD) is the main limitation to long-term survival after lung transplantation. Because effective therapies are lacking, early identification and mitigation of risk factors is a pragmatic approach to improve outcomes. Acute cellular rejection (ACR) is the most pervasive risk factor for CLAD, but diagnosis requires transbronchial biopsy, which carries risks. We hypothesized that gene expression in the bronchoalveolar lavage (BAL) cell pellet (CP) could replace biopsy and inform on mechanisms of CLAD.
Methods
We performed RNA sequencing on BAL CPs from 219 lung transplant recipients with A-grade ACR (n = 61), lymphocytic bronchiolitis (n = 58), infection (n = 41), or no rejection/infection (n = 59). Differential gene expression was based on absolute fold difference >2.0 and Benjamini-adjusted p-value ≤0.05. We used the Database for Annotation, Visualization and Integrated Discovery Bioinformatics Resource for pathway analyses. For classifier modeling, samples were randomly split into training (n = 154) and testing sets (n = 65). A logistic regression model using recursive feature elimination and 5-fold cross-validation was trained to optimize area under the curve (AUC).
Results
Differential gene expression identified 72 genes. Enriched pathways included T-cell receptor signaling, natural killer cell-mediated cytotoxicity, and cytokine-cytokine receptor interaction. A 4-gene model (AUC = 0.72) and classification threshold defined in the training set exhibited fair performance in the testing set; accuracy was 76%, specificity 82%, and sensitivity 60%. In addition, classification as ACR was associated with worse CLAD-free survival (hazard ratio = 2.42; 95% confidence interval = 1.29-4.53).
Conclusions
BAL CP gene expression during ACR is enriched for immune response pathways and shows promise as a diagnostic tool for ACR, especially ACR that is a precursor of CLAD.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Jul 2019; 38:845-855
Weigt SS, Wang X, Palchevskiy V, Li X, ... Palmer S, Belperio JA
J Heart Lung Transplant: 30 Jul 2019; 38:845-855 | PMID: 31122726
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Abstract

Extended criteria donor lungs do not impact recipient outcomes in pediatric transplantation.

Sommer W, Ius F, Müller C, Bobylev D, ... Schwerk N, Warnecke G
Background
Pediatric lung transplantation remains the only curative treatment option for some end-stage lung diseases in childhood. Recipient numbers outnumber potential donor organs, and therefore a broader group of donor organs must be considered for pediatric lung transplantation. Herein we describe the outcome of utilizing extended criteria donor organs in pediatric lung transplantation.
Methods
A retrospective analysis was performed on all pediatric lung transplantations performed at the Hannover Medical School between April 2010 and December 2016. Donors were assigned to a group fulfilling standard donor criteria (International Society for Heart and Lung Transplantation [ISHLT] 2003) or not. Recipients\' early- and mid-term morbidity and mortality were recorded.
Results
A total of 57 pediatric lung transplantations were performed: 27 donors fulfilled standard donor criteria (standard criteria donor [SCD] group) and 30 donors were extended criteria donors not fulfilling standard donor criteria (extended criteria donor [ECD] group). Pre-operative recipient characteristics, including age (median [IQR]: 14 [10‒15] vs 13 [10.8‒15] years, p = 0.71), underlying disease, admission to intensive care unit (37.0% vs 50%, p = 0.42), mechanical ventilation (14.8% vs 10.0%, p = 0.70), and extracorporeal membrane oxygenation (ECMO) support (11.1% vs 23.3%, p = 0.30) of both groups were similar. In the ECD group, more atypical volume reductions of the allograft were performed (0% vs 16.7%, p = 0.05), yet incidence of post-operative ECMO support was similar for the 2 groups. ECD recipients spent significantly less time on mechanical ventilation (median [IQR]: 2 [1‒2] vs 1 [1‒2] days, p = 0.04)] after surgery, but total intensive care unit stay and total hospital stay were similar between groups. Pulmonaryfunction testing results at discharge from initial hospital stay, after 1 year, and at last assessment were also similar. Freedom from chronic lung allograft dysfunction at 1 and 5years after transplantation showed no significant differences between groups. Survival rates up to 5years (67.9% vs 90.5%, p = 0.35) after transplantation were comparable between groups, yet, counterintuitively, long-term survival in the ECD group showed superior trends compared with the SCD group.
Conclusions
ECD lungs can be used safely for pediatric lung transplantation without compromising short- and mid-term results.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Apr 2019; 38:560-569
Sommer W, Ius F, Müller C, Bobylev D, ... Schwerk N, Warnecke G
J Heart Lung Transplant: 29 Apr 2019; 38:560-569 | PMID: 30852096
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Abstract

Consequences of donor-derived passengers (pathogens, cells, biological molecules and proteins) on clinical outcomes.

Snell G, Hiho S, Levvey B, Sullivan L, Westall G

It is recognized that 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, focusing 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.

Copyright © 2019 International Society for Heart and Lung Transplantation. All rights reserved.

J Heart Lung Transplant: 30 Aug 2019; 38:902-906
Snell G, Hiho S, Levvey B, Sullivan L, Westall G
J Heart Lung Transplant: 30 Aug 2019; 38:902-906 | PMID: 31307786
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Abstract

Lack of association of Aspergillus colonization with the development of bronchiolitis obliterans syndrome in lung transplant recipients: An international cohort study.

Law N, Hamandi B, Fegbeutel C, Silveira FP, ... Singer LG, Husain S
Background
Bronchiolitis obliterans syndrome (BOS) is a major limitation in the long-term survival of lung transplant recipients (LTRs). However, the risk factors in the development of BOS remain undetermined. We conducted an international cohort study of LTRs to assess whether Aspergillus colonization with large or small conidia is a risk factor for the development of BOS.
Methods
Consecutive LTRs from January 2005 to December 2008 were evaluated. Rates of BOS and associated risk factors were recorded at 4 years. International Society of Heart and Lung Transplantation criteria were used to define fungal and other infections. A Cox proportional-hazards-model was constructed to assess the association between Aspergillus colonization and the development of BOS controlling for confounders.
Results
A total of 747 LTRs were included. The cumulative incidence of BOS at 4 years after transplant was 33% (250 of 747). Additionally, 22% of LTRs experienced Aspergillus colonization after transplantation. Aspergillus colonization with either large (hazard ratio [HR] = 0.6, 95% confidence interval [CI] = 0.3-1.2, p = 0.12) or small conidia (HR = 0.9, 95% CI = 0.6-1.4, p = 0.74) was not associated with the development of BOS. Factors associated with increased risk of development of BOS were the male gender (HR = 1.4, 95% CI = 1.1-1.8, p = 0.02) and episodes of acute rejection (1-2 episodes, HR = 1.5, 95% CI = 1.1-2.1, p = 0.014; 3-4 episodes, HR = 1.6, 95% CI = 1.0-2.6, p = 0.036; >4 episodes, HR = 2.2, 95% CI = 1.1-4.3, p = 0.02), whereas tacrolimus use was associated with reduced risk of BOS (HR = 0.6, 95% CI = 0.5-0.9, p = 0.007).
Conclusions
We conclude from this large multicenter cohort of lung transplant patients, that Aspergillus colonization with large or small conidia did not show an association with the development of BOS.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Aug 2019; 38:963-971
Law N, Hamandi B, Fegbeutel C, Silveira FP, ... Singer LG, Husain S
J Heart Lung Transplant: 30 Aug 2019; 38:963-971 | PMID: 31300191
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Abstract

ICAM-1 promotes the abnormal endothelial cell phenotype in chronic thromboembolic pulmonary hypertension.

Arthur Ataam J, Mercier O, Lamrani L, Amsallem M, ... Fadel E, Eddahibi S
Background
Pulmonary endothelial cells play a key role in the pathogenesis of Chronic Thromboembolic Pulmonary Hypertension (CTEPH). Increased synthesis and/or the release of intercellular adhesion molecule-1 (ICAM-1) by pulmonary endothelial cells of patients with CTEPH has been recently reported, suggesting a potential role for ICAM-1 in CTEPH.
Methods
We studied pulmonary endarterectomy specimens from 172 patients with CTEPH and pulmonary artery specimens from 97 controls undergoing lobectomy for low-stage cancer without metastasis.
Results
ICAM-1 was overexpressed in vitro in isolated and cultured endothelial cells from endarterectomy specimens. Endothelial cell growth and apoptosis resistance were significantly higher in CTEPH specimens than in the controls (p < 0.001). Both abnormalities were abolished by pharmacological inhibition of ICAM-1 synthesis or activity. The overexpression of ICAM-1 contributed to the acquisition and maintenance of abnormal EC growth and apoptosis resistance via the phosphorylation of SRC, p38 and ERK1/2 and the overproduction of survivin. Regarding the ICAM-1 E469K polymorphism, the KE heterozygote genotype was significantly more frequent in CTEPH than in the controls, but it was not associated with disease severity among patients with CTEPH.
Conclusions
ICAM-1 contributes to maintaining the abnormal endothelial cell phenotype in CTEPH.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Aug 2019; 38:982-996
Arthur Ataam J, Mercier O, Lamrani L, Amsallem M, ... Fadel E, Eddahibi S
J Heart Lung Transplant: 30 Aug 2019; 38:982-996 | PMID: 31324443
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Impact:
Abstract

A comparison of low and standard anti-coagulation regimens in extracorporeal membrane oxygenation.

Raman J, Alimohamed M, Dobrilovic N, Lateef O, Aziz S
Background
Bleeding and need for blood products are major complications associated with extracorporeal membrane oxygenation (ECMO) use. This study evaluated bleeding complications with low and standard heparinization protocols in the maintenance of venoarterial (VA)-ECMO.
Methods
A retrospective comparison was performed of 2 methods of heparinization in a contemporaneous series of adult patients supported with VA-ECMO at Rush University Medical Center, between November 2011 and November 2016. CentriMag (Thoratec, Pleasanton, CA) pumps, Quadrox (Maquet, Wayne, NJ) oxygenators, and heparin-bonded circuitry were used in all patients. Group 1 was a control group of 50 patients who had ECMO support with an initiation dose of 5,000 U of heparin, followed by standard heparinization at a goal activated clotting time of 180 to 220 seconds. Group 2 comprised 52 adult patients supported with a \"low heparin protocol\" ECMO, receiving a standard heparin bolus of 5,000 U for cannulation but without subsequent, ongoing heparin administration. Acuity of illness was similar in both groups as assessed by the Mortality Probability Model (59% in Group 1 vs 62.9% in Group 2, p = 0.08). Data were submitted to the Extracorporeal Life Support Organization prospectively. Clots in the circuit, limb ischemia, oxygenator failure, and embolic complications were recorded.
Results
Weaning off ECMO was successful in 26 patients (50%) in Group 2 compared with 18 (36%) in Group 1 (p = 0.05). Hemorrhage from the cannulation site occurred in 11 (21%) in Group 2 vs 21 (42%) in Group 1 and from the surgical site in 11 (21%) in Group 2 vs 18 (36%) in Group 1. Severe bleeding complications were higher in the control group (Group 1, 32%) compared with Group 2 (11.5%; p = 0.012).
Conclusions
Maintenance with low heparin is safe in patients supported by VA-ECMO. This strategy may reduce risk of severe bleeding and associated complications.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Mar 2019; 38:433-439
Raman J, Alimohamed M, Dobrilovic N, Lateef O, Aziz S
J Heart Lung Transplant: 30 Mar 2019; 38:433-439 | PMID: 30744940
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Abstract

Epidemiology of infection in mechanical circulatory support: A global analysis from the ISHLT Mechanically Assisted Circulatory Support Registry.

Hannan MM, Xie R, Cowger J, Schueler S, ... Nakatani T, Kirklin JK
Background
Despite advances in device technology and treatment strategies, infection remains a major cause of adverse events (AEs) in mechanical circulatory support (MCS) patients. To characterize the epidemiology of MCS infection, we examined the type, location, and timing of infection in the International Society for Heart and Lung Transplantation Registry (ISHLT) for Mechanically Assisted Circulatory Support (IMACS) over 3 years, 2013 to 2015.
Methods
Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) definitions were used to categorize AE infections occurring in MCS patients within IMACS. The IMACS infection variables were mapped to ISHLT definitions for infection where feasible. Three categories of MCS infection were defined as ventricular assist device (VAD) specific, VAD related, and non-VAD.
Results
There were 10,171 patients enrolled from January 2013 through December 2015. Infection was the most common AE, with 3,788 patients (37%) experiencing ≥ 1 infection, and 6,758 AE infections reported overall. Non-VAD infection was the largest category, 4,501: 34.0% pneumonias, 30.6% non-VAD-related bloodstream infections (BSIs), 24.15% urinary tract infections (UTIs), and 10.2% gastrointestinal infections. VAD-specific infection was the second largest category, 1,756: 82.9% driveline, 12.8% pocket, and 4.3% pump/or cannula infections. VAD-related infection was the smallest category, 501: 47.5% BSIs, 47.5% mediastinitis, and 5.0% mediastinitis/pocket infections. All 3 categories were more frequently reported ≤ 3 months after implant.
Conclusions
Non-VAD infection, including pneumonia, BSI, UTI, and gastrointestinal infection, was the leading category of infection in MCS patients and the most frequently reported ≤ 3 months after implant. These results provide evidence to support resourcing and strengthening infection prevention strategy early after implantation in MCS.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Mar 2019; 38:364-373
Hannan MM, Xie R, Cowger J, Schueler S, ... Nakatani T, Kirklin JK
J Heart Lung Transplant: 30 Mar 2019; 38:364-373 | PMID: 30733158
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Impact:
Abstract

Registry Evaluation of Vital Information for VADs in Ambulatory Life (REVIVAL): Rationale, design, baseline characteristics, and inclusion criteria performance.

Aaronson KD, Stewart GC, Pagani FD, Stevenson LW, ... Mann DL,
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 ventricular assist device (VAD) centers enrolled 400 subjects in the Registry Evaluation of Vital Information for VADs in Ambulatory Life (REVIVAL), a prospective, observational study in ambulatory, chronic, advanced systolic heart failure, designed to identify a cohort with an approximately 25% 1-year risk of the primary composite outcome of death, urgent transplant, or durable mechanical circulatory support. 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 Medical Arm for Mechanically Assisted Circulatory Support or Risk Assessment (MedaMACS) and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management in Ambulatory Heart Failure Patients (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.

Copyright © 2019 International Society for Heart and Lung Transplantation. All rights reserved.

J Heart Lung Transplant: 13 Sep 2019; epub ahead of print
Aaronson KD, Stewart GC, Pagani FD, Stevenson LW, ... Mann DL,
J Heart Lung Transplant: 13 Sep 2019; epub ahead of print | PMID: 31679943
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Impact:
Abstract

Outcomes of children with congenital heart disease implanted with ventricular assist devices: An analysis of the Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs).

Peng DM, Koehl DA, Cantor RS, McMillan KN, ... Kirklin JK, Kindel SJ
Background
The reported ventricular assist device (VAD) experience in the pediatric congenital heart disease (CHD) population is limited. We sought to describe contemporary use and outcomes of VADs in children with CHD and compare these outcomes to those of non-CHD children.
Methods
Patients enrolled in the Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) between September 19, 2012 through June 30, 2017 were included. CHD was classified as biventricular vs single ventricle (Stages 1, 2, or 3). Outcomes were compared between groups and multivariable analysis was used to identify factors associated with mortality on the device.
Results
Among the 471 patients enrolled, 108 (24%) had CHD (45 biventricular and 63 single ventricle). CHD patients were younger (5.7 ± 5.7 years vs 9.8 ± 6.5 years; p < 0.0001) and smaller (0.8 ± 0.5 m vs 1.2 ± 0.7 m; p < 0.0001) compared with non-CHD patients. CHD patients were more likely to receive a paracorporeal continuous-flow VAD (36.1% vs 12.9%; p < 0.0001) and less likely to receive an implantable continuous-flow VAD (27.8% vs 55.0%; p < 0.0001) compared with non-CHD patients. After 6 months on a VAD, CHD patients had higher mortality (36.4% vs 12.1%) and a lower transplantation rate (29.1% vs 59.9%) than non-CHD patients (p < 0.0001). In the multivariable analysis, CHD was the factor most strongly associated with mortality on VAD (hazard ratio [HR] = 2.9; p < 0.0001), whereas the factors implantable continuous-flow device and high-volume center were protective (HR = 0.3, p < 0.0001, and HR = 0.6, respectively; p = 0.02).
Conclusions
VAD use in children with CHD is associated with increased mortality and decreased transplant rates compared to children without CHD. For the subgroup of children with CHD who received implantable continuous-flow VADs, survival rates were higher and comparable to those of children without CHD. Increased experience correlated with better survival in pediatric VADs.

Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Mar 2019; 38:420-430
Peng DM, Koehl DA, Cantor RS, McMillan KN, ... Kirklin JK, Kindel SJ
J Heart Lung Transplant: 30 Mar 2019; 38:420-430 | PMID: 30459063
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Impact:
Abstract

INTERMACS profiles and outcomes of ambulatory advanced heart failure patients: A report from the REVIVAL Registry.

Kittleson MM, Shah P, Lala A, McLean RC, ... Stewart GC,
Background
Ambulatory patients with advanced heart failure (HF) 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
Registry Evaluation of Vital Information on Ventricular Assist Devices in Ambulatory Life is a prospective observational study of 400 outpatients from 21 MCS and cardiac transplant centers. Eligible patients had New York Heart Association Class II to IV symptoms despite optimal medical and electrical therapies with a recent HF hospitalization, heart transplant listing, or evidence of high neurohormonal activation.
Results
The cohort included 33 INTERMACS Profile 4 (8%), 83 Profile 5 (21%), 155 Profile 6 (39%), and 129 Profile 7 (32%). 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 end point 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 HF, a lower INTERMACS profile was associated with a greater burden of HF 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.

Copyright © 2019 International Society for Heart and Lung Transplantation. All rights reserved.

J Heart Lung Transplant: 27 Aug 2019; epub ahead of print
Kittleson MM, Shah P, Lala A, McLean RC, ... Stewart GC,
J Heart Lung Transplant: 27 Aug 2019; epub ahead of print | PMID: 31522912
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Impact:
Abstract

Outcomes of heart transplantation from hepatitis C virus-positive donors.

Aslam S, Yumul I, Mariski M, Pretorius V, Adler E
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 the acceptance of HCV+ organs for HCV- patients who underwent heart transplantation (HT) and retrospectively reviewed the outcomes at our institution. Inclusion criteria were as follows: all adult patients listed for HT. Exclusion criteria were as follows: pre-existing HIV or active hepatitis B viremia in the recipient/donor.
Results
We transplanted 21 patients from HCV+ donors. Nineteen were viremic donors, and 2 were non-viremic donors. The recipients included 18 patients who underwent HT alone, and 3 patients who underwent combined heart-kidney transplants. There was no HCV transmission from the non-viremic donors (n = 2). All 19 recipients of the viremic donors developed HCV infection (100% transmission). The median age of the viremic donors was 34 years (interquartile range 30-46), and 84.2% were considered US Public Health Service-increased risk. Induction immunosuppression consisted of anti-thymocyte globulin (7/21), basiliximab (7/21), or none (8/21). Maintenance immunosuppression comprised tacrolimus, mycophenolate mofetil, and prednisone. Post-operative Week 2 HCV viral load was not related to induction. Direct anti-viral agent (DAA) therapy for a 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 the patients on DAA therapy cleared viremia. The sustained virological response rate at 12 weeks in 18 evaluable patients was 100%.
Conclusions
We report successful single-center experience using HCV+ organs for HT into HCV- recipients. We believe that there is utility in using such organs to expand the current donor pool. Further long-term follow-up is needed.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 23 Aug 2019; epub ahead of print
Aslam S, Yumul I, Mariski M, Pretorius V, Adler E
J Heart Lung Transplant: 23 Aug 2019; epub ahead of print | PMID: 31521479
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Impact:
Abstract

Endothelin-1, cardiac morphology, and heart failure: the MESA angiogenesis study.

Leary PJ, Jenny NS, Bluemke DA, Kawut SM, ... Hinckley Stukovsky KD, Tedford RJ
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 this study, we evaluated the 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 in 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% confidence interval 17.1-0.7, p = 0.03) with an increased left ventricular ejection fraction (2.8% per log increase in ET1, 95% confidence interval 0.5%-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 p = 0.05, respectively). Lower risk for heart failure with higher ET1 levels 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.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 09 Aug 2019; epub ahead of print
Leary PJ, Jenny NS, Bluemke DA, Kawut SM, ... Hinckley Stukovsky KD, Tedford RJ
J Heart Lung Transplant: 09 Aug 2019; epub ahead of print | PMID: 31515065
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Abstract

Usefulness of standard computed tomography pulmonary angiography performed for acute pulmonary embolism for identification of chronic thromboembolic pulmonary hypertension: results of the InShape III study.

Ende-Verhaar YM, Meijboom LJ, Kroft LJM, Beenen LFM, ... Vonk Noordegraaf A, Klok FA
Background
Chronic thromboembolic pulmonary hypertension (CTEPH) is often diagnosed after a long delay, even though signs may already be present on the computed tomography pulmonary angiogram (CTPA) used to diagnose a preceding acute pulmonary embolism (PE). In this setting of suspected acute PE, we evaluated the diagnostic accuracy of dedicated CTPA reading for the diagnosis of already existing CTEPH.
Methods
Three blinded expert radiologists scored radiologic signs of CTEPH on initial CTPA scans with confirmed acute PE in 50 patients who were subsequently diagnosed with CTEPH during follow-up (cases), and in 50 patients in whom sequential echocardiograms performed >2 years after the acute PE diagnosis did not show any signs of pulmonary hypertension (controls). All 50 control index CTPA scans had signs of right ventricular (RV) overload. Sensitivity and specificity of expert CTPA reading was calculated, and best-predicting radiologic parameters were identified.
Results
The overall expert reading yielded a sensitivity of 72% (95% confidence interval [CI] 58%-84%) and a specificity of 94% (95% CI 83%-99%) for CTEPH diagnosis. Multivariate analysis identified 6 radiologic parameters as independent predictors: intravascular webs; pulmonary artery retraction or dilatation; bronchial artery dilatation; right ventricular (RV) hypertrophy; and interventricular septum flattening. The presence of 3 or more these parameters was associated with a sensitivity of 70% (95% CI 55%-82%), a specificity of 96% (95% CI 86%-100%), and a c-statistic of 0.92.
Conclusions
Standardized reading of CTPA scans performed for acute PE can be useful for the diagnosis of CTEPH when structured identification of 6 characteristics is employed during interpretation. The use of this strategy may help reduce diagnostic delay of CTEPH.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Jun 2019; 38:731-738
Ende-Verhaar YM, Meijboom LJ, Kroft LJM, Beenen LFM, ... Vonk Noordegraaf A, Klok FA
J Heart Lung Transplant: 29 Jun 2019; 38:731-738 | PMID: 30962147
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Impact:
Abstract

Elevated pre-transplant left ventricular end-diastolic pressure increases primary graft dysfunction risk in double lung transplant recipients.

Li D, Weinkauf J, Hirji A, Kapasi A, ... Ezekowitz J, Halloran K
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.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Jun 2019; 38:710-718
Li D, Weinkauf J, Hirji A, Kapasi A, ... Ezekowitz J, Halloran K
J Heart Lung Transplant: 29 Jun 2019; 38:710-718 | PMID: 30850154
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Impact:
Abstract

Risk of anastomotic dehiscence in patients with pulmonary fibrosis transplanted while receiving anti-fibrotics: Experience of the Australian Lung Transplant Collaborative.

Mackintosh JA, Munsif M, Ranzenbacher L, Thomson C, ... Chambers DC, Hopkins P
Background
The new anti-fibrotics pirfenidone and nintedanib are now in widespread use for idiopathic pulmonary fibrosis (IPF), but they may have an adverse impact on pathways involved in wound-healing. This study aimed to establish the safety of anti-fibrotic therapy in the peri-transplant period, particularly with regard to healing of the bronchial anastomosis.
Methods
In this work we assessed a retrospective cohort of patients who had undergone lung transplantation with a diagnosis of pulmonary fibrosis between January 2012 and December 2017. Pre-transplant use of pirfenidone and nintedanib was identified. Anastomotic dehiscence of any extent was determined at bronchoscopy. Known risk factors for anastomotic dehiscence were evaluated in both anti-fibrotic and control groups.
Results
Two hundred twenty-six patients (160 males; mean age 59.7 ± 7.8 years) underwent transplantation in Australia for pulmonary fibrosis during the study period. Forty (17.7%) were receiving anti-fibrotics at the time of transplantation (29 with pirfenidone and 11 with nintedanib). There were 7 anastomotic dehiscence events, with overall incidence rates of 7.5% and 2.2% in the anti-fibrotic and control groups, respectively (p = 0.08). All episodes of dehiscence in the anti-fibrotic group and 2 of 4 in the comparator group occurred <6 weeks post-transplant. Survival at 30days was 100% and 96% (p = 0.21) and at 1 year was 93% and 88% (p = 0.01) in the anti-fibrotic and comparator groups, respectively. Two patients with dehiscence died. The other 5 anastomotic defects resolved, with 1 requiring stent insertion.
Conclusions
The incidence of bronchial dehiscence after transplantation for IPF is low and is not significantly higher in patients receiving anti-fibrotic therapy at the time of transplantation.

Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Apr 2019; 38:553-559
Mackintosh JA, Munsif M, Ranzenbacher L, Thomson C, ... Chambers DC, Hopkins P
J Heart Lung Transplant: 29 Apr 2019; 38:553-559 | PMID: 30824289
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Impact:
Abstract

An integrated molecular diagnostic report for heart transplant biopsies using an ensemble of diagnostic algorithms.

Parkes MD, Aliabadi AZ, Cadeiras M, Crespo-Leiro MG, ... Zuckermann A, Halloran PF
Background
We previously reported a microarray-based diagnostic system for heart transplant endomyocardial biopsies (EMBs), using either 3-archetype (3AA) or 4-archetype (4AA) unsupervised algorithms to estimate rejection. In the present study we examined the stability of machine-learning algorithms in new biopsies, compared 3AA vs 4AA algorithms, assessed supervised binary classifiers trained on histologic or molecular diagnoses, created a report combining many scores into an ensemble of estimates, and examined possible automated sign-outs.
Methods
We studied 889 EMBs from 454 transplant recipients at 8 centers: the initial cohort (N = 331) and a new cohort (N = 558). Published 3AA algorithms derived in Cohort 331 were tested in Cohort 558, the 3AA and 4AA models were compared, and supervised binary classifiers were created.
Results
A`lgorithms derived in Cohort 331 performed similarly in new biopsies despite differences in case mix. In the combined cohort, the 4AA model, including a parenchymal injury score, retained correlations with histologic rejection and DSA similar to the 3AA model. Supervised molecular classifiers predicted molecular rejection (areas under the curve [AUCs] >0.87) better than histologic rejection (AUCs <0.78), even when trained on histology diagnoses. A report incorporating many AA and binary classifier scores interpreted by 1 expert showed highly significant agreement with histology (p < 0.001), but with many discrepancies, as expected from the known noise in histology. An automated random forest score closely predicted expert diagnoses, confirming potential for automated signouts.
Conclusions
Molecular algorithms are stable in new populations and can be assembled into an ensemble that combines many supervised and unsupervised estimates of the molecular disease states.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 May 2019; 38:636-646
Parkes MD, Aliabadi AZ, Cadeiras M, Crespo-Leiro MG, ... Zuckermann A, Halloran PF
J Heart Lung Transplant: 30 May 2019; 38:636-646 | PMID: 30795962
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Impact:
Abstract

Differential effects of ischemia/reperfusion on endothelial function and contractility in donation after circulatory death.

Méndez-Carmona N, Wyss RK, Arnold M, Joachimbauer A, ... Tevaearai Stahel HT, Longnus SL
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.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Jun 2019; 38:767-777
Méndez-Carmona N, Wyss RK, Arnold M, Joachimbauer A, ... Tevaearai Stahel HT, Longnus SL
J Heart Lung Transplant: 29 Jun 2019; 38:767-777 | PMID: 30952549
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Abstract

Prognostic value of vasoactive-inotropic score following continuous flow left ventricular assist device implantation.

Han J, Pinsino A, Sanchez J, Takayama H, ... Takeda K, Yuzefpolskaya M
Background
The purpose of this study is to evaluate the utility of vasoactive-inotropic score (VIS) in predicting outcomes after left ventricular assist device (LVAD) implantation and explore possible mechanisms of post-operative hemodynamic instability.
Methods
Retrospective review was performed in 418 consecutive patients with LVAD implantation. VIS was calculated as dopamine + dobutamine + 10 × milrinone + 100 × epinephrine + 100 × norepinephrine (all μg/kg/min) + 10000 × vasopressin (U/kg/min) after initial stabilization in the operating room and upon arrival at the intensive care unit. The primary outcome was in-hospital mortality. The secondary outcomes were a composite of in-hospital mortality, delayed right ventricular assist device (RVAD) implantation, and continuous renal replacement therapy. The pre-operative biomarkers of inflammation, oxidative stress, endotoxemia and gut-derived metabolite trimethylamine-N-oxide (TMAO) were measured in a subset of 61 patients.
Results
Median VIS was 20.0 (interquartile range 13.3-27.9). VIS was an independent predictor of in-hospital mortality (odds ratio [OR] 1.06, 95% confidence interval [CI] 1.03-1.09, p < 0.001) and composite outcome (OR 1.03, 95% CI 1.01-1.06, p = 0.008). In-hospital mortality increased for each VIS quartile (0% vs 3.9% vs 7.6% vs 12.3%, p = 0.002). VIS was superior to other established LVAD risk models as a predictor of in-hospital mortality (area under the curve 0.73, 95% CI 0.64-0.82). The optimal cut-off point for VIS as a predictor of in-hospital mortality was 20. Pre-operative hemoglobin level was the only independent predictor of VIS ≥ 20 (p = 0.003). Patients with a high VIS were more likely to have elevated TMAO pre-operatively (53.6% vs 25.8%, p = 0.03).
Conclusions
A high post-operative VIS is associated with adverse in-hospital outcomes and is a better predictor of in-hospital mortality compared with existing LVAD risk models. Whether early hemodynamic stabilization using RVAD may benefit patients with a high VIS remains to be investigated.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Aug 2019; 38:930-938
Han J, Pinsino A, Sanchez J, Takayama H, ... Takeda K, Yuzefpolskaya M
J Heart Lung Transplant: 30 Aug 2019; 38:930-938 | PMID: 31201088
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Abstract

The added value of cardiopulmonary exercise testing in the follow-up of pulmonary arterial hypertension.

Badagliacca R, Papa S, Poscia R, Valli G, ... Fedele F, Vizza CD
Background
The added value of cardiopulmonary exercise testing (CPET) in the follow-up of patients with stable pulmonary arterial hypertension (PAH) remains undefined.
Methods
Idiopathic, heritable, and drug-induced PAH patients free from clinical worsening (CW) after 1 year of treatment were enrolled in derivation (n = 80) and validation (n = 80) cohorts at an interval of 6 years and followed for 3 years. Prognostic models were constructed and validated in low-risk patients in World Health Organization (WHO) Functional Class I or II with cardiac index (CI) ≥2.5 liters/min/m and right atrial pressure (RAP) <8 mm Hg. Discrimination and calibration were assessed.
Results
Forty-one derivation cohort patients had CW (51.2%) during 722 ± 349 days. Changes (∆) in WHO classification and CI and absolute value of RAP were independent predictors of CW. With addition of CPET variables, peak oxygen uptake (VO peak) and ∆CI independently improved the power of the prognostic model. Receiver operating characteristic (ROC)-derived cut-off values for ∆CI and VO peak were 0.40 liter/min/m and 15.7 ml/kg/min (≥60% predicted value), respectively. Twenty-nine validation cohort patients had CW (36.2%) during 710 ± 282 days. Different combinations of cut-off values of VO peak and ∆CI defined 4 groups. The event-free survival rates at 1, 2, and 3 years were 100%, 100%, and 100%, respectively, for the high ∆CI with high VO peak combination; 100%, 88%, and 71% for low ∆CI/high VO peak; 80%, 54%, and 40% for high ∆CI/low VO peak; and 72%, 54%, and 33% for low ∆CI/low VO peak.
Conclusions
The combinations of baseline VO peak and change in CI during follow-up is important in prognostication of low-risk patients with idiopathic, heritable, and drug-induced PAH.

Copyright © 2018 Elsevier Ltd. All rights reserved.

J Heart Lung Transplant: 27 Feb 2019; 38:306-314
Badagliacca R, Papa S, Poscia R, Valli G, ... Fedele F, Vizza CD
J Heart Lung Transplant: 27 Feb 2019; 38:306-314 | PMID: 30581051
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Impact:
Abstract

A donor PaO/FiO < 300 mm Hg does not determine graft function or survival after lung transplantation.

Whitford H, Kure CE, Henriksen A, Hobson J, ... Martin C, McGiffin DC
Background
A donor arterial PO/FiO (P/F ratio) of 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 before procurement and each of the 4 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. The 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 < 300 was largely driven by a low P/F ratio in the lower lobes. There were no differences between the recipients receiving donor lungs where the ICU P/F ratio was < 300 compared with ≥ 300 in the 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, and (2) The donor P/F ratio threshold of 300 is excessively conservative and results in the wastage of donor lungs and the application of unnecessary EVLP.

Copyright © 2019. Published by Elsevier Inc.

J Heart Lung Transplant: 01 Sep 2019; epub ahead of print
Whitford H, Kure CE, Henriksen A, Hobson J, ... Martin C, McGiffin DC
J Heart Lung Transplant: 01 Sep 2019; epub ahead of print | PMID: 31636045
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Impact:
Abstract

Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension.

Hiraide T, Kataoka M, Suzuki H, Aimi Y, ... Kosaki K, Fukuda K
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 I 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 who are 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.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 01 Sep 2019; epub ahead of print
Hiraide T, Kataoka M, Suzuki H, Aimi Y, ... Kosaki K, Fukuda K
J Heart Lung Transplant: 01 Sep 2019; epub ahead of print | PMID: 31542298
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Impact:
Abstract

Prognostic implications of serial outpatient blood pressure measurements in patients with an axial continuous-flow left ventricular assist device.

Pinsino A, Castagna F, Zuver AM, Royzman EA, ... Yuzefpolskaya M, Colombo PC
Background
Elevated blood pressure (BP) has been linked to adverse events during left ventricular assist device support. In this study we investigated the association between outpatient BP and stroke or suspected pump thrombosis among HeartMate II (HMII) recipients.
Methods
We retrospectively studied 220 HMII patients. Serial outpatient BP measurements were averaged. Patients were categorized by: (1) mean arterial pressure (MAP), high (>90 mm Hg) vs intermediate (80 mm Hg ≤ MAP ≤ 90 mm Hg) vs low (<80 mm Hg); (2) systolic BP (SBP), high (≥101 mm Hg, median) vs low; and (3) pulse pressure (PP), high (≥22 mm Hg, median) vs low. To assess visit-to-visit BP variability, patients were divided in quartiles of standard deviation of MAP and SBP. The primary end-point was the composite of stroke or suspected pump thrombosis.
Results
The risk for the primary end-point was increased in the high MAP group (adjusted hazard ratio [HR] 2.75, 95% confidence interval [CI] 1.49 to 5.05, vs intermediate MAP; and 6.73, 1.9 to 23.9, vs low MAP). MAP had higher predictive value for the primary end-point compared with SBP (p = 0.05). Patients with high SBP had a higher rate of stroke (HR 2.8, 95% CI 1.09 to 7.17, vs low SBP). The combination of high SBP and low PP was associated with the highest risk for stroke. The lowest quartile of visit-to-visit MAP variability was associated with the highest risk for the primary end-point.
Conclusions
Elevated outpatient BP is associated with increased risk for stroke or suspected pump thrombosis in HMII recipients. Reduced PP and low visit-to-visit BP variability may confer additional risk.

Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Mar 2019; 38:396-405
Pinsino A, Castagna F, Zuver AM, Royzman EA, ... Yuzefpolskaya M, Colombo PC
J Heart Lung Transplant: 30 Mar 2019; 38:396-405 | PMID: 30559034
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Impact:
Abstract

Long-term outcomes after transplantation after support with a pulsatile pediatric ventricular assist device.

Jeewa A, Imamura M, Canter C, Niebler RA, ... Gajarski R, Fraser CD
Background
There has been increasing use of durable ventricular assist devices (VAD) in children as a bridge to transplantation (BTT). The Berlin Heart investigational device exemption (IDE) trial was the first pediatric VAD trial to demonstrate excellent survival outcomes as a BTT.
Objectives
Our aim was to compare the expanded post-transplant outcomes for children enrolled in the Berlin Heart IDE trial to a matched Pediatric Heart Transplant Study (PHTS) cohort not requiring mechanical circulatory support (MCS).
Setting
University Hospitals.
Methods
This was a retrospective review of linked PHTS and Berlin Heart IDE databases for pediatric (≤18 years) recipients transplanted from 2007-2011. Subjects with <5 years of follow up were excluded. VAD supported patients were matched 1:2 to non-VAD supported controls from the PHTS database.
Results
Among 109 Berlin Heart IDE study enrollees, 83 were merged with the PHTS database and matched to 166 non-MCS supported patients. There was no difference in diagnosis, status at listing, and age between groups with the expected difference in inotrope use in the non-MCS supported patients. Compared to their matched cohort, there was no statistical difference in 5-year patient survival between VAD and non-VAD patients (81% vs 88%; p = 0.09) nor was there a difference in freedom from rejection or infection.
Conclusions
This data suggests that children supported with a Berlin Heart VAD had similar survival, infection and rejection rates compared to those not requiring MCS support. Continued surveillance of the Berlin Heart IDE trial population post heart transplantation is warranted.

Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Mar 2019; 38:449-455
Jeewa A, Imamura M, Canter C, Niebler RA, ... Gajarski R, Fraser CD
J Heart Lung Transplant: 30 Mar 2019; 38:449-455 | PMID: 30466802
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Impact:
Abstract

Impact of organ prioritization for immunologic sensitization and waiting times for heart transplantation.

Aleksova N, Alba AC, Fan CS, Mueller B, ... Ross HJ, Chih S
Background
The Canadian status 4S category prioritizes highly sensitized patients with a calculated panel reactive antibody (CPRA) > 80% awaiting heart transplantation. We examined the effect of sensitization and status 4S and developed a predictive model to estimate waiting time in Canada.
Methods
A retrospective review was performed of patients listed for heart transplant at the Ottawa Heart Institute and Toronto General Hospital (Ontario, Canada). We evaluated the association of CPRA and priority listing status on waiting time and post-transplant outcomes. Waiting time risk factor analysis was performed using a multivariable parametric accelerated failure time model with a Weibull distribution.
Results
Of 394 patients listed (75% male, 51 ± 12 years), 291 (74%) received a transplant and 33 (8%) died waiting. The cumulative incidence of transplant decreased across higher CPRA groups but was similar for moderately and highly sensitized groups: 67%, 70%, 50%, and 40% at 12 months for CPRA 0%, 1% to 50%, 51% to 80%, and > 80%, respectively (p = 0.020). Status 4S patients experienced longer waiting times compared with other high priority status 3.5 and 4 and had increased risk of death on the waiting list (p = 0.014). Over a median follow-up of 2.4 years (interquartile range, 1.2-4.1), rejection occurred in 64 sensitized patients (24%) compared with 24 non-sensitized patients (9%; p = 0.019), but there was no difference in survival, allograft dysfunction, or cardiac allograft vasculopathy. A model predicting transplant waiting time, including CPRA, blood group, priority listing status, age, and weight, was developed and showed adequate discrimination and calibration.
Conclusions
Waiting time to heart transplant is increased for highly and moderately sensitized patients, suggesting the need to reevaluate the CPRA > 80% threshold for status 4S prioritization in Canada. Extended waiting times, despite 4S prioritization, supports consideration of additional factors to CPRA in ensuring equitable organ access for sensitized patients.

Copyright © 2019 Elsevier Ltd. All rights reserved.

J Heart Lung Transplant: 27 Feb 2019; 38:285-294
Aleksova N, Alba AC, Fan CS, Mueller B, ... Ross HJ, Chih S
J Heart Lung Transplant: 27 Feb 2019; 38:285-294 | PMID: 30658880
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Impact:
Abstract

Mesenchymal stem cell-derived extracellular vesicles improve the molecular phenotype of isolated rat lungs during ischemia/reperfusion injury.

Lonati C, Bassani GA, Brambilla D, Leonardi P, ... Camussi G, Gatti S
Background
Lung ischemia/reperfusion (IR) injury contributes to the development of severe complications in patients undergoing transplantation. Mesenchymal stem cell (MSC)-derived extracellular vesicles (EVs) exert beneficial actions comparable to those of MSCs without the risks of the cell-based strategy. This research investigated EV effects during IR injury in isolated rat lungs.
Methods
An established model of 180-minutes ex vivo lung perfusion (EVLP) was used. At 60 minutes EVs (n = 5) or saline (n = 5) were administered. Parallel experiments used labeled EVs to determine EV biodistribution (n = 4). Perfusate samples were collected to perform gas analysis and to assess the concentration of nitric oxide (NO), hyaluronan (HA), inflammatory mediators, and leukocytes. Lung biopsies were taken at 180 minutes to evaluate HA, adenosine triphosphate (ATP), gene expression, and histology.
Results
Compared with untreated lungs, EV-treated organs showed decreased vascular resistance and a rise of perfusate NO metabolites. EVs prevented the reduction in pulmonary ATP caused by IR. Increased medium-high-molecular-weight HA 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 upregulated genes involved in the 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.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 23 Aug 2019; epub ahead of print
Lonati C, Bassani GA, Brambilla D, Leonardi P, ... Camussi G, Gatti S
J Heart Lung Transplant: 23 Aug 2019; epub ahead of print | PMID: 31530458
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Impact:
Abstract

Adipose tissue quantification and primary graft dysfunction after lung transplantation: The Lung Transplant Body Composition study.

Anderson MR, Udupa JK, Edwin E, Diamond JM, ... Christie JD, Lederer DJ
Background
Obesity is associated with an increased risk of primary graft dysfunction (PGD) after lung transplantation. The contribution of specific adipose tissue depots is unknown.
Methods
We performed a prospective cohort study of adult lung transplant recipients at 4 U.S. transplant centers. We measured cross-sectional areas of subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) on chest and abdominal computed tomography (CT) scans and indexed each measurement to height. We used logistic regression to examine the 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 the patterns of adipose distribution. We examined the associations of adipose indices with plasma biomarkers of obesity and PGD.
Results
A total of 262 and 117 subjects had available chest CT scans and underwent protocol abdominal CT scans, respectively. In the adjusted models, a greater abdominal SAT index was associated with an increased risk of PGD (odds ratio 1.9, 95% CI 1.02-3.4, p = 0.04) but not with survival time. VAT indices were not associated with PGD risk or survival time. A greater abdominal SAT index correlated with greater pre- and post-transplant leptin (r = 0.61, p < 0.001, and r = 0.44, p < 0.001), pre-transplant IL-1RA (r = 0.25, p = 0.04), and post-transplant ICAM-1 (r = 0.25, p = 0.04). We identified 3 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 an increased risk of PGD after lung transplantation.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 09 Aug 2019; epub ahead of print
Anderson MR, Udupa JK, Edwin E, Diamond JM, ... Christie JD, Lederer DJ
J Heart Lung Transplant: 09 Aug 2019; epub ahead of print | PMID: 31474492
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Impact:
Abstract

Acute kidney injury following left ventricular assist device implantation: Contemporary insights and future perspectives.

Yalcin YC, Bunge JJH, Guven G, Muslem R, ... Bogers AJJC, Caliskan K

Currently, an increasing number of patients with end-stage heart failure are being treated with left ventricular assist device (LVAD) therapy as bridge-to-transplantation, bridge-to-candidacy, or destination therapy (DT). Potential life-threatening complications may occur, specifically in the early post-operative phase, which positions LVAD implantation as a high-risk surgical procedure. Acute kidney injury (AKI) is a frequently observed complication after LVAD implantation and is associated with high morbidity and mortality. The rapidly growing number of LVAD implantations necessitates better approaches of identifying high-risk patients, optimizing peri-operative management, and preventing severe complications such as AKI. This holds especially true for those patients receiving an LVAD as DT, who are typically older (with higher burden of comorbidities) with impaired renal function and at increased post-operative risk. Herein we outline the definition, diagnosis, frequency, pathophysiology, and risk factors for AKI in patients with an LVAD. We also review possible strategies to prevent and manage AKI in this patient population.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Jul 2019; 38:797-805
Yalcin YC, Bunge JJH, Guven G, Muslem R, ... Bogers AJJC, Caliskan K
J Heart Lung Transplant: 30 Jul 2019; 38:797-805 | PMID: 31352996
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Abstract

HFSA/SAEM/ISHLT clinical expert consensus document on the emergency management of patients with ventricular assist devices.

Givertz MM, DeFilippis EM, Colvin M, Darling CE, ... Vierecke J, Bonnell M

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.

Copyright © 2019 Dr. Michael M. Givertz. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Jun 2019; 38:677-698
Givertz MM, DeFilippis EM, Colvin M, Darling CE, ... Vierecke J, Bonnell M
J Heart Lung Transplant: 29 Jun 2019; 38:677-698 | PMID: 31272557
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Abstract

Effects of a fully magnetically levitated centrifugal-flow or axial-flow left ventricular assist device on von Willebrand factor: A prospective multicenter clinical trial.

Bansal A, Uriel N, Colombo PC, Narisetty K, ... Connors JM, Mehra MR
Background
Increased shear stress conferred upon the circulation by continuous-flow pumps is associated with hemocompatibility-related adverse events, principally bleeding within the gastrointestinal system, and linked to the degradation of high-molecular-weight multimers (HMWMs) of von Willebrand factor (vWF). We evaluated the structure and functional characteristics of vWF HMWMs in patients with the fully magnetically levitated centrifugal-flow HeartMate 3 (HM3) and the continuous axial-flow HeartMate II (HMII) pump. Findings were correlated with bleeding events.
Methods
In a prospective, multicenter, comparative cohort study, 60 patients from the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3 Continued Access Protocol (NCT02892955) with an HM3 pump were compared with 30 randomly selected HMII patients from the PREVENtion of HeartMate II Pump Thrombosis study (NCT02158403) biobank. The primary end point was the difference in the normalized vWF HMWM ratio (ratio of the HMWMs to the intermediate- and low-molecular-weight multimers, normalized to pooled plasma from healthy volunteers) between the HM3 and the HMII pump at 90 days after implantation. Assay tests for vWF activity, vWF antigen, vWF activity to antigen ratio, coagulation factor VIII activity, and ADAMTS13 activity were measured by using standard protocols. Differences in these markers were compared in the context of clinical characteristics and correlated with adjudicated bleeding events within the HM3 group.
Results
Of 51 and 29 evaluable patients in the HM3 and HMII arms, respectively, those implanted with the HM3 pump exhibited greater preservation of the vWF HMWM ratio than those with the HMII pump at 90 days after implantation (54.1% vs 42.4%, p < 0.0001). Laboratory values for all vWF assays (antigen, activity, and coagulation factor VIII activity) remained within the normal functional range with no significant differences observed between the pumps at 90 days after implantation. At baseline, there was a decrease in the structural integrity of vWF HMWMs that correlated with increasing heart failure severity as measured by the Interagency Registry for Mechanically Assisted Circulatory Support profile. Multivariable modeling identified the HM3 pump as the only independent variable that determined post-implantation preservation of the structural integrity of vWF HMWMs.
Conclusions
This prospective, multicenter comparative analysis study demonstrates that the fully magnetically levitated centrifugal-flow HM3 left ventricular assist device is associated with greater preservation of the structure of vWF HMWMs than the HMII mechanical bearing axial-flow pump.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Jul 2019; 38:806-816
Bansal A, Uriel N, Colombo PC, Narisetty K, ... Connors JM, Mehra MR
J Heart Lung Transplant: 30 Jul 2019; 38:806-816 | PMID: 31147187
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Abstract

Intravenous treprostinil as an add-on therapy in patients with pulmonary arterial hypertension.

Olsson KM, Richter MJ, Kamp JC, Gall H, ... Ewert R, Hoeper MM
Background
In patients with pulmonary arterial hypertension who have an insufficient response to oral or inhaled therapies, current guidelines recommend the use of parenteral prostacyclin analogues, although the efficacy of this approach is unknown.
Methods
This retrospective multicenter study evaluated patients with pulmonary arterial hypertension who received intravenous treprostinil as an add-on therapy. The risk at baseline and follow-up (6-12 months after the initiation of treprostinil) was classified as low, intermediate, or high according to current recommendations. The outcome was measured as transplant-free survival after the initiation of treprostinil therapy.
Results
A total of 126 patients were analyzed, almost all of them pre-treated with combinations of other pulmonary arterial hypertension medications. Before the initiation of intravenous treprostinil, 2 (2%) patients had a low-risk profile; 100 (79%), an intermediate-risk profile; and 24 (19%), a high-risk profile. At follow-up, 24 (19%) patients were classified as low-risk. These patients had a 5-year transplant-free survival rate >90%. In contrast, patients who remained at intermediate or high risk had transplant-free survival rates of 76%, 43%, and 28% at 1, 3, and 5 years, respectively. Failure to reach a low risk at follow-up was an independent predictor of transplant-free survival (hazard ratio, 9.25; 95% confidence interval, 1.20-71.60; p = 0.033 1).
Conclusions
Risk assessment at 6-12 months after the initiation of add-on intravenous treprostinil in patients with an insufficient response to nonparenteral treatments allows the prediction of transplant-free survival over the ensuing years. Achieving a low-risk profile is associated with excellent outcomes, whereas mortality is high in patients who remain at intermediate or high risk.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Jun 2019; 38:748-756
Olsson KM, Richter MJ, Kamp JC, Gall H, ... Ewert R, Hoeper MM
J Heart Lung Transplant: 29 Jun 2019; 38:748-756 | PMID: 31128966
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Abstract

Gene expression profiling and racial disparities in outcomes after heart transplantation.

Moayedi Y, Fan CS, Miller RJH, Tremblay-Gravel M, ... Ross HJ, Teuteberg JJ
Background
African Americans (AAs) have lower survival rates after heart transplantation (HTx) than Caucasians. The aim of this analysis was to evaluate racial differences in gene expression and their associations with survival and the composite outcome of death, retransplant, rejection with hemodynamic compromise, and graft dysfunction in the Outcomes AlloMap Registry.
Methods
Registry participants included low-risk Caucasian and AA heart transplant recipients with a baseline and at least 1 follow-up gene expression test (AlloMap(C)) within the first year after HTx. The Kaplan-Meier method with delayed entry was used to describe differences in outcomes. Multivariable Cox hazard regression was used to evaluate the associations of overall gene expression profiling score, MARCH8 and FLT3 expression, and tacrolimus levels with each outcome, and stratified Cox models were developed to quantify race-specific associations.
Results
Among 933 eligible recipients, 737 (79%) were Caucasian and 196 (21%) were AA. Compared with Caucasians, AAs were significantly younger (55 vs 59 years, p < 0.001), with higher rates of non-ischemic cardiomyopathy (68% vs 50%, p < 0.001), sensitization (>10% panel reactive antibody, 16% vs 9.1%, p = 0.009), and human leukocyte antigen mismatches (7 vs 7, p = 0.01), but less frequent primary cytomegalovirus serostatus mismatch (14.31% vs 27.3%, p < 0.001). Overall, AAs had an increased adjusted mortality risk (hazard ratio [HR] 4.13, p = 0.007). Higher tacrolimus levels were associated with decreased mortality in AAs (HR 0.62, p = 0.009). Overall gene expression profiling score was associated with increased mortality among Caucasians (HR 1.21, p = 0.048). In Caucasians, but not AAs, overexpression of MARCH8 was associated with increased mortality (HR 2.90, p = 0.001). FLT3 upregulation was associated with increased mortality (HR 2.42, p = 0.033) in AAs. There was an inverse relationship between FLT3 expression and tacrolimus levels (-0.029 and -0.176, respectively) in Caucasians and AAs.
Conclusions
AAs have a significantly higher mortality risk after HTx than Caucasians, even in the low-risk Outcomes AlloMap Registry population. AAs and Caucasians had differential outcomes based upon the varying expression of MARCH8 and FLT3 genes following HTx.

Copyright © 2019 International Society for Heart and Lung Transplantation. All rights reserved.

J Heart Lung Transplant: 30 Jul 2019; 38:820-829
Moayedi Y, Fan CS, Miller RJH, Tremblay-Gravel M, ... Ross HJ, Teuteberg JJ
J Heart Lung Transplant: 30 Jul 2019; 38:820-829 | PMID: 31201087
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Abstract

Frailty trajectories in adult lung transplantation: A cohort study.

Venado A, McCulloch C, Greenland JR, Katz P, ... Blanc P, Singer JP
Background
Frailty is common in adults with advanced lung disease and is associated with death before and after lung transplantation. We aimed to determine whether frailty changes from before to after the lung transplant.
Methods
In a single-center, prospective cohort study among adults undergoing lung transplantation from 2010 to 2017, we assessed frailty by the Short Physical Performance Battery (SPPB; higher scores reflect less frailty) and Fried Frailty Phenotype (FFP; higher scores reflect greater frailty) before and repeatedly up to 36 months after transplant. We tested for changes in frailty scores over time using segmented mixed effects models, adjusting for age, sex, and diagnosis. We quantified the proportion of subjects transitioning between frailty states (frail vs not frail) from before to after the transplant.
Results
In 246 subjects, changes in frailty occurred within the first 6 post-operative months and remained stable thereafter. The overall change in frailty was attributable to improvements among those subjects who were frail before transplant. They experienced a 5.1-point improvement in SPPB (95% confidence interval [CI] 4.6-5.7) and a 1.8-point improvement in FFP (95% CI -2.1 to -1.6) during the early period. Frailty by SPPB and FFP did not change in those who were not frail before transplant. Approximately 84% of survivors who were frail before transplant became not frail after transplant.
Conclusions
Pre-operative frailty resolves in many patients after lung transplantation. Because a large proportion of frailty may be attributable to advanced lung disease, frailty alone should not be an absolute contraindication to transplantation.

Copyright © 2019 International Society for Heart and Lung Transplantation. All rights reserved.

J Heart Lung Transplant: 29 Jun 2019; 38:699-707
Venado A, McCulloch C, Greenland JR, Katz P, ... Blanc P, Singer JP
J Heart Lung Transplant: 29 Jun 2019; 38:699-707 | PMID: 31005571
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Abstract

DireCt Lung Ultrasound Evaluation (CLUE): A novel technique for monitoring extravascular lung water in donor lungs.

Ayyat KS, Okamoto T, Niikawa H, Itoda Y, ... Moghekar A, McCurry KR
Background
Extravascular lung water (EVLW) could change in donor lungs in a time-dependent fashion during procurement or ex-vivo lung perfusion (EVLP) and may vary across different zones. Current techniques for EVLW assessment are either subjective, general estimation, or not feasible in the clinical setting. An accurate and non-invasive diagnostic tool for EVLW would be desirable for donor lung assessment and management. Therefore, we studied the feasibility and accuracy of direCt Lung Ultrasound Evaluation (CLUE) technique.
Methods
Eleven lungs were utilized for the human model and 6 lungs for the porcine model. Lungs underwent EVLP for 2 hours. In CLUE, ultrasound images were taken directly from the lungs. A scoring system was created for each point based on the percentage of B-lines. Images were graded according to the degree of edema. An equation was used to calculate total lung and lobe scores based on number of images of each grade.
Results
CLUE point score correlated with wet/dry ratio in human and porcine models (n = 99, r = 0.863, p < 0.001; and n = 31, r = 0.916, p < 0.001, respectively). CLUE total lung score correlated with lung weight (n = 19, r = 0.812, p < 0.001; and n = 12, r = 0.895, p < 0.001, respectively). CLUE lobe score correlated negatively with partial pressure of oxygen/fraction of inspired oxygen ratio in the human model (n = 20, r = -0.775, p < 0.001).
Conclusions
EVLW monitoring in donor lungs with CLUE after procurement is feasible and CLUE scores were found to be significantly correlated with lung weight, wet/dry, and PaO/FIO ratio.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Jun 2019; 38:757-766
Ayyat KS, Okamoto T, Niikawa H, Itoda Y, ... Moghekar A, McCurry KR
J Heart Lung Transplant: 29 Jun 2019; 38:757-766 | PMID: 31000373
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Abstract

Thrombotic events with proliferation signal inhibitor‒based immunosuppression in cardiac transplantation.

Witkowsky O, Teuteberg J, Althouse AD, Shullo M
Background
Some literature exists potentially linking proliferation signal inhibitors (PSIs) to venous thromboembolism (VTE). We sought to determine the impact of PSIs on development of VTE in heart transplant (HT) patients while controlling for other risk factors.
Methods
The incidence and predisposing factors of VTE were analyzed in this retrospective review of patients >18 years who underwent HT January 2000 to October 2016. Re-transplants, multiorgan transplants, or patients that expired within 30 days post-HT were excluded. VTE incidence rates are reported as number of events per 100 person-years. Cox proportional hazards models were used to assess the relationship between PSI exposure (time-varying covariate) and VTE.
Results
Of 561 HT recipients, 112 received PSIs, started a median of 1.5 years post-HT. There were 102 total VTE events: 78 in PSI-naive patients during 2,547 patient-years (3.0 events per 100 person-years) vs 24 in PSI-exposed patients during 544 patient-years (4.4 events per 100 person-years). Cox proportional hazards models with PSI exposure as a time-varying covariate indicated the increased risk was statistically significant (unadjusted hazard ratio [HR] 2.14, 95% confidence interval [CI] 1.31 to 3.49, p = 0.002). A VTE history was significantly associated with increased risk of VTE post-HT (HR 1.58, 95% CI 1.07 to 2.35, p = 0.022); however, the risk remained significant when adjusting for potential confounders, including previous VTE (HR 2.0, 95% CI 1.18 to 3.38, p = 0.010).
Conclusions
Exposure to PSIs is associated with a significant increase in risk for VTE even when controlling for other risk factors. When considering the use of PSI-based immunosuppression after HT, the risk of VTE over time should be weighed against the potential benefit.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 May 2019; 38:619-626
Witkowsky O, Teuteberg J, Althouse AD, Shullo M
J Heart Lung Transplant: 30 May 2019; 38:619-626 | PMID: 30685236
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Abstract

Outcomes with ambulatory advanced heart failure from the Medical Arm of Mechanically Assisted Circulatory Support (MedaMACS) Registry.

Ambardekar AV, Kittleson MM, Palardy M, Mountis MM, ... Stevenson LW, Stewart GC
Background
The outlook for ambulatory patients with advanced heart failure (HF) and the appropriate timing for left ventricular assist device (LVAD) or transplant remain uncertain. The aim of this study was to better understand disease trajectory and rates of progression to subsequent LVAD therapy and transplant in ambulatory advanced HF.
Methods
Patients with advanced HF who were New York Heart Association (NYHA) Class III or IV and Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Profiles 4 to 7, despite optimal medical therapy (without inotropic therapy), were enrolled across 11 centers and followed for the end-points of survival, transplantation, LVAD placement, and health-related quality of life. A secondary intention-to-treat survival analysis compared outcomes for MedaMACS patients with a matched group of Profile 4 to 7 patients with LVADs from the INTERMACS registry.
Results
Between May 2013 and October 2015, 161 patients were enrolled with INTERMACS Profiles 4 (12%), 5 (32%), 6 (49%), and 7 (7%). By 2 years after enrollment, 75 (47%) patients had reached a primary end-point with 39 (24%) deaths, 17 (11%) undergoing LVAD implantation, and 19 (12%) receiving a transplant. Compared with 1,753 patients with Profiles 4 to 7 receiving LVAD therapy, there was no overall difference in intention-to-treat survival between medical and LVAD therapy, but survival with LVAD therapy was superior to medical therapy among Profile 4 and 5 patients (p = 0.0092). Baseline health-related quality of life was lower among patients receiving a LVAD than those enrolled on continuing oral medical therapy, but increased after 1 year for survivors in both cohorts.
Conclusions
Ambulatory patients with advanced HF are at high risk for poor outcomes, with only 53% alive on medical therapy after 2 years of follow-up. Survival was similar for medical and LVAD therapy in the overall cohort, which included the lower severity Profiles 6 and 7, but survival was better with LVAD therapy among patients in Profiles 4 and 5. Given the poor outcomes in this group of advanced HF patients, timely consideration of transplant and LVAD is of critical importance.

Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Mar 2019; 38:408-417
Ambardekar AV, Kittleson MM, Palardy M, Mountis MM, ... Stevenson LW, Stewart GC
J Heart Lung Transplant: 30 Mar 2019; 38:408-417 | PMID: 30948210
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Abstract

Third Annual Report From the ISHLT Mechanically Assisted Circulatory Support Registry: A comparison of centrifugal and axial continuous-flow left ventricular assist devices.

Goldstein DJ, Meyns B, Xie R, Cowger J, ... Yanase M, Kirklin JK
Background
The IMACS Registry compiles and analyzes worldwide data from patients undergoing implantation of durable left ventricular assist devices.
Methods
Data encompassing 16,286 LVAD recipients from 4 collectives and 24 individual hospitals was collected and analyzed. In this 3rd annual report we compare and contrast outcomes, adverse events and risks factors between axial flow and centrifugal flow device recipients.
Results
Significant differences were found in the baseline characteristics of axial vs centrifugal flow LVAD recipients. Survival was similar between pump types. INTERMACS profile 1-3 constitute 85% of implants. A survival gap persists in destination therapy compared to bridge patients. RVAD need and delay impact survival dramatically. Centrifugal flow outperforms axial flow recipients in regards to GI bleeding and freedom from hemocompatibility related adverse events. No significant difference in the actuarial freedom from all strokes or either stroke subtype (hemorrhagic or ischemic) was seen among the two types of pumps. New end points to guide decision making are proposed.
Conclusions
We demonstrate a transition from axial to centrifugal flow with four-year survival that approximates 60%. A high frequency of adverse events remains an impediment to the wider adoption of these technologies. In the future, composite study endpoints examining life quality and adverse events beyond survival may help in shared decision making prior to MCS implant, and may provide the requisite data to support extension of MCS therapy into the lesser ill heart failure population.

Copyright © 2019. Published by Elsevier Inc.

J Heart Lung Transplant: 30 Mar 2019; 38:352-363
Goldstein DJ, Meyns B, Xie R, Cowger J, ... Yanase M, Kirklin JK
J Heart Lung Transplant: 30 Mar 2019; 38:352-363 | PMID: 30945637
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Abstract

Combined heart and kidney transplantation-Is there a protective effect against cardiac allograft vasculopathy using intravascular ultrasound?

Sato T, Cheng R, Azarbal B, Kittleson M, ... Esmailian F, Kobashigawa J
Background
Because cardiac and renal disease are physiologically related and often coexist, the prevalence of combined heart and kidney transplantation (HKTx) has significantly increased over the last few years. It has been suggested that combined organ allografts modulate the immune system favorably for one or both allografts resulting in successful clinical outcomes. However, whether the addition of kidney transplantation has a protective immune effect against developing cardiac allograft vasculopathy (CAV) has not been fully investigated.
Methods
From March 2010 to September 2018, 30 HKTx recipients who had baseline (4-6 weeks) and 1-year intravascular ultrasound (IVUS) were matched with 60 isolated heart transplant (HTx-alone) recipients using propensity scores. First-year changes in maximal intimal thickness (MIT), maximal intimal area (MIA), maximal percent stenosis (MPS), percent atheroma volume (PAV), and incidence of rapid plaque progression were compared between the groups.
Results
First-year coronary plaque progression was significantly decreased in HKTx recipients compared with HTx-alone recipients by change in the MIT (0.11 ± 0.14 mm vs 0.40 ± 0.32 mm, p < 0.001), MIA (0.52 ± 1.52 mm vs 1.86 ± 2.68 mm, p = 0.002), MPS (2.10% ± 5.64 percentage points vs 7.22% ± 8.59 percentage points, p = 0.001), and PAV (1.62% ± 3.07 percentage points vs 5.90% ± 5.92 percentage points, p < 0.001). Rapid plaque progression occurred in 2 of 30 in HKTx (6.7%) and in 22 of 60 HTx alone (36.7%), p = 0.002.
Conclusions
Combined heart and kidney transplantation is associated with a decrease in CAV by coronary plaque progression on IVUS. These results suggest that HKTx may have an immune modulating benefit over HTx alone.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Aug 2019; 38:956-962
Sato T, Cheng R, Azarbal B, Kittleson M, ... Esmailian F, Kobashigawa J
J Heart Lung Transplant: 30 Aug 2019; 38:956-962 | PMID: 31301966
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Impact:
Abstract

Short-term results with transcatheter aortic valve replacement for treatment of left ventricular assist device patients with symptomatic aortic insufficiency.

Yehya A, Rajagopal V, Meduri C, Kauten J, ... Hrobowski T, Dean D
Background
After 3 years 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.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Aug 2019; 38:920-926
Yehya A, Rajagopal V, Meduri C, Kauten J, ... Hrobowski T, Dean D
J Heart Lung Transplant: 30 Aug 2019; 38:920-926 | PMID: 30898555
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Impact:
Abstract

Evaluation of a lateral thoracotomy implant approach for a centrifugal-flow left ventricular assist device: The LATERAL clinical trial.

McGee E, Danter M, Strueber M, Mahr C, ... Vassiliades T, Cheung A
Background
The HeartWare centrifugal-flow ventricular assist device system (HVAD) is a viable option for treatment of advanced heart failure. There is a growing trend toward the use of less invasive techniques in cardiac surgery, and the thoracotomy technique for HVAD implantation may provide benefits not available with conventional approaches.
Methods
The LATERAL trial is a multicenter, prospective, non-randomized, single-arm trial that utilized data from 144 patients enrolled in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database at 26 centers in the United States and Canada. The primary composite end-point was success at 180 days defined as alive on the originally implanted device and free from disabling stroke (modified Rankin Scale score >3), transplanted or explanted for recovery. The key secondary end-point was mean length of initial hospital stay.
Results
The primary end-point was successfully achieved in 88.1% of patients and was significantly greater than the pre-defined performance goal of 77.5% set from historical sternotomy data (p = 0.0012). The key secondary end-point-mean length of initial hospital stay -was 18 days and was significantly shorter than the pre-defined performance goal of 26.1 days obtained from historical sternotomy data (p < 0.0001). The adverse event profile further demonstrated the safety of the thoracotomy approach. The overall patient survival was good, and bleeding requiring reoperation was significantly less frequent than that observed in previous studies using the sternotomy approach.
Conclusions
This prospective clinical trial provides validation that implantation of the HVAD system via the thoracotomy approach used in the LATERAL study represents a safe and effective alternative to median sternotomy in selected patients intended for a bridge-to-transplant indication.

Copyright © 2019. Published by Elsevier Inc.

J Heart Lung Transplant: 30 Mar 2019; 38:344-351
McGee E, Danter M, Strueber M, Mahr C, ... Vassiliades T, Cheung A
J Heart Lung Transplant: 30 Mar 2019; 38:344-351 | PMID: 30945636
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Impact:
Abstract

End of life for patients with left ventricular assist devices: Insights from INTERMACS.

McIlvennan CK, Grady KL, Matlock DD, Helmkamp LJ, Abshire M, Allen LA
Background
Trial and registry data have reported mortality rates and causes of death in patients with left ventricular assist devices (LVADs); however, a more granular description is needed of end of life, including location of death and quality of life (QOL), to better guide expectations and care.
Methods
To identify where patients with an LVAD died, characterize QOL before death, and cause of death over time, we evaluated patients in the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) implanted with a continuous-flow LVAD.
Results
From 18,733 patients implanted with an LVAD during the period 2008 to 2016, 4,916 patients were known to have died, of whom 98% had a recorded location of death. Overall, 76.9% died in the hospital, with progressively more patients dying outside of the hospital further post-LVAD implant: <1 month, 2.3%; 1 to 12 months, and 16.8%; and >12 months, 37.4%. In a multivariable analysis, increased age (RR (risk ratio) 1.06, 95% confidence interval [CI] 1.02 to 1.12, p = 0.01) and destination therapy indication (RR 1.15, 95% CI 1.03 to 1.28, p = 0.01) increased the likelihood of dying outside the hospital. Comparing 3 months post-implant with 6 months before death in a subset of patients, QOL remained clinically stable (EQ-5D Visual Analog Scale [mean ± SD]: 68.3 ± 22.2 to 66.7 ± 21.7, p = 0.11; KCCQ: 61.0 ± 22.2 to 57.8 ± 23.2, p = 0.003). The most common cause of death <1 month post-implant was multiple-organ failure (20.4%) and at >1 month post-implant it was neurologic dysfunction (28.2%).
Conclusions
Most patients with an LVAD died in the hospital. QOL remained stable months before death and causes of death were varied, but increasingly dominated by stroke. By understanding death with an LVAD in place, clinicians are in a better position to educate patients and caregivers about what to expect and provide to support tailored to patient and caregiver needs.

Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Mar 2019; 38:374-381
McIlvennan CK, Grady KL, Matlock DD, Helmkamp LJ, Abshire M, Allen LA
J Heart Lung Transplant: 30 Mar 2019; 38:374-381 | PMID: 30642799
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Impact:
Abstract

Evaluation of flow-modulation approaches in ventricular assist devices using an in-vitro endothelial cell culture model.

Haglund TA, Rajasekaran NS, Smood B, Giridharan GA, ... Kirklin JK, Sethu P
Background
Continuous-flow ventricular assist devices (CF-VADs) produce non-physiologic flow with diminished pulsatility, which is a major risk factor for development of adverse events, including gastrointestinal (GI) bleeding and arteriovenous malformations (AVMs). Introduction of artificial pulsatility by modulating CF-VAD flow has been suggested as a potential solution. However, the levels of pulsatility and frequency of CF-VAD modulation necessary to prevent adverse events are currently unknown and need to be evaluated.
Methods
The purpose of this study was to use human aortic endothelial cells (HAECs) cultured within an endothelial cell culture model (ECCM) to: (i) identify and validate biomarkers to determine the effects of pulsatility; and (ii) conclude whether introduction of artificial pulsatility using flow-modulation approaches can mitigate changes in endothelial cells seen with diminished pulsatile flow. Nuclear factor erythroid 2-related factor 2 (Nrf-2)-regulated anti-oxidant genes and proteins and the endothelial nitric oxide synthase/endothelin-1 (eNOS/ET-1) signaling pathway are known to be differentially regulated in response to changes in pulsatility.
Results
Comparison of HAECs cultured within the ECCM (normal pulsatile vs CF-VAD) with aortic wall samples from patients (normal pulsatile [n = 5] vs CF-VADs [n = 5]) confirmed that both the Nrf-2-activated anti-oxidant response and eNOS/ET-1 signaling pathways were differentially regulated in response to diminished pulsatility. Evaluation of 2 specific CF-VAD flow-modulation protocols to introduce artificial pulsatility, synchronous (SYN, 80 cycles/min, pulse pressure 20 mm Hg) and asynchronous (ASYN, 40 cycles/min, pulse pressure 45 mm Hg), suggested that both increased expression of Nrf-2-regulated anti-oxidant genes and proteins along with changes in levels of eNOS and ET-1 can potentially be minimized with ASYN and, to a lesser extent, with SYN.
Conclusions
HAECs cultured within the ECCM can be used as an accurate model of large vessels in patients to identify biomarkers and select appropriate flow-modulation protocols. Pressure amplitude may have a greater effect in normalizing anti-oxidant response compared with frequency of modulation.

Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Mar 2019; 38:456-465
Haglund TA, Rajasekaran NS, Smood B, Giridharan GA, ... Kirklin JK, Sethu P
J Heart Lung Transplant: 30 Mar 2019; 38:456-465 | PMID: 30503074
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Impact:
Abstract

Validation of the International Society for Heart and Lung Transplantation primary graft dysfunction instrument in heart transplantation.

Foroutan F, Alba AC, Stein M, Krakovsky J, ... Guyatt G, Ross H
Background
In 2014, the International Society for Heart and Lung Transplantation (ISHLT) developed a classification instrument for left ventricular (LV) and isolated right ventricular (RV) primary graft dysfunction post‒heart transplant. The instrument classifies LV-PGD as mild, moderate, or severe. In this study, we evaluated the predictive validity of this instrument.
Methods
We conducted a cohort study of 412 consecutive patients transplanted between 2004 and 2015 at the Toronto General Hospital and Ottawa Heart Institute (Canada). We classified LV-PGD as mild, moderate, or severe, using the ISHLT instrument. To assess predictive validity, we evaluated the association between LV-PGD severity and 1-year post-transplant mortality using a Cox regression model adjusted for recipient age.
Results
The cohort was predominantly male (71%), mean age 50 ± 13 years, mean donor age 38 ± 14 years, with 25% female donors. Mean ischemic time was 3.7 ± 1.1 hours. LV-PGD was mild in 3.6% of patients, moderate in 9.5%, and severe in 3.9%. All levels of LV-PGD were associated with increased 1-year mortality, with a gradient in the association between mild, moderate, and severe. We only observed a statistically significant association for moderate and severe forms of LV-PGD (mild: hazard ratio [HR] 2.4, 95% confidence interval [CI] 0.6 to 10.2; moderate: HR 7.0, 95% CI 3.4 to 14.6; severe: HR 15.9, 95% CI 7.2 to 35.0).
Conclusions
The ISHLT LV-PGD classification convincingly identifies a substantial increase in the risk of death at 1 year, and an increased gradient of risk, in those with moderate or severe LV-PGD.

Copyright © 2019 Elsevier Ltd. All rights reserved.

J Heart Lung Transplant: 27 Feb 2019; 38:260-266
Foroutan F, Alba AC, Stein M, Krakovsky J, ... Guyatt G, Ross H
J Heart Lung Transplant: 27 Feb 2019; 38:260-266 | PMID: 30642796
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Impact:
Abstract

Outcomes of children supported with an intracorporeal continuous-flow left ventricular assist system.

VanderPluym CJ, Adachi I, Niebler R, Griffiths E, ... Morales D, Lorts A
Background
Since 2012, there has been growing use of the HeartWare (Medtronic, Mounds View, MN) intracorporeal continuous flow (CF) ventricular assist device (VAD) in children, despite it not being labeled for use in pediatric patients. We sought to describe the use and outcomes of children with HeartWare VADs.
Methods
We identified all patients aged < 19 years and young adults aged 19 to 30 years supported with HeartWare who were entered into the pediatric portion (Pedimacs) of the Interagency Registry for Mechanically Assisted Circulatory Support (Intermacs) and the Intermacs registries, respectively, between September 2012 and June 2017. Adverse events and outcomes were analyzed and compared.
Results
We identified 192 children and 247 young adult HeartWare patients. Baseline characteristics of children differed from young adults, with lower median weight of 51.5 kg (range, 13.1-162) vs 75.8 kg (range, 29.8-191; p ≤ 0.0001) and body surface area of 1.5 m (range, 0.6-2.9 m) vs 1.9 m (range, 1.1-3.2 m; p ≤ 0.0001) . At the time of implant, 12 children weighed < 20 kg, and 58.3% of these children had congenital heart disease compared with 11.7% in children who weighed ≥ 20 kg and 6.1% in young adults (p ≤ 0.0001). Median duration of support was 2.8 months (IQR, 1.3-6.0 months) in children and 9.7 months (IQR 4.0-19.2 months) in young adults (p ≤ 0.0001). Serious adverse events in children and young adults included infection in 27% and 44% of patients, respectively (p=0.0002), major bleeding in 23% and 23%, respectively (p = 0.9), device malfunction/pump thrombosis in 11% and 19.0%, respectively (p = 0.04), and stroke in 10% and 12%, respectively (p = 0.5). Of the children who weighed < 20 kg at time of implant, 0% had major bleeding, 16.7% had infections, and 8.3% had stroke. Overall survival was not statistically different between children and young adults, and there was no increased mortality in children who weighed < 20 kg. Rate of discharge on HeartWare was 80% in young adults vs 48% in children who weighed ≥ 20 kg and only 33% in children who weighed < 20 kg.
Conclusions
Survival in children supported with HeartWare is encouraging and comparable to young adults; however, adverse events are not uncommon in children. Ongoing evaluation of the HeartWare use in children is necessary to further decrease the rate of adverse events and understand obstacles to discharge.

Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Mar 2019; 38:385-393
VanderPluym CJ, Adachi I, Niebler R, Griffiths E, ... Morales D, Lorts A
J Heart Lung Transplant: 30 Mar 2019; 38:385-393 | PMID: 30391197
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Impact:
Abstract

Risk factors for death or heart transplantation in single-ventricle physiology (tricuspid atresia, pulmonary atresia, and heterotaxy): A systematic review and meta-analysis.

Kulkarni A, Patel N, Singh TP, Mossialos E, Mehra MR
Background
In this study we sought to evaluate risk factors (RFs) for death or heart transplantation (D-HT) in single-ventricle (SV) physiology due to tricuspid atresia (TA), pulmonary atresia‒intact ventricular septum (PA-IVS), and heterotaxy with SV (HX), clinical conditions for which outcome data are limited.
Methods
To conduct a systematic review, we included citations that evaluated occurrence of D-HT in SV physiology of TA, PA-IVS, and HX in English articles published between January 1998 and December 2017 based on inclusion and exclusion criteria, following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The Cochrane Risk of Bias in Non-Randomized Studies-Interventions (ROBINS-I) tool for non-randomized studies was used to assess the risk of bias. Meta-analysis was performed if RF data were available in more than 3 studies.
Results
Of 11,629 citations reviewed, 30 met inclusion criteria. All 30 were observational, retrospective studies. In all, 1,770 patients were included, 481 died and 21 underwent HT (63 lost to follow-up); 723 patients reached Fontan completion. We found that systemic ventricular dysfunction (odds ratio [OR] 20.7, confidence interval [CI] 10.0-42.5, I = 0%) and atrioventricular valve regurgitation (AVR) were associated with risk of D-HT (OR 3.7, CI 1.9-6.9, I = 14%). RF associations with D-HT could not be derived for right ventricle‒dependent coronary circulation, pulmonary arteriovenous malformations, total anomalous pulmonary venous return, arrhythmias, and pulmonary atresia.
Conclusions
This systematic review and meta-analysis has identified a high mortality rate in children born with non-HLHS SV heart disease and points to potential under-utilization of HT. Systemic ventricular dysfunction and AVR were identified as RFs for D-HT in this subset of patients SV with TA, PA-IVS, and HX.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Jun 2019; 38:739-747
Kulkarni A, Patel N, Singh TP, Mossialos E, Mehra MR
J Heart Lung Transplant: 29 Jun 2019; 38:739-747 | PMID: 31006521
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Impact:
Abstract

Predictors of survival in patients with not-operated chronic thromboembolic pulmonary hypertension.

Taniguchi Y, Jaïs X, Jevnikar M, Boucly A, ... Sitbon O, Simonneau G
Background
Treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH) have recently evolved with the availability of balloon pulmonary angioplasty (BPA) and pulmonary vasodilators. Our aim was to analyze the prognostic variables associated with long-term outcome in a cohort of patients with not-operated CTEPH.
Methods
From January 2006 to December 2016, 343 newly diagnosed consecutive patients with not-operated CTEPH were diagnosed and followed up in the French Reference Center for Pulmonary Hypertension. Overall long-term survival and prognostic factors according to the diagnosis period (early period, 2006-2012, vs recent period, since 2013, i.e., one year before availability of BPA) were analyzed.
Results
In the overall population, baseline New York Heart Association functional class, right atrial pressure, 6-minute walk distance (6MWD), and diagnosis period were independent predictors of survival. The 1- and 3-year survival rates of patients diagnosed in the recent period (n = 170) were 91.6% and 85.0%, compared with 89.0% and 74.3% in patients diagnosed in the early period (n = 173), respectively (p = 0.030). Multivariate analysis from patients diagnosed in the recent period found that baseline 6MWD (per 20 m increase in distance) (hazard ratio [HR], 0.879; 95% confidence interval [CI], 0.832-0.928, p < 0.001) and BPA (HR, 0.307; 95% CI, 0.099-0.957; p = 0.042) were independently associated with survival.
Conclusions
Survival of not-operated patients with CTEPH has significantly improved in the recent management era. New treatment options, including BPA, might have the potential to improve the prognosis of patients with inoperable CTEPH.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Jul 2019; 38:833-842
Taniguchi Y, Jaïs X, Jevnikar M, Boucly A, ... Sitbon O, Simonneau G
J Heart Lung Transplant: 30 Jul 2019; 38:833-842 | PMID: 31103383
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Impact:
Abstract

Post-transplant outcome in patients bridged to transplant with temporary mechanical circulatory support devices.

Yin MY, Wever-Pinzon O, Mehra MR, Selzman CH, ... Drakos SG, Stehlik J
Background
The new heart allocation system in the United States prioritizes patients supported by temporary mechanical circulatory support (TMCS) devices over those with uncomplicated durable continuous-flow left ventricular assist devices (CF-LVADs), which may increase the number of patients bridged to transplant with TMCS. Limited data are available in guiding post-transplant outcomes with various TMCS devices. We sought to describe post-transplant outcome and identify clinical variables associated with post-transplant outcome in patients bridged to transplant with TMCS.
Methods
Using data from the International Society for Heart and Lung Transplantation Thoracic Transplant Registry, we included subjects who underwent transplantation between 2005 and 2016 with known use of mechanical circulatory support. Pre-transplant recipient, donor, and transplant-specific variables were abstracted. The primary outcome was patient survival at 1-year post-transplant. Outcomes of patients bridged to transplant with TMCS were compared with those of patients bridged with CF-LVADs. Cox regression analyses were performed to identify clinical variables associated with the outcomes.
Results
There were 6,528 patients bridged to transplant with the following types of mechanical circulatory support: durable CF-LVADs (n = 6,206), extracorporeal membrane oxygenation (ECMO, n = 134), percutaneous temporary CF-LVADs (n = 75), surgically implanted temporary CF-LVADs (n = 38) or surgically implanted temporary BiVAD (n = 75). Bridging with ECMO (hazard ratio 3.79, 95% confidence interval [CI] 2.69-5.34, p < 0.001) or percutaneous temporary CF-LVADs (hazard ratio 1.83, 95% CI 1.09-3.08, p = 0.02) was independently associated with higher risk of mortality. Additional risk factors included older donor age, female/male donor-recipient match, older recipient age, higher recipient body mass index, higher recipient creatinine, and prolonged ischemic time.
Conclusions
This analysis of a large international cohort of patients bridged to transplant with mechanical circulatory support identified ECMO and percutaneous temporary CF-LVADs as predictors of mortality after transplant, along with additional donor and recipient clinical characteristics. These findings may provide guidance to clinicians in decisions on mechanical circulatory support device selection, transplant eligibility, and timing of transplant.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Jul 2019; 38:858-869
Yin MY, Wever-Pinzon O, Mehra MR, Selzman CH, ... Drakos SG, Stehlik J
J Heart Lung Transplant: 30 Jul 2019; 38:858-869 | PMID: 31072751
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Impact:
Abstract

Hypothermic perfusion of donor heart with a preservation solution supplemented by mesenchymal stem cells.

Korkmaz-Icöz S, Li S, Hüttner R, Ruppert M, ... Karck M, Szabó G
Background
Heart transplantation is the definitive treatment for end-stage heart failure. A shortage of donor hearts forced transplant programs to accept older donors and longer ischemic times. Previous studies have suggested that administration of mesenchymal stem cells (MSCs) or their conditioned medium (CM) protects the heart against ischemia/reperfusion injury (IRI). We hypothesized that the preservation of donor hearts with a CM would protect the graft from IRI after prolonged storage in 15-month-old rats and investigated mRNA changes attributable to CM.
Methods
Rat MSCs were isolated and cultured. The CM was used and characterized by a 90-antibody array, revealing the presence of 28 factors involved in apoptosis, inflammation, and oxidative stress. Hearts from 15-month-old donor rats were explanted and continuously perfused for 5 hours with oxygenated, 4°C cardioplegic solution, and supplemented with either regular cell culture medium (control group) or CM. The hearts were then heterotopically transplanted. We evaluated in-vivo left ventricular graft function 1.5 hours after transplantation and the myocardial expression of 120 genes using polymerase chain reaction arrays.
Results
Systolic contractility and relaxation parameters were significantly reduced in 15-month-old rats compared with the young rats. After transplantation, systolic function (dP/dt: 1,197 ± 94 vs 1,825 ± 279 mm Hg/s at 140 µl; p < 0.05) and diastolic function (dP/dt: 737 ± 168 vs 1,200 ± 166 mm Hg/s at 140 µl, p < 0.05) were significantly improved in the CM group compared with controls. Among the genes surveyed, the expressions of 66 were altered. Genes of pro-inflammatory cytokines and interleukins were down-regulated, whereas expression of the anti-oxidant gene superoxide dismutase-2 was up-regulated in the CM-treated grafts compared with the control group grafts.
Conclusions
Perfusion of donor hearts with CM protects against myocardial IRI in 15-month-old rats.

Copyright © 2018 Elsevier Ltd. All rights reserved.

J Heart Lung Transplant: 27 Feb 2019; 38:315-326
Korkmaz-Icöz S, Li S, Hüttner R, Ruppert M, ... Karck M, Szabó G
J Heart Lung Transplant: 27 Feb 2019; 38:315-326 | PMID: 30638838
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Impact:
Abstract

Successful clinical transplantation of hearts donated after circulatory death using normothermic regional perfusion.

Tchana-Sato V, Ledoux D, Detry O, Hans G, ... Sakalihasan N, Defraigne JO
Background
Heart transplantation (HT) from donation after circulatory death (DCD) has yet to achieve wide clinical application despite the encouraging resultsreported recently. In this study we describe 2 cases of successful adult DCD HT performed at our institution using an original protocol.
Methods
Our local abdominal DCD protocol was updated to allow DCD heart procurement, and was accepted by the institutional ethics committee. The main features of the protocol include: pre-mortem insertion of peripheral venoarterial extracorporeal membrane oxygenation cannulas; thoracoabdominal normothermic regional perfusion (NRP) by clamping the 3 aortic arch vessels to exclude cerebral circulation; and in-situ heart resuscitation. The retrieved hearts were directly transplanted into recipients located in an adjoining operating room.
Results
The procurement warm ischemic time was 25 minutes for the first donor, and 26 minutes for the second donor. The cold ischemic time was 16 minutes for the first recipient and 17 minutes for the second recipient. The suture time was 30 minutes for the first recipient, and 53 minutes for the second recipient. Both recipients were easily weaned off cardiopulmonary bypass in sinus rhythm and inotropic support. Post-operative evaluation of cardiac function was excellent and the patients were subsequently discharged home.
Conclusions
Transplantation of hearts from DCD donors is now a clinical reality.NRP is a useful tool for resuscitation, reperfusion, and preservation of transplanted hearts. It also offers the opportunity to assess the function and viability of organs before transplantation. However,due to ethical issues, some may object to ante-mortem intervention.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 May 2019; 38:593-598
Tchana-Sato V, Ledoux D, Detry O, Hans G, ... Sakalihasan N, Defraigne JO
J Heart Lung Transplant: 30 May 2019; 38:593-598 | PMID: 31128600
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Impact:
Abstract

Stroke and death risk in ventricular assist device patients varies by ISHLT infection category: An INTERMACS analysis.

Shah P, Birk SE, Cooper LB, Psotka MA, ... Pagani FD, Cowger JA
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.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Jun 2019; 38:721-730
Shah P, Birk SE, Cooper LB, Psotka MA, ... Pagani FD, Cowger JA
J Heart Lung Transplant: 29 Jun 2019; 38:721-730 | PMID: 30954340
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Impact:
Abstract

Incidence, predictors, and outcomes after severe primary graft dysfunction in pediatric heart transplant recipients.

Profita EL, Gauvreau K, Rycus P, Thiagarajan R, Singh TP
Background
Previous reports of primary graft dysfunction (PGD) in pediatric heart transplant (HT) recipients are limited to descriptive series of children who required extracorporeal membrane oxygenation (ECMO) support shortly after HT. In this study we sought to determine the incidence, risk factors, and survival after severe PGD in pediatric HT recipients.
Methods
We identified all children <18 years old who underwent HT in the United States during 1996 to 2015 using the Organ Procurement and Transplant Network database and then identified those who developed severe PGD by linking patient variables to Extracorporeal Life Support Organization registry data. Logistic regression models were used to assess risk factors for developing severe PGD.
Results
The overall incidence of severe PGD was 4.7% over 20 years (95% confidence interval 4.2% to 5.3%). The incidence was 4.1%, 4.5%, 5.3%, and 4.6%, respectively, in consecutive 5-year periods (p for trend = 0.48). Independent risk factors for developing severe PGD were younger age, congenital heart disease, HT while supported on ECMO, higher serum bilirubin, and graft ischemic time ≥4 hours. Ventricular assist device support as bridge to HT and available donor variables were not associated. Death (or graft loss) before discharge occurred in 40.6% of children with PGD (105 deaths, 7 re-transplants) and in 5.6% of children without PGD.
Conclusions
Severe PGD remains an important clinical morbidity in pediatric HT recipients in the current era and is associated with high mortality. These findings highlight the need for research in preventing and treating PGD in pediatric HT recipients for improving overall post-transplant survival.

Copyright © 2019. Published by Elsevier Inc.

J Heart Lung Transplant: 30 May 2019; 38:601-608
Profita EL, Gauvreau K, Rycus P, Thiagarajan R, Singh TP
J Heart Lung Transplant: 30 May 2019; 38:601-608 | PMID: 30733156
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Impact:
Abstract

Pulmonary cuff dysfunction after lung transplant surgery: A systematic review of the evidence and analysis of its clinical implications.

Kumar N, Essandoh M, Bhatt A, Whitson BA, ... Saklayen S, Hussain N
Background
Pulmonary cuff dysfunction, either due to pulmonary vein obstruction, pulmonary vein stenosis, or pulmonary vein thrombosis, is an uncommon, yet serious complication after lung transplantation. Although there have been numerous reports of its occurrence, there is little consensus regarding the hemodynamic parameters associated with its presentation and diagnostic considerations. This systematic review summarizes the evidence surrounding pulmonary cuff dysfunction after lung transplantation surgery and empirically analyzes its implications.
Methods
Databases were examined for all articles and abstracts reporting on pulmonary cuff dysfunction. Data collected included: number of patients studied; patients\' characteristics; incidences of pulmonary vein stenosis and pulmonary vein thrombosis; and timing and imaging modality utilized for diagnosis.
Results
Thirty-four full-text citations were included in this review. The point prevalence of pulmonary vein stenosis and thrombosis were 1.4% and 2.5%, respectively. The peak pulmonary cuff velocity associated with dysfunction was found to be 1.59 ± 0.66 m/sec. The diameter of the dysfunctional pulmonary vein was noted to be 0.48 ± 0.20 cm. The majority of diagnoses were made in the early post-operative period using transesophageal echocardiography. Overall, 41.3% of patients (26 of 63) required emergent procedural reintervention, and 32% of patients (20 of 63) diagnosed with pulmonary cuff dysfunction died during their hospital stay.
Conclusions
This systematic review underscores the importance of identifying pulmonary cuff dysfunction after lung transplant surgery, and the usefulness of transesophageal echocardiography for detection of this complication. The clinical implications of these results warrant the further development of identification and management strategies for lung transplant patients.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Apr 2019; 38:530-544
Kumar N, Essandoh M, Bhatt A, Whitson BA, ... Saklayen S, Hussain N
J Heart Lung Transplant: 29 Apr 2019; 38:530-544 | PMID: 30718043
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Impact:
Abstract

Montelukast in chronic lung allograft dysfunction after lung transplantation.

Vos R, Eynde RV, Ruttens D, Verleden SE, ... Verleden GM,
Background
Chronic lung allograft dysfunction (CLAD) is a major cause of post‒lung transplant mortality, with limited medical treatment options. In this study we assessed the association of montelukast treatment with pulmonary function and outcome in lung transplant recipients with progressive CLAD.
Methods
We performed a retrospective study of all lung transplant recipients transplanted between July 1991 and December 2016 at our center and who were treated for at least 3 months with montelukast for progressive CLAD, despite at least 3 months of prior azithromycin therapy. Main outcome parameters included evolution of pulmonary function and progression-free and overall survival.
Results
A total of 153 patients with CLAD (115 with bronchiolitis obliterans syndrome and 38 with restrictive allograft syndrome) were included, of whom 46% had a forced expiratory volume in 1 second (FEV) measure of between 66% and 80%, 31% an FEV between 51% and 65%, and 23% an FEV ≤50% of best post-operative FEV at start of montelukast. Montelukast was associated with attenuation in rate of FEV decline after 3 and 6 months, respectively (both p < 0.0001). Patients in whom FEV improved or stabilized after 3 months of montelukast (81%) had significantly better progression-free (p < 0.0001) and overall (p = 0.0002) survival after CLAD onset, as compared to those with further decline of FEV (hazard ratio [HR] 2.816, 95% confidence interval [CI] 1.450 to 5.467, p = 0.0022 for overall survival after CLAD onset in risk-adjusted multivariate analysis).
Conclusions
Montelukast was associated with a significant attenuation in rate of FEV decline in a substantial proportion of patients with established CLAD, which correlated with better outcome. Further study is required regarding use of montelkast.

Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Apr 2019; 38:516-527
Vos R, Eynde RV, Ruttens D, Verleden SE, ... Verleden GM,
J Heart Lung Transplant: 29 Apr 2019; 38:516-527 | PMID: 30638839
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Impact:
Abstract

First human use of a wireless coplanar energy transfer coupled with a continuous-flow left ventricular assist device.

Pya Y, Maly J, Bekbossynova M, Salov R, ... Zilbershlag M, Netuka I

The drive-line to power contemporary ventricular assist devices exiting the skin is associated with infection, and requires a holstered performance of the cardiac pump, which reduces overall quality of life. Attempts to eliminate the drive-line using transcutaneous energy transfer systems have been explored but have not succeeded in viable widespread application. The unique engineering of the coplanar energy transfer system is characterized by 2 large rings utilizing a coil-within-the-coil topology, ensuring robust resonance energy transfer while allowing for a substantial (>6 hours) unholstered circulatory support powered by an implantable battery source. Herein we report the first known human experience with this novel technology, coupled with a continuous-flow assist left ventricular assist device, in 2 consecutive patients evaluated with the primary end-point of system performance at 30 days post-implantation.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Mar 2019; 38:339-343
Pya Y, Maly J, Bekbossynova M, Salov R, ... Zilbershlag M, Netuka I
J Heart Lung Transplant: 30 Mar 2019; 38:339-343 | PMID: 30945635
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Impact:
Abstract

Outcomes from a recovery protocol for patients with continuous-flow left ventricular assist devices.

Knierim J, Heck R, Pieri M, Schoenrath F, ... Krabatsch T, Potapov E
Background
In this retrospective analysis we evaluated a standardized echocardiographic assessment and an invasive technique for patient selection for successful continuous-flow left ventricular assist device (CF-LVAD) explantation.
Methods
Inclusion criteria for LVAD recovery assessment were: clinically stable condition; LVAD support for >6 months; physical activity; normal echocardiography findings; and no more than mild valvular disease and aortic valve opening. In a second step, echocardiography was performed under CF-LVAD reduction and stop conditions (PStopE). In the third step, patients who presented with stable parameters underwent right heart catheterization under CF-LVAD stoppage and occlusion of the outflow graft with a balloon catheter. Criteria for explantation were normal pulmonary artery pressure and pulmonary capillary wedge pressure <16 mmHg.
Results
Thirty-three of 424 patients entered the second step of evaluation and 20 entered the third step. Fourteen presented positive results and the pump was successfully explanted. The PCWP at baseline was 8.5 (2.8) mmHg in the explantation group and 10.6 (2.8) mmHg in the non-explantation group (p = 0.105). It increased to 10.9 (3.0) mmHg vs 20.8 (4.9) mmHg under outflow graft occlusion. The wedge pressure was significantly higher in the non-explantation group (p < 0.001). Median duration of follow-up after explantation was 9.74 (interquartile range 4.3 to 20.60) months, with survival of 93%.
Conclusions
The protocol presented is feasible and safe. The criteria applied provide good patient selection for sustained mid-term myocardial recovery after LVAD explantation.

Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Mar 2019; 38:440-448
Knierim J, Heck R, Pieri M, Schoenrath F, ... Krabatsch T, Potapov E
J Heart Lung Transplant: 30 Mar 2019; 38:440-448 | PMID: 30503053
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Impact:
Abstract

Azithromycin and early allograft function after lung transplantation: A randomized, controlled trial.

Van Herck A, Frick AE, Schaevers V, Vranckx A, ... Verleden GM, Vos R
Background
Chronic lung allograft dysfunction (CLAD) is the single most important factor limiting long-term survival after lung transplantation (LTx). Azithromycin has been shown to improve CLAD-free and long-term survival, yet the possible impact on early lung allograft function is unclear.
Methods
A prospective, randomized, double-blind, placebo-controlled trial of pre-transplant and prompt post-transplant azithromycin treatment was performed at the University Hospitals Leuven. In each arm, 34 patients, transplanted between October 2013 and October 2015, were included for analysis. Study drug was added to standard of care and was administered once before LTx (1,000 mg of azithromycin or placebo) and every other day from Day 1 until Day 31 after LTx (250 mg of azithromycin or placebo). Primary outcome was an anticipated 15% improvement of forced expiratory volume in 1 second (FEV, percent predicted) during the first 3 months post-LTx. Secondary end-points included length of intubation, days on ventilator, duration of intensive care unit and hospital stay, prevalence and severity of primary graft dysfunction, acute rejection, infection, and CLAD-free and overall survival.
Results
FEV was not significantly different between the 2 groups (p = 0.41). Patients treated with azithromycin demonstrated less airway inflammation, with lower bronchoalveolar lavage (BAL) neutrophilia and BAL interleukin-8 protein levels at Day 30 (p = 0.09 and p = 0.04, respectively) and Day 90 (p = 0.002 and p = 0.08, respectively) after LTx. Other secondary outcomes were not significantly different between placebo and azithromycin groups.
Conclusions
Pre-transplant and prompt post-transplant azithromycin treatment was not able to improve early lung allograft function. However, the known anti-inflammatory properties of azithromycin were confirmed (NCT01915082).

Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 27 Feb 2019; 38:252-259
Van Herck A, Frick AE, Schaevers V, Vranckx A, ... Verleden GM, Vos R
J Heart Lung Transplant: 27 Feb 2019; 38:252-259 | PMID: 30686699
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Abstract

Prothrombotic activity of cytokine-activated endothelial cells and shear-activated platelets in the setting of ventricular assist device support.

Apostoli A, Bianchi V, Bono N, Dimasi A, ... Slepian MJ, Consolo F
Background
We systematically analyzed the synergistic effect of: (i) cytokine-mediated inflammatory activation of endothelial cells (ECs) with and (ii) shear-mediated platelet activation (SMPA) as a potential contributory mechanism to intraventricular thrombus formation in the setting of left ventricular assist device (LVAD) support.
Methods
Intact and shear-activated human platelets were exposed to non-activated and cytokine-activated ECs. To modulate the level of LVAD-related shear activation, platelets were exposed to shear stress patterns of varying magnitude (30, 50, and 70 dynes/cm, 10 minutes) via a hemodynamic shearing device. ECs were activated via exposure to inflammatory tumor necrosis factor-α (TNF-α 10 and 100 ng/ml, 24 hours), consistent with inflammatory activation recorded in patients on LVAD circulatory support.
Results
Adhesivity of shear-activated platelets to ECs was significantly higher than that of intact/unactivated platelets, regardless of the initial activation level (70 dynes/cm shear-activated platelets vs intact platelets: +80%, p < 0.001). Importantly, inflammatory activation of ECs amplified platelet prothrombinase activity progressively with increasing shear stress magnitude and TNF-α concentration: thrombin generation of 70 dynes/cm shear-activated platelets was 2.6-fold higher after exposure and adhesion to 100 ng/ml TNF-α‒activated ECs (p < 0.0001).
Conclusions
We demonstrated synergistic effect of SMPA and cytokine-mediated EC inflammatory activation to enhance EC‒platelet adhesion and platelet prothrombotic function. These mechanisms may contribute to intraventricular thrombosis in the setting of mechanical circulatory support.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 May 2019; 38:658-667
Apostoli A, Bianchi V, Bono N, Dimasi A, ... Slepian MJ, Consolo F
J Heart Lung Transplant: 30 May 2019; 38:658-667 | PMID: 30846234
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Abstract

Infectious complications after heart transplantation in patients screened with gene expression profiling.

Moayedi Y, Gomez CA, Fan CPS, Miller RJH, ... Montoya JG, Teuteberg JJ
Background
The risk of infection after heart transplantation is highest within the first year and represents the leading cause of early mortality. In this cohort of patients enrolled in the Outcomes AlloMap Registry (OAR), we sought to describe infection episodes (IEp) resulting in hospitalization, in the early (<1 year) and late (≥1 year) post-transplant period and determine the impact of immunosuppression on incidence of infection.
Methods
The primary aim was to assess the incidence and nature of IEp. The secondary aim was to evaluate the effect of potential risk factors, such as recipient age; sex; body mass index; panel-reactive antibodies; cytomegalovirus (CMV) primary mismatch; prednisone, tacrolimus, and sirolimus levels; and gene expression profile (GEP) score, in the development of IEp.
Results
The OAR comprises 1,504 patients, of whom 220 patients (14.6%) had an IEp during a median follow-up period of 382 days (interquartile range [IQR] 230 to 579 days). The cause-specific 5-year hazard ratio for any infection was 2.029 (p = 0.12). The pattern of early infection was consistent with nosocomial and opportunistic causes, whereas later infection was consistent with late-onset opportunistic and community-acquired etiologies. Sixty-two percent of the infections occurred early. In the time-dependent analysis, higher prednisone dose (log prednisone, hazard ratio [HR] 1.30, p = 0.022) was the most significant risk factor for all IEp.
Conclusions
In the OAR cohort, the majority of infections occurred within 1 year after transplantation. Clinicians may consider more aggressive prednisone withdrawal in low-risk patients to reduce IEp.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 May 2019; 38:611-618
Moayedi Y, Gomez CA, Fan CPS, Miller RJH, ... Montoya JG, Teuteberg JJ
J Heart Lung Transplant: 30 May 2019; 38:611-618 | PMID: 30704838
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Abstract

Mitochondrial integrity during early reperfusion in an isolated rat heart model of donation after circulatory death-consequences of ischemic duration.

Wyss RK, Méndez-Carmona N, Sanz MN, Arnold M, ... Tevaearai Stahel HT, Longnus SL
Background
Cardioprotection and graft evaluation after ischemia-reperfusion (IR) are essential in facilitating heart transplantation with donation after circulatory death. Given the key role of mitochondria in IR, we aimed to investigate the tolerance of cardiac mitochondria to warm, global ischemia and to determine the predictive value of early reperfusion mitochondria-related parameters for post-ischemic cardiac recovery.
Methods
Isolated, working rat hearts underwent 0, 21, 24, 27, 30, or 33 minutes of warm, global ischemia, followed by 60 minutes of reperfusion. Functional recovery (developed pressure × heart rate) was determined at 60 minutes of reperfusion, whereas mitochondrial integrity was measured at 10 minutes of reperfusion.
Results
Functional recovery at 60 minutes of reperfusion decreased with ≥ 27 minutes of ischemia vs no ischemia (n = 7-8/group; p < 0.01). Cytochrome c, succinate release, and mitochondrial Ca content increased with ≥ 27 minutes of ischemia vs no ischemia (p < 0.05). Ischemia at ≥ 21 minutes decreased mitochondrial coupling, adenosine 5\'-triphosphate content, mitochondrial Ca retention capacity, and increased oxidative damage vs no ischemia (p < 0.05). Reactive oxygen species (ROS) from reverse electron transfer increased with 21 and 27 minutes of ischemia vs no ischemia and 33 minutes of ischemia (p < 0.05), whereas ROS from forward electron transfer increased only with 33 minutes of ischemia vs no ischemia (p < 0.05). Mitochondrial coupling and adenosine 5\'-triphosphate content correlated positively and cytochrome c, succinate, oxidative damage, and mitochondrial Ca content correlated negatively with cardiac functional recovery (p < 0.05).
Conclusions
Mitochondrial dysfunction occurs with shorter periods of ischemia than cardiac dysfunction. Mitochondrial coupling, ROS emission from reverse electron transfer, and calcium retention are particularly sensitive to early reperfusion injury, reflecting potential targets for cardioprotection. Indicators of mitochondrial integrity may be of aid in evaluating suitability of donation after circulatory death grafts for transplantation.

Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 May 2019; 38:647-657
Wyss RK, Méndez-Carmona N, Sanz MN, Arnold M, ... Tevaearai Stahel HT, Longnus SL
J Heart Lung Transplant: 30 May 2019; 38:647-657 | PMID: 30655178
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Abstract

Cardiac allograft vasculopathy and graft failure in pediatric heart transplant recipients after rejection with severe hemodynamic compromise.

Kleinmahon JA, Gralla J, Kirk R, Auerbach SR, ... Savage AJ, Everitt MD
Background
Rejection with severe hemodynamic compromise (RSHC) carries a mortality risk approaching 50%. We aimed to identify current risk factors for RSHC and predictors of graft failure after RSHC.
Methods
Data from 3,259 heart transplant (HT) recipients between January 2005 and December 2015 in the Pediatric Heart Transplant Study (PHTS) were analyzed. Predictors for RSHC and outcome after RSHC were sought. Time to RSHC was analyzed using the Cox proportional hazards regression model. Cardiac allograft vasculopathy (CAV) after HT and CAV after RSHC were analyzed as time-dependent covariates. Timing of RSHC was analyzed as occurring before and after 4 years after RSHC.
Results
There were 309 patients (9.5%) with ≥ 1 RSHC episodes. In 143 patients with RSHC, the first episode was within 1 year after HT. Independent risk factors for RSHC were age 1 to 5 years at HT (hazard ratio [HR], 1.51; 95% confidence interval [CI], 1.04-2.18), age > 10 years at HT (HR, 1.83; 95% CI, 1.29-2.60), black race (HR, 1.64; 95% CI, 1.25-2.15), prior cardiac surgery (HR, 1.55; 95% CI, 1.03-2.31), ventricular assist device support at HT (HR, 1.65; 95% CI, 1.18-2.29), maintenance steroids (HR, 1.39; 95% CI, 1.06-1.82), and recipient on inotropes, pressors, or thyroid hormones (HR, 1.45; 95% CI, 1.09-1.94). Graft survival at 5 years after RSHC was 45.7%. RSHC was a greater risk factor for earlier CAV (HR, 7.78; 95% CI, 5.82-10.40) than other rejection types (HR, 2.31; 95% CI, 1.79-3.00). Patients with late RSHC, after 1 year after RSHC had increased risk of graft loss 4 years after RSHC (HR, 7.12; 95% CI, 2.18-23.22). The 5-year graft survival after RSHC was 50.5% for early RSHC and 39.0% for late RSHC.
Conclusions
Mortality after RSHC is high in the current treatment era. Many patient risk factors for RSHC cannot be modified, including age, race, prior cardiac surgery, and ventricular assist device support. After RSHC, CAV is the only predictor of graft failure. Patients who have late RSHC fare worse than those who have RSHC within the first year after HT.

Copyright © 2019 Elsevier Ltd. All rights reserved.

J Heart Lung Transplant: 27 Feb 2019; 38:277-284
Kleinmahon JA, Gralla J, Kirk R, Auerbach SR, ... Savage AJ, Everitt MD
J Heart Lung Transplant: 27 Feb 2019; 38:277-284 | PMID: 30638837
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Abstract

Feasibility of lung microdialysis to assess metabolism during clinical ex vivo lung perfusion.

Mazzeo AT, Fanelli V, Boffini M, Medugno M, ... Ranieri VM, Mascia L
Background
Lung metabolism during ex vivo lung perfusion (EVLP) is increasingly studied. Microdialysis (MD) allows metabolic monitoring by sampling parenchymal interstitial fluid. This study investigated lung metabolism using MD during EVLP and evaluated whether microdialysate metabolites could improve selection and discriminate outcome of donor lungs.
Methods
MD monitoring was used during 14 clinical EVLP procedures. Paired microdialysate and perfusate samples were analyzed for glucose, lactate, pyruvate, glutamate, and the lactate/pyruvate (L/P) ratio, and values that best discriminated an unfavorable outcome were determined. Outcome was defined as unfavorable (lungs not transplanted or transplanted with primary graft dysfunction at 72 hours ≥ 2) or favorable (lungs transplanted with primary graft dysfunction < 2).
Results
Microdialysate markers and the perfusate L/P ratio could discriminate unfavorable outcome with sensitivity and specificity of 0.85 and 0.81 for MD glutamate > 18.4 μmol/liter, 0.81 and 0.74 for MD lactate > 685 μmol/liter, 0.92 and 0.75 for MD glucose > 530 μmol/liter, 0.85 and 0.65 for MD pyruvate > 25 μmol/liter, and 0.73 and 0.67 for perfusate L/P ratio > 24.17. All microdialysate markers, perfusate and microdialysate L/P ratio, and perfusate lactate discriminated outcome when we limited analysis only to transplanted lungs.
Conclusions
We report the use of MD to evaluate lung metabolism during clinical EVLP, demonstrating that MD metabolites can contribute to selection of reconditioned lungs and discriminate early outcome after transplantation. Furthermore, glutamate as a marker of lung injury during EVLP is proposed and could hence be used as a potential target for future therapies.

Copyright © 2018 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 27 Feb 2019; 38:267-276
Mazzeo AT, Fanelli V, Boffini M, Medugno M, ... Ranieri VM, Mascia L
J Heart Lung Transplant: 27 Feb 2019; 38:267-276 | PMID: 30642797
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This program is still in alpha version.