Journal: J Heart Lung Transplant

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Abstract

Implantable cardioverter defibrillators in left ventricular assist device patients: Α systematic review and meta-analysis.

Rorris FP, Antonopoulos CN, Kyriakopoulos CP, Drakos SG, Charitos C
Implantable cardioverter-defibrillators (ICDs) remain the standard of care in advanced heart failure with reduced ejection fraction patients for the prevention of sudden cardiac death. However, current guidelines remain conflicting with respect to the use of ICDs in patients supported with a continuous flow left ventricular assist device (CF-LVAD). The current review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Studies comparing the use of ICD in patients with CF-LVADs were included. The 2 primary outcomes studied were all-cause mortality, and a successful bridge to heart transplantation. We calculated pooled odds ratios (ORs) with 95% confidence intervals (CIs). We also compared baseline characteristics between US and European studies, for CF-LVAD patients with an ICD. Among all studies, the use of an ICD was not associated with all-cause mortality in patients with CF-LVADs (OR: 0.85, 95% CIs: 0.64-1.12, p = 0.24). The presence of an ICD was associated with a trend towards increased likelihood of successful bridge to heart transplantation (OR: 1.12, 95% CI: 1.0-1.3, p = 0.06). A subgroup analysis of studies published by European centers revealed a significant decrease in pooled mortality (OR: 0.58, 95% CI: 0.4-0.83, p = 0.003) with the use of ICD, contrary to an increase in pooled mortality among studies published by US centers (OR: 1.2, 95% CI 1.02-1.33, p = 0.025). Moreover, we identified significant differences in baseline characteristics such as bridge to transplantation rate, Interagency Registry for Mechanically Assisted Circulatory Support profiles, and use of an intra-aortic balloon pump or extracorporeal membrane oxygenation preoperatively, between the US and European populations. While this meta-analysis did not show an overall survival benefit with the use of an ICD in CF-LVAD patients, it revealed significant differences in the derived benefit, in distinct patient populations. This might reflect differences in baseline patient characteristics and warrants further investigation.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1098-1106
Rorris FP, Antonopoulos CN, Kyriakopoulos CP, Drakos SG, Charitos C
J Heart Lung Transplant: 29 Sep 2021; 40:1098-1106 | PMID: 34176727
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Abstract

IRF4 ablation in B cells abrogates allogeneic B cell responses and prevents chronic transplant rejection.

Wang G, Zou D, Wang Y, Gonzalez NM, ... Chen W, Gaber AO
Backgound
B cells contribute to chronic transplant rejection by producing donor-specific antibodies and promoting T cell response, but how these processes are regulated at the transcriptional level remains unclear. Herein, we investigate the role of transcription factor interferon regulatory factor 4 (IRF4) in controlling B cell response during chronic transplant rejection.
Methods
We generated the Irf4gfp reporter mice to determine IRF4 expression in B cell lineage. We then used mice with B cell-specific IRF4 deletion to define the role of IRF4 in B cell response after NP-KLH immunization or allogeneic heart transplantation. In particular, graft survival and histology, as well as B and T cell responses, were evaluated after transplantation.
Results
IRF4 is dynamically expressed at different stages of B cell development and is absent in germinal center (GC) B cells. However, IRF4 ablation in the B cell lineage primarily eliminates GC B cells in both naïve and NP-KLH immunized mice. In the transplantation setting, IRF4 functions intrinsically in B cells and governs allogeneic B cell responses at multiple levels, including GC B cell generation, plasma cell differentiation, donor-specific antibody production, and support of T cell response. B cell-specific IRF4 deletion combined with transient CTLA4-Ig treatment abrogates acute and chronic cardiac allograft rejection in naïve recipient mice but not in donor skin-sensitized recipients.
Conclusions
B cells require IRF4 to mediate chronic transplant rejection. IRF4 ablation in B cells abrogates allogeneic B cell responses and may also inhibit the ability of B cells to prime allogenic T cells. Targeting IRF4 in B cells represents a potential therapeutic strategy for eliminating chronic transplant rejection.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1122-1132
Wang G, Zou D, Wang Y, Gonzalez NM, ... Chen W, Gaber AO
J Heart Lung Transplant: 29 Sep 2021; 40:1122-1132 | PMID: 34253454
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Abstract

Development and validation of specific post-transplant risk scores according to the circulatory support status at transplant: A UNOS cohort analysis.

Coutance G, Bonnet G, Kransdorf EP, Loupy A, ... Kobashigawa JA, Patel JK
Background
The clinical use of post-transplant risk scores is limited by their poor statistical performance. We hypothesized that developing specific prognostic models for each type of circulatory support at transplant may improve risk stratification.
Methods
We analyzed the UNOS database including contemporary, first, non-combined heart transplantations (2013-2018). The endpoint was death or retransplantation during the first year post-transplant. Three different circulatory support statuses at transplant were considered: no support, durable mechanical support and temporary support (inotropes, temporary mechanical support). We generated 1,000 bootstrap samples that we randomly split into derivation and test sets. In each sample, we derived an overall model and 3 specific models (1 for each type of circulatory support) using Cox regressions, and compared, in the test set, their statistical performance for each type of circulatory support.
Results
A total of 13,729 patients were included; 1,220 patients (8.9%) met the composite endpoint. Circulatory support status at transplant was associated with important differences in baseline characteristics and distinct prognosis (p = 0.01), interacted significantly with important predictive variables included in the overall model, and had a major impact on post-transplant predictive models (type of variables included and their corresponding hazard ratios). However, specific models suffered from poor discriminative performance and significantly improved risk stratification (discrimination, reclassification indices, calibration) compared to overall models in a very limited proportion of bootstrap samples (<15%). These results were consistent across several sensitivity analyzes.
Conclusion
Circulatory support status at transplant reflected different disease states that influenced predictive models. However, developing specific models for each circulatory support status did not significantly improve risk stratification.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1235-1246
Coutance G, Bonnet G, Kransdorf EP, Loupy A, ... Kobashigawa JA, Patel JK
J Heart Lung Transplant: 29 Sep 2021; 40:1235-1246 | PMID: 34274182
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Abstract

Outcomes of pre- heart transplantation desensitization in a series of highly sensitized patients bridged with left ventricular assist devices.

Saadi TA, Lawrecki T, Narang N, Joshi A, ... Cotts W, Andrade A
Desensitization therapy for heart transplantation (HT) candidates can shorten transplant wait times and broaden the donor pool. Specific evidence-based recommendations on both protocols and indications are lacking. We retrospectively assessed left ventricular assist devices-bridged candidates who received pre-HT desensitization therapy. The therapeutic protocol consisted of intravenous immunoglobulin and rituximab followed by bortezomib and plasmapheresis if an insufficient response was achieved. Desensitization was attempted in 10 patients; only 7 tolerated therapy and underwent transplant. For those patients, median decrease in unacceptable calculated panel reactive antibody was 11%; there was no significant decrease for 3 patients. Post-desensitization adverse events were observed in all patients which included coagulopathy, bone marrow suppression, and infection. Median time to first infection was 16 days. One patient had clinically significant rejection and 3 patients had uptrending donor-specific antibodies. Decisions to proceed with desensitization should be individualized understanding potential risks and benefits.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1107-1111
Saadi TA, Lawrecki T, Narang N, Joshi A, ... Cotts W, Andrade A
J Heart Lung Transplant: 29 Sep 2021; 40:1107-1111 | PMID: 34281777
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Abstract

Serial right heart catheter assessment between balloon pulmonary angioplasty sessions identify procedural factors that influence response to treatment.

Hug KP, Gerry Coghlan J, Cannon J, Taboada D, ... Pepke-Zaba J, Hoole SP
Background
Balloon pulmonary angioplasty (BPA) is delivered as a series of treatments for patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) however, there is little published data on the procedural determinants of outcome.
Methods
Pre- and post-BPA clinical and hemodynamic data, as well as serial hemodynamic and procedural data at each BPA session were evaluated to determine patient and procedure-related factors that influence hemodynamic response.
Results
Per procedure data from 210 procedures in 84 patients and per patient data from 182 procedures in 63 patients with completed treatment and 3-month follow-up were analyzed. A median of 3 (range 1-6) BPA procedures treating a median of 2 segments per procedure (range 1-3) were performed per patient with a median interval between procedures of 42 (range 5-491) days. Clinical outcome correlated with hemodynamic change (pulmonary vascular resistance [ΔPVR] vs Cambridge Pulmonary Hypertension Outcome Review [CAMPHOR] symptom score: p < 0.001, Pearson\'s r = 0.48, n = 49). Responders to BPA had more severe disease at baseline and 37.5 % of non-responders were post-PEA. There was a dose-response relationship between per procedure and total number of segments treated and hemodynamic improvement (ΔPVR: 1 segment: -0.9%, 2: -14.5%, 3 or more: -16.1%, p < 0.001). Treating totally occluded vessels had a greater hemodynamic effect (mean pulmonary artery pressure [ΔmPAP]: sessions with occlusion: -8.0%, without occlusion treated: -3.2%, p < 0.05) without an increased complication rate.
Conclusions
The magnitude of clinical benefit is related to the hemodynamic effect of BPA which in turn is related to the number of segments treated and lesion severity. Patients who were post-PEA were less likely to respond to BPA.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1223-1234
Hug KP, Gerry Coghlan J, Cannon J, Taboada D, ... Pepke-Zaba J, Hoole SP
J Heart Lung Transplant: 29 Sep 2021; 40:1223-1234 | PMID: 34303575
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Abstract

Favorable outcomes after heart transplantation in Barth syndrome.

Li Y, Godown J, Taylor CL, Dipchand AI, Bowen VM, Feingold B
Background
Barth Syndrome (BTHS) is a rare, X-linked disease characterized by cardioskeletal myopathy and neutropenia. Comparative outcomes after heart transplantation have not been reported.
Methods
We identified BTHS recipients across 3 registries (Pediatric Heart Transplant Study Registry [PHTS], Barth Syndrome Research Registry and Repository, and Scientific Registry of Transplant Recipient-Pediatric Health Information System) and matched them 1:4 to non-BTHS, male heart transplant (HT) recipients listed with dilated cardiomyopathy in PHTS. Demographics and survival data were analyzed for all recipients, whereas post-HT infection, malignancy, allograft vasculopathy, and acute rejection were only available for analysis for individuals with PHTS data.
Results
Forty-seven BTHS individuals with 51 listings and 43 HTs (including 2 re-transplants) were identified. Age at primary HT was 1.7 years (IQR: 0.6-4.5). Mechanical circulatory support at HT was common (ventricular assist device 29%, extracorporeal membrane oxygenation 5%). Over a median follow-up of 4.5 years (IQR 2.7-9.1), survival for BTHS HT recipients was no different than non-BTHS HT recipients (HR 0.91, 95% CI 0.40-2.12, p = 0.85). Among those with PHTS data (n = 28), BTHS HT recipients showed no difference in freedom from infection (HR 0.64, 0.34-1.22; p = 0.18), malignancy (HR 0.22, 0.02-2.01, p = 0.18), and allograft vasculopathy (HR 0.58, 0.16-2.1, p = 0.41). Freedom from acute rejection (HR 0.39, 0.17-0.86, p = 0.02) was greater for BTHS HT recipients despite similar use of induction (61 vs 73%, p = 0.20), steroids at 30-days (75 vs 62%, p = 0.27), and dual/triple drug immunosuppression at 1-year (80 vs 84%, p = 0.55).
Conclusions
In this largest cohort yet reported, individuals with BTHS have equivalent survival with less acute rejection and no difference in infection or malignancy after HT. When indicated, HT for individuals with BTHS is appropriate.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1191-1198
Li Y, Godown J, Taylor CL, Dipchand AI, Bowen VM, Feingold B
J Heart Lung Transplant: 29 Sep 2021; 40:1191-1198 | PMID: 34330606
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Abstract

Serum biomarkers of acute rejection: Towards precision medicine in heart transplant.

Ortiz-Bautista C, Fernández-Avilés F, Delgado Jiménez JF
Despite the important changes in the management of heart transplantation in the recent decades, the use of endomyocardial biopsy is still necessary for the follow-up of these patients. However, this technique has several limitations, the most important being the substantial interobserver variability. In the last years multiple attempts have been made to find non-invasive assays for cardiac allograft surveillance, such as imaging modalities and serum biomarkers. This state-of-the-art review focuses on describing the different serum biomarkers that have been proposed for non-invasive diagnosis of acute rejection and that are paving the way towards precision medicine in the field of heart transplantation.

Copyright © 2021. Published by Elsevier Inc.

J Heart Lung Transplant: 29 Sep 2021; 40:1090-1097
Ortiz-Bautista C, Fernández-Avilés F, Delgado Jiménez JF
J Heart Lung Transplant: 29 Sep 2021; 40:1090-1097 | PMID: 34330605
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Abstract

Phosphorylated S6 ribosomal protein expression by immunohistochemistry correlates with de novo donor-specific HLA antibodies in lung allograft recipients.

Cone BD, Zhang JQ, Sosa RA, Calabrese F, Reed EF, Fishbein GA
Background
Per the ISHLT 2016 definition, a C4d-positive lung biopsy is required to meet criteria for definite antibody-mediated rejection (AMR). Unfortunately, C4d has poor sensitivity and specificity, and low inter-rater reliability. Phosphorylated S6 ribosomal protein (p-S6RP) expressed via the mTOR pathway has been shown to be a biomarker of AMR and correlates with donor-specific antibodies (DSA) in heart allografts. However, p-S6RP immunohistochemistry (IHC) in the setting of pulmonary AMR has yet to be evaluated. We sought to determine whether p-S6RP IHC performed on lung biopsies correlates with de novo DSA.
Methods
IHC for p-S6RP performed on 26 biopsies from lung transplant recipients with de novo HLA DSA (DSA+) and 28 biopsies from patients with no DSA (DSA-) were evaluated by 3 pathologists who independently scored the degree of alveolar macrophage and pneumocyte staining. Staining in ≥50% of the biopsy as determined by at least 2 pathologists was considered positive.
Results
Twenty-one (81%) DSA+ biopsies stained positive for p-S6RP in pneumocytes and 21 (81%) in macrophages. Six DSA- biopsies (21%) stained positive for p-S6RP in pneumocytes, 6 (21%) were positive in macrophages. Pneumocyte p-S6RP staining was 81% sensitive and 79% specific for DSA. Macrophage staining showed the same sensitivity and specificity but with lower inter-rater agreement (κ = 0.53 vs 0.68).
Conclusions
This study demonstrates a positive relationship between de novo DSA and p-S6RP expression in pneumocytes and macrophages using IHC. p-S6RP is relatively sensitive and specific, and has superior inter-rater reliability compared to C4d.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1164-1171
Cone BD, Zhang JQ, Sosa RA, Calabrese F, Reed EF, Fishbein GA
J Heart Lung Transplant: 29 Sep 2021; 40:1164-1171 | PMID: 34330604
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Abstract

Plasma kallikrein predicts primary graft dysfunction after heart transplant.

Giangreco NP, Lebreton G, Restaino S, Jane Farr M, ... Tatonetti NP, Fine BM
Background
Primary graft dysfunction (PGD) is the leading cause of early mortality after heart transplant. Pre-transplant predictors of PGD remain elusive and its etiology remains unclear.
Methods
Microvesicles were isolated from 88 pre-transplant serum samples and underwent proteomic evaluation using TMT mass spectrometry. Monte Carlo cross validation (MCCV) was used to predict the occurrence of severe PGD after transplant using recipient pre-transplant clinical characteristics and serum microvesicle proteomic data. Putative biological functions and pathways were assessed using gene set enrichment analysis (GSEA) within the MCCV prediction methodology.
Results
Using our MCCV prediction methodology, decreased levels of plasma kallikrein (KLKB1), a critical regulator of the kinin-kallikrein system, was the most predictive factor identified for PGD (AUROC 0.6444 [0.6293, 0.6655]; odds 0.1959 [0.0592, 0.3663]. Furthermore, a predictive panel combining KLKB1 with inotrope therapy achieved peak performance (AUROC 0.7181 [0.7020, 0.7372]) across and within (AUROCs of 0.66-0.78) each cohort. A classifier utilizing KLKB1 and inotrope therapy outperforms existing composite scores by more than 50 percent. The diagnostic utility of the classifier was validated on 65 consecutive transplant patients, resulting in an AUROC of 0.71 and a negative predictive value of 0.92-0.96. Differential expression analysis revealed a enrichment in inflammatory and immune pathways prior to PGD.
Conclusions
Pre-transplant level of KLKB1 is a robust predictor of post-transplant PGD. The combination with pre-transplant inotrope therapy enhances the prediction of PGD compared to pre-transplant KLKB1 levels alone and the resulting classifier equation validates within a prospective validation cohort. Inflammation and immune pathway enrichment characterize the pre-transplant proteomic signature predictive of PGD.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1199-1211
Giangreco NP, Lebreton G, Restaino S, Jane Farr M, ... Tatonetti NP, Fine BM
J Heart Lung Transplant: 29 Sep 2021; 40:1199-1211 | PMID: 34330603
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Impact:
Abstract

Improved heart transplant survival for children with congenital heart disease and heterotaxy syndrome in the current era: An analysis from the pediatric heart transplant society.

Khan A, Pahl E, Koehl DA, Cantor RS, ... Azeka E, Everitt MD
Background
Challenges exist with heterotaxy due to the complexity of heart disease, abnormal venous connections, and infection risks. This study aims to understand heart transplant outcomes for children with heterotaxy.
Methods
All children with congenital heart disease listed for transplant from 1993 to 2018 were included. Those with and without heterotaxy were compared. Waitlist outcomes and survival post-listing and transplant were analyzed. Post-transplant risk factors were identified using multiphase parametric hazard modeling.
Results
There were 4814 children listed, of whom 196 (4%) had heterotaxy. Heterotaxy candidates were older (5.8 ± 5.7 vs 4.2 ± 5.5 years, p < 0.01), listed at a lower urgency status (29.8% vs 18.4%, p < 0.01), more commonly single ventricle physiology (71.3% vs 59.2%, p < 0.01), and less often supported by mechanical ventilation (22% vs 29.1%, p < 0.05) or extracorporeal membrane oxygenation (3.6% vs 7.5%, p < 0.05). There were no differences in waitlist outcomes of transplant, death, or removal. Overall, post-transplant survival was worse for children with heterotaxy: one-year survival 77.2% vs 85.1%, with and without heterotaxy, respectively. Heterotaxy was an independent predictor for early mortality in the earliest era (1993-2004), HR 2.09, CI 1.16-3.75, p = 0.014. When stratified by era, survival improved with time. Heterotaxy patients had a lower freedom from infection and from severe rejection, but no difference in vasculopathy or malignancy.
Conclusions
Mortality risk associated with heterotaxy is mitigated in the recent transplant era. Early referral may improve waitlist outcomes for heterotaxy patients who otherwise have a lower status at listing. Lower freedom from both infection and severe rejection after transplant in heterotaxy highlights the challenges of balancing immune suppression.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1153-1163
Khan A, Pahl E, Koehl DA, Cantor RS, ... Azeka E, Everitt MD
J Heart Lung Transplant: 29 Sep 2021; 40:1153-1163 | PMID: 34366230
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Impact:
Abstract

Increasing the efficacy and safety of a human complement inhibitor for treating post-transplant cardiac ischemia reperfusion injury by targeting to a graft-specific neoepitope.

Zheng C, Sleiman MM, Yang X, He S, Atkinson C, Tomlinson S
Background
Post-transplant ischemia reperfusion injury (IRI) is a recognized risk factor for subsequent organ dysfunction, alloresponsiveness, and rejection. The complement system is known to play a role in IRI and represents a therapeutic target. Complement is activated in transplanted grafts when circulating IgM antibodies bind to exposed ischemia-induced neoepitopes upon reperfusion, and we investigated the targeting of a human complement inhibitor, CR1, to a post-transplant ischemia-induced neoepitope.
Methods
A fragment of human CR1 was linked to a single chain antibody construct (C2 scFv) recognizing an injury-specific neoepitope to yield C2-CR1. This construct, along with a soluble untargeted counterpart, was characterized in a cardiac allograft transplantation model of IRI in terms of efficacy and safety.
Results
CR1 was similarly effective against mouse and human complement. C2-CR1 provided effective protection against cardiac IRI at a lower dose than untargeted CR1. The increased efficacy of C2-CR1 relative to CR1 correlated with decreased C3 deposition, and C2-CR1, but not CR1, targeted to cardiac allografts. At a dose necessary to reduce IRI, C2-CR1 had minimal impact on serum complement activity, in contrast to CR1 which resulted in a high level of systemic inhibition. The circulatory half-life of CR1 was markedly longer than that of C2-CR1, and whereas a minimum therapeutic dose of CR1 severely impaired host susceptibility to infection, C2-CR1 had no impact.
Conclusion
We show the translational potential of a human complement inhibitor targeted to a universal ischemia-induced graft-specific epitope, and demonstrate advantages compared to an untargeted counterpart in terms of efficacy and safety.

Published by Elsevier Inc.

J Heart Lung Transplant: 29 Sep 2021; 40:1112-1121
Zheng C, Sleiman MM, Yang X, He S, Atkinson C, Tomlinson S
J Heart Lung Transplant: 29 Sep 2021; 40:1112-1121 | PMID: 34334299
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Impact:
Abstract

The modified US heart allocation system improves transplant rates and decreases status upgrade utilization for patients with hypertrophic cardiomyopathy.

Fowler CC, Helmers MR, Smood B, Iyengar A, ... Kelly J, Atluri P
Background
On October 18, 2018, the US heart allocation policy was restructured to improve transplant waitlist outcomes. Previously, hypertrophic cardiomyopathy (HCM) patients experienced significant waitlist mortality and functional decline, often requiring status exemptions to be transplanted. This study aims to examine changes in waitlist mortality and transplant rates of HCM patients in the new system.
Methods
Retrospective analysis was performed of the United Network for Organ Sharing Transplant Database for all isolated adult single-organ first-time heart transplant patients with HCM listed between October 17, 2013 and September 4, 2020. Patients were divided by listing date into eras based on allocation system. Era 1 spanned October 17, 2013 to October 17th, 2018 and Era 2 spanned October 18th, 2018 to September 4, 2020.
Results
During the study period, 436 and 212 HCM patients were listed in Eras 1 and 2, respectively. Across eras, no differences in gender, ethnicity, BMI or functional status were noted (p>0.05). LVAD utilization remained low (Era 1: 3.7% vs Era 2: 3.3%, p = 0.297). Status upgrades decreased from 49.1% to 31.6% across eras (p = 0.001). There was no statistically significant difference in waitlist mortality across eras (p = 0.332). Transplant rates were improved in Era 2 (p = 0.005). Waitlist time among transplanted patients decreased in Era 2 from 97.1 to 63.9 days (p<0.001). There was no difference in one-year survival post-transplant (p = 0.602).
Conclusions
The new allocation system has significantly increased transplant rates, shortened waitlist times, and decreased status upgrade utilization for HCM patients. Moreover, waitlist mortality remained unchanged in the new system.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1181-1190
Fowler CC, Helmers MR, Smood B, Iyengar A, ... Kelly J, Atluri P
J Heart Lung Transplant: 29 Sep 2021; 40:1181-1190 | PMID: 34332861
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Impact:
Abstract

Venous thromboembolism in lung transplant recipients real world experience from a high volume center.

Zheng M, Yousef I, Mamary AJ, Zhao H, ... Rali P, Sehgal S
Background
Venous thromboembolism (VTE) post lung transplantation is common and has been associated with worse post transplant survival. We report a comprehensive single center review of VTE incidence in the first post transplant year, investigate modifiable risk factors and assess impact on short term outcomes.
Methods
Retrospective review of all lung transplant recipients between August 2016 to 2018 at Temple University Hospital. Patients were followed for 1 year post transplant. All patients were screened for deep venous thrombosis (DVT) within the first 2 weeks with a venous duplex study. Pre transplant, intra operative, post operative variables, and peri-operative practice patterns were compared between VTE positive and VTE negative groups. Logistic regression modeling was used to identify risk factors for early VTE (VTE within 30 days after transplant).
Results
A total of 235 patients were included in the study, 58 patients (24.7%) developed a VTE in the first post transplant year. Median time to diagnosis was 17 days. Of the patients with VTE, 76% had an isolated DVT, 13.5 % had an isolated pulmonary embolism (PE), and 10.3% had concomitant DVT and PE. In a multivariate logistic regression model, cardiopulmonary bypass (CPB) (OR 1.93 p = 0.015) and interruption of VTE prophylaxis (OR 4.42 p < 0.0001) were predictive of early VTE.
Conclusion
VTE post lung transplant is common despite the use of prophylactic anticoagulation. CPB use and interruption of DVT prophylaxis are risk factors for early post transplant VTE. Measures to ensure consistent and uninterrupted prophylaxis may help decrease VTE incidence after lung transplantation.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1145-1152
Zheng M, Yousef I, Mamary AJ, Zhao H, ... Rali P, Sehgal S
J Heart Lung Transplant: 29 Sep 2021; 40:1145-1152 | PMID: 34389222
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Impact:
Abstract

Effect of riociguat on right ventricular function in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

Benza RL, Ghofrani HA, Grünig E, Hoeper MM, ... Meier C, Ghio S
Background
In the Phase III PATENT-1 (NCT00810693) and CHEST-1 (NCT00855465) studies, riociguat demonstrated efficacy vs placebo in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Clinical effects were maintained at 2 years in the long-term extension studies PATENT-2 (NCT00863681) and CHEST-2 (NCT00910429).
Methods
This post hoc analysis of hemodynamic data from PATENT-1 and CHEST-1 assessed whether riociguat improved right ventricular (RV) function parameters including stroke volume index (SVI), stroke volume, RV work index, and cardiac efficiency. REVEAL Risk Score (RRS) was calculated for patients stratified by SVI and right atrial pressure (RAP) at baseline and follow-up. The association between RV function parameters and SVI and RAP stratification with long-term outcomes was assessed.
Results
In PATENT-1 (n = 341) and CHEST-1 (n = 238), riociguat improved RV function parameters vs placebo (p < 0.05). At follow-up, there were significant differences in RRS between patients with favorable and unfavorable SVI and RAP, irrespective of treatment arm (p < 0.0001). Multiple RV function parameters at baseline and follow-up were associated with survival and clinical worsening-free survival (CWFS) in PATENT-2 (n = 396; p < 0.05) and CHEST-2 (n = 237). In PATENT-2, favorable SVI and RAP at follow-up only was associated with survival and CWFS (p < 0.05), while in CHEST-2, favorable SVI and RAP at baseline and follow-up were associated with survival and CWFS (p < 0.05).
Conclusion
This post hoc analysis of PATENT and CHEST suggests that riociguat improves RV function in patients with PAH and CTEPH.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1172-1180
Benza RL, Ghofrani HA, Grünig E, Hoeper MM, ... Meier C, Ghio S
J Heart Lung Transplant: 29 Sep 2021; 40:1172-1180 | PMID: 34353714
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Impact:
Abstract

Lung protective ventilation based on donor size is associated with a lower risk of severe primary graft dysfunction after lung transplantation.

Tague LK, Bedair B, Witt C, Byers DE, ... Gelman A, Hachem RR
Background
Mechanical ventilation immediately after lung transplantation may impact the development of primary graft dysfunction (PGD), particularly in cases of donor-recipient size mismatch as ventilation is typically based on recipient rather than donor size.
Methods
We conducted a retrospective cohort study of adult bilateral lung transplant recipients at our center between January 2010 and January 2017. We defined donor-based lung protective ventilation (dLPV) as 6 to 8 ml/kg of donor ideal body weight and plateau pressure <30 cm H2O. We calculated the donor-recipient predicted total lung capacity (pTLC) ratio and used logistic regression to examine relationships between pTLC ratio, dLPV and PGD grade 3 at 48 to 72 hours. We used Cox proportional hazards modelling to examine the relationship between pTLC ratio, dLPV and 1-year survival.
Results
The cohort included 373 recipients; 24 (6.4%) developed PGD grade 3 at 48 to 72 hours, and 213 (57.3%) received dLPV. Mean pTLC ratio was 1.04 ± 0.18. dLPV was associated with significantly lower risks of PGD grade 3 (OR = 0.44; 95% CI: 0.29-0.68, p < 0.001) and 1-year mortality (HR = 0.49; 95% CI: 0.29-0.8, p = 0.018). There was a significant association between pTLC ratio and the risk of PGD grade 3, but this was attenuated by the use of dLPV.
Conclusions
dLPV is associated with decreased risk of PGD grade 3 at 48 to 72 hours and decreased 1-year mortality. Additionally, dLPV attenuates the association between pTLC and both PGD grade 3 and 1-year mortality. Donor-based ventilation strategies may help to mitigate the risk of PGD and other adverse outcomes associated with size mismatch after lung transplantation.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1212-1222
Tague LK, Bedair B, Witt C, Byers DE, ... Gelman A, Hachem RR
J Heart Lung Transplant: 29 Sep 2021; 40:1212-1222 | PMID: 34353713
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Impact:
Abstract

Reconditioning of circulatory death hearts by ex-vivo machine perfusion with a novel HTK-N preservation solution.

Saemann L, Korkmaz-Icöz S, Hoorn F, Veres G, ... Karck M, Szabó G
Background
Warm ischemia followed by blood reperfusion is associated with reduced myocardial contractility. Circulatory death (CD) hearts are maintained by machine perfusion (MP) with blood. However, the impact of MP with histidine-tryptophane-ketoglutarate (HTK) or novel HTK-N solution on reconditioning of CD-heart contractility is unknown.
Methods
In a porcine model, native hearts were directly harvested (control), or CD was induced before harvesting, followed by left ventricular (LV) contractile assessment. In MP-groups, CD-hearts were maintained for 4 h by MP with blood (CD-B), cold oxygenated HTK (CD-HTK) or HTK-N (CD-HTK-N) before contractile evaluation (all groups n = 8). We performed immunohistochemistry of LV myocardial samples. We profiled myocardial expression of 84 oxidative stress-related genes and correlated the findings with myocardial contractility via a machine learning algorithm.
Results
HTK-N improved end-systolic pressure (ESP=172±10 vs 132±5 mmHg, p = 0.02) and maximal slope of pressure increment (dp/dtmax=2161±214 vs 1240±167 mmHg/s, p = 0.005) compared to CD, whereas CD-B failed to improve contractility. Dp/dtmax (2161±214 vs 1177±156, p = 0.08) and maximal rate of pressure decrement (dp/dtmin=-1501±228 vs -637±79, p = 0.005) were also superior in CD-HTK-N compared to CD-B. In CD-HTK-N, myocardial 4-hydroxynonenal (marker for oxidative stress; p<0.001), nitrotyrosine (marker for nitrosative stress; p = 0.004), poly(adenosine diphosphate-ribose)polymerase (marker for necrosis; p = 0.028) immunoreactivity and cell swelling (p = 0.008) were decreased compared to CD-B. Strong correlation of gene expression with ESP was identified for oxidative stress defense genes in CD-HTK-N.
Conclusion
During harvesting procedure, MP with HTK-N reconditions CD-heart systolic and diastolic function by reducing oxidative and nitrosative stress and preventing cardiomyocytes from cell swelling and necrosis.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2021; 40:1135-1144
Saemann L, Korkmaz-Icöz S, Hoorn F, Veres G, ... Karck M, Szabó G
J Heart Lung Transplant: 29 Sep 2021; 40:1135-1144 | PMID: 34420849
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Impact:
Abstract

The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-eighth adult lung transplantation report - 2021; Focus on recipient characteristics.

Chambers DC, Perch M, Zuckermann A, Cherikh WS, ... Stehlik J, International Society for Heart and Lung Transplantation
For over 30 years, the International Society for Heart and Lung Transplantation (ISHLT) International Thoracic Organ Transplant (TTX) Registry has gathered data regarding transplant procedures, donor and recipient characteristics, and outcomes from a global community of transplant centers. Almost 70,000 adult lung transplant procedures have been reported to the Registry since its inception, each one providing an opportunity for a recipient with end-stage lung disease to regain quality of life and longevity. With each year\'s report, we provide more detailed analyses on a particular focus theme important to recipient outcomes. Since 2013, these have been donor and recipient age; retransplantation; early graft failure; indication for transplant; allograft ischemic time; multiorgan transplantation; and donor and recipient size matching.1-7 In response to a changing regulatory environment, the ISHLT TTX Registry is undergoing an update in data acquisition, and the patient cohort examined in this report is therefore derived from the same data source or datasets as that examined in the 2019 annual reports.2,8-10 We refer the reader to the 2019 and prior reports for a detailed description of the baseline characteristics of the cohort, and additional core analyses not directly related to the focus explored in this year\'s report. To complement the 2020 report which focussed on donor characteristics, the goal of this year\'s report was to focus entirely on changes in recipient factors over the past 3 decades and to identify important recipient characteristics and transplant processes that may influence post-transplant outcomes. Due to small numbers, heart-lung transplant recipient characteristics and transplant outcomes have not been included. This 38th annual adult lung transplant report is hence based on data submitted to the ISHLT TTX Registry on 67,493 adult recipients of deceased recipient transplants between January 1, 1992 and June 30, 2018.

Published by Elsevier Inc.

J Heart Lung Transplant: 29 Sep 2021; 40:1060-1072
Chambers DC, Perch M, Zuckermann A, Cherikh WS, ... Stehlik J, International Society for Heart and Lung Transplantation
J Heart Lung Transplant: 29 Sep 2021; 40:1060-1072 | PMID: 34446355
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Impact:
Abstract

Relationship of ventricular assist device support duration with pediatric heart transplant outcomes.

Butto A, Mao CY, Wright L, Wetzel M, ... Villa C, Mahle WT
Background
There is wide variability in the timing of heart transplant (HTx) after pediatric VAD implant. While some centers wait months before listing for HTx, others accept donor heart offers within days of VAD surgery. We sought to determine if HTx within 30 days versus ≥ 30 after VAD impacts post-HTx outcomes.
Methods
Children on VAD pre-HTx were extracted from the Pediatric Heart Transplant Study database. The primary endpoints were post-HTx length of hospital stay (LOS) and one-year survival. Confounding was addressed by propensity score weighting using inverse probability of treatment. Propensity scores were calculated based on age, blood type, primary cardiac diagnosis, decade, VAD type, and allosensitization status.
Results
A total of 1064 children underwent VAD prior to HTx between 2000 to 2018. Most underwent HTx ≥ 30 days post-VAD (70%). Infants made up 22% of both groups. Patients ≥ 12 years old were 42% of the < 30 days group and children 1 to 11 years comprised 47% of the ≥ 30 days group (p < 0.001). There was no difference in the prevalence of congenital heart disease vs. cardiomyopathy (p = 0.8) or high allosensitization status (p = 0.9) between groups. Post-HTx LOS was similar between groups (p = 0.11). One-year survival was lower in the < 30 days group (adjusted mortality HR 1.76, 95% CI 1.11-2.78, p = 0.016).
Conclusions
A longer duration of VAD support prior to HTx is associated with a one-year survival benefit in children, although questions of patient complexity, post-VAD complications and the impact on causality remain. Additional studies using linked databases to understand these factors will be needed to fully assess the optimal timing for post-VAD HTx.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 28 Sep 2021; epub ahead of print
Butto A, Mao CY, Wright L, Wetzel M, ... Villa C, Mahle WT
J Heart Lung Transplant: 28 Sep 2021; epub ahead of print | PMID: 34688547
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Impact:
Abstract

Diagnosing heparin-induced thrombocytopenia in mechanical circulatory support device patients.

Halprin C, Czer LS, Cole R, Emerson D, ... Yur J, Volod O
Background
Mechanical circulatory support device (MCSD) patients with positive heparin-induced thrombocytopenia (HIT) screening pose a unique challenge, as clinicians must make rapid decisions about their anticoagulation and whether they can safely undergo cardiopulmonary bypass. We identified screening practices at our institution and other institutions nationwide that differed from American Society of Hematology (ASH) guidelines. This discovery prompted a data review to confirm the applicability of guidelines to this unique population and to highlight complications of \"gestalt\" screening.
Methods
Our study included MCSD patients with HIT testing from April 2014 to August 2020. We evaluated 510 PF4 IgG ELISA results.
Results
HIT was confirmed in 4.2% of patients. There was an increased prevalence of HIT in patients with nondurable (5.3%) vs durable devices (2.9%) or those in the preimplantation setting (1.3%), however this difference was not statistically significant (p = 0.26). None of the patients with a low probability 4T Score had HIT. All patients with a high probability 4T Score and PF4 immunoassay OD >2.0 had HIT. False positive results occurred in 22% of assays ordered for patients with a low probability 4T Score. Twelve patients with a low probability 4T Score and a false positive immunoassay were switched to a direct thrombin inhibitor (DTI) while awaiting confirmatory results. Two patients experienced clinically significant bleeding after conversion to a DTI. An organ was refused in one patient with false positive HIT screening.
Conclusions
Our findings demonstrate that an opportunity exists to improve clinical outcomes by re-emphasizing the utility of established guidelines and highlighting their safe use in the MCSD patient population.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 16 Sep 2021; epub ahead of print
Halprin C, Czer LS, Cole R, Emerson D, ... Yur J, Volod O
J Heart Lung Transplant: 16 Sep 2021; epub ahead of print | PMID: 34656418
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Impact:
Abstract

Magnetic resonance relaxometry of the liver - a new imaging biomarker to assess right heart failure in pulmonary hypertension.

Bogaert J, Claessen G, Dresselaers T, Masci PG, ... Delcroix M, Symons R
Background
Right heart failure (RHF) in pulmonary hypertension (PH) patients is manifested by increased right atrial (RA) pressure. We hypothesized liver relaxation times measured at cardiovascular magnetic resonance (CMR) can be used to noninvasively assess increased right-sided filling pressure.
Methods
Forty-five consecutive patients, that is, 37 PH patients and 8 chronic thromboembolic pulmonary disease patients without PH underwent right heart catheterization and CMR. CMR findings were compared to 40 control subjects. Native T1, T2, and extracellular volume (ECV) liver values were measured on the cardiac maps.
Results
Patients with increased RA pressure (i.e.,≥8 mm Hg)(n = 19, RA+ group) showed higher NT-proBNP and CRP values, lower LVEF, MAPSE values, larger atrial size, and higher native T1 and T2 values of the myocardium than patients with normal RA pressure (RA- group, n = 26). Liver T1, T2 and ECV was significantly higher in RA+ than RA- patients and controls, that is, T1: 684 ± 129 ms vs 563 ± 72 ms and 540 ± 34 ms; T2: 60 ± 10 ms vs 49 ± 6 ms and 46 ± 4 ms; ECV: 36 ± 8% vs 29 ± 4% and 30 ± 3%. A positive correlation was found between liver T1, T2 and ECV and RA pressure, that is, r2 of 0.61, 0.82, and 0.58, respectively (p < 0.001). ROC analysis to depict increased RA pressure showed an AUC of 0.847, 0.904, 0.816, and 0.645 for liver T1, T2, NT-proNBP and gamma-glutamyl transpeptidase, respectively. Excellent intra- and inter-observer agreement was found for assessment of T1/T2/ECV liver values.
Conclusions
Assessment of liver relaxation times as part of a comprehensive CMR exam in PH patients may provide valuable information with regard to the presence of passive liver congestion.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 15 Sep 2021; epub ahead of print
Bogaert J, Claessen G, Dresselaers T, Masci PG, ... Delcroix M, Symons R
J Heart Lung Transplant: 15 Sep 2021; epub ahead of print | PMID: 34686407
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Impact:
Abstract

An early relook identifies high-risk trajectories in ambulatory advanced heart failure.

Kittleson MM, Ambardekar AV, Stevenson LW, Gilotra NA, ... Stewart GC, REVIVAL Investigators
Introduction
Patients with ambulatory advanced heart failure (HF) are increasingly considered for durable mechanical circulatory support (MCS) and heart transplantation and their effective triage requires careful assessment of the clinical trajectory.
Methods
REVIVAL, a prospective, observational study, enrolled 400 ambulatory advanced HF patients from 21 MCS/transplant centers in 2015-2016. Study design included a clinical re-assessment of Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile within 120 days after enrollment. The prognostic impact of a worsening INTERMACS Profile assigned by the treating physician was assessed at 1 year after the Early Relook.
Results
Early Relook was done in 325 of 400 patients (81%), of whom 24% had a worsened INTERMACS Profile, associated with longer HF history and worse baseline INTERMACS profile, but no difference in baseline LVEF (median 0.20), 6-minute walk, quality of life, or other baseline parameters. Early worsening predicted higher rate of the combined primary endpoint of death, urgent MCS, or urgent transplant by 1 year after Early Relook, (28% vs 15%), with hazard ratio 2.2 (95% CI 1.2- 3.8; p = .006) even after adjusting for baseline INTERMACS Profile and Seattle HF Model score. Deterioration to urgent MCS occurred in 14% vs 5% (p = .006) during the year after Early Relook.
Conclusions
Early Relook identifies worsening of INTERMACS Profile in a significant population of ambulatory advanced HF, who had worse outcomes over the subsequent year. Early reassessment of ambulatory advanced HF patients should be performed to better define the trajectory of illness and inform triage to advanced therapies.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 15 Sep 2021; epub ahead of print
Kittleson MM, Ambardekar AV, Stevenson LW, Gilotra NA, ... Stewart GC, REVIVAL Investigators
J Heart Lung Transplant: 15 Sep 2021; epub ahead of print | PMID: 34629234
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Impact:
Abstract

A challenge to equity in transplantation: Increased center-level variation in short-term mechanical circulatory support use in the context of the updated U.S. heart transplant allocation policy.

Cascino TM, Stehlik J, Cherikh WS, Cheng Y, ... Likosky DS, Aaronson KD
Background
The United States National Organ Procurement Transplant Network (OPTN) implemented changes to the adult heart allocation system to reduce waitlist mortality by improving access for those at greater risk of pre-transplant death, including patients on short-term mechanical circulatory support (sMCS). While sMCS increased, it is unknown whether the increase occurred equitably across centers.
Methods
The OPTN database was used to assess changes in use of sMCS at time of transplant in the 12 months before (pre-change) and after (post-change) implementation of the allocation system in October 2018 among 5,477 heart transplant recipients. An interrupted time series analysis comparing use of bridging therapies pre- and post-change was performed. Variability in the proportion of sMCS use at the center level pre- and post-change was determined.
Results
In the month pre-change, 9.7% of patients were transplanted with sMCS. There was an immediate increase in sMCS transplant the following month to 32.4% - an absolute and relative increase of 22.7% and 312% (p < 0.001). While sMCS use was stable pre-change (monthly change 0.0%, 95% CI [-0.1%,0.1%]), there was a continuous 1.2%/month increase post-change ([0.6%,1.8%], p < 0.001). Center-level variation in sMCS use increased substantially after implementation, from a median (interquartile range) of 3.85% (10%) pre-change to 35.7% (30.6%) post-change (p < 0.001).
Conclusions
Use of sMCS at time of transplant increased immediately and continued to expand following heart allocation policy changes. Center-level variation in use of sMCS at the time of transplant increased compared to pre-change, which may have negatively impacted equitable access to heart transplantation.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 15 Sep 2021; epub ahead of print
Cascino TM, Stehlik J, Cherikh WS, Cheng Y, ... Likosky DS, Aaronson KD
J Heart Lung Transplant: 15 Sep 2021; epub ahead of print | PMID: 34666942
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Impact:
Abstract

A decline in club cell secretory proteins in lung transplantation is associated with release of natural killer cells exosomes leading to chronic rejection.

Ravichandran R, Itabashi Y, Liu W, Bansal S, ... Smith M, Mohanakumar T
Background
In human lung transplant recipients, a decline in club cell secretory protein (CCSP) in bronchoalveolar lavage fluid has been associated with chronic lung allograft dysfunction (CLAD) as well as the induction of exosomes and immune responses that lead to CLAD. However, the mechanisms by which CCSP decline contributes to CLAD remain unknown.
Methods
To define the mechanisms leading to CCSP decline and chronic rejection, we employed two mouse models: 1) chronic rejection after orthotopic single lung transplantation and 2) anti-major histocompatibility complex (MHC) class I-induced obliterative airway disease.
Results
In the chronic rejection mouse model, we detected circulating exosomes with donor MHC (H2b) and lung self-antigens and also development of antibodies to H2b and lung self-antigens and then a decline in CCSP. Furthermore, DBA2 mice that received injections of these exosomes developed antibodies to donor MHC and lung self-antigens. In the chronic rejection mouse model, natural killer (NK) and CD8 T cells were the predominant graft-infiltrating cells on day 14 of rejection followed by exosomes containing NK cell-associated and cytotoxic molecules on day 14 and 28. When NK cells were depleted, exosomes with NK cell-associated and cytotoxic molecules as well as fibrosis decreased.
Conclusions
Induction of exosomes led to immune responses to donor MHC and lung self-antigens, resulting in CCSP decline, leading to NK cell infiltration and release of exosomes from NK cells. These results suggest a novel role for exosomes derived from NK cells in the pathogenesis of chronic lung allograft rejection.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 14 Sep 2021; epub ahead of print
Ravichandran R, Itabashi Y, Liu W, Bansal S, ... Smith M, Mohanakumar T
J Heart Lung Transplant: 14 Sep 2021; epub ahead of print | PMID: 34627707
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Impact:
Abstract

Cost-effectiveness and system-wide impact of using Hepatitis C-viremic donors for heart transplant.

Wayda B, Sandhu AT, Parizo J, Teuteberg JJ, Khush KK
Background
The advent of direct-acting antiviral therapy for Hepatitis C (HCV) has made using HCV-viremic donors a viable strategy to address the donor shortage in heart transplantation. We employed a large-scale simulation to evaluate the impact and cost-effectiveness of using HCV-viremic donors for heart transplant.
Methods
We simulated detailed histories from time of listing until death for the real-world cohort of all adults listed for heart transplant in the United States from July 2014 to June 2019 (n = 19,346). This population was imputed using historical data and captures \"real-world\" heterogeneity in geographic and clinical characteristics. We estimated the impact of an intervention in which all candidates accept HCV+ potential donors (n = 472) on transplant volume, waitlist outcomes, and lifetime costs and quality-adjusted life years (QALYs).
Results
The intervention produced 232 more transplants, 132 fewer delistings due to deterioration, and 50 fewer waitlist deaths within this 5-year cohort and reduced wait times by 3% to 11% (varying by priority status). The intervention was cost-effective, adding an average of 0.08 QALYs per patient at a cost of $124 million ($81,892 per QALY). DAA therapy and HCV care combined account for 11% this cost, with the remainder due to higher costs of transplant procedures and routine post-transplant care. The impact on transplant volume varied by blood type and region and was correlated with donor-to-candidate ratio (ρ = 0.71).
Conclusions
Transplanting HCV+ donor hearts is likely to be cost-effective and improve waitlist outcomes, particularly in regions and subgroups experiencing high donor scarcity.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 12 Sep 2021; epub ahead of print
Wayda B, Sandhu AT, Parizo J, Teuteberg JJ, Khush KK
J Heart Lung Transplant: 12 Sep 2021; epub ahead of print | PMID: 34635381
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Impact:
Abstract

Restrictive allograft syndrome vs bronchiolitis obliterans syndrome: Immunological and molecular characterization of circulating exosomes.

Bansal S, Arjuna A, Perincheri S, Poulson C, ... Tokman S, Mohanakumar T
Background
Chronic lung allograft dysfunction in lung transplant recipients (LTxRs) has 2 phenotypes: obstructive bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS). Our goal was to define distinct immunologic markers of exosomes from LTxRs with BOS or RAS.
Methods
Plasma was collected from LTxRs with BOS (n = 18), RAS (n = 13), and from stable LTxRs (n = 5). Antibodies to lung self-antigens (SAgs) were determined by ELISA. Exosomes were isolated by ultracentrifugation. Donor specific antibodies to HLA were quantified using Luminex. Exosomes were characterized for lung SAgs, transcription factors, 20S proteasome, HLA class I and II, and polymeric immunoglobulin receptor protein using western blot. Exosome miRNA was analyzed using NanoString. The exosome-induced immune response was determined in mice.
Results
LTxRs with RAS, but not BOS, had donor specific antibodies at diagnosis. CIITA, NFkB, polymeric immunoglobulin receptor protein, 20S proteasome, HLA-DQ, and HLA-DR were significantly higher in RAS exosomes than in BOS exosomes. RAS plasma had high levels of proinflammatory cytokines and distinct exosomal miRNA. Immunization of C57BL/6 mice with RAS exosomes showed severe inflammation and peribronchial fibrosis, whereas BOS exosomes induced patchy inflammation and fibrosis.
Conclusion
LTxRs with BOS or RAS had exosomes with distinct molecular and immunologic profiles. RAS samples had a higher concentration of proinflammatory factors, HLA class II, lung SAgs, and antibodies to HLA class II molecules, indicating severe allograft injury. Mice immunized with RAS exosomes developed lesions in airways, pleura, interlobular septum, and alveoli, whereas BOS exosomes induced mild to patchy inflammation with lung fibrosis.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 09 Sep 2021; epub ahead of print
Bansal S, Arjuna A, Perincheri S, Poulson C, ... Tokman S, Mohanakumar T
J Heart Lung Transplant: 09 Sep 2021; epub ahead of print | PMID: 34602310
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Impact:
Abstract

Impact of renin-angiotensin-aldosterone system inhibition on morbidity and mortality during long-term continuous-flow left ventricular assist device support: An IMACS report.

Brinkley DM, Wang L, Yu C, Grandin EW, Kiernan MS
Background
Inhibition of the renin angiotensin aldosterone system (RAAS) improves survival and reduces adverse cardiac events in heart failure with reduced ejection fraction, but the benefit is not well-defined following left ventricular assist device (LVAD).
Methods
We analyzed the ISHLT IMACS registry for adults with a primary, continuous-flow LVAD from January 2013 to September 2017 who were alive at postoperative month 3 without a major adverse event, and categorized patients according to treatment an angiotensin converting enzyme inhibitor (ACEI/ARB) or mineralocorticoid receptor antagonist (MRA). Propensity score matching was performed separately for ACEI/ARB vs none (n = 4,118 each) and MRA vs none (n = 3,892 each).
Results
Of 11,494 patients included, 50% were treated with ACEI/ARB and 38% with MRA. Kaplan-Meier survival was significantly better for patients receiving ACEI/ARB (p < 0.001) but not MRA (p = 0.31). In Cox proportional hazards analyses adjusted for known predictors of mortality following LVAD, ACEI/ARB use (hazard ratio 0.81 [95% confidence interval 0.71-0.93], p < 0.0001) but not MRA use (hazard ratio 1.03 [95% confidence interval 0.88-1.21], p = 0.69) was independently associated with lower mortality. Among patients treated with an ACEI/ARB, there was a significantly lower unadjusted risk of cardiovascular death (p < 0.001), risk of gastrointestinal bleeding (p = 0.01), and creatinine level (p < 0.001). MRA therapy was associated with lower risk of gastrointestinal bleeding (p = 0.01) but higher risk of hemolysis (p < 0.01). Potential limitations include residual confounding and therapy crossover.
Conclusion
These findings suggest a benefit for ACEI/ARB therapy in patients with heart failure after LVAD implantation.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 08 Sep 2021; epub ahead of print
Brinkley DM, Wang L, Yu C, Grandin EW, Kiernan MS
J Heart Lung Transplant: 08 Sep 2021; epub ahead of print | PMID: 34663529
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Impact:
Abstract

Pulmonary hypertension in fibrosing idiopathic interstitial pneumonia: Uncertainties, challenges and opportunities.

Girgis RE, Hoeper MM
Pulmonary hypertension is a serious complication of chronic fibrosing idiopathic interstitial pneumonia (PH-fIIP) leading to greater morbidity and mortality. The pathophysiologic basis for PH in fIIP is not completely understood, but microvascular rarefaction may play a key role. Severe hypoxemia and reduced diffusion capacity are characteristic. Doppler echocardiography has limited diagnostic utility and right heart catheterization is required to confirm the diagnosis. Lung volumes can be minimally affected, and radiographic findings can be subtle, making the distinction from pulmonary arterial hypertension challenging. Several randomized controlled trials of pulmonary arterial hypertension targeted therapies have recently been completed. Endothelin-receptor antagonists have shown either no benefit or harm. Sildenafil may have some favorable short-term effects but does not appear to impact long-term outcomes. Riociguat treatment increased hospitalizations and mortality. A recent trial of inhaled treprostinil demonstrated improved exercise capacity, but the impact on long-term morbidity and mortality are unknown. Currently, the only viable option for improved survival is lung transplantation. Early referral is imperative to optimize post-transplant outcomes.

Copyright © 2021 International Society for Heart and Lung Transplantation. All rights reserved.

J Heart Lung Transplant: 30 Aug 2021; 40:872-881
Girgis RE, Hoeper MM
J Heart Lung Transplant: 30 Aug 2021; 40:872-881 | PMID: 33832831
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Impact:
Abstract

Association between chronic lung allograft dysfunction and human Cytomegalovirus UL40 peptide variants in lung-transplant recipients.

Vietzen H, Hartenberger S, Jaksch P, Puchhammer-Stöckl E
Natural-Killer cells play an important role in the pathogenesis of chronic lung allograft dysfunction (CLAD) in lung-transplant recipients. Activating NKG2C+ and inhibitory NKG2A+ NK cells proliferate in response to human Cytomegalovirus (HCMV) infection via the presentation of virally encoded UL40 peptides on HLA-E molecules. We aimed to clarify whether infection with HCMV strains carrying different UL40 peptide variants is associated with the development of CLAD. We included 82 lung-transplant recipients, 18 patients developing CLAD and 64 matched control patients without CLAD. In all patients 1 episode of high-level HCMV-replication occurred. HCMV UL40 variants and Natural-Killer-cell proliferation with distinct UL40 peptides were assessed. The VMTPRTLIL variant was significantly overrepresented in patients developing CLAD (p < 0.0001) and lead to a significantly lower proliferation of inhibitory NKG2A+ cells, compared to the VMAPRTLIL, VMAPRTLVL and VMAPRTLLL variants (p < 0.0001). Thus, HCMV UL40 variants may contribute to development of CLAD over the NK cell response.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Aug 2021; 40:900-904
Vietzen H, Hartenberger S, Jaksch P, Puchhammer-Stöckl E
J Heart Lung Transplant: 30 Aug 2021; 40:900-904 | PMID: 34183227
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Impact:
Abstract

Heart transplantation following donation after circulatory death: Expanding the donor pool.

Scheuer SE, Jansz PC, Macdonald PS
Heart transplantation from donation after circulatory death (DCD) donors is a rapidly expanding practice. In this review, we describe the history and challenges of DCD heart transplantation and overview the procurement protocols and methods of limiting ischemic injury, current outcomes, and future directions. There are now at least three protocols that permit resuscitation and viability assessment of the DCD heart either in situ or ex situ. While the retrieval protocol for hearts from DCD donors will depend on local regulations, the outcomes of DCD heart transplant recipients reported to date are excellent regardless of the retrieval protocol and are comparable to the outcomes of heart transplant recipients from donation after brain death (DBD) donors. In the two centers with the largest published experience, DCD heart transplantation now accounts for one third of their heart transplant activity. With international trends indicating that there is an increasing utilisation of the DCD pathway, it is expected that DCD donors will become a major source of heart donation worldwide.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Aug 2021; 40:882-889
Scheuer SE, Jansz PC, Macdonald PS
J Heart Lung Transplant: 30 Aug 2021; 40:882-889 | PMID: 33994229
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Impact:
Abstract

The growing dilemma of legalized cannabis and heart transplantation.

Olt C, Faulkenberg KD, Hsich EM
This in-depth review discusses cannabis as it relates to heart transplantation and the growing dilemma of legalization around the world creating disparities in transplant candidacy. One will learn about two of the most common cannabinoids: Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). These cannabinoids are metabolized by cytochrome P-450 and P glycoprotein, which are essential for the metabolism of drugs for transplantation, such as calcineurin inhibitors. Addiction, withdrawal, and cannabis use disorder will be reviewed as well as hyperemesis syndrome. Maintaining adequate immunosuppression will depend on a variety of factors, including drug-drug interactions, pharmacokinetics of cannabinoids and chronicity of cannabis usage. These drug interactions are further confounded by varying concentrations of cannabis products available at medical dispensaries. One will also learn about the outcomes of transplant recipients using cannabis such as graft failure and the risk of infections. Although more research is needed to establish transplant guidelines, the available data is concerning and fairness in organ distribution should not vary by transplant program or institution.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Aug 2021; 40:863-871
Olt C, Faulkenberg KD, Hsich EM
J Heart Lung Transplant: 30 Aug 2021; 40:863-871 | PMID: 34006449
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Impact:
Abstract

Inflammatory responses in lungs from donation after brain death: Mechanisms and potential therapeutic targets.

Wong A, Liu M
The vast majority of lungs used in clinical transplantation are donated after brain death (DBD). The utilization of DBD lungs is low due to brain death-induced lung injury. Moreover, inflammatory responses in DBD lungs used for transplantation contribute to ischemia-reperfusion injury and primary graft dysfunction. Work from human observational studies has demonstrated overexpression of cytokines, activation of endothelial cells, and cell death in DBD lungs, are associated with the activation of signaling pathways. Animal models have characterized the pulmonary injury induced by brain death and identified potential strategies to improve donor management. Interestingly, transcriptomic studies comparing DBD and donated after circulatory death (DCD) lungs have found that inflammatory responses are elevated in DBD lungs, while cell death pathways are elevated in DCD lungs. Development of the ex vivo lung perfusion technique, has made it possible to assess donor lungs using inflammation and cell death biomarkers. In the future, identification of potential therapeutic targets and development of novel treatments strategies may allow for lung repair during EVLP prior to transplantation.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Aug 2021; 40:890-896
Wong A, Liu M
J Heart Lung Transplant: 30 Aug 2021; 40:890-896 | PMID: 34167864
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Abstract

Aspiration of conjugated bile acids predicts adverse lung transplant outcomes and correlates with airway lipid and cytokine dysregulation.

Urso A, Leiva-Juárez MM, Briganti DF, Aramini B, ... Cremers S, D\'Ovidio F
Introduction
Duodeno-gastroesophageal reflux aspiration is associated with chronic lung allograft dysfunction (CLAD). Reflux aspirate can contain bile acids (BA), functional molecules in the gastro-intestinal tract with emulsifying properties. We sought to determine and quantify the various BA species in airways of the lung transplant recipients to better understand the various effects of aspirated BA that contribute to post-transplantation outcomes.
Methods
Bronchial washings (BW) were prospectively collected from lung transplant recipients and subsequently assayed by liquid chromatography-mass spectrometry for 13 BA and 25 lipid families. Patients were monitored for CLAD, rejection, inflammation and airway infections.
Results
Detectable BA were present in 45/50 patients (90%) at 3 months after transplant. Elevated BA and predominance of conjugated species were independent predictors of CLAD (hazard ratio 7.9; 95% confidence interval 2.7-23.6; p < 0.001 and 7.3; 2.4-22; p < 0.001, respectively) and mortality (hazard ratio 4.4; 1.5-12.7; p = 0.007 and 4.8; 1.4-15.8; p = 0.01, respectively). High BA associated with increased positive bacterial cultures (60% vs 25%, p = 0.02). Primary conjugated species independently correlated with the rate of bacterial cultures during the first-year post-transplant (Beta coefficient: 0.77; 0.28-1.26; p = 0.003) and changes in airway lipidome and cytokines.
Conclusions
Higher BA levels and predominance of conjugated BA are independent predictors of chronic lung allograft dysfunction, mortality and bacterial infections. Primary conjugated BA are related to distinct changes in airway lipidome and inflammatory cytokines. This elucidates novel evidence into the mechanism following BA aspiration and proposes novel markers for prediction of adverse post-transplant outcomes.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Aug 2021; 40:998-1008
Urso A, Leiva-Juárez MM, Briganti DF, Aramini B, ... Cremers S, D'Ovidio F
J Heart Lung Transplant: 30 Aug 2021; 40:998-1008 | PMID: 34183226
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Impact:
Abstract

Effects of cold or warm ischemia and ex-vivo lung perfusion on the release of damage associated molecular patterns and inflammatory cytokines in experimental lung transplantation.

Hasenauer A, Bédat B, Parapanov R, Lugrin J, ... Krueger T, Liaudet L
Background
Lung transplantation (LTx) is associated with sterile inflammation, possibly related to the release of damage associated molecular patterns (DAMPs) by injured allograft cells. We have measured cellular damage and the release of DAMPs and cytokines in an experimental model of LTx after cold or warm ischemia and examined the effect of pretreatment with ex-vivo lung perfusion (EVLP).
Methods
Rat lungs were exposed to cold ischemia alone (CI group) or with 3h EVLP (CI-E group), warm ischemia alone (WI group) or with 3 hour EVLP (WI-E group), followed by LTx (2 hour). Bronchoalveolar lavage (BAL) was performed before (right lung) or after (left lung) LTx to measure LDH (marker of cellular injury), the DAMPs HMGB1, IL-33, HSP-70 and S100A8, and the cytokines IL-1β, IL-6, TNFα, and CXCL-1. Graft oxygenation capacity and static compliance after LTx were also determined.
Results
Compared to CI, WI displayed cellular damage and inflammation without any increase of DAMPs after ischemia alone, but with a significant increase of HMGB1 and functional impairment after LTx. EVLP promoted significant inflammation in both cold (CI-E) and warm (WI-E) groups, which was not associated with cell death or DAMP release at the end of EVLP, but with the release of S100A8 after LTx. EVLP reduced graft damage and dysfunction in warm ischemic, but not cold ischemic, lungs.
Conclusions
The pathomechanisms of sterile lung inflammation during LTx are significantly dependent on the conditions. The release of HMGB1 (in the absence of EVLP) and S100A8 (following EVLP) may be important factors in the pathogenesis of LTx.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Aug 2021; 40:905-916
Hasenauer A, Bédat B, Parapanov R, Lugrin J, ... Krueger T, Liaudet L
J Heart Lung Transplant: 30 Aug 2021; 40:905-916 | PMID: 34193360
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Impact:
Abstract

Severe pulmonary hypertension associated with chronic obstructive pulmonary disease: A prospective French multicenter cohort.

Dauriat G, Reynaud-Gaubert M, Cottin V, Lamia B, ... Laouenan C, Mal H
Background
A small proportion of patients with chronic obstructive pulmonary disease (COPD) patients present severe pulmonary hypertension (PH), defined by mean pulmonary artery pressure (mPAP) ≥35 mm Hg measured by right heart catheterization. Little is known about the characteristics of severe PH-COPD. The aim of the study based on a national registry was to describe this phenotype.
Methods
We prospectively included and followed patients with incident PH-COPD. Clinical, functional, hemodynamic data at inclusion and follow-up were retrieved. Survival assessed by Kaplan-Meier analysis was the primary end-point.
Results
From 2012 to 2016, 99 patients from 13 French centers were included in the study (82 males; median age 66.0 years [interquartile range 62.0-72.0]). At inclusion, most patients had marked dyspnea (55.6% and 22.2% New York Heart Association class III and IV, respectively). During 12 months before inclusion, 42.9% had an exacerbation requiring a hospitalization. Pulmonary function tests showed a moderate obstructive pattern with median (interquartile range) FEV1 50.0 [35.0-63.0] % predicted and low diffusing capacity for carbon monoxide, median 20.0 [16.5-30.6] % predicted. The median values for PaO2 and PaCO2 on room air were 50.0 [44.8-62.0] and 36.0 [31.1-43.0] mm Hg. Median values of mPAP, pulmonary artery occlusion pressure, cardiac index and pulmonary vascular resistance were 42.0 [37.0-48.0] mm Hg, 11.0 [9.0-14.0] mm Hg, 3.0 [2.4-3.6] L/min/m2, and 6.3 [4.2-7.9] WU, respectively. Mean restricted survival was 15.0 [13.9-16.0] months.
Conclusions
Severe PH-COPD is characterized by moderate airway obstruction but marked dyspnea and marked hypoxemia, low DLCO and high mPAP. This phenotype is associated with poor prognosis.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Aug 2021; 40:1009-1018
Dauriat G, Reynaud-Gaubert M, Cottin V, Lamia B, ... Laouenan C, Mal H
J Heart Lung Transplant: 30 Aug 2021; 40:1009-1018 | PMID: 34218966
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Impact:
Abstract

Inferior outcomes in lung transplant recipients with serum Pseudomonas aeruginosa specific cloaking antibodies.

Divithotawela C, Pham A, Bell PT, Ledger EL, ... Wells TJ, Chambers DC
Background
Chronic Lung Allograft Dysfunction (CLAD) limits long-term survival following lung transplantation. Colonization of the allograft by Pseudomonas aeruginosa is associated with an increased risk of CLAD and inferior overall survival. Recent experimental data suggests that \'cloaking\' antibodies targeting the O-antigen of the P. aeruginosa lipopolysaccharide cell wall (cAbs) attenuate complement-mediated bacteriolysis in suppurative lung disease.
Methods
In this retrospective cohort analysis of 123 lung transplant recipients, we evaluated the prevalence, risk factors and clinical impact of serum cAbs following transplantation.
Results
cAbs were detected in the sera of 40.7% of lung transplant recipients. Cystic fibrosis and younger age were associated with increased risk of serum cAbs (CF diagnosis, OR 6.62, 95% CI 2.83-15.46, p < .001; age at transplant, OR 0.69, 95% CI 0.59-0.81, p < .001). Serum cAbs and CMV mismatch were both independently associated with increased risk of CLAD (cAb, HR 4.34, 95% CI 1.91-9.83, p < .001; CMV mismatch (D+/R-), HR 5.40, 95% CI 2.36-12.32, p < .001) and all-cause mortality (cAb, HR 2.75, 95% CI 1.27-5.95, p = .010, CMV mismatch, HR 3.53, 95% CI 1.62-7.70, p = .002) in multivariable regression analyses.
Conclusions
Taken together, these findings suggest a potential role for \'cloaking\' antibodies targeting P. aeruginosa LPS O-antigen in the immunopathogenesis of CLAD.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Aug 2021; 40:951-959
Divithotawela C, Pham A, Bell PT, Ledger EL, ... Wells TJ, Chambers DC
J Heart Lung Transplant: 30 Aug 2021; 40:951-959 | PMID: 34226118
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Impact:
Abstract

Impact of thoracotomy approach on right ventricular failure and length of stay in left ventricular assist device implants: an intermacs registry analysis.

Lampert BC, Teuteberg JJ, Cowger J, Mokadam NA, ... Kirklin JK, Whitson BA
Introduction
Traditionally, implantation of Left Ventricular Assist Devices (LVADs) is performed via median sternotomy. Recently, less invasive thoracotomy approaches are growing in popularity as they involve less surgical trauma, potentially less bleeding, and may preserve right ventricular function. We hypothesized implantation of LVADs via thoracotomy has less perioperative right ventricular failure (RVF) and shorter postoperative length of stay (LOS).
Methods
Continuous flow LVAD implants from Intermacs between February 6, 2014 - December 31, 2018 were identified. Patients implanted via thoracotomy were propensity matched in a 1:1 ratio with patients implanted via sternotomy. Outcomes were compared between sternotomy and thoracotomy approach and by device type (axial, centrifugal-flow with hybrid levitation (CF-HL), centrifugal-flow with full magnetic levitation devices (CF-FML)). The primary outcome was time to first moderate or severe RVF. Secondary outcomes included survival and LOS.
Results
Overall 978 thoracotomy patients were matched with 978 sternotomy patients. Over the study period, 242 thoracotomy patients and 219 sternotomy patients developed RVF with no significant difference in time to first moderate to severe RVF by surgical approach overall (p = 0.27) or within CF-HL (p = 0.36) or CF-FML devices (p = 0.25). Survival did not differ by implant technique (150 deaths in thoracotomy group, 154 deaths in sternotomy group; p = 0.58). However, sternotomy approach was associated with a significantly shorter LOS (17 Vs 18 days, p = 0.009).
Conclusion
As compared to sternotomy, implantation of continuous flow LVADs via thoracotomy approach does not reduce moderate to severe RVF or improve survival but does reduce post-operative LOS. Device type did not influence outcomes and most centers did a small volume of thoracotomy implants.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Aug 2021; 40:981-989
Lampert BC, Teuteberg JJ, Cowger J, Mokadam NA, ... Kirklin JK, Whitson BA
J Heart Lung Transplant: 30 Aug 2021; 40:981-989 | PMID: 34229917
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Impact:
Abstract

Study results suggest less invasive HeartMate 3 implantation is a safe and effective approach for obese patients.

Bjelic M, Ayers B, Paic F, Bernstein W, ... Prasad S, Gosev I
Background
Historically, obesity was considered a relative contraindication to left ventricular assist device (LVAD) implantation with less invasive surgery (LIS). The present study aimed to compare the outcomes of obese patients who underwent LVAD implantation through LIS with those who received full sternotomy (FS) implantation.
Methods
We retrospectively reviewed all patients implanted with HeartMate 3 LVAD in our institution between September 2015 and June 2020. Obese patients (BMI ≥ 30 kg/m2) were included and dichotomized based on surgical approach into the FS or LIS cohort.
Results
Of 231 implanted patients, 107 (46%) were obese and included in the study. FS was performed in 26 (24%) patients and LIS approach in 81 (76%) patients. Preoperative patient characteristics were similar between the cohorts. Postoperatively, patients in LIS cohort had less bleeding (p = 0.029), fewer transfusions (p = 0.042), shorter duration of inotropic support (p = 0.049), and decreased incidence of severe RV failure (11.1% vs 30.8%, p = 0.028). Survival to discharge for the obese population was 87.5% overall and did not differ based on an approach (91.4% LIS vs 76.9% FS, p = 0.079). More LIS patients were discharged home (60.0% vs 82.4%, p = 0.041) rather than to rehabilitation center.
Conclusion
Our results showed that the LIS approach in obese patients is associated with fewer postoperative complications and a trend towards better short-term survival. These results suggest that less invasive LVAD implantation is a safe and effective approach for obese patients. Future prospective randomized trials are required to substantiate these results.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Aug 2021; 40:990-997
Bjelic M, Ayers B, Paic F, Bernstein W, ... Prasad S, Gosev I
J Heart Lung Transplant: 30 Aug 2021; 40:990-997 | PMID: 34229916
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Impact:
Abstract

Gender and racial disparities in lung transplantation in the United States.

Riley LE, Lascano J
Background
Lung transplant (LT) allocation utilizes a scoring system to prioritize patients, although data evaluating the access by gender and race remains limited. The study objective was to determine whether gender and racial disparities exist in patients listed for LT.
Methods
This was a retrospective analysis using the Organ Procurement and Transplant Network database of patients listed for a LT from 1984 until 2019. Nominal multivariate logistic regression analysis was performed to evaluate LT allocation by gender, race, and primary lung disease. Kaplan-Meier curves were constructed to compare rates of mortality over time.
Results
Sixty thousand eight hundred and forty-seven patients were listed between February 1984 and September 2019. Males comprised the majority of listed and transplanted patients at 51.7% and 55.8% respectively. In the LAS era, the median waiting list time for transplanted males was 43 days (interquartile range [IQR] 13-126), and females waited a median of 80 days (IQR 24-233) (p < .001). Persons of White race accounted for 82.6% and 84.3% of listed and transplanted patients respectively. Logistic regression analysis found that in the LAS era, males had an increased odds for LT allocation (OR 1.19, CI 1.12-1.27, p < .001) compared to females, and persons of White race (OR 1.23, CI 1.16-1.32, p < .001) compared to all other races combined.
Conclusions
The majority of listed and transplanted patients in the United States were males and persons of White race. Also, being a male or person of White race had an outcome favoring lung transplant allocation compared to an appropriately matched person of another gender or race.

Published by Elsevier Inc.

J Heart Lung Transplant: 30 Aug 2021; 40:963-969
Riley LE, Lascano J
J Heart Lung Transplant: 30 Aug 2021; 40:963-969 | PMID: 34246564
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Impact:
Abstract

Variants in mycophenolate and CMV antiviral drug pharmacokinetic and pharmacodynamic genes and leukopenia in heart transplant recipients.

Oreschak K, Saba LM, Rafaels N, Ambardekar AV, ... Lindenfeld J, Aquilante CL
Background
The objective was to assess the relationship between single nucleotide polymorphisms in mycophenolate and cytomegalovirus antiviral drug pharmacokinetic and pharmacodynamic genes and drug-induced leukopenia in adult heart transplant recipients.
Methods
This retrospective analysis included n = 148 patients receiving mycophenolate and a cytomegalovirus antiviral drug. In total, 81 single nucleotide polymorphisms in 21 pharmacokinetic and 23 pharmacodynamic genes were selected for investigation. The primary and secondary outcomes were mycophenolate and/or cytomegalovirus antiviral drug-induced leukopenia, defined as a white blood cell count <3.0 × 109/L, in the first six and 12 months post-heart transplant, respectively.
Results
Mycophenolate and/or cytomegalovirus antiviral drug-induced leukopenia occurred in 20.3% of patients. HNF1A rs1169288 A>C (p.I27L) was associated with drug-induced leukopenia (unadjusted p = 0.002; false discovery rate <20%) in the first six months post-transplant. After adjusting for covariates, HNF1A rs1169288 variant C allele carriers had significantly higher odds of leukopenia compared to A/A homozygotes (odds ratio 6.19; 95% CI 1.97-19.43; p = 0.002). Single nucleotide polymorphisms in HNF1A, SLC13A1, and MBOAT1 were suggestively associated (p < 0.05) with the secondary outcome but were not significant after adjusting for multiple comparisons.
Conclusion
Our data suggest genetic variation may play a role in the development of leukopenia in patients receiving mycophenolate and cytomegalovirus antiviral drugs after heart transplantation. Following replication, pharmacogenetic markers, such as HNF1A rs1169288, could help identify patients at higher risk of drug-induced leukopenia, allowing for more personalized immunosuppressant therapy and cytomegalovirus prophylaxis following heart transplantation.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Aug 2021; 40:917-925
Oreschak K, Saba LM, Rafaels N, Ambardekar AV, ... Lindenfeld J, Aquilante CL
J Heart Lung Transplant: 30 Aug 2021; 40:917-925 | PMID: 34253456
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Impact:
Abstract

Recipient and surgical factors trigger severe primary graft dysfunction after heart transplant.

Benck L, Kransdorf EP, Emerson DA, Rushakoff J, ... Kobashigawa JA, Patel JK
Background
Primary graft dysfunction (PGD) is a major cause of early mortality following heart transplant (HT). The International Society for Heart and Lung Transplantation (ISHLT) subdivides PGD into 3 grades of increasing severity. Most studies have assessed risk factors for PGD without distinguishing between PGD severity grade. We sought to identify recipient, donor and surgical risk factors specifically associated with mild/moderate or severe PGD.
Methods
We identified 734 heart transplant recipients at our institution transplanted between January 1, 2012 and December 31, 2018. PGD was defined according to modified ISHLT criteria. Recipient, donor and surgical variables were analyzed by multinomial logistic regression with mild/moderate or severe PGD as the response. Variables significant in single variable modeling were subject to multivariable analysis via penalized logistic regression.
Results
PGD occurred in 24% of the cohort (n = 178) of whom 6% (n = 44) had severe PGD. One-year survival was reduced in recipients with severe PGD but not in those with mild or moderate PGD. Multivariable analysis identified 3 recipient factors: prior cardiac surgery, recipient treatment with ACEI/ARB/ARNI plus MRA, recipient treatment with amiodarone plus beta-blocker, and 3 surgical factors: longer ischemic time, more red blood cell transfusions, and more platelet transfusions, that were associated with severe PGD. We developed a clinical risk score, ABCE, which provided acceptable discrimination and calibration for severe PGD.
Conclusions
Risk factors for mild/moderate PGD were largely distinct from those for severe PGD, suggesting a differing pathophysiology involving several biological pathways. Further research into mechanisms underlying the development of PGD is urgently needed.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Aug 2021; 40:970-980
Benck L, Kransdorf EP, Emerson DA, Rushakoff J, ... Kobashigawa JA, Patel JK
J Heart Lung Transplant: 30 Aug 2021; 40:970-980 | PMID: 34272125
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Impact:
Abstract

Significance of pre and post-implant MELD-XI score on survival in children undergoing VAD implantation.

Amdani S, Boyle GJ, Cantor RS, Conway J, ... Lorts A, Rosenthal DN
Background
Derangements in liver and renal function often accompany end-stage heart failure. We sought to assess the utility of an objective risk assessment tool, the Model for End-stage Liver Disease eXcluding INR (MELD-XI), to identify pediatric patients at increased risk for adverse outcomes post-ventricular assist device (VAD) implantation.
Methods
The Pedimacs database was queried for all pediatric patients who underwent VAD implantation from September 19, 2012 to December 31, 2019. Pre-implant and early (1-week) post-implant MELD-XI scores were used to stratify patients into low, intermediate and high score cohorts. Comparison of pre-implant characteristics and post-implant outcomes were conducted across groups. Multiphase parametric hazard modeling was utilized to identify independent predictors of post-implant mortality.
Results
A total of 742 patients had a calculable MELD-XI score pre-implant. When stratified by MELD-XI scores pre-implant, patients in the high MELD-XI score cohort (score >13.6) had inferior survival and increased bleeding, renal dysfunction and respiratory failure post-implant compared to intermediate and low score cohorts. Risk factors for mortality post-VAD implantation were: increasing MELD-XI scores (HR 1.1 per 1 unit rise), Pedimacs profile 1 (HR 1.6), congenital heart disease (HR 2.3) and being on a percutaneous VAD (HR 2.7). Importantly, MELD-XI score was a better predictor of post-VAD implant mortality than bilirubin or creatinine alone, neither of which were significant in the final model. Patients with increasing or continued high MELD-XI scores early post-implant had the worst survival.
Conclusion
The MELD-XI is an easily calculated score that serves as a promising risk assessment tool in identifying children at risk for poor outcomes post VAD implantation.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Aug 2021; epub ahead of print
Amdani S, Boyle GJ, Cantor RS, Conway J, ... Lorts A, Rosenthal DN
J Heart Lung Transplant: 29 Aug 2021; epub ahead of print | PMID: 34598872
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Impact:
Abstract

Third dose of the BNT162b2 vaccine in heart transplant recipients: Immunogenicity and clinical experience.

Peled Y, Ram E, Lavee J, Segev A, ... Lustig Y, Rahav G
Background
The repeated waves of the COVID-19 pandemic have highlighted the necessity to optimize vaccine responses in immunocompromised populations. We investigated the safety and immunogenicity of a third, booster, dose of the Pfizer BNT162b2 vaccine in heart transplant (HT) patients.
Methods
The cohort comprised 96 adult HT patients who received a third homologous dose of the BNT162b2 vaccine 168 days after the second dose. The vaccine-induced antibody responses of both receptor-binding domain (RBD) IgG and neutralizing antibodies were assessed in all patients, with a positive antibody response being defined as the presence of either IgG anti-RBD or neutralizing antibodies. For a subset of patients, T cell response was also studied.
Results
The third dose was associated with a low rate of adverse events, mostly mild pain at the injection site. No serious adverse events were recorded, and there were no episodes of rejection. At 18 days following the third dose of the vaccine, the positive antibody response increased from 23% to 67%, with a corresponding increase in neutralizing capacity. The third dose elicited SARS-CoV-2 neutralization titers >9-fold and IgG anti-RBD antibodies >3-fold of the range achieved after the two primary doses. Mycophenolate use, lower eGFR and higher C-reactive protein were independently associated with a reduced likelihood of generating an immune response. Importantly, a specific T-cell response following the third dose was evident in the majority of transplant recipients.
Conclusions
An homologous third booster dose of the BNT162b2 vaccine gave overall consistent tolerability and a good safety profile, while eliciting humoral and cellular immune responses.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 27 Aug 2021; epub ahead of print
Peled Y, Ram E, Lavee J, Segev A, ... Lustig Y, Rahav G
J Heart Lung Transplant: 27 Aug 2021; epub ahead of print | PMID: 34565682
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Impact:
Abstract

Evidence supporting total cardiac volumes instead of weight for transplant size-matching.

Szugye NA, Morales DLS, Lorts A, Zafar F, Moore RA
Total cardiac volume (TCV)-based size matching for heart transplantation offers individualization in size matching that increases the number of suitable donors. Here we describe our clinical protocol for using TCV to determine an acceptable donor weight range for heart transplant candidates. We compare candidate imaging-derived TCV to a nomogram of subjects with normal TCV to determine a precise maximum donor weight at the time of listing. For nearly half of our transplant patients, we have increased weight range by an average of 70% with no oversizing related adverse events, such as delayed chest closure to avoid tamponade or bronchial compression. Widespread adoption of TCV-based size matching can lead to a more efficient heart allocation system by the data-driven bypass of poor size matches.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 26 Aug 2021; epub ahead of print
Szugye NA, Morales DLS, Lorts A, Zafar F, Moore RA
J Heart Lung Transplant: 26 Aug 2021; epub ahead of print | PMID: 34551864
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Impact:
Abstract

CFTR modulator use in post lung transplant recipients.

Benninger LA, Trillo C, Lascano J
Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator therapy has previously been contraindicated in solid organ transplant recipients. This was due to lack of data and concern for interactions with immunosuppressive drug regimens. However, in post-lung transplant recipients, CFTR modulators may improve extrapulmonary manifestations of cystic fibrosis without impacting graft function or immunosuppressive drug levels. Herein, we present our single center experience with the use of elexacaftor/tezacaftor/ivacaftor, Trikafta, in adult post-lung transplant recipients.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 25 Aug 2021; epub ahead of print
Benninger LA, Trillo C, Lascano J
J Heart Lung Transplant: 25 Aug 2021; epub ahead of print | PMID: 34538541
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Impact:
Abstract

Economic evaluations and costing studies of lung transplantation: A scoping review.

Peel JK, Keshavjee S, Krahn M, Sander B
Background
Evaluation of the joint clinical and economic impacts of lung transplant and associated technologies is crucial for evidence-informed decision-making and wise allocation of scarce healthcare resources. We performed a scoping review to summarize and categorize the available evidence of the costs and cost-effectiveness of lung transplantation.
Methods
A systematic search of MEDLINE, EMBASE, NHS EED, and EconLit was performed to identify studies involving lung transplantation for adults that measured costs, cost-effectiveness, or which described themselves as economic evaluations. A scoping review was performed in adherence to the framework described by Arksey & O\'Malley. Risk of bias was assessed in included studies using the ECOBIAS and CHEC-list tools.
Results
In total, 324 studies were identified, of which 28 met inclusion criteria. Cost-utility estimates of lung transplant versus waitlist, from the healthcare payer perspective and a time-horizon of at least 10-years ranged between $42,459 and $154,051 per quality-adjusted life year. Common topics of study included lung transplant versus waitlist care, immunosuppression, organ retrieval and allocation, and mechanical life support.
Conclusions
Sources of variation in costs-assessments and economic evaluations included differences in the type of study performed, payer perspective adopted, study time horizon, and variation in clinical practice. The best available cost-utility estimates for lung transplant versus waitlist may represent cost-effectiveness under some circumstances, but high-quality evidence is lacking. Further cost-utility analyses, with sufficient methodologic rigour, are required to overcome the observed variation in results and confirm cost-effectiveness of the current standard of care in lung transplantation.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 25 Aug 2021; epub ahead of print
Peel JK, Keshavjee S, Krahn M, Sander B
J Heart Lung Transplant: 25 Aug 2021; epub ahead of print | PMID: 34538540
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Impact:
Abstract

Many heart transplant biopsies currently diagnosed as no rejection have mild molecular antibody-mediated rejection-related changes.

Halloran PF, Madill-Thomsen K, Aliabadi-Zuckermann AZ, Cadeiras M, ... Stehlik J, Zuckermann A
Background
The Molecular Microscope (MMDx) system classifies heart transplant endomyocardial biopsies as No-rejection (NR), Early-injury, T cell-mediated (TCMR), antibody-mediated (ABMR), mixed, and possible rejection (possible TCMR, possible ABMR). Rejection-like gene expression patterns in NR biopsies have not been described. We extended the MMDx methodology, using a larger data set, to define a new \"Minor\" category characterized by low-level inflammation in non-rejecting biopsies.
Methods
Using MMDx criteria from a previous study, molecular rejection was assessed in 1,320 biopsies (645 patients) using microarray expression of rejection-associated transcripts (RATs). Of these biopsies, 819 were NR. A new archetypal analysis model in the 1,320 data set split the NRs into NR-Normal (N = 462) and NR-Minor (N = 359).
Results
Compared to NR-Normal, NR-Minor were more often histologic TCMR1R, with a higher prevalence of donor-specific antibody (DSA). DSA positivity increased in a gradient: NR-Normal 24%; NR-Minor 34%; possible ABMR 42%; ABMR 66%. The top 20 transcripts distinguishing NR-Minor from NR-Normal were all ABMR-related and/or IFNG-inducible, and also exhibited a gradient of increasing expression from NR-Normal through ABMR. In random forest analysis, TCMR and Early-injury were associated with reduced LVEF and increased graft loss, but NR-Minor and ABMR scores were not. Surprisingly, hearts with MMDx ABMR showed comparatively little graft loss.
Conclusions
Many heart transplants currently diagnosed as NR by histologic or molecular assessment have minor increases in ABMR-related and IFNG-inducible transcripts, associated with DSA positivity and mild histologic inflammation. These results suggest that low-level ABMR-related molecular stress may be operating in many more hearts than previously estimated. (ClinicalTrials.gov #NCT02670408).

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 25 Aug 2021; epub ahead of print
Halloran PF, Madill-Thomsen K, Aliabadi-Zuckermann AZ, Cadeiras M, ... Stehlik J, Zuckermann A
J Heart Lung Transplant: 25 Aug 2021; epub ahead of print | PMID: 34548198
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Impact:
Abstract

Lung transplantation disparities based on diagnosis for patients bridging to transplant on extracorporeal membrane oxygenation.

Furfaro D, Rosenzweig EB, Shah L, Robbins H, ... Arcasoy S, Benvenuto L
Background
Extracorporeal membrane oxygenation (ECMO) is increasingly utilized as a bridge to lung transplantation, but ECMO status is not explicitly accounted for in the Lung Allocation Score (LAS). We hypothesized that among waitlist patients on ECMO, patients with pulmonary arterial hypertension (PAH) would have lower transplantation rates.
Methods
Using United Network for Organ Sharing data, we conducted a retrospective cohort study of patients who were ≥12 years old, active on the lung transplant waitlist, and required ECMO support from June 1, 2015 through June 12, 2020. Multivariable competing risk analysis was used to examine waitlist outcomes.
Results
1064 waitlist subjects required ECMO support; 40 (3.8%) had obstructive lung disease (OLD), 97 (9.1%) had PAH,138 (13.0%) had cystic fibrosis (CF), and 789 (74.1%) had interstitial lung disease (ILD). Ultimately, 671 (63.1%) underwent transplant, while 334 (31.4%) died or were delisted. The transplant rate per person-years on the waitlist on ECMO was 15.41 for OLD, 6.05 for PAH, 15.66 for CF, and 15.62 for ILD. Compared to PAH patients, OLD, CF, and ILD patients were 78%, 69%, and 62% more likely to undergo transplant throughout the study period, respectively (adjusted SHRs 1.78 p = 0.007, 1.69 p = 0.002, and 1.62 p = 0.001). The median LAS at waitlist removal for transplantation, death, or delisting were 75.1 for OLD, 79.6 for PAH, 91.0 for CF, and 88.3 for ILD (p < 0.001).
Conclusions
Among patients bridging to transplant on ECMO, patients with PAH had a lower transplantation rate than patients with OLD, CF, and ILD.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 24 Aug 2021; epub ahead of print
Furfaro D, Rosenzweig EB, Shah L, Robbins H, ... Arcasoy S, Benvenuto L
J Heart Lung Transplant: 24 Aug 2021; epub ahead of print | PMID: 34548196
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Impact:
Abstract

Abnormal one-year post-lung transplant spirometry is a significant predictor of increased mortality and chronic lung allograft dysfunction.

Paraskeva MA, Borg BM, Paul E, Fuller J, Westall GP, Snell GI
Background
The prognostic value of evaluating spirometry at a fixed time point using standardized population reference has not previously been evaluated. Our aim was to assess the association between spirometric phenotype at 12 months (Spiro12M), survival and incidence of chronic lung allograft dysfunction (CLAD) in bilateral lung transplant recipients.
Methods
We conducted a retrospective cohort study of bilateral lung transplant recipients transplanted between January 2003 and September 2012. We defined Spiro12M as the mean of the 2 prebronchodilator FEV1 measurements 12-month post-transplant. Normal spirometry was defined as FEV1/FVC ≥0.7 and FEV1≥80% and FVC≥80% predicted population-based values for that recipient. Abnormal spirometry was defined as failure to attain normal function by 12-months. We used a Cox regression model to assess the association between Spiro12M, survival, and CLAD. We used logistic regression to assess potential pretransplant donor and recipient factors associated with abnormal Spiro12M
Results:
One hundred and eleven (51%) lung transplant recipients normalized their Spiro12M. Normal Spiro12M was associated improved survival (hazard ratio [HR] 0.60, 95% confidence interval [CI] 0.41-0.88], p = 0.009. Each 10% decrement in FEV1 increased the risk of death in a stepwise fashion. Additionally, CLAD was reduced in those with normal Spiro12M (HR:0.65, 95%CI:0.46-0.92, p = 0.016). Donor smoking history (OR:2.93, 95% CI:1.21-7.09; p = 0.018) and mechanical ventilation time in hours (OR:1.03, 95% CI:1.004-1.05; p = 0.02) were identified as independent predictors of abnormal Spiro12M.
Conclusions
Abnormal Spiro12M is associated with increased mortality and the development of CLAD. The effect is dose dependent with increased dysfunction corresponding to increased risk. This assessment of phenotype at 12-months can easily be incorporated into standard of care.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 20 Aug 2021; epub ahead of print
Paraskeva MA, Borg BM, Paul E, Fuller J, Westall GP, Snell GI
J Heart Lung Transplant: 20 Aug 2021; epub ahead of print | PMID: 34548197
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Impact:
Abstract

Practice variation in the diagnosis of acute rejection among pediatric heart transplant centers: An analysis of the pediatric heart transplant society (PHTS) registry.

Godown J, Cantor R, Koehl D, Cummings E, ... Kirklin JK, Hsu DT
Background
Freedom from rejection in pediatric heart transplant recipients is highly variable across centers. This study aimed to assess the center variation in methods used to diagnose rejection in the first-year post-transplant and determine the impact of this variation on patient outcomes.
Methods
The PHTS registry was queried for all rejection episodes in the first-year post-transplant (2010-2019). The primary method for rejection diagnosis was determined for each event as surveillance biopsy, echo diagnosis, or clinical. The percentage of first-year rejection events diagnosed by surveillance biopsy was used to approximate the surveillance strategy across centers. Methods of rejection diagnosis were described and patient outcomes were assessed based on surveillance biopsy utilization among centers.
Results
A total of 3985 patients from 56 centers were included. Of this group, 873 (22%) developed rejection within the first-year post-transplant. Surveillance biopsy was the most common method of rejection diagnosis (71.7%), but practices were highly variable across centers. The majority (73.6%) of first rejection events occurred within 3-months of transplantation. Diagnosis modality in the first-year was not independently associated with freedom from rejection, freedom from rejection with hemodynamic compromise, or overall graft survival.
Conclusions
Rejection in the first-year after pediatric heart transplant occurs in 22% of patients and most commonly in the first 3 months post-transplant. Significant variation exists across centers in the methods used to diagnose rejection in pediatric heart transplant recipients, however, these variable strategies are not independently associated with freedom from rejection, rejection with hemodynamic compromise, or overall graft survival.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 18 Aug 2021; epub ahead of print
Godown J, Cantor R, Koehl D, Cummings E, ... Kirklin JK, Hsu DT
J Heart Lung Transplant: 18 Aug 2021; epub ahead of print | PMID: 34598871
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Impact:
Abstract

LVAD decommissioning for myocardial recovery: Long-term ventricular remodeling and adverse events.

Gerhard EF, Wang L, Singh R, Schueler S, ... MacGowan GA, Shah P
Background
Left ventricular assist devices (LVADs) mechanically unload the heart and coupled with neurohormonal therapy can promote reverse cardiac remodeling and myocardial recovery. Minimally invasive LVAD decommissioning with the device left in place has been reported to be safe over short-term follow-up. Whether device retention reduces long-term safety, or sustainability of recovery is unknown.
Methods
This is a dual-center retrospective analysis of patients who had achieved responder status (left ventricular ejection fraction, LVEF ≥40% and left ventricular internal diastolic diameter, LVIDd ≤6.0 cm) and underwent elective LVAD decommissioning for myocardial recovery from May 2010 to January 2020. All patients had outflow graft closure and driveline resection with the LVAD left in place. Emergent LVAD decommissioning for an infection or device thrombosis was excluded. Patients were followed with serial echocardiography for up to 3-years. The primary clinical outcome was survival free of heart failure hospitalization, LVAD reimplantation, or transplant.
Results
During the study period 515 patients received an LVAD and 29 (5.6%) achieved myocardial recovery, 12 patients underwent total device explantation or urgent device decommissioning, 17 patients underwent elective LVAD decommissioning, and were included in the analysis. Median age of patients at LVAD implantation was 42 years (interquartile range, IQR: 25-54 years), all had a nonischemic cardiomyopathy, and 5 (29%) were female. At LVAD implantation, median LVEF was 10% (IQR: 5%-15%), and LVIDd 6.6 cm (IQR: 5.8-7.1 cm). There were 11 hydrodynamically levitated centrifugal-flow (65%), and 6 axial-flow LVADs (35%). The median duration of LVAD support before decommissioning was 28.7 months (range 13.5-36.2 months). As compared to the turndown study parameters, 1-month post-decommissioning, median LVEF decreased from 55% to 48% (p = 0.03), and LVIDd increased from 4.8 cm to 5.2 cm (p = 0.10). There was gradual remodeling until 6 months, after which there was no statistical difference on follow-up through 3-years (LVEF 42%, LVIDd 5.6 cm). Recurrent infections affected 41% of patients leading to 3 deaths and 1 complete device explant. Recurrent HF occurred in 1 patient who required a transplant. Probability of survival free of HF, LVAD, or transplant was 94% at 1-year, and 78% at 3-years.
Conclusions
LVAD decommissioning for myocardial recovery was associated with excellent long-term survival free from recurrent heart failure and preservation of ventricular size and function up to 3-years. Reducing the risk of recurrent infections, remains an important therapeutic goal for this management strategy.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 10 Aug 2021; epub ahead of print
Gerhard EF, Wang L, Singh R, Schueler S, ... MacGowan GA, Shah P
J Heart Lung Transplant: 10 Aug 2021; epub ahead of print | PMID: 34479776
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Impact:
Abstract

Proteomic profiling identifies CLEC4C expression as a novel biomarker of primary graft dysfunction after heart transplantation.

Truby LK, Kwee LC, Agarwal R, Grass E, ... Shah SH, Holley CL
Purpose
Clinical models to identify patients at high risk of primary graft dysfunction (PGD) after heart transplantation (HT) are limited, and the underlying pathophysiology of this common post-transplant complication remains poorly understood. We sought to identify whether pre-transplant levels of circulating proteins reporting on immune activation and inflammation are associated with incident PGD.
Methods
The study population consisted of 219 adult heart transplant recipients identified between 2016 and 2020 at Duke University Medical Center, randomly divided into derivation (n = 131) and validation (n = 88) sets. PGD was defined using modified ISHLT criteria. Proteomic profiling was performed using Olink panels (n = 354 proteins) with serum samples collected immediately prior to transplantation. Association between normalized relative protein expression and PGD was tested using univariate and multivariable (recipient age, creatinine, mechanical circulatory support, and sex; donor age; ischemic time) models. Significant proteins identified in the derivation set (p < 0.05 in univariate models), were then tested in the validation set. Pathway enrichment analysis was used to test candidate biological processes. The predictive performance of proteins was compared to that of the RADIAL score.
Results
Nine proteins were associated with PGD in univariate models in the derivation set. Of these, only CLEC4C remained associated with PGD in the validation set after Bonferroni correction (OR [95% CI] = 3.04 [1.74,5.82], p = 2.8 × 10-4). Patterns of association were consistent for CLEC4C in analyses stratified by biventricular/left ventricular and isolated right ventricular PGD. Pathway analysis identified interferon-alpha response and C-type lectin signaling as significantly enriched biologic processes. The RADIAL score was a poor predictor of PGD (AUC = 0.55). CLEC4C alone (AUC = 0.66, p = 0.048) and in combination with the clinical covariates from the multivariable model (AUC = 0.69, p = 0.018) improved discrimination for the primary outcome.
Conclusions
Pre-transplantation circulating levels of CLEC4C, a protein marker of plasmacytoid dendritic cells (pDCs), may identify HT recipients at risk for PGD. Further studies are needed to better understand the potential role pDCs and the innate immune response in PGD.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 10 Aug 2021; epub ahead of print
Truby LK, Kwee LC, Agarwal R, Grass E, ... Shah SH, Holley CL
J Heart Lung Transplant: 10 Aug 2021; epub ahead of print | PMID: 34511330
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Impact:
Abstract

SARS-CoV-2 messenger RNA vaccine antibody response and reactogenicity in heart and lung transplant recipients.

Hallett AM, Greenberg RS, Boyarsky BJ, Shah PD, ... Segev DL, Bush EL
Background
While several studies have observed that solid organ transplant recipients experience diminished antibody responses to SARS-CoV-2 mRNA vaccination, data specific to heart and lung transplant (HT/LT) recipients remains sparse.
Methods
US adult HT and LT recipients completed their vaccine series between January 7 and April 10, 2021. Reactogencity and SARS-CoV-2 anti-spike antibody were assessed after a priming dose (D1) and booster dose (D2). Modified Poisson regression with robust variance estimator was used to evaluate associations between participant characteristics and antibody development.
Results
Of 134 heart recipients, there were 38% non-responders (D1-/D2-), 48% booster responders (D1-/D2+), and 14% priming dose responders (D1+/D2+). Of 103 lung recipients, 64% were non-responders, 27% were booster responders, and 9% were priming dose responders. Lung recipients were less likely to develop antibodies (p < .001). Priming dose antibody response was associated with younger recipient age (p = .04), transplant-to-vaccination time ≥6 years (p < .01), and lack of anti-metabolite maintenance immunosuppression (p < .001). Pain at injection site was the most commonly reported reaction (85% after D1, 76% after D2). Serious reactions were rare, the most common being fatigue (2% after D1 and 3% after D2). No serious adverse events were reported.
Conclusions
HT and LT recipients experienced diminished antibody response following vaccination; reactogenicity was comparable to that of the general population. LT recipients may exhibit a more impaired antibody response than HT recipients. While current recommendations are to vaccinate eligible candidates and recipients, further studies characterizing the cell-mediated immune response and clinical efficacy of these vaccines in this population are needed.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 07 Aug 2021; epub ahead of print
Hallett AM, Greenberg RS, Boyarsky BJ, Shah PD, ... Segev DL, Bush EL
J Heart Lung Transplant: 07 Aug 2021; epub ahead of print | PMID: 34456108
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Impact:
Abstract

Effects of graft preservation conditions on coronary endothelium and cardiac functional recovery in a rat model of donation after circulatory death.

Méndez-Carmona N, Wyss RK, Arnold M, Segiser A, ... Carrel TP, Longnus SL
Background
Use of cardiac grafts obtained with donation after circulatory death (DCD) could significantly improve donor heart availability. As DCD hearts undergo potentially deleterious warm ischemia and reperfusion, clinical protocols require optimization to ensure graft quality. Thus, we investigated effects of alternative preservation conditions on endothelial and/or vascular and contractile function in comparison with the current clinical standard.
Methods
Using a rat DCD model, we compared currently used graft preservation conditions, St. Thomas n°2 (St. T) at 4°C, with potentially more suitable conditions for DCD hearts, adenosine-lidocaine preservation solution (A-L) at 4°C or 22°C. Following general anesthesia and diaphragm transection, hearts underwent either 0 or 18 min of in-situ warm ischemia, were explanted, flushed and stored for 15 min with either St. T at 4°C or A-L at 4°C or 22°C, and then reperfused under normothermic, aerobic conditions. Endothelial integrity and contractile function were determined.
Results
Compared to 4°C preservation, 22°C A-L significantly increased endothelial nitric oxide synthase (eNOS) dimerization and reduced oxidative tissue damage (p < 0.05 for all). Furthermore, A-L at 22°C better preserved the endothelial glycocalyx and coronary flow compared with St. T, tended to reduce tissue calcium overload, and stimulated pro-survival signaling. No significant differences were observed in cardiac function among ischemic groups.
Conclusions
Twenty-two-degree Celsius A-L solution better preserves the coronary endothelium compared to 4°C St. T, which likely results from greater eNOS dimerization, reduced oxidative stress, and activation of the reperfusion injury salvage kinase (RISK) pathway. Improving heart preservation conditions immediately following warm ischemia constitutes a promising approach for the optimization of clinical protocols in DCD heart transplantation.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 07 Aug 2021; epub ahead of print
Méndez-Carmona N, Wyss RK, Arnold M, Segiser A, ... Carrel TP, Longnus SL
J Heart Lung Transplant: 07 Aug 2021; epub ahead of print | PMID: 34509349
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Impact:
Abstract

Accuracy of risk models used for public reporting of heart transplant center performance.

Dolgner SJ, Nguyen VP, Cowger J, Dardas TF
Background
Heart transplant programs and regulatory entities require highly accurate performance metrics to support internal quality improvement activities and national oversight of transplant programs, respectively. We assessed the accuracy of publicly reported performance measures.
Methods
We used the United Network for Organ Sharing registry to study patients who underwent heart transplantation between January 1, 2016 and June 30, 2018. We used tests of calibration to compare the observed rate of 1-year graft failure to the expected risk of 1-year graft failure, which was calculated for each recipient using the July 2019 method published by the Scientific Registry of Transplant Recipients (SRTR). The primary study outcome was the joint test of calibration, which accounts for both the total number of events predicted (calibration-in-the-large) and dispersion of risk predictions (calibration slope).
Results
6,528 heart transplants were analyzed. The primary test of calibration failed (p <0.0001), indicating poor accuracy of the SRTR model. The calibration-in-the-large statistic (0.63, 95% confidence interval [CI] 0.58-0.68, p < 0.0001) demonstrated overestimation of event rates while the calibration slope statistic (0.56, 95% CI 0.49-0.62, p <0.0001) indicated over-dispersion of event rates. Pre-specified subgroup analyses demonstrated poor calibration for all subgroups (each p <0.01). After recalibration, program-level observed/expected ratios increased by a median of 0.14 (p <0.0001).
Conclusions
Risk models employed for publicly-reported graft survival at U.S. heart transplant centers lack accuracy in general and in all subgroups tested. The use of disease-specific models may improve the accuracy of program performance metrics.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 05 Aug 2021; epub ahead of print
Dolgner SJ, Nguyen VP, Cowger J, Dardas TF
J Heart Lung Transplant: 05 Aug 2021; epub ahead of print | PMID: 34465530
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Impact:
Abstract

Evaluation and management of patients with chronic thromboembolic pulmonary hypertension - consensus statement from the ISHLT.

de Perrot M, Gopalan D, Jenkins D, Lang IM, ... Frantz RP, Auger WR
ISHLT members have recognized the importance of a consensus statement on the evaluation and management of patients with chronic thromboembolic pulmonary hypertension. The creation of this document required multiple steps, including the engagement of the ISHLT councils, approval by the Standards and Guidelines Committee, identification and selection of experts in the field, and the development of 6 working groups. Each working group provided a separate section based on an extensive literature search. These sections were then coalesced into a single document that was circulated to all members of the working groups. Key points were summarized at the end of each section. Due to the limited number of comparative trials in this field, the document was written as a literature review with expert opinion rather than based on level of evidence.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 02 Aug 2021; epub ahead of print
de Perrot M, Gopalan D, Jenkins D, Lang IM, ... Frantz RP, Auger WR
J Heart Lung Transplant: 02 Aug 2021; epub ahead of print | PMID: 34420851
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Impact:
Abstract

Influence of the microbiome on solid organ transplant survival.

Pirozzolo I, Li Z, Sepulveda M, Alegre ML
The microbiome is an environmental factor in intricate symbiotic relationship with its hosts\' immune system, potentially shaping anticancer immunity, autoimmunity, and transplant responses. The focus of this review is to discuss recent findings tying the microbiota to transplant outcomes and alloimmunity. The microbiota changes dynamically following transplantation, but whether these changes affect transplant outcomes can be difficult to parse out. New data reveal effects of the microbiota locally, as well as systemically, depending on the mucosal/epithelial surface colonized, the specific commensal communities present and the nature of microbial-derived molecules produced. These complex interactions result in the microbiota potentially impacting transplantation at different levels, including modulation of donor and/or recipient cells, alterations in the priming and/or effector phases of the alloimmune response, availability or metabolism of immunosuppressive drugs, transplant fate or post-transplant complications.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Jul 2021; 40:745-753
Pirozzolo I, Li Z, Sepulveda M, Alegre ML
J Heart Lung Transplant: 30 Jul 2021; 40:745-753 | PMID: 34030971
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Impact:
Abstract

First in man evaluation of a novel circulatory support device: Early experience with the Impella 5.5 after CE mark approval in Germany.

Bernhardt AM, Potapov E, Schibilsky D, Ruhparwar A, ... Reichenspurner H, Schulte-Eistrup S
Background
The Abiomed Impella 5.5 (Danvers, MA) is a newly developed axial flow transaortic cardiac support device mounted on a 9 Fr steering catheter with a 21 Fr pump cannula. Impella 5.5 is intended for longer use and was approved for 30 days in 2018. This study evaluated the first-in-man series at six high-volume mechanical circulatory support centers in Germany after CE approval.
Methods
The first 46 consecutive patients worldwide underwent implantation in six German centers between March 2018 and September 2019 for post-CE approval evaluation. The primary end-point was 30 days and 90 days all-cause mortality.
Results
The mean age of patients was 59.0 ± 11.5 years, and 43 (93.4%) were men. Half of the patients had acute on chronic heart failure. The main indication for Impella 5.5 implantation was ischemic cardiomyopathy and acute myocardial infarction (47.8%). The mean support time was 15.5 ± 24.2 days (range 0-164, median 10 days (IQR = 7-19)) with a total of 712 patient-days on support. The 30 days and 90 days survival rates were 73.9% (95% CI: 63.3-88.9%) and 71.7% (95% CI: 60.7-87.1%), respectively. Additionally, 16 patients (34.8%) were weaned from the device for native heart recovery, and 19 (41.3%) were bridged to a durable device. Fifteen patients (32.6%) were mobilized to a chair, and 15 (32.6%) were ambulatory. We only noted one stroke and found no other thromboembolic complications. No aortic valve damage was observed in the study cohort. Finally, seven patients (15.2 %) had pump thrombosis, and nine (19.6 %) underwent device exchange. Sixteen patients (34.8 %) suffered from bleeding requiring transfusions during the whole treatment course. In ten patients (21.7%), the inflow cannula dislocated into the aortic root.
Conclusions
The first version of the Impella 5.5 presents promising early outcomes for patients with acute heart failure and expands the spectrum of available devices. The adverse event profile is favorable for short-term devices. Dislocations have been addressed by design changes. With increasing experience with this device, our study suggests that the indications for use will expand to other cardiac shock etiologies and may improve myocardial recovery and survival in patients with cardiogenic shock.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Jul 2021; 40:850-855
Bernhardt AM, Potapov E, Schibilsky D, Ruhparwar A, ... Reichenspurner H, Schulte-Eistrup S
J Heart Lung Transplant: 30 Jul 2021; 40:850-855 | PMID: 34030970
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Impact:
Abstract

Association of low center performance evaluations and pediatric heart transplant center behavior in the United States.

Amdani S, Boyle G, Rossano J, Scheel J, ... Arrigain S, Schold JD
Background
To date, no study has evaluated the effects of low center performance evaluations (CPE) on pediatric heart transplant center behavior. We sought to assess the impact of low CPE flags on pediatric heart transplant center listing and transplant volumes and center recipient and donor characteristics.
Methods
We included centers performing at least 10 pediatric (age <18 years) transplants during the Scientific Registry of Transplant Recipients reporting period January 2009-June 2011 and evaluated consecutive biannual program specific reports until the last reporting period January 2016-June 2018. We evaluated changes in center behavior at following time points: a year before flagging, a year and two years after the flag; and at last reporting period.
Results
During our study period, 24 pediatric centers were non-flagged and 6 were flagged. Compared to non-flagged centers, there was a decline in candidate listings in flagged centers at the last reporting period (mean increase of 5.5 ± 12.4 listings vs\"?> mean decrease of 14.0 ± 14.9 listings; p = .003). Similarly, the number of transplants declined in flagged centers (mean increase of 2.6 ± 9.6 transplants vs\"?> mean decrease of 10.0 ± 12.8 transplants; p = .012). Flagged centers had declines in listings for patients with restrictive cardiomyopathy, re-transplant, renal dysfunction, those on mechanical ventilation and extracorporeal membrane oxygenation. There was no significant change in donor characteristics between flagged and non-flagged centers.
Conclusions
Low CPE may have unintended negative consequences on center behavior leading to declines in listing and transplant volumes and potentially leading to decreased listing for higher risk recipients.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Jul 2021; 40:831-840
Amdani S, Boyle G, Rossano J, Scheel J, ... Arrigain S, Schold JD
J Heart Lung Transplant: 30 Jul 2021; 40:831-840 | PMID: 34078559
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Impact:
Abstract

The impact of donor sex on heart transplantation outcomes-a study of over 60,000 patients in the United States.

Zhu Y, Shudo Y, Lingala B, Joseph Woo Y
Background
The impact of donor sex on heart transplantation outcomes irrespective of recipient sex remains unclear. The objective of this study was to evaluate the impact of donor sex on heart transplantation outcomes in the United States.
Methods
From 1987 to March 2019, 63,775 adult patients who underwent heart transplantation were matched to 27,509 male and 11,474 female donors in the United States. Data were prospectively collected by the United Network for Organ Sharing (UNOS). Patients without missing data were stratified by donor sex and donor menopause status. The groups were matched 1:1 using the propensity score of each patient. Kaplan-Meier survival and cox proportional hazards regression analyses were performed. The primary endpoint was all-cause mortality. Secondary endpoints were postoperative complications.
Results
Propensity matching generated 15,506 and 1,094 patients based on donor sex and menopause status, respectively. Recipients who received female donor allografts were more likely to have acute rejection episodes requiring anti-rejection medical treatment (11.9% vs 10.1%, p = .007) and require post-transplant dialysis (10.9% vs 9.3%, p = .001) than those who received male donor allografts. Overall survival using female vs male donor allografts was similar (p = .34). Recipients who received pre- vs post-menopausal female donor hearts had similar postoperative outcomes and overall survival (p = .23).
Conclusions
Analysis of the UNOS database showed similar median survival using female vs male donor hearts in adult heart transplantation, irrespective of donor menopause status. Female donor allografts are used far less frequently, thus these results represent an opportunity to maximize usage by better utilization of suitable female donor organs.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Jul 2021; 40:814-821
Zhu Y, Shudo Y, Lingala B, Joseph Woo Y
J Heart Lung Transplant: 30 Jul 2021; 40:814-821 | PMID: 34083118
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Impact:
Abstract

Therapeutic efficacy of large aligned cardiac tissue derived from induced pluripotent stem cell in a porcine ischemic cardiomyopathy model.

Suzuki K, Miyagawa S, Liu L, Kawamura T, ... Kawamura A, Sawa Y
Background
Although induced pluripotent stem (iPS) cell-derived cardiac constructs may have a potential in cardiomyogenesis of a distressed myocardium, obtaining polarity in cardiac constructs, such as via myocyte alignment, may be crucial to achieve a maximum contractile force for better clinical outcomes. We herein hypothesized that transplantation of an aligned cardiac tissue derived from iPS cells has therapeutic effects in a porcine ischemic cardiomyopathy model as a preclinical trial.
Methods
Aligned cardiac tissues were developed by culturing high-purity iPS cell-derived cardiomyocytes in xeno-free conditions and transplanting them into infarct porcine hearts (iPS-CM group, n = 7; control, n = 6). Three months after treatment, therapeutic efficacy was evaluated functionally and histologically.
Results
In vitro assessment revealed that the aligned cardiac tissue containing high purity cardiomyocytes contracted homogeneously and had excellent mechanical properties. In the in vivo study, the left ventricular ejection fraction of the iPS-CM group was significantly greater than that of the control group, 3 months after transplantation (37.8% ± 2.3% vs 28.3% ± 2.5%, p < 0.05). Pathologically, attenuated interstitial fibrosis, attenuation of hypertrophied cardiomyocytes, and an increased capillary density were also prominent in the iPS-CM group. A limited amount of engraftment of the transplanted tissue maintaining tissue alignment was observed at 2 weeks after transplantation.
Conclusions
The creation of large-scale functional aligned cardiac tissue was feasible, and the transplantation of the aligned tissue improved cardiac function with angiogenesis and antifibrotic effects in a porcine cardiomyopathy model.

Copyright © 2021. Published by Elsevier Inc.

J Heart Lung Transplant: 30 Jul 2021; 40:767-777
Suzuki K, Miyagawa S, Liu L, Kawamura T, ... Kawamura A, Sawa Y
J Heart Lung Transplant: 30 Jul 2021; 40:767-777 | PMID: 34108109
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Impact:
Abstract

Waitlist and post-transplant outcomes for eisenmenger syndrome: A comparison of transplant strategies.

Kearney K, Lau EM, Darley D, Romfh A, ... Khush K, Keogh A
Background
End-stage Eisenmenger syndrome (ES) due to unrepaired atrial septal defect (ASD) or ventricular septal defect (VSD) is an indication for lung transplantation (LTx) or heart-lung transplantation (HLTx). Limited evidence exists as to the optimal transplant strategy for this unique population.
Aim
To describe waitlist characteristics and post-transplant outcomes in patients with ES-ASD or ES-VSD.
Methods
Using the ISHLT Registry, data were extracted for all ES-ASD or ES-VSD patients who underwent transplantation between 1987 and 2018. Additional data were sought for patients listed for LTx or HLTx in the OPTN Registry during the same period. Early era was defined as 1987-2004, and current era was defined as 2005-2018.
Results
In the current era, patients with ES-ASD or ES-VSD represented a lessening proportion of all LTx and HLTx. Compared to LTx for other indications, the odds of transplantation were significantly less for both ES-ASD 0.18 [0.07-0.50] and ES-VSD 0.03 [0.004-0.22]. In the early era, an equivalent survival was observed for ES-ASD who underwent HLTx versus LTx (p = 0.47), and superior survival for ES-VSD (p = 0.015). In contrast, ES-ASD patients who underwent LTx from the current era displayed better survival compared with HLTx, 10-year survival 52% vs 30% p = 0.036. Similar survival were observed for ES-VSD for both transplant strategies (p = 0.68).
Conclusion
LTx shows superior survival outcomes in the current era for ES ASD patients, and equivalent outcomes for ES-VSD. In the current era, ES-ASD or ES-VSD patients were less likely to be transplanted than other candidates for LTx.

Copyright © 2021 International Society for Heart and Lung Transplantation. All rights reserved.

J Heart Lung Transplant: 30 Jul 2021; 40:841-849
Kearney K, Lau EM, Darley D, Romfh A, ... Khush K, Keogh A
J Heart Lung Transplant: 30 Jul 2021; 40:841-849 | PMID: 34112578
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Impact:
Abstract

Assessing predicted heart mass size matching in obese heart transplant recipients.

Kim ST, Helmers MR, Iyengar A, Smood B, ... Altshuler P, Atluri P
Background
Predicted heart mass (PHM) is currently the most reliable metric for donor-recipient size matching in heart transplantation. Undersizing PHM donor-recipient match more than 20% independently predicts reduced survival. However, it is unclear if this is the case in obese recipients, in whom size matching can be challenging. We examined the use of PHM undersized hearts in obese recipients and assessed its impact on survival.
Methods
The United Network for Organ Sharing database was queried for adult patients undergoing heart transplantation from 1995 to 2020. Obese recipients (BMI ≥ 30) were categorized based on donor-recipient PHM match ≤-20% (undersized) or >-20% (size-matched). Nearest-neighbor propensity score matching was performed to adjust for baseline differences between cohorts. Temporal outcomes were compared by Kaplan-Meier survival analysis.
Results
A total of 13,668 obese recipients met inclusion criteria, with 9.6% receiving undersized and 90.4% receiving size-matched hearts. The proportion of undersized donor hearts in obese recipients significantly decreased over the study period (16.2% [1995] to 7.4% [2019], NP-trend < 0.001). Propensity-score matching resulted in 984 well-matched pairs of undersized and size-matched obese recipients. Recipients of undersized hearts saw similar 30-day mortality (5.5% vs 6.0%, p= 0.11) and re-transplantation rates (1.2% vs 1.2%, p = 1.00) as size-matched recipients. Survival at 1 year (88.4% vs 87.9%, p = 0.14), and 15 years (35.1% vs 31.0%, p = 0.12) was similar across cohorts.
Conclusions
A decreasing proportion of PHM undersized hearts are being utilized in obese recipients. However, utilizing PHM undersized hearts in obese recipients was not associated with a detriment in survival.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Jul 2021; 40:805-813
Kim ST, Helmers MR, Iyengar A, Smood B, ... Altshuler P, Atluri P
J Heart Lung Transplant: 30 Jul 2021; 40:805-813 | PMID: 34127356
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Impact:
Abstract

The lung microbiome in lung transplantation.

McGinniss JE, Whiteside SA, Simon-Soro A, Diamond JM, ... Bushman FD, Collman RG
Culture-independent study of the lower respiratory tract after lung transplantation has enabled an understanding of the microbiome - that is, the collection of bacteria, fungi, and viruses, and their respective gene complement - in this niche. The lung has unique features as a microbial environment, with balanced entry from the upper respiratory tract, clearance, and local replication. There are many pressures impacting the microbiome after transplantation, including donor allograft factors, recipient host factors such as underlying disease and ongoing exposure to the microbe-rich upper respiratory tract, and transplantation-related immunosuppression, antimicrobials, and postsurgical changes. To date, we understand that the lung microbiome after transplant is dysbiotic; that is, it has higher biomass and altered composition compared to a healthy lung. Emerging data suggest that specific microbiome features may be linked to host responses, both immune and non-immune, and clinical outcomes such as chronic lung allograft dysfunction (CLAD), but many questions remain. The goal of this review is to put into context our burgeoning understanding of the lung microbiome in the postlung transplant patient, the interactions between microbiome and host, the role the microbiome may play in post-transplant complications, and critical outstanding research questions.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Jul 2021; 40:733-744
McGinniss JE, Whiteside SA, Simon-Soro A, Diamond JM, ... Bushman FD, Collman RG
J Heart Lung Transplant: 30 Jul 2021; 40:733-744 | PMID: 34120840
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Impact:
Abstract

Cerebral vasoreactivity in HeartMate 3 patients.

Stöhr EJ, Ji R, Akiyama K, Mondellini G, ... McDonnell BJ, Willey JZ
Background
While rates of stroke have declined with the HeartMate3 (HM3) continuous- flow (CF) left ventricular assist device (LVAD), the impact of non-pulsatile flow and artificial pulse physiology on cerebrovascular function is not known. We hypothesized that improved hemodynamics and artificial pulse physiology of HM3 patients would augment cerebrovascular metabolic reactivity (CVR) compared with HeartMate II (HMII) CF-LVAD and heart failure (HF) patients.
Methods
Mean, peak systolic and diastolic flow velocities (MFV, PSV, MinFV, respectively) and cerebral pulsatility index were determined in the middle cerebral artery (MCA) before and after a 30 sec breath-hold challenge in 90 participants: 24 healthy controls; 30 HF, 15 HMII, and 21 HM3 patients.
Results
In HM3 patients, breath-holding increased MFV (Δ8 ± 10 cm/sec, p < .0001 vs baseline) to levels similar to HF patients (Δ9 ± 8 cm/sec, p > .05), higher than HMII patients (Δ2 ± 8 cm/sec, p < .01) but lower than healthy controls (Δ13 ± 7 cm/sec, p < .05). CF-LVAD altered the proportion of systolic and diastolic flow responses as reflected by a differential cerebral pulsatility index (p = .03). Baseline MFV was not related to CVR (r2 = 0.0008, p = .81). However, CF-LVAD pump speed was strongly inversely associated with CVR in HM II (r2 = 0.51, p = .003) but not HM3 patients (r2 = 0.01, p = .65).
Conclusions
Compared with HMII, HM3 patients have a significantly improved CVR. However, CVR remains lower in HM3 and HF patients than in healthy controls, therefore suggesting that changes in cerebral hemodynamics are not reversed by CF-LVAD therapy. Further research on the mechanisms and the long-term impact of altered cerebral hemodynamics in this unique patient population are warranted.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Jul 2021; 40:786-793
Stöhr EJ, Ji R, Akiyama K, Mondellini G, ... McDonnell BJ, Willey JZ
J Heart Lung Transplant: 30 Jul 2021; 40:786-793 | PMID: 34134913
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Impact:
Abstract

HLA-DRB1 mismatch-based identification of donor-derived cell free DNA (dd-cfDNA) as a marker of rejection in heart transplant recipients: A single-institution pilot study.

Sorbini M, Togliatto GM, Simonato E, Boffini M, ... Vaisitti T, Deaglio S
Background
Donor-derived cell-free DNA (dd-cfDNA) is considered a reliable marker of organ damage with potential applications in the follow-up of transplant recipients.
Methods
In this work we present an assay based on the donor-recipient HLA-mismatch (human leukocyte antigen) at the HLA-DRB1 locus to monitor rejection by quantifying the percentage of dd-cfDNA using a droplet digital PCR (polymerase chain reaction) technique. A panel of probes targeting the HLA-DRB1 locus and covering >85% genetic variability was validated and used to assess dd-cfDNA levels in a prospective cohort of 19 adult heart transplant recipients (mean age 50.9±14.8 years). The assay was carried out on a total of 232 liquid biopsies collected at the same time as endomyocardial biopsy (EMB) during routine post-transplant follow-up.
Results
Results show a significant increase of dd-cfDNA related to ischemia-reperfusion injury (2.22±2.09%) and to acute cellular rejection (1.71±3.10%) compared to stable conditions (0.43±1.04%, p < 0.0001). On the contrary, no increase was observed during infections or vascular complications, underlining the potential role of this biomarker for rejection monitoring. With a cut-off of 0.11%, the test showed 70.8% specificity (95% CI, 58.17% - 81.40%) and 64.2% sensitivity (95% CI, 49.80% - 76.86%) in discriminating acute rejection from no rejection.
Conclusions
These data demonstrate that this HLA mismatch-based droplet digital PCR method is effective for monitoring rejection in heart transplant recipients. Compared to next generation sequencing approaches, it is far more flexible, less expensive and provides faster results.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Jul 2021; 40:794-804
Sorbini M, Togliatto GM, Simonato E, Boffini M, ... Vaisitti T, Deaglio S
J Heart Lung Transplant: 30 Jul 2021; 40:794-804 | PMID: 34134912
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Impact:
Abstract

Long-term survival in patients with post-LVAD right ventricular failure: multi-state modelling with competing outcomes of heart transplant.

Shad R, Fong R, Quach N, Bowles C, ... Teuteberg J, Hiesinger W
Background
Multicenter data on long term survival following LVAD implantation that make use of contemporary definitions of RV failure are limited. Furthermore, traditional survival analyses censor patients who receive a bridge to heart transplant. Here we compare the outcomes of LVAD patients who develop post-operative RV failure accounting for the transitional probability of receiving an interim heart transplantation.
Methods
We use a retrospective cohort of LVAD patients sourced from multiple high-volume centers based in the United States. Five- and ten-year survival accounting for transition probabilities of receiving a heart transplant were calculated using a multi-state Aalen Johansen survival model.
Results
Of the 897 patients included in the study, 238 (26.5%) developed post-operative RV failure at index hospitalization. At 10 years the probability of death with post-op RV failure was 79.28% vs 61.70% in patients without (HR 2.10; 95% CI 1.72 - 2.57; p = < .001). Though not significant, patients with RV failure were less likely to be bridged to a heart transplant (HR 0.87, p = .4). Once transplanted the risk of death between both patient groups remained equivalent; the probability of death after a heart transplant was 3.97% in those with post-operative RV failure shortly after index LVAD implant, as compared to 14.71% in those without.

Conclusions:
and relevance
Long-term durable mechanical circulatory support is associated with significantly higher mortality in patients who develop post-operative RV failure. Improving outcomes may necessitate expeditious bridge to heart transplant wherever appropriate, along with critical reassessment of organ allocation policies.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Jul 2021; 40:778-785
Shad R, Fong R, Quach N, Bowles C, ... Teuteberg J, Hiesinger W
J Heart Lung Transplant: 30 Jul 2021; 40:778-785 | PMID: 34167863
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Impact:
Abstract

Donor-derived cell-free DNA accurately detects acute rejection in lung transplant patients, a multicenter cohort study.

Jang MK, Tunc I, Berry GJ, Marboe C, ... Nathan SD, Agbor-Enoh S
Background
Acute rejection, which includes antibody-mediated rejection and acute cellular rejection, is a risk factor for lung allograft loss. Lung transplant patients often undergo surveillance transbronchial biopsies to detect and treat acute rejection before irreversible chronic rejection develops. Limitations of this approach include its invasiveness and high interobserver variability. We tested the performance of percent donor-derived cell-free DNA (%ddcfDNA), a non-invasive blood test, to detect acute rejection.
Methods
This multicenter cohort study monitored 148 lung transplant subjects over a median of 19.6 months. We collected serial plasma samples contemporaneously with TBBx to measure %ddcfDNA. Clinical data was collected to adjudicate for acute rejection. The primary analysis consisted of computing the area-under-the-receiver-operating-characteristic-curve of %ddcfDNA to detect acute rejection. Secondary analysis determined %ddcfDNA rule-out thresholds for acute rejection.
Results
ddcfDNA levels were high after transplant surgery and decayed logarithmically. With acute rejection, ddcfDNA levels rose six-fold higher than controls. ddcfDNA levels also correlated with severity of lung function decline and histological grading of rejection. %ddcfDNA area-under-the-receiver-operating-characteristic-curve for acute rejection, AMR, and ACR were 0.89, 0.93, and 0.83, respectively. ddcfDNA levels of <0.5% and <1.0% showed a negative predictive value of 96% and 90% for acute rejection, respectively. Histopathology detected one-third of episodes with ddcfDNA levels ≥1.0%, even though >90% of these events were coincident to clinical complications missed by histopathology.
Conclusions
This study demonstrates that %ddcfDNA reliably detects acute rejection and other clinical complications potentially missed by histopathology, lending support to its use as a non-invasive marker of allograft injury.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Jul 2021; 40:822-830
Jang MK, Tunc I, Berry GJ, Marboe C, ... Nathan SD, Agbor-Enoh S
J Heart Lung Transplant: 30 Jul 2021; 40:822-830 | PMID: 34130911
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Impact:
Abstract

ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part III: Pharmacology, medical and surgical management of post-transplant extrapulmonary conditions statements.

Crespo MM, Claridge T, Domsic RT, Hartwig M, ... Vos R, Glanville AR
Patients with connective tissues disease (CTD) are often on immunomodulatory agents before lung transplantation (LTx). Till now, there\'s no consensus on the safety of using these agents perioperative and post-transplant. The International Society for Heart and Lung Transplantation-supported consensus document on LTx in patients with CTD addresses the risk and contraindications of perioperative and post-transplant management of the biologic disease-modifying antirheumatic drugs (bDMARD), kinase inhibitor DMARD, and biologic agents used for LTx candidates with underlying CTD, and the recommendations and management of non-gastrointestinal extrapulmonary manifestations, and esophageal disorders by medical and surgical approaches for CTD transplant recipients.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Jul 2021; epub ahead of print
Crespo MM, Claridge T, Domsic RT, Hartwig M, ... Vos R, Glanville AR
J Heart Lung Transplant: 30 Jul 2021; epub ahead of print | PMID: 34474940
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Impact:
Abstract

ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part II: Cardiac, surgical, perioperative, operative, and post-operative challenges and management statements.

Bermudez CA, Crespo MM, Shlobin OA, Cantu E, ... Douglas A, Mercier O
Patients with connective tissue disease (CTD) present unique surgical, perioperative, operative, and postoperative challenges related to the often underlying severe pulmonary hypertension and right ventricular dysfunction. The International Society for Heart and Lung Transplantation-supported consensus document on lung transplantation in patients with CTD standardization addresses the surgical challenges and relevant cardiac involvement in the perioperative, operative, and postoperative management in patients with CTD.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 28 Jul 2021; epub ahead of print
Bermudez CA, Crespo MM, Shlobin OA, Cantu E, ... Douglas A, Mercier O
J Heart Lung Transplant: 28 Jul 2021; epub ahead of print | PMID: 34404570
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Impact:
Abstract

Clinical and hemodynamic characteristics of the pediatric failing Fontan.

Dykes JC, Rosenthal DN, Bernstein D, McElhinney DB, ... Chen S, Pediatric Heart Transplant Society
Aim
To describe the clinical and hemodynamic characteristics of Fontan failure in children listed for heart transplant.
Methods
In a nested study of the Pediatric Heart Transplant Society, 16 centers contributed information on Fontan patients listed for heart transplant between 2005and 2013. Patients were classified into four mutually exclusive phenotypes: Fontan with abnormal lymphatics (FAL), Fontan with reduced systolic function (FRF), Fontan with preserved systolic function (FPF), and Fontan with \"normal\" hearts (FNH). Primary outcome was waitlist and post-transplant mortality.
Results
177 children listed for transplant were followed over a median 13 (IQR 4-31) months, 84 (47%) were FAL, 57 (32%) FRF, 22 (12%) FNH, and 14 (8%) FPF. Hemodynamic characteristics differed between the 4 groups: Fontan pressure (FP) was most elevated with FPF (median 22, IQR 18-23, mmHg) and lowest with FAL (16, 14-20, mmHg); cardiac index (CI) was lowest with FRF (2.8, 2.3-3.4, L/min/m2). In the entire cohort, 66% had FP >15 mmHg, 21% had FP >20 mmHg, and 10% had CI <2.2 L/min/m2. FRF had the highest risk of waitlist mortality (21%) and FNH had the highest risk of post-transplant mortality (36%).
Conclusions
Elevated Fontan pressure is more common than low cardiac output in pediatric failing Fontan patients listed for transplant. Subtle hemodynamic differences exist between the various phenotypes of pediatric Fontan failure. Waitlist and post-transplant mortality risks differ by phenotype.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 28 Jul 2021; epub ahead of print
Dykes JC, Rosenthal DN, Bernstein D, McElhinney DB, ... Chen S, Pediatric Heart Transplant Society
J Heart Lung Transplant: 28 Jul 2021; epub ahead of print | PMID: 34412962
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Impact:
Abstract

ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part I: Epidemiology, assessment of extrapulmonary conditions, candidate evaluation, selection criteria, and pathology statements.

Crespo MM, Lease ED, Sole A, Sandorfi N, ... Bhorade S, Budev M
Patients with connective tissue disease (CTD) and advanced lung disease are often considered suboptimal candidates for lung transplantation (LTx) due to their underlying medical complexity and potential surgical risk. There is substantial variability across LTx centers regarding the evaluation and listing of these patients. The International Society for Heart and Lung Transplantation-supported consensus document on lung transplantation in patients with CTD standardization aims to clarify definitions of each disease state included under the term CTD, to describe the extrapulmonary manifestations of each disease requiring consideration before transplantation, and to outline the absolute contraindications to transplantation allowing risk stratification during the evaluation and selection of candidates for LTx.

Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 28 Jul 2021; epub ahead of print
Crespo MM, Lease ED, Sole A, Sandorfi N, ... Bhorade S, Budev M
J Heart Lung Transplant: 28 Jul 2021; epub ahead of print | PMID: 34417111
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Impact:

This program is still in alpha version.