Journal: J Heart Lung Transplant

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Abstract

ProT-α gene transfer attenuates cardiopulmonary remedying and mortality in a flow-induced pulmonary hypertension rat model.

Roan JN, Hsu CH, Fang SY, Chiu MS, ... Shiau AL, Lam CF
Background
ProT is a cell survival gene, which modulates oxidative stress and transforming growth factor (TGF)-β signaling. We hypothesized that the delivery of the ProT cDNA gene in rats could protect against right heart dysfunction secondary to pulmonary hypertension (PH) induced by left-to-right shunt.
Methods
A 2-hit rat model of flow-induced PH was used, and a single intravenous injection of adenoviral vectors (2 billion plaque-forming unit) carrying ProT or Luc gene was administered. The animals were euthanized 21 days after gene delivery to assess cardiopulmonary function, serum biochemistry, pulmonary artery (PA), and vasomotor reactivity. Immunohistology and immunoblotting of PA tissues were also performed.
Results
ProT transduction significantly reduced PA pressure, right ventricle muscle mass, and wall stress, thereby improving the overall survival of the treated rat. Increased production of ProT through gene therapy preserved both the smooth muscle myosin heavy chain-II and α-smooth muscle actin while counteracting the abundance of TGF-β in PA. Protein abundances of phosphorylated p47-phox, heme oxygenase-1, caspase-3, inducible nitric oxide synthase, cyclo-oxygenase 2, and monocyte chemoattractant protein-1 in PA tissues were reduced. ProT also preserved microRNA-223, thereby suppressing the abundance of PARP-1, which is independent of hypoxia-inducible factor-1α signaling.
Conclusions
ProT gene transduction improved PA function by reducing oxidative stress, attenuating inflammation, and preserving the contractile phenotype of vascular smooth muscle cells. The modification of microRNA-223-associated downstream signaling through ProT transduction may play an important role in mitigating cardiopulmonary remodeling in flow-induced PH.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2020; 39:1126-1135
Roan JN, Hsu CH, Fang SY, Chiu MS, ... Shiau AL, Lam CF
J Heart Lung Transplant: 29 Sep 2020; 39:1126-1135 | PMID: 32593559
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Abstract

Incidence and outcome of post-transplant lymphoproliferative disorders in lung transplant patients: Analysis of ISHLT Registry.

Zaffiri L, Long A, Neely ML, Cherikh WS, Chambers DC, Snyder LD
Background
Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication following lung transplant. We studied incidence and risk factors for PTLD in adult lung transplant recipients (LTRs) using the International Society for Heart and Lung Transplantation Registry.
Methods
The International Society for Heart and Lung Transplantation Registry was used to identify adult, first-time, single and bilateral LTRs with at least 1 year of follow-up between 2006 and 2016. Kaplan-Meier method was used to describe the timing and distribution of PTLD. Univariable and multivariable Cox proportional hazards regression models were used to examine clinical characteristics associated with PTLD.
Results
Of 19,309 LTRs in the analysis cohort, we identified 454 cases of PTLD. Cumulative incidence of PTLD was 1.1% (95% CI = 1.0%-1.3%) at 1 year and 4.1% (95% CI = 3.6%-4.6%) at 10 years. Of the PTLD cases, 47.4% occurred within the first year following lung transplantation. In the multivariable model, independent risk factors for PTLD included age, Epstein-Barr virus serostatus, restrictive lung diseases, and induction. Risk of PTLD during the first year after transplant increased with increasing age in patients between 45 and 62 years at time of transplantation; the inverse was true for ages <45 years or >62 years. Finally, receiving a donor organ with human leukocyte antigen types A1 and A24 was associated with an increased risk of PTLD, whereas the recipient human leukocyte antigen type DR11 was associated with a decreased risk.
Conclusions
Our study indicates that PTLD is a relatively rare complication among adult LTRs. We identified clinical characteristics that are associated with an increased risk of PTLD.

Copyright © 2020. Published by Elsevier Inc.

J Heart Lung Transplant: 29 Sep 2020; 39:1089-1099
Zaffiri L, Long A, Neely ML, Cherikh WS, Chambers DC, Snyder LD
J Heart Lung Transplant: 29 Sep 2020; 39:1089-1099 | PMID: 32654913
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Abstract

Circulating miR-181a-5p as a new biomarker for acute cellular rejection in heart transplantation.

Constanso-Conde I, Hermida-Prieto M, Barge-Caballero E, Núñez L, ... Vázquez-Rodríguez JM, Crespo-Leiro MG
Background
Acute cellular rejection (ACR) is a major complication in heart transplantation (HTx). Endomyocardial biopsy is the reference method for early detection of ACR, but a new non-invasive approach is needed. Tentative candidates could be circulating microRNAs. This study aimed to discover and validate microRNAs in serum for ACR detection after HTx.
Methods
This prospective, observational, single-center study included 121 HTx patients. ACR was graded according to International Society of Heart and Lung Transplantation classification (0R-3R). First, in the discovery phase, microRNA expression profile was carried out in serum samples from patients at pre-rejection, during, and post-rejection time (0R → 2R → 0R). Relative expression (2) of 179 microRNAs per sample was analyzed by reverse transcription quantitative polymerase chain reaction. Second, a microRNA with a significant rise and fall pattern during ACR was selected for the next validation phase, where it was analyzed (reverse transcription quantitative polymerase chain reaction) in serum samples from 2 groups of patients: the no-ACR group (0R grade) and the ACR group (≥2R grade). Finally, a sensitivity analysis (receiver operating characteristic curve) was done to assess microRNA accuracy for ACR detection in HTx.
Results
A total of 21 ACR episodes (0R → 2R → 0R) with their respective serum samples (n = 63) were included in the discovery phase. Among the 179 microRNAs analyzed, only miR-181a-5p met the rise and fall criteria. In the validation phase, miR-181a-5p relative expression (2) in the ACR group (n = 45) was significantly overexpressed (p < 0.0001) vs the no-ACR group (n = 45). miR-181a-5p showed an area under the curve of 0.804 (95% confidence interval: 0.707-0.880); sensitivity and specificity of 78% and 76%, respectively; and a negative predicted value of 98%.
Conclusions
miR-185a-5p in serum is a candidate as a non-invasive ACR biomarker (area under the curve = 0.80 and negative predicted value = 98%). Thus, this biomarker could reduce the need for endomyocardial biopsies and the associated risks and costs of this invasive procedure.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2020; 39:1100-1108
Constanso-Conde I, Hermida-Prieto M, Barge-Caballero E, Núñez L, ... Vázquez-Rodríguez JM, Crespo-Leiro MG
J Heart Lung Transplant: 29 Sep 2020; 39:1100-1108 | PMID: 32654912
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Abstract

The introduction of a super-urgent heart allocation scheme in the UK: A 2-year review.

Rushton S, Parameshwar J, Lim S, Dar O, ... Tsui S, MacGowan GA
Background
In response to a growing number of patients on the UK urgent heart transplant waiting list, the UK donor heart allocation scheme was revised in October 2016 with the introduction of a new super-urgent category. Patients with temporary mechanical circulatory support (tMCS) became eligible for super-urgent registration. The aim of this study was to compare activity, indications, and outcomes before and after the change.
Methods
Data on adult (aged ≥16 years) heart transplant registrations and recipients in the 2 years before (Era 1: July 1, 2014-June 30, 2016) and after (Era 2: January 2017-December 2018) the introduction of the new scheme were extracted from the UK Transplant Registry and analyzed using competing risks analysis, Kaplan-Meier analysis, and Cox proportional-hazards regression.
Results
There were 525 waiting-list registrations in Era 1 and 594 in Era 2, including 14% super-urgent registrations, with 90% having some form of tMCS. Median waiting time to transplant was 41 days for all urgent registrations in Era 1 compared with 17 days for super-urgent registrations and 71 days for urgent registrations in Era 2. Numbers of non-urgent transplants were not affected. Deaths on the waiting list significantly decreased from 5% to 2% at 6 months between Era 1 and Era 2 (adjusted hazard ratio = 0.29, 95% CI = 0.13-0.62). In addition, total number of patients with tMCS were not different between both eras, suggesting no significant change in this area of clinical decision making. Post-transplant survival at 1 year for super-urgent recipients was not significantly different from post-transplant survival at 1 year for other categories.
Conclusions
The Introduction of a super-urgent heart allocation scheme in the UK reduces waiting time to transplant for the sickest patients, with comparable post-transplant survival while reducing deaths on the waiting list.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2020; 39:1109-1117
Rushton S, Parameshwar J, Lim S, Dar O, ... Tsui S, MacGowan GA
J Heart Lung Transplant: 29 Sep 2020; 39:1109-1117 | PMID: 32660781
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Abstract

Circulating extracellular vesicles as non-invasive biomarker of rejection in heart transplant.

Castellani C, Burrello J, Fedrigo M, Burrello A, ... Angelini A, Barile L
Background
Circulating extracellular vesicles (EVs) are raising considerable interest as a non-invasive diagnostic tool, as they are easily detectable in biologic fluids and contain a specific set of nucleic acids, proteins, and lipids reflecting pathophysiologic conditions. We aimed to investigate differences in plasma-derived EV surface protein profiles as a biomarker to be used in combination with endomyocardial biopsies (EMBs) for the diagnosis of allograft rejection.
Methods
Plasma was collected from 90 patients (53 training cohort, 37 validation cohort) before EMB. EV concentration was assessed by nanoparticle tracking analysis. EV surface antigens were measured using a multiplex flow cytometry assay composed of 37 fluorescently labeled capture bead populations coated with specific antibodies directed against respective EV surface epitopes.
Results
The concentration of EVs was significantly increased and their diameter decreased in patients undergoing rejection as compared with negative ones. The trend was highly significant for both antibody-mediated rejection and acute cellular rejection (p < 0.001). Among EV surface markers, CD3, CD2, ROR1, SSEA-4, human leukocyte antigen (HLA)-I, and CD41b were identified as discriminants between controls and acute cellular rejection, whereas HLA-II, CD326, CD19, CD25, CD20, ROR1, SSEA-4, HLA-I, and CD41b discriminated controls from patients with antibody-mediated rejection. Receiver operating characteristics curves confirmed a reliable diagnostic performance for each single marker (area under the curve range, 0.727-0.939). According to differential EV-marker expression, a diagnostic model was built and validated in an external cohort of patients. Our model was able to distinguish patients undergoing rejection from those without rejection. The accuracy at validation in an independent external cohort reached 86.5%. Its application for patient management has the potential to reduce the number of EMBs. Further studies in a higher number of patients are required to validate this approach for clinical purposes.
Conclusions
Circulating EVs are highly promising as a new tool to characterize cardiac allograft rejection and to be complementary to EMB monitoring.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2020; 39:1136-1148
Castellani C, Burrello J, Fedrigo M, Burrello A, ... Angelini A, Barile L
J Heart Lung Transplant: 29 Sep 2020; 39:1136-1148 | PMID: 32665078
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Abstract

Risk assessment in severe pulmonary hypertension due to interstitial lung disease.

Yogeswaran A, Tello K, Faber M, Sommer N, ... Richter MJ, Gall H
Background
The updated hemodynamic definition of pulmonary hypertension (PH) due to interstitial lung disease (ILD) differentiates severe and non-severe phenotypes, but no further risk stratification strategy has been established or validated for severe PH due to ILD. We aimed to assess the prognostic value of a truncated version of the European Society of Cardiology/European Respiratory Society (ESC/ERS) PH risk stratification scheme in severe PH due to ILD.
Methods
We retrospectively analyzed 185 patients with severe PH (mean pulmonary artery pressure of ≥35 mm Hg or ≥25 mm Hg with cardiac index <2.0 liter/min/m) due to ILD who were enrolled in the Giessen PH Registry after being referred for invasive diagnostic work-up of suspected PH during 1995‒2018. A truncated ESC/ERS risk stratification scheme (based on 8 parameters from the full scheme) was applied. Kaplan-Meier and univariate Cox regression analyses were used to evaluate transplant-free survival and hazard ratios, respectively.
Results
During follow-up (median [interquartile range]: 19 [7-40] months), 146 events occurred. Using baseline data for risk stratification, 5-year transplant-free survival of low-, intermediate-, and high-risk groups was 43%, 15%, and 4%, respectively (log-rank p = 0.010; hazard ratio of high- vs low-risk group: 3.116 [95% CI: 1.428-6.800]). Using follow-up data (at 11 [6.0-32.5] months) for risk stratification, 5-year survival of low-, intermediate-, and high-risk groups was 22%, 3%, and 0%, respectively (log-rank p = 0.005).
Conclusions
The truncated ESC/ERS scheme was clinically useful and demonstrated prognostic relevance in severe PH due to ILD.

Copyright © 2020. Published by Elsevier Inc.

J Heart Lung Transplant: 29 Sep 2020; 39:1118-1125
Yogeswaran A, Tello K, Faber M, Sommer N, ... Richter MJ, Gall H
J Heart Lung Transplant: 29 Sep 2020; 39:1118-1125 | PMID: 32690230
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Impact:
Abstract

Donor thyroid hormone therapy and heart transplantation outcomes: ISHLT transplant registry analysis.

Peled Y, Ram E, Klempfner R, Lavee J, Cherikh WS, Stehlik J
Background
Donor thyroid hormone (TH) supplementation therapy is widely used. Recent reports suggested an increased risk of graft dysfunction in heart transplant (HTx) recipients not receiving TH supplementation. Our aim was to determine the effect of a donor TH supplementation in a large contemporary HTx cohort.
Methods
We analyzed data reported to the International Society for Heart and Lung Transplantation Registry on adult HTx recipients transplanted from 2006 to 2016. Early graft loss (EGL) was defined as death or retransplant because of graft failure within 48 hours of transplant. Logistic regression and propensity score analyses were performed.
Results
There were 23,002 adult HTx recipients transplanted during the study period for whom data on the use of donor TH supplementation were provided to the Registry. There were 15,821 recipients whose donors had received TH supplementation, and 7,181 who had not. Multivariable analysis showed donor TH therapy to be associated with an increased risk for EGL (odds ratio, 1.51; 95% CI, 1.13-2.06; p < 0.001). Long-term survival was similar, irrespective of donor TH supplementation. Recipients whose donors had received TH supplementation exhibited a lower 8-year incidence of vasculopathy (hazard ratio, 0.90; 95% CI, 0.85-0.97; p = 0.003). These results remained consistent in a propensity-matched analysis.
Conclusions
Donor TH therapy is independently associated with an increased risk of EGL. Whether this is a result of the donor allograft intrinsic characteristics related to the reasons why TH was used or whether this is a result of a TH withdrawal effect, which could be mitigated by administration of TH to the recipient, should be further studied.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2020; 39:1070-1078
Peled Y, Ram E, Klempfner R, Lavee J, Cherikh WS, Stehlik J
J Heart Lung Transplant: 29 Sep 2020; 39:1070-1078 | PMID: 32771439
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Impact:
Abstract

Report from the 2018 consensus conference on immunomodulating agents in thoracic transplantation: Access, formulations, generics, therapeutic drug monitoring, and special populations.

Cochrane AB, Lyster H, Lindenfeld J, Doligalski C, ... Dipchand A, Page RL

In 2009, the International Society for Heart and Lung Transplantation recognized the importance and challenges surrounding generic drug immunosuppression. As experience with generics has expanded and comfort has increased, substantial issues have arisen since that time with other aspects of immunomodulation that have not been addressed, such as access to medicines, alternative immunosuppression formulations, additional generics, implications on therapeutic drug monitoring, and implications for special populations such as pediatrics and older adults. The aim of this consensus document is to address critically each of these concerns, expand on the challenges and barriers, and provide therapeutic considerations for practitioners who manage patients who need to undergo or have undergone cardiothoracic transplantation.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2020; 39:1050-1069
Cochrane AB, Lyster H, Lindenfeld J, Doligalski C, ... Dipchand A, Page RL
J Heart Lung Transplant: 29 Sep 2020; 39:1050-1069 | PMID: 32883559
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Abstract

Donor-specific antibody characteristics, including persistence and complement-binding capacity, increase risk for chronic lung allograft dysfunction.

Iasella CJ, Ensor CR, Marrari M, Mangiola M, ... McDyer JF, Zeevi A
Background
Chronic lung allograft dysfunction (CLAD) is the major complication limiting long-term survival in lung transplant recipients (LTRs), with those developing donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) previously found to have increased risk for CLAD. However, as DSA responses vary in timing of development, specificity, breadth, persistence, and complement-binding capacity, we hypothesized that these characteristics would impact CLAD and survival outcomes.
Methods
We retrospectively analyzed DSA characteristics and outcomes in a single-center cohort of 582 LTRs who had serum samples collected prospectively from 2010 to 2016. Luminex-based single antigen bead assays were performed to assess DSA.
Results
DSAs were detected in 247 LTRs (42%), of which 124 (21.3%) were de novo DSAs and 53 (9.1%) were complement-binding (C1q+). CLAD developed in 208 LTRs (35.7%) during the follow-up period, with 67.8% determined as bronchiolitis obliterans syndrome phenotype and 32.2% as restrictive allograft syndrome phenotype. We found a shorter time to CLAD in LTRs with persistent DSAs (p = 0.04) and HLA-DQ-specific DSAs (p = 0.03). LTRs who developed C1q+ DSAs had significantly shorter time to CLAD (p < 0.001), with 100% of C1q+ DSAs being persistent and no differences between CLAD phenotypes. CLAD-free survival was significantly reduced in LTRs who developed C1q+ DSAs (p = 0.001), HLA-DQ-specific DSAs (p = 0.03), and multiple DSAs (p = 0.02).
Conclusions
Together, our findings demonstrate that DSA characteristics of persistence, HLA-DQ specificity, and C1q+ DSAs are associated with shorter time to CLAD. Additionally, C1q+, HLA-DQ-specific, and multiple DSAs are associated with decreased CLAD-free survival. These characteristics may improve DSA risk stratification for deleterious outcomes in LTRs.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 09 Sep 2020; epub ahead of print
Iasella CJ, Ensor CR, Marrari M, Mangiola M, ... McDyer JF, Zeevi A
J Heart Lung Transplant: 09 Sep 2020; epub ahead of print | PMID: 32981841
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Impact:
Abstract

MitraClip in secondary mitral regurgitation as a bridge to heart transplantation: 1-year outcomes from the International MitraBridge Registry.

Godino C, Munafò A, Scotti A, Estévez-Loureiro R, ... Crimi G, Saia F
Background
Patients awaiting heart transplantation (HTx) often need bridging therapies to reduce worsening and progression of underlying disease. Limited data are available regarding the use of the MitraClip procedure in secondary mitral regurgitation for this clinical condition.
Methods
We evaluated an international, multicenter (17 centers) registry including 119 patients (median age: 58 years) with moderate-to-severe or severe secondary mitral regurgitation and advanced heart failure (HF) (median left ventricular ejection fraction: 26%) treated with MitraClip as a bridge strategy according to 1 of the following criteria: (1) patients active on HTx list (in list group) (n = 31); (2) patients suitable for HTx but awaiting clinical decision (bridge to decision group) (n = 54); or (3) patients not yet suitable for HTx because of potentially reversible relative contraindications (bridge to candidacy group) (n = 34).
Results
Procedural success was achieved in 87.5% of cases, and 30-day survival was 100%. At 1 year, Kaplan-Meier estimates of freedom from the composite primary end-point (death, urgent HTx or left ventricular assist device implantation, first rehospitalization for HF) was 64%. At the time of last available follow-up (median: 532 days), 15% of patients underwent elective transplant, 15.5% remained or could be included in the HTx waiting list, and 23.5% had no more indication to HTx because of clinical improvement.
Conclusions
MitraClip procedure as a bridge strategy to HTx in patients with advanced HF with significant mitral regurgitation was safe, and two thirds of patients remained free from adverse events at 1 year. These findings should be considered exploratory and hypothesis-generating to guide further study for percutaneous intervention in high-risk patients with advanced HF.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 16 Sep 2020; epub ahead of print
Godino C, Munafò A, Scotti A, Estévez-Loureiro R, ... Crimi G, Saia F
J Heart Lung Transplant: 16 Sep 2020; epub ahead of print | PMID: 33008726
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Abstract

Preservation by cold storage vs ex vivo normothermic perfusion of marginal donor hearts: clinical, histopathologic, and ultrastructural features.

Sponga S, Bonetti A, Ferrara V, Beltrami AP, ... Ortolani F, Livi U
Background
The aim of this study was to match clinical outcomes of heart transplantation (HTx) against histopathologic and ultrastructural characteristics of marginal grafts preserved by cold storage (CS) or ex vivo normothermic perfusion.
Methods
Since 2011, 100 patients had undergone HTx at our institution by using marginal donors (aged ≥55 years, expected ischemic time of >4 hours, left ventricular ejection fraction of ≤50%, interventricular septum thickness of ≥14 mm, drug abuse history, episodes of cardiac arrest, and presence of mild coronary artery disease). CS was utilized in 79 cases (Group 1, 79%), and ex vivo perfusion was utilized in 21 (Group 2, 21%). Pre-operative data, survival, and complications in the first 5 years after HTx were analyzed. Myocardial biopsies were collected at graft harvesting, just before implantation, and immediately after aortic declamping.
Results
Pre-operative demographics were similar in the 2 groups. Graft utilization rate with ex vivo perfusion was 81%. Ischemic, cardiopulmonary bypass, and surgical times were shorter in Group 2 patients, who showed a lower incidence of overall complications (33% vs 13%, p = 0.04) and better 5-year survival (log-rank, p = 0.04). Moreover, restoration of hypertrophy-related sarcomere changes and mitigation of reperfusion-dependent myocardium injuries were more frequently observed in Group 2 hearts.
Conclusions
Ex vivo perfusion allows for continuous evaluation of marginal donor hearts, favoring exclusion of unsuitable grafts, reduction of complications, and optimal survival of up to 5 years. Such results, supported by consistent histopathologic and ultrastructural findings, suggest better myocardial preservation.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 03 Sep 2020; epub ahead of print
Sponga S, Bonetti A, Ferrara V, Beltrami AP, ... Ortolani F, Livi U
J Heart Lung Transplant: 03 Sep 2020; epub ahead of print | PMID: 33041182
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Abstract

Azithromycin prophylaxis after lung transplantation is associated with improved overall survival.

Li D, Duan Q, Weinkauf J, Kapasi A, ... Nagendran J, Halloran K
Background
Azithromycin prophylaxis (AP) in lung transplant recipients has been shown to reduce the composite end-point of death or chronic lung allograft dysfunction (CLAD) onset but without a clear effect on overall survival. Our program began using AP in 2010. We sought to evaluate the association between AP and survival and the risk of CLAD and baseline lung allograft dysfunction (BLAD).
Methods
We studied double lung recipients transplanted between 2004 and 2016. We defined AP as chronic use of azithromycin initiated before CLAD onset. We analyzed the association between AP and death or retransplant using Cox regression with adjustment for potential confounders. We further used Cox and logistic models to assess the relationship between AP and post-transplant CLAD onset and BLAD, respectively.
Results
A total of 445 patients were included, and 344 (77%) received AP (median time from transplant: 51 days). Patients receiving AP were more likely to receive induction with interleukin-2 receptor antagonists (57% vs 35%; p < 0.001). AP was associated with improved survival (hazard ratio [HR]: 0.59; 95% confidence interval [CI]: 0.42-0.82; p = 0.0020) in our fully adjusted model, with a reduced adjusted risk of BLAD (odds ratio: 0.53; 95% CI: 0.33-0.85; p = 0.0460) but no clear reduction in the adjusted risk of CLAD (HR: 0.69; 95% CI: 0.47-1.03; p = 0.0697).
Conclusions
AP is associated with improved survival after lung transplantation, potentially through improved baseline function. These findings build on prior trial results and suggest that AP is beneficial for lung transplant recipients.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 16 Sep 2020; epub ahead of print
Li D, Duan Q, Weinkauf J, Kapasi A, ... Nagendran J, Halloran K
J Heart Lung Transplant: 16 Sep 2020; epub ahead of print | PMID: 33041181
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Abstract

The impact of HLA-DR mismatch status on retransplant-free survival and bronchiolitis obliterans syndrome‒free survival among sensitized lung transplant recipients.

Courtwright AM, Kamoun M, Kearns J, Diamond JM, Golberg HJ
Introduction
Donor‒recipient HLA-DR locus matching may be protective against bronchiolitis obliterans syndrome (BOS) in lung transplant recipients. It is unknown whether this benefit is more significant among sensitized (calculated panel reactive antibodies (CPRAs) of >0%) and highly sensitized (CPRAs of ≥80%) recipients who may be at a higher risk for BOS.
Methods
This was a retrospective cohort study of adults in the Scientific Registry of Transplant Recipients who underwent lung transplantation between May 5, 2005 and May 31, 2019. Retransplant-free survival and BOS-free survival were compared among recipients with 0 vs ≥1 DR mismatches, grouped according to sensitization.
Results
Among all 20,355 included recipients, 0 DR mismatch status was associated with improved retransplant-free survival (hazard ratio [HR] = 0.83, 95% CI = 0.74-0.93, p = 0.002) and BOS-free survival (HR = 0.86, 95% CI = 0.77-0.96, p = 0.007). Among sensitized recipients, 0 DR mismatch status was also associated with improved retransplant-free survival (HR = 0.79, 95% CI = 0.65-0.97, p = 0.02) and BOS-free survival (HR = 0.82, 95% CI = 0.67-1.00, p = 0.04). There was however no difference in retransplant-free or BOS-free survival between sensitized and non-sensitized recipients with 0 DR mismatches. Among highly sensitized recipients, 0 DR mismatch status was not associated with retransplant-free or BOS-free survival. Among sensitized and highly sensitized recipients, 0 DR mismatch status was not associated with reduced use of plasmapheresis or reduced biopsy-proven, treated acute cellular rejection compared with non-sensitized recipients.
Conclusions
HLA-DR matching is associated with a similar improvement in retransplant-free and BOS-free survival among non-sensitized and sensitized lung transplant recipients. DR matching does not confer a more substantial retransplant-free or BOS-free survival benefit to highly sensitized recipients than to non-sensitized recipients.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2020; epub ahead of print
Courtwright AM, Kamoun M, Kearns J, Diamond JM, Golberg HJ
J Heart Lung Transplant: 29 Sep 2020; epub ahead of print | PMID: 33071182
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Impact:
Abstract

Prophylactic vaccination with a live-attenuated herpes zoster vaccine in lung transplant candidates.

Wang L, Verschuuren EAM, Paap D, Rondaan C, ... Westra J, Bos NA
Background
Herpes zoster (HZ) is caused by the reactivation of varicella-zoster virus (VZV). Patients with lung transplants are at high risk for HZ owing to their immunocompromised status and the need for lifelong immunosuppression. In this study, patients on the waiting list for lung transplantation were vaccinated by a live-attenuated HZ vaccine (Zostavax, Merck Sharp & Dohme), and the safety and immunogenicity of this vaccine were studied.
Methods
In total, 105 patients with end-stage pulmonary disease (ESPD) were enrolled (68 participants received 1 dose of Zostavax and 37 participants were enrolled as unvaccinated controls). Among them, 43 patients underwent lung transplantation and were followed up for further analysis. VZV immunoglobulin G antibody titers and VZV-specific cell-mediated immunity (CMI) on multiple time points before and after vaccination and before and after transplantation were measured.
Results
Immune response to Zostavax was higher in younger patients, highest within 3 months after vaccination, and not influenced by gender or type of ESPD. Age, cytomegalovirus serostatus, and immunity to VZV at baseline impacted the subsequent immune response to the vaccine. Short-term immunosuppressant treatment had strong effects on VZV CMI levels, which returned to a high level at 6 months after transplantation in vaccinated patients. Zostavax did not impact infection or rejection rate after transplantation.
Conclusions
Zostavax was safe and induced a robust humoral and cellular response for patients awaiting lung transplantation regardless of the type of ESPD. Patients younger than the recommended vaccination age of over 50 years showed a strong response and could also benefit from pre-transplant immunization.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 24 Sep 2020; epub ahead of print
Wang L, Verschuuren EAM, Paap D, Rondaan C, ... Westra J, Bos NA
J Heart Lung Transplant: 24 Sep 2020; epub ahead of print | PMID: 33071180
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Impact:
Abstract

MicroRNA-206 antagomiR‒enriched extracellular vesicles attenuate lung ischemia‒reperfusion injury through CXCL1 regulation in alveolar epithelial cells.

Cai J, Gehrau R, Tu Z, Leroy V, ... Upchurch GR, Sharma AK
Background
Our hypothesis is that the immunomodulatory capacities of mesenchymal stem cell‒derived extracellular vesicles (EVs) can be enhanced by specific microRNAs (miRNAs) to effectively attenuate post-transplant lung ischemia‒reperfusion (IR) injury.
Methods
The expression of miR-206 was analyzed in bronchoalveolar lavage (BAL) fluid of patients on Days 0 and 1 after lung transplantation. Lung IR injury was evaluated in C57BL/6 mice using a left lung hilar-ligation model with or without treatment with EVs or antagomiR-206‒enriched EVs. Murine lung tissue was used for miRNA microarray hybridization analysis, and cytokine expression, lung injury, and edema were evaluated. A donation after circulatory death and murine orthotopic lung transplantation model was used to evaluate the protection by enriched EVs against lung IR injury. In vitro studies analyzed type II epithelial cell activation after coculturing with EVs.
Results
A significant upregulation of miR-206 was observed in the BAL fluid of patients on Day 1 after lung transplantation compared with Day 0 and in murine lungs after IR injury compared with sham. Treatment with antagomiR-206‒enriched EVs attenuated lung dysfunction, injury, and edema compared with treatment with EVs alone after murine lung IR injury. Enriched EVs reduced lung injury and neutrophil infiltration as well as improved allograft oxygenation after murine orthotopic lung transplantation. Enriched EVs significantly decreased proinflammatory cytokines, especially epithelial cell‒dependent CXCL1 expression, in the in vivo and in vitro IR injury models.
Conclusions
EVs can be used as biomimetic nanovehicles for protective immunomodulation by enriching them with antagomiR-206 to mitigate epithelial cell activation and neutrophil infiltration in the lungs after IR injury.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 27 Sep 2020; epub ahead of print
Cai J, Gehrau R, Tu Z, Leroy V, ... Upchurch GR, Sharma AK
J Heart Lung Transplant: 27 Sep 2020; epub ahead of print | PMID: 33067103
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Impact:
Abstract

Idiopathic pulmonary arterial hypertension phenotypes determined by cluster analysis from the COMPERA registry.

Hoeper MM, Pausch C, Grünig E, Klose H, ... Ulrich S, Held M

The term idiopathic pulmonary arterial hypertension (IPAH) is used to categorize patients with pre-capillary pulmonary hypertension of unknown origin. There is considerable variability in the clinical presentation of these patients. Using data from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension, we performed a cluster analysis of 841 patients with IPAH based on age, sex, diffusion capacity of the lung for carbon monoxide (DLCO; <45% vs ≥45% predicted), smoking status, and presence of comorbidities (obesity, hypertension, coronary heart disease, and diabetes mellitus). A hierarchical agglomerative clustering algorithm was performed using Ward\'s minimum variance method. The clusters were analyzed in terms of baseline characteristics; survival; and response to pulmonary arterial hypertension (PAH) therapy, expressed as changes from baseline to follow-up in functional class, 6-minute walking distance, cardiac biomarkers, and risk. Three clusters were identified: Cluster 1 (n = 106; 12.6%): median age 45 years, 76% females, no comorbidities, mostly never smokers, DLCO ≥45%; Cluster 2 (n = 301; 35.8%): median age 75 years, 98% females, frequent comorbidities, no smoking history, DLCO mostly ≥45%; and Cluster 3 (n = 434; 51.6%): median age 72 years, 72% males, frequent comorbidities, history of smoking, and low DLCO. Patients in Cluster 1 had a better response to PAH treatment than patients in the 2 other clusters. Survival over 5 years was 84.6% in Cluster 1, 59.2% in Cluster 2, and 42.2% in Cluster 3 (unadjusted p < 0.001 for comparison between all groups). The population of patients diagnosed with IPAH is heterogenous. This cluster analysis identified distinct phenotypes, which differed in clinical presentation, response to therapy, and survival.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Sep 2020; epub ahead of print
Hoeper MM, Pausch C, Grünig E, Klose H, ... Ulrich S, Held M
J Heart Lung Transplant: 29 Sep 2020; epub ahead of print | PMID: 33082079
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Impact:
Abstract

Ventilation parameters and early graft function in double lung transplantation.

Schwarz S, Benazzo A, Dunkler D, Muckenhuber M, ... Klepetko W, Hoetzenecker K
Background
Currently, the primary graft dysfunction (PGD) score is used to measure allograft function in the early post-lung transplant period. Although PGD grades at later time points (T48 hours and T72 hours) are useful to predict mid- and long-term outcomes, their predictive value is less relevant within the first 24 hours after transplantation. This study aimed to evaluate the capability of PGD grades to predict prolonged mechanical ventilation (MV) and compare it with a model derived from ventilation parameters measured on arrival at the intensive care unit (ICU).
Methods
A retrospective single-center analysis of 422 double lung transplantations (LTxs) was performed. PGD was assessed 2 hours after arrival at ICU, and grades were associated with length of MV (LMV). In addition, peak inspiratory pressure (P), ratio of the arterial partial pressure of oxygen to fraction of inspired oxygen (P/F ratio), and dynamic compliance (cDyn) were collected, and a logistic regression model was created. The predictive capability for prolonged MV was calculated for both (the PGD score and the model). In a second step, the created model was externally validated using a prospective, international multicenter cohort including 102 patients from the lung transplant centers of Vienna, Toronto, and Budapest.
Results
In the retrospective cohort, a high percentage of extubated patients was reported at 24 hours (35.1%), 48 hours (68.0%), and 72 hours (80.3%) after transplantation. At T0 (time point defined as 2 hours after arrival at the ICU), patients with PGD grade 0 had a shorter LMV with a median of 26 hours (interquartile range [IQR]: 16-47 hours) than those with PGD grade 1 (median: 42 hours, IQR: 27-50 hours), PGD grade 2 (median: 37.5 hours, IQR: 15.5-78.5 hours), and PGD grade 3 (median: 46 hours, IQR: 27-86 hours). However, IQRs largely overlapped for all grades, and the value of PGD to predict prolonged MV was poor. A total of 3 ventilation parameters (P, cDyn, and P/F ratio), determined at T0, were chosen on the basis of clinical reasoning. A logistic regression model including these parameters predicted prolonged MV (>72 hours) with an optimism-corrected area under the curve (AUC) of 0.727. In the prospective validation cohort, the model proved to be stable and achieved an AUC of 0.679.
Conclusions
The prediction model reported in this study combines 3 easily obtainable variables. It can be employed immediately after LTx to quantify the risk of prolonged MV, an important early outcome parameter.

Copyright © 2020. Published by Elsevier Inc.

J Heart Lung Transplant: 12 Oct 2020; epub ahead of print
Schwarz S, Benazzo A, Dunkler D, Muckenhuber M, ... Klepetko W, Hoetzenecker K
J Heart Lung Transplant: 12 Oct 2020; epub ahead of print | PMID: 33144029
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Impact:
Abstract

Ex situ heart perfusion: The past, the present, and the future.

Wang L, MacGowan GA, Ali S, Dark JH

Despite the advancements in medical treatment, mechanical support, and stem cell therapy, heart transplantation remains the most effective treatment for selected patients with advanced heart failure. However, with an increase in heart failure prevalence worldwide, the gap between donor hearts and patients on the transplant waiting list keeps widening. Ex situ machine perfusion has played a key role in augmenting heart transplant activities in recent years by enabling the usage of donation after circulatory death hearts, allowing longer interval between procurement and implantation, and permitting the safe use of some extended-criteria donation after brainstem death hearts. This exciting field is at a hinge point, with 1 commercially available heart perfusion machine, which has been used in hundreds of heart transplantations, and a number of devices being tested in the pre-clinical and Phase 1 clinical trial stage. However, no consensus has been reached over the optimal preservation temperature, perfusate composition, and perfusion parameters. In addition, there is a lack of objective measurement for allograft quality and viability. This review aims to comprehensively summarize the lessons about ex situ heart perfusion as a platform to preserve, assess, and repair donor hearts, which we have learned from the pre-clinical studies and clinical applications, and explore its exciting potential of revolutionizing heart transplantation.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 13 Oct 2020; epub ahead of print
Wang L, MacGowan GA, Ali S, Dark JH
J Heart Lung Transplant: 13 Oct 2020; epub ahead of print | PMID: 33162304
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Impact:
Abstract

Risk factors for mortality in lung transplant recipients aged ≥65 years: A retrospective cohort study of 5,815 patients in the scientific registry of transplant recipients.

Mosher CL, Weber JM, Frankel CW, Neely ML, Palmer SM
Background
Lung transplantation is increasingly performed in recipients aged ≥65 years. However, the risk factors for mortality specific to this population have not been well studied. In lung transplant recipients aged ≥65 years, we sought to determine post-transplant survival and clinical factors associated with post-transplant mortality.
Methods
We investigated 5,815 adult lung transplants recipients aged ≥65 years in the Scientific Registry of Transplant Recipients. Mortality was defined as a composite of recipient death or retransplantation. The Kaplan-Meier method was used to estimate the median time to mortality. Univariable and multivariable Cox proportional hazards regression models were used to examine the association between time to mortality and 23 donor, recipient, or center characteristics.
Results
Median survival in lung transplant recipients aged ≥65 years was 4.41 years (95% CI: 4.21-4.60 years) and significantly worsened by increasing age strata. In the multivariable model, increasing recipient age strata, creatinine level, bilirubin level, hospitalization at the time of transplantation, single lung transplant operation, steroid use at the time of transplantation, donor diabetes, and cytomegalovirus mismatch were independently associated with increased mortality.
Conclusions
Among the 8 risk factors we identified, 5 factors are readily available, which can be used to optimize post-transplant survival by informing risk during candidate selection of patients aged ≥65 years. Furthermore, bilateral lung transplantation may confer improved survival in comparison with single lung transplantation. Our results support that after careful consideration of risk factors, lung transplantation can provide life-extending benefits in individuals aged ≥65 years.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Oct 2020; epub ahead of print
Mosher CL, Weber JM, Frankel CW, Neely ML, Palmer SM
J Heart Lung Transplant: 30 Oct 2020; epub ahead of print | PMID: 33208278
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Abstract

Donor ventilation parameters as predictors for length of mechanical ventilation after lung transplantation: Results of a prospective multicenter study.

Benazzo A, Schwarz S, Frommlet F, Sinn K, ... Cypel M, Hoetzenecker K
Background
The evaluation of donor lungs heavily depends on the subjective judgment of the retrieval surgeon. As a consequence, acceptance rates vary significantly among transplant centers. We aimed to determine donor ventilation parameters in a prospective study and test if they could be used as objective quality criteria during organ retrieval.
Methods
A prospective evaluation of lung donors was performed in 3 transplant centers. Ventilation parameters were collected at the time of retrieval using a standardized ventilation protocol. Recipient length of mechanical ventilation (LMV) was defined as the primary end point, and collected data was used to build linear models predicting LMV.
Results
In total, 166 donors were included in this study. Median LMV after transplantation was 32 hours (interquartile range: 20-63 hours). Peak inspiratory pressure and dynamic compliance (C) at the time of retrieval, but not the partial pressure of oxygen/fraction of inspired oxygen (P/F) ratio, correlated with recipient LMV in Spearman correlations (r = 0.280, p = 0.002; r = -0.245, p = 0.003; and r = 0.064, p = 0.432, respectively). Linear models were built to further evaluate the impact of donor ventilation parameters on LMV. The first model was based on donor P/F ratio, donor age, donor intubation time, donor smoking history, donor partial pressure of carbon dioxide, aspiration, chest trauma, and pathologic chest X-ray. This model performed poorly (multiple R-squared = 0.063). In a second model, donor ventilation parameters were included, and C was identified as the strongest predictor for LMV. The third model was extended by recipient factors, which significantly improved the robustness of the model (multiple R-squared = 0.293).
Conclusion
In this prospective evaluation of donor lung parameters, currently used donor quality criteria poorly predicted recipient LMV. Our data suggest that C is a strong donor-bound parameter to predict short-term graft performance; however, recipient factors are similarly relevant.

Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 27 Oct 2020; epub ahead of print
Benazzo A, Schwarz S, Frommlet F, Sinn K, ... Cypel M, Hoetzenecker K
J Heart Lung Transplant: 27 Oct 2020; epub ahead of print | PMID: 33246712
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Impact:
Abstract

A 5-year single-center early experience of heart transplantation from donation after circulatory-determined death donors.

Messer S, Cernic S, Page A, Berman M, ... Catarino P, Large SR
Background
In an effort to address the increasing demand for heart transplantation within the United Kingdom (UK), we established a clinical program of heart transplantation from donation after circulatory-determined death (DCD) donors in 2015. After 5 years, we report the clinical early outcomes and impact of the program.
Methods
This is a single-center, retrospective, matched, observational cohort study comparing outcomes of hearts transplanted from DCD donors from March 1, 2015 to February 29, 2020 with those from matched donation after brain death (DBD) donors at Royal Papworth Hospital (RPH) (Cambridge, UK). DCD hearts were either retrieved using thoracoabdominal normothermic regional perfusion or the direct procurement and perfusion technique. All DBD hearts were procured using standard cold static storage. The primary outcomes were recipient 30-day and 1-year survival.
Results
During the 5-year study, DCD heart donation increased overall heart transplant activity by 48% (79 for DCD and 164 for DBD). There was no difference in survival at 30 days (97% for DCD vs 99% for DBD, p = 1.00) or 1 year (91% for DCD vs 89% for DBD, p = 0.72). There was no difference in the length of stay in the intensive care unit (7 for DCD vs 6 for DBD days, p = 0.24) or in the hospital (24 for DCD vs 25 for DBD days, p = 0.84).
Conclusions
DCD heart donation increased overall heart transplant activity at RPH by 48%, with no difference in 30-day or 1-year survival in comparison with conventional DBD heart transplantations. DCD heart donation is set to make a dramatic difference in the number of patients who can benefit from heart transplantation.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Nov 2020; 39:1463-1475
Messer S, Cernic S, Page A, Berman M, ... Catarino P, Large SR
J Heart Lung Transplant: 29 Nov 2020; 39:1463-1475 | PMID: 33248525
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Impact:
Abstract

International experience using a durable, centrifugal-flow ventricular assist device for biventricular support.

Marasco S, Simon AR, Tsui S, Schramm R, ... Zimpfer D, Schmitto JD
Background
Heart transplantation is limited by the scarcity of suitable donors. Patients with advanced biventricular failure may require biventricular support to provide optimal cardiac output and end-organ perfusion. We highlight the outcomes of using the HeartWare HVAD System (HVAD) in a biventricular configuration.
Methods
This retrospective study included patients implanted with HVAD as a biventricular assist device (BiVAD) between 2009 and 2017 at 12 participating centers. When used as a right ventricular assist device (VAD) (RVAD), the HVAD can be attached to the right ventricle (RV) or the right atrium (RA). Kaplan-Meier survival estimates were calculated comparing the 2 RVAD implant locations. Comparisons were also made between the timing of RVAD implantation (primary vs staged) on adverse event (AE) profiles and survival.
Results
Among the 93 patients who were implanted with a HVAD BiVAD, Kaplan-Meier survivals at 1-year and 2-year were 56% and 47%, respectively. Survival was independent of the location of the HVAD RVAD implant or whether there was an interval between left VAD and RVAD implantation. The most common AEs were bleeding (35.5%), infection (25.8%), and respiratory failure (20.4%).
Conclusions
This study illustrated similar survival in patients receiving a primary or staged HVAD BiVAD implant at 1 year and 2 years. This study also established that the locations of the RVAD implant (RV or RA) result in similar AE profiles.

Copyright © 2020 International Society for Heart and Lung Transplantation. All rights reserved.

J Heart Lung Transplant: 29 Nov 2020; 39:1372-1379
Marasco S, Simon AR, Tsui S, Schramm R, ... Zimpfer D, Schmitto JD
J Heart Lung Transplant: 29 Nov 2020; 39:1372-1379 | PMID: 32917479
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Impact:
Abstract

Hemodynamics and risk assessment 2 years after the initiation of upfront ambrisentan‒tadalafil in pulmonary arterial hypertension.

D\'Alto M, Badagliacca R, Lo Giudice F, Argiento P, ... Golino P, Naeije R
Background
Upfront combination therapy with ambrisentan and tadalafil has been reported to improve the condition of patients with pulmonary arterial hypertension (PAH) more than with either drug alone. However, little is known about the long-term associated changes in hemodynamics and risk assessment scores.
Methods
This was a multicenter, retrospective analysis of clinical data in 106 patients with newly diagnosed PAH. Clinical evaluations, including demographics, medical history, World Health Organization (WHO) functional class (FC) and 6-minute walk distance (6MWD), right heart catheterization, and Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) risk score 2.0, were assessed over 48 months of ambrisentan‒tadalafil therapy.
Results
At baseline, 9 patients (9%) showed a low (<7), 48 patients (45%) showed an intermediate (7-8), and 49 patients (46%) showed a high (>8) REVEAL risk score. At a median follow-up of 2 years, 45 patients (43%) showed a low, 47 patients (44%) showed an intermediate, and 14 patients (13%) showed a high REVEAL score, along with improvements in WHO FC, 6MWD and a decrease in mean pulmonary artery pressure and N-terminal pro brain natriuretic peptide (all p < 0.001). Pulmonary vascular resistance (PVR) decreased by 37% from 11.5 ± 6.5 to 7.2 ± 4.1 Wood units (p < 0.001). A total of 61 patients (57%) remained in intermediate-risk or high-risk categories. Low-risk patients had either a decrease in PVR of >50% or a stroke volume within the limits of normal.
Conclusions
Initial combination therapy with ambrisentan and tadalafil in PAH improves the REVEAL risk score in proportion to decreased PVR and preserved stroke volume but still insufficiently so in approximately 50% of the patients.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Nov 2020; 39:1389-1397
D'Alto M, Badagliacca R, Lo Giudice F, Argiento P, ... Golino P, Naeije R
J Heart Lung Transplant: 29 Nov 2020; 39:1389-1397 | PMID: 32933828
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Impact:
Abstract

Molecular T-cell‒mediated rejection in transbronchial and mucosal lung transplant biopsies is associated with future risk of graft loss.

Halloran K, Parkes MD, Timofte I, Snell G, ... Weinkauf J, Halloran PF
Background
We previously developed molecular assessment systems for lung transplant transbronchial biopsies (TBBs) with high surfactant and bronchial mucosal biopsies, identifying T-cell‒mediated rejection (TCMR) on the basis of the expression of rejection-associated transcripts, but the relationship of rejection to graft loss is unknown. This study aimed to develop molecular assessments for TBBs and mucosal biopsies and to establish the impact of molecular TCMR on graft survival.
Methods
We used microarrays and machine learning to assign TCMR scores to an expanded cohort of 457 TBBs (367 high surfactant plus 90 low surfactant) and 314 mucosal biopsies. We tested the score agreement between TBB-TBB, mucosal-mucosal, and TBB-mucosal biopsy pairs in the same patient. We also assessed the association of molecular TCMR scores with graft loss (death or retransplantation) and compared it with the prognostic associations for histology and donor-specific antibodies.
Results
The molecular TCMR scores assigned in all the TBBs performed similarly to those in high-surfactant TBBs, indicating that variation in alveolation in TBBs does not prevent the detection of TCMR. Mucosal biopsy pieces showed less piece-to-piece variation than TBBs. TCMR scores in TBBs agreed with those in mucosal biopsies. In both TBBs and mucosal biopsies, molecular TCMR was associated with graft loss, whereas histologic rejection and donor-specific antibodies were not.
Conclusions
Molecular TCMR can be detected in TBBs regardless of surfactant and in mucosal biopsies, which show less variability in the sampled tissue than TBBs. On the basis of these findings, molecular TCMR appears to be an important predictor of the risk of future graft failure.
Trial registration
ClinicalTrials.gov NCT02812290.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Nov 2020; 39:1327-1337
Halloran K, Parkes MD, Timofte I, Snell G, ... Weinkauf J, Halloran PF
J Heart Lung Transplant: 29 Nov 2020; 39:1327-1337 | PMID: 32943286
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Impact:
Abstract

High-intensity interval training in patients with left ventricular assist devices: A pilot randomized controlled trial.

Moreno-Suarez I, Scheer A, Lam K, Dembo L, ... Green DJ, Maiorana A
Background
Left ventricular assist device (LVAD) implantation is an established treatment for patients with advanced heart failure. To date, studies evaluating the impact of aerobic training in patients with LVADs have focused on moderate-intensity exercise.
Methods
This pilot randomized controlled trial compared the effects of high-intensity interval training (HIIT) with those of moderate-intensity continuous training (MICT) on peak oxygen consumption (V̇O peak) in patients with LVADs. Secondary outcomes included 6-minute walk test distance, flow-mediated dilation, and anthropometry. Assessments were conducted at baseline and after 12 weeks of supervised training performed 3 times weekly. Participants were randomized to HIIT (4 sets of 4 minutes at 80%-90% V̇O reserve, alternating with 3 minutes at 50%-60% V̇O reserve) or MICT groups (28 minutes continuously at 50%-60% V̇O reserve). Within and between-group differences were analyzed using linear mixed models. Data are expressed as marginal means with 95% confidence intervals or as mean ± SD.
Results
A total of 21 participants were randomized (HIIT: age 57.7 ± 13.1 years; n = 11 and MICT: age 55.6 ± 14.2 years; n = 10) (mean ± SD). No major adverse events occurred in response to training in either group. HIIT significantly improved V̇O peak (15.6 [13.2-17.8] to 18.4 [16.0-20.8] ml/kg/min) (marginal mean [95% CI]) compared with MICT (16.2 [13.8-18.7] to 17.2 [14.6-19.7] ml/kg/min; p < 0.05 between groups). No significant group differences were detected in secondary outcomes.
Conclusion
In patients with LVADs, HIIT was well tolerated and increased aerobic capacity more than MICT. These preliminary findings support the prescription of high-intensity exercise in clinically stable patients with LVADs but warrant validation in a larger sample and across a broader range of physiologic and clinical outcomes.
Clinical trial registration
URL: https://www.anzctr.org.au, unique identifier: ACTRN12616001596493.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Nov 2020; 39:1380-1388
Moreno-Suarez I, Scheer A, Lam K, Dembo L, ... Green DJ, Maiorana A
J Heart Lung Transplant: 29 Nov 2020; 39:1380-1388 | PMID: 32958408
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Impact:
Abstract

Combined heart-lung transplantation from a donation after circulatory death donor.

Messer S, Abu-Omar Y, Large SR, Berman M, ... Parmar J, Catarino P

Combined heart-lung transplantation is the optimal treatment option for many patients with end-stage heart failure and fixed severe pulmonary hypertension. It offers the only possibility of long-term survival and a return to a normal quality of life. Unfortunately, it is rarely performed because of donor organ allocation policies. We present the case of a critically ill 24-year-old man, who after waiting for >100 days in-hospital on the urgent transplant list, deteriorated further and underwent the first successful heart-lung transplant with organs from a donation after circulatory death.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Nov 2020; 39:1366-1371
Messer S, Abu-Omar Y, Large SR, Berman M, ... Parmar J, Catarino P
J Heart Lung Transplant: 29 Nov 2020; 39:1366-1371 | PMID: 32958407
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Impact:
Abstract

Right ventricular area strain from 3-dimensional echocardiography: Mechanistic insight of right ventricular dysfunction in pediatric pulmonary hypertension.

Jone PN, Duchateau N, Pan Z, Ivy DD, Moceri P
Background
Right ventricular (RV) function is a major contributor to the outcome of pulmonary arterial hypertension (PAH). Adult studies demonstrated that regional and global changes in RV deformation are prognostic in PAH using 3-dimensional echocardiography (3DE). However, regional and global dynamic changes in RV mechanics have not been described in pediatric PAH. We compared 3DE RV regional and global deformation between pediatric patients who had associated PAH with congenital heart disease (APAH-CHD), pediatric patients who had idiopathic PAH (IPAH), and normal controls, and evaluated the clinical outcomes.
Methods
A total of 48 controls, 47 patients with APAH-CHD, and 45 patients with IPAH were evaluated. 3DE RV sequences were analyzed and post-processed to extract global and regional deformation (circumferential, longitudinal, and area strain). Statistical analyses compared the sub-groups on the basis of global and regional deformation, and outcome analysis was performed.
Results
Patients with PAH had significantl8y different global and regional deformation (p < 0.001) compared with controls. Patients with APAH-CHD and and those with IPAH significantly differed in global circumferential strain (p < 0.010), area strain (inlet septum, p = 0.041), and circumferential strain at the inlet septum (p < 0.019), apex free wall (p < 0.004), and inlet free wall (p < 0.004). Circumferential strain at the inlet free wall and circumferential, longitudinal, and area strain at the apex free wall were predictors of adverse events.
Conclusions
RV regional and global strain differ between controls and pediatric patients with PAH. RV apical free-wall area strain provides insight into the mechanism of RV dysfunction in pediatric patients with PAH, with regional strain emerging as outcome predictors, suggesting that this novel measure may be considered as a future measure of RV function.

Published by Elsevier Inc.

J Heart Lung Transplant: 14 Nov 2020; epub ahead of print
Jone PN, Duchateau N, Pan Z, Ivy DD, Moceri P
J Heart Lung Transplant: 14 Nov 2020; epub ahead of print | PMID: 33268039
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Impact:

This program is still in alpha version.