Journal: J Heart Lung Transplant

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Abstract

High torque tenovirus (TTV) load before first vaccine dose is associated with poor serological response to COVID-19 vaccination in lung transplant recipients.

Hoek RA, Verschuuren EA, de Vries RD, Vonk JM, ... GeurtsvanKessel CH, Buter CVL
Background
Serological responses to COVID-19 vaccination are diminished in recipients of solid organ transplants, especially in lung transplant recipients (LTR), probably as result of immunosuppressive treatment. There is currently no marker of immunosuppression that can be used to predict the COVID-19 vaccination response. Here, we study whether torque tenovirus (TTV), a highly prevalent virus can be used as an indicator of immunosuppression.
Methods
The humoral response to the mRNA 1273 vaccine was assessed in 103 LTR, who received a transplant between 4 and 237 months prior to vaccination, by measuring Spike (S)-specific IgG levels at baseline, 28 days after first, and 28 days after the second vaccination. TTV loads were determined by RT-PCR and Pearson\'s correlation coefficient was calculated to correlate serological responses to TTV load.
Results
Humoral responses to COVID-19 vaccination were observed in 41 of 103 (40%) LTR at 28 days after the second vaccination. Sixty-two of 103 (60%) were non-responders. Lower TTV loads at baseline (significantly) correlated with higher S-specific antibodies and a higher percentage of responders. Lower TTV loads also strongly correlated with longer time since transplantation, indicating that participants with lower TTV loads were longer after transplantation.
Conclusions
This study shows a better humoral response to the SARS-CoV-2 vaccine in subjects with a lower TTV load pre-vaccination. In addition, TTV load correlates with the time after transplantation. Further studies on the use of TTV load in vaccination efficacy studies in immunocompromised cohorts should provide leads for the potential use of this marker for optimizing vaccination response.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 01 Jun 2022; 41:765-772
Hoek RA, Verschuuren EA, de Vries RD, Vonk JM, ... GeurtsvanKessel CH, Buter CVL
J Heart Lung Transplant: 01 Jun 2022; 41:765-772 | PMID: 35606065
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Abstract

A novel donor-derived cell-free DNA assay for the detection of acute rejection in heart transplantation.

Kim PJ, Olymbios M, Siu A, Wever Pinzon O, ... Billings PR, Stehlik J
Background
Endomyocardial biopsy (EMB), the reference surveillance test for acute rejection (AR) in heart transplant (HTx) recipients, is invasive, costly, and shows significant interobserver variability. Recent studies indicate that donor-derived cell-free DNA (dd-cfDNA), obtained non-invasively from blood, is associated with AR and could reduce the frequency of EMB surveillance. The aim of this study was to examine the performance characteristics of a novel test for detecting AR in adult HTx recipients.
Methods
Plasma samples with contemporaneous EMBs were obtained from HTx recipients. A clinically available SNP-based massively multiplexed-PCR dd-cfDNA assay was used to measure dd-cfDNA fraction. dd-cfDNA fractions were compared with EMB-defined rejection status and test performance was assessed by constructing ROC curves and calculating accuracy measures.
Results
A total of 811 samples from 223 patients with dd-cfDNA testing and contemporaneous EMB were eligible for the study. dd-cfDNA fraction was significantly higher in AR (median 0.58%, IQR, 0.13%-1.68%) compared to non-AR (median 0.04%, IQR, 0.01%-0.11%, pc < 0.001). ROC analysis produced an area under the curve (AUC-ROC) of 0.86 (95% CI, 0.77-0.96). Defining samples with dd-cfDNA fraction ≥0.15% as AR yielded 78.5% sensitivity (95% CI, 60.7%-96.3%) and 76.9% specificity (95% CI, 71.1%-82.7%). Positive and negative predictive values were 25.1% (95% CI, 18.8%-31.5%) and 97.3% (95% CI, 95.1%-99.5%) respectively, calculated using the cohort AR prevalence of 9.0% (95% CI, 5.3%-12.8%) with adjustment for repeat samples.
Conclusions
This novel dd-cfDNA test detects AR in HTx recipients with good accuracy and holds promise as a noninvasive test for AR in HTx recipients.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 10 Apr 2022; epub ahead of print
Kim PJ, Olymbios M, Siu A, Wever Pinzon O, ... Billings PR, Stehlik J
J Heart Lung Transplant: 10 Apr 2022; epub ahead of print | PMID: 35577713
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Abstract

Outcomes of bariatric surgery in patients with left ventricular assist device.

McElderry B, Alvarez P, Hanna M, Chaudhury P, ... Desai M, Mentias A
Background
Class II obesity affects 1 in 5 patients with left ventricular assist device (LVAD) and is considered a potential barrier to heart transplantation (HT). Studies about the outcomes of bariatric surgery in this population are scarce.
Methods
We identified Medicare beneficiaries who had an LVAD placed from 2012 to 2019 and had at least class II obesity at the time of LVAD placement and identified patients who underwent bariatric surgery during or after the LVAD implantation admission. The primary outcome was major adverse cardiovascular events (MACE) at 30 days (mortality, cerebral hemorrhage, or ischemic stroke) after bariatric surgery.
Results
Among patients who underwent LVAD implantation from 2012 to 2019, 2798 (19.4%) had at least class II obesity, and 198 (7.1%) patients had bariatric surgery (24 on same admission and 174 after a median of 702 days). After bariatric surgery in LVAD patients, 30-day MACE was 6.1%, 30-day mortality was <5.5%, and 1-year mortality was 12.6%. Heart failure readmission burden declined after bariatric surgery (incidence rate ratio 0.20 (95% CI 0.11-0.38), p < 0.001). Thirty-seven patients underwent HT after a median of 371 days (IQR 246-575 days), and 13 patients underwent LVAD explant due to recovery. On time-dependent, competing risk, Cox regression, bariatric surgery was associated with a 3-fold higher probability of HT in follow-up compared to patients who did not get bariatric surgery (sub-distribution HR 2.95, 95% CI 2.09-4.17, p < 0.001).
Conclusions
Bariatric surgery in patients with LVAD support is associated with decreased heart failure events and higher chances of heart transplantation.

Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 10 Apr 2022; epub ahead of print
McElderry B, Alvarez P, Hanna M, Chaudhury P, ... Desai M, Mentias A
J Heart Lung Transplant: 10 Apr 2022; epub ahead of print | PMID: 35537903
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Abstract

Diagnostic yield of genetic testing in heart transplant recipients with prior cardiomyopathy.

Boen HM, Loeys BL, Alaerts M, Saenen JB, ... Heidbuchel H, Van Craenenbroeck EM
Background
The importance of genetic testing for cardiomyopathies has increased in the last decade. However, in heart transplant patients with former cardiomyopathy, genetic testing in retrospect is not routinely performed. We hypothesize that the yield of genetic testing in this population is considerable, and will have a major impact for both patients and relatives.
Methods
Patients that underwent heart transplantation (HTx) between 1995 and 2020 and were still in follow-up, were offered genetic testing if the primary etiology was non-ischemic cardiomyopathy. Next generation sequencing (NGS) of known cardiomyopathy genes was performed and variants were classified as variant of unknown significance (class 3), likely pathogenic (class 4) or pathogenic (class 5) variant.
Results
Of the 99 HTx patients in active follow-up, only 6 patients had a genetic diagnosis at the time of HTx. In this study, 31 selected patients with prior non-ischemic cardiomyopathy underwent genetic testing post HTx. 23/31 patients (74.2%) carried a variant that was classified as class 3 or higher. In 12/31 patients a class 4/5 variant (38.7%) was identified, and in 11/31 patients (35.5%) a class 3 variant. Class 5 Variants in TTN were the most prevalent (7/31), followed by class 5 variants in MYBPC3 (2/31). A positive family history was present in 21/31 (67.7%) and a second precipitating factor (e.g., alcohol abuse, pregnancy) was present in 17/31 patients (54.8%). Diagnostic yield of genetic testing was similar between patients with or without familial history and/or second hit. Through cascade screening 48 family members were screened for presence of a class 4/5 variant, of whom 19 (39.6%) were genotype positive, of whom 10 (52.6%) showed a cardiac phenotype. Appropriate follow-up was offered.
Conclusions
Genetic testing for cardiomyopathy genes established a molecular diagnosis in 38.7% of patients post HTx. These results highlight the importance of genetic testing in this population as it is still often overlooked in patients that already underwent HTx in the past. Genetic testing is highly recommended, independent of family history or second precipitating factors, as it might identify relatives at risk.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 09 Apr 2022; epub ahead of print
Boen HM, Loeys BL, Alaerts M, Saenen JB, ... Heidbuchel H, Van Craenenbroeck EM
J Heart Lung Transplant: 09 Apr 2022; epub ahead of print | PMID: 35581137
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Abstract

Prevalence and clinical significance of conduction disease in patients with idiopathic pulmonary arterial hypertension.

Reddy SA, Nethercott SL, Teh W, De Bie EM, ... Toshner MR, Martin CA
Anatomical and physiological changes in the right heart as a direct consequence of the upstream pressure overload characteristic of idiopathic pulmonary hypertension (IPAH) are likely to lead to conduction disease in these patients. However, the prevalence and clinical implications of atrioventricular conduction disease in IPAH patients are not well-characterized. In this observational cohort study, we show that conduction disease is far more prevalent in a cohort of 175 IPAH patients than a group of matched comparators (37.1% vs 10.8%), and is associated with older age, male sex and more severe right heart dilatation. However, conduction disease is independently associated with worse functionality and higher mortality in this patient group. Prospective study is required to substantiate this, and whether intervention such as prophylactic pacing could restore prognosis.

Crown Copyright © 2022. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 07 Apr 2022; epub ahead of print
Reddy SA, Nethercott SL, Teh W, De Bie EM, ... Toshner MR, Martin CA
J Heart Lung Transplant: 07 Apr 2022; epub ahead of print | PMID: 35501236
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Impact:
Abstract

Temporal shift and predictive performance of machine learning for heart transplant outcomes.

Miller RJH, Sabovčik F, Cauwenberghs N, Vens C, ... Haddad F, Kuznetsova T
Background
Outcome prediction following heart transplant is critical to explaining risks and benefits to patients and decision-making when considering potential organ offers. Given the large number of potential variables to be considered, this task may be most efficiently performed using machine learning (ML). We trained and tested ML and statistical algorithms to predict outcomes following cardiac transplant using the United Network of Organ Sharing (UNOS) database.
Methods
We included 59,590 adult and 8,349 pediatric patients enrolled in the UNOS database between January 1994 and December 2016 who underwent cardiac transplantation. We evaluated 3 classification and 3 survival methods. Algorithms were evaluated using shuffled 10-fold cross-validation (CV) and rolling CV. Predictive performance for 1 year and 90 days all-cause mortality was characterized using the area under the receiver-operating characteristic curve (AUC) with 95% confidence interval.
Results
In total, 8,394 (12.4%) patients died within 1 year of transplant. For predicting 1-year survival, using the shuffled 10-fold CV, Random Forest achieved the highest AUC (0.893; 0.889-0.897) followed by XGBoost and logistic regression. In the rolling CV, prediction performance was more modest and comparable among the models with XGBoost and Logistic regression achieving the highest AUC 0.657 (0.647-0.667) and 0.641(0.631-0.651), respectively. There was a trend toward higher prediction performance in pediatric patients.
Conclusions
Our study suggests that ML and statistical models can be used to predict mortality post-transplant, but based on the results from rolling CV, the overall prediction performance will be limited by temporal shifts inpatient and donor selection.

Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 31 Mar 2022; epub ahead of print
Miller RJH, Sabovčik F, Cauwenberghs N, Vens C, ... Haddad F, Kuznetsova T
J Heart Lung Transplant: 31 Mar 2022; epub ahead of print | PMID: 35568604
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Abstract

Immunologic risk stratification of pediatric heart transplant patients by combining HLAMatchmaker and PIRCHE-II.

Mangiola M, Ellison MA, Marrari M, Bentlejewski C, ... Zeevi A, CTOTC-09 site investigators
Background
Molecular-level human leukocyte antigen (HLA) mismatch is a powerful biomarker of rejection; however, few studies have explored its use in heart transplant recipients, and none have attempted to use the results of separate algorithms synergistically. Here we tested the hypothesis that a combination of HLAMatchmaker and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE-II) can be used to identify more patients at low risk of rejection.
Methods
We studied 274 recipient/donor pairs enrolled in the Clinical Trials in Organ Transplantation in Children (CTOTC) performing class I and II HLA genotyping by next-generation sequencing to determine eplet mismatch (epMM) load and PIRCHE-II score. Correlation with clinical outcomes was performed on 131 cases.
Results
Of the 131 patients, 100 without pre-formed donor specific antibody (DSA) were used to identify cutoffs for the Class I, HLA-DR, and HLA-DQ epMM load and PIRCHE-II score for risk of developing post-transplant DSA (epMM: Class I/DR/DQ = 9/9/6; PIRCHE-II: 141/116/111) and antibody-mediated rejection (ABMR) (epMM: 9/8/8; PIRCHE-II: 157/80/201). Patients with above cut-off epMM load appear to be less likely to develop DSA and ABMR if their PIRCHE-II score is below cut-off (high epMM/high PIRCHE-II: 12.3%-20.3% DSA and 9%-13.5% ABMR vs high epMM/low PIRCHE-II: 4%-10% DSA and 0%-2% ABMR).
Conclusion
For the first time in a pediatric heart transplant cohort, immunologic risk cut-offs for DSA and ABMR have been established. When used together, epMM load and PIRCHE-II score allow us to reclassify a portion of cases with high epMM load as having a lower risk for developing DSA and ABMR.

Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Mar 2022; epub ahead of print
Mangiola M, Ellison MA, Marrari M, Bentlejewski C, ... Zeevi A, CTOTC-09 site investigators
J Heart Lung Transplant: 30 Mar 2022; epub ahead of print | PMID: 35437211
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Impact:
Abstract

Size matching in combined heart-lung transplant: An undersized predicted heart mass is associated with increased mortality.

Firoz A, Yanagida R, Kashem M, Toyoda Y
Background
Numerous studies have analyzed the consequences of donor-recipient organ size mismatch within both heart and lung transplantation. However, there is very little data on size matching in combined heart-lung transplantation (HLTx). We reviewed how donor/recipient predicted total lung capacity (pTLC), predicted heart mass (pHM), weight, and height ratios affect HLTx survival and graft rejection outcome.
Methods
We performed a retrospective analysis on adult HLTx patients using the UNOS database. Overall survival at 1- and 5-years, as well as 5-years bronchiolitis obliterans syndrome (BOS) and coronary artery vasculopathy (CAV) development, were the outcomes of interest. Each sizing modality was split into 5 groups for survival analysis and 3 groups for graft rejection analysis based on an approximately equal size-matched reference group.
Results
In total, 747 patients were analyzed in our study. Of the 4 sizing modalities, only pHM ratio had a significant difference in acute and long-term survival. In particular, a severely undersized pHMr of < 83% was associated with an increased risk of mortality compared to an approximately equally sized match (1-year: HR=1.95, 95% CI=1.30-2.91, p = 0.001; 5-year: HR = 1.47, 95% CI = 1.05-2.06, p = 0.027). No sizing metric was predictive of BOS or CAV development.
Conclusion
Our analysis supports the use of pHM ratio for size matching in HLTx. Based on our results, a donor/recipient pHM ratio of >83% should be achieved to minimize mortality risk associated with sizing mismatch.

Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Mar 2022; epub ahead of print
Firoz A, Yanagida R, Kashem M, Toyoda Y
J Heart Lung Transplant: 29 Mar 2022; epub ahead of print | PMID: 35450737
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Abstract

Temporary mechanical circulatory support: Devices, outcomes, and future directions.

Baran DA, Jaiswal A, Hennig F, Potapov E
Faced with a chronic donor shortage, clinicians and regulators both struggle to develop allocation systems which balance the challenges of waitlist mortality and donor availability. Most organ allocation systems across the globe have prioritized transplantation of patients supported on temporary mechanical circulatory support (tMCS) with regional variations. There are concerns that this approach might not produce optimal outcomes and is not without major drawbacks including lack of strict criteria for tMCS as bridge strategy, choice of optimal devices and wait time on tMCS. The current manuscript outlines characteristics and limitations of current devices used for tMCS as a bridging strategy. The outcomes of transplantation following device support are evolving and are highlighted as well. Lastly, the allocation schema for heart transplantation in various countries are reviewed and compared. Additionally, we propose key principles to guide changes in next iteration of donor allocation systems to balance waitlist mortality with optimal post-transplant outcomes. First, allocation should be on the basis of calculated scores which take into account a variety of pre-and post-transplant factors and cannot be easily manipulate by choice of support therapy. Next, time at high urgency statuses should be time-limited with strict criteria for renewal. Emphasis should be placed on the further refinement of durable mechanical support therapies. Patients on durable support need a pathway to qualify for transplantation in the absence of complications, and lastly, peer review of exceptions to organ allocation policy are critically important to ensure the appropriate allocation of donor organs.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Mar 2022; epub ahead of print
Baran DA, Jaiswal A, Hennig F, Potapov E
J Heart Lung Transplant: 29 Mar 2022; epub ahead of print | PMID: 35461760
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Impact:
Abstract

Predictors of 1-year mortality after adult lung transplantation: Systematic review and meta-analyses.

Foroutan F, Malik A, Clark KE, Buchan TA, ... Guyatt G, Meade MO
Background
Prognostic factors in lung transplantation are those variables that are associated with transplant outcomes. Knowledge of donor and recipient prognostic variables can aid in the optimal allocation of donor lungs to transplant recipients and can also inform post-operative discussions with patients about prognosis. Current research findings related to prognostic factors in lung transplantation are inconsistent and the relative importance of various factors is unclear. This review aims to provide the best possible estimates of the association between putative prognostic variables and 1-year all-cause mortality in adult lung transplant recipients.
Methods
We searched 5 bibliographic databases for studies assessing the associations between putative predictors (related to lung donors, recipients, or the transplant procedure) and 1-year recipient mortality. We pooled data across studies when justified and utilized GRADE methodology to assess the certainty in the evidence.
Results
From 72 eligible studies (2002-2020), there were 34 recipient variables, 4 donor variables, 10 procedural variables, and 7 post-transplant complication variables that were amenable to a meta-analysis. With a high degree of certainty in the evidence only post-transplant need for extra-corporeal membrane oxygenation (ECMO) (HR 1.91, 95% CI 1.79-2.04) predicted 1-year mortality. No donor variables appeared to predict transplant outcome with high or even moderate certainty.
Conclusion
Across the range of contemporary donors and recipients that clinicians accept for lung transplantation, this review, with high certainty, found 1 prognostic factor that predicted 1-year mortality, and 37 additional factors with a moderate degree of certainty. The lack of prognostic significance for some widely accepted factors (e.g., donor smoking, age) likely relates to existing limits in the range of these variables at the time of donor and recipient selection.

Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 29 Mar 2022; epub ahead of print
Foroutan F, Malik A, Clark KE, Buchan TA, ... Guyatt G, Meade MO
J Heart Lung Transplant: 29 Mar 2022; epub ahead of print | PMID: 35570129
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Impact:
Abstract

Prognostic value of improvement endpoints in pulmonary arterial hypertension trials: A COMPERA analysis.

Hoeper MM, Pausch C, Olsson KM, Huscher D, ... Rosenkranz S, Lange TJ
Background
The prognostic value of improvement endpoints that have been used in clinical trials of treatments for pulmonary arterial hypertension (PAH) needs to be further investigated.
Methods
Using the COMPERA database, we evaluated the prognostic value of improvements in functional class (FC) and absolute or relative improvements in 6-min walking distance (6MWD) and N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP). In addition, we investigated multicomponent endpoints based on prespecified improvements in FC, 6MWD and NT-proBNP that have been used in recent PAH trials. Finally, we assessed the predictive value of improvements determined by risk stratification tools. The effects of changes from baseline to first follow-up (3-12 months after initiation of PAH therapy) on consecutive survival were determined by Kaplan-Meier analysis with Log-Rank testing and Cox proportional hazard analyses.
Results
All analyses were based on 596 patients with newly diagnosed PAH for whom complete data were available at baseline and first follow-up. Improvements in FC were associated with improved survival, whereas absolute or relative improvements in 6MWD had no predictive value. For NT-proBNP, absolute declines conferred no prognostic information while relative declines by ≥35% were associated with better survival. Improvements in multicomponent endpoints were associated with improved survival and the same was found for risk stratification tools.
Conclusion
While sole improvements in 6MWD and NT-proBNP had minor prognostic relevance, improvements in multicomponent endpoints and risk stratification tools based on FC, 6MWD, and NT-proBNP were associated with improved survival. These tools should be further explored as outcome measures in PAH trials.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 22 Mar 2022; epub ahead of print
Hoeper MM, Pausch C, Olsson KM, Huscher D, ... Rosenkranz S, Lange TJ
J Heart Lung Transplant: 22 Mar 2022; epub ahead of print | PMID: 35430147
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Impact:
Abstract

Noninvasive monitoring of allograft rejection in a rat lung transplant model: Application of machine learning-based F-fluorodeoxyglucose positron emission tomography radiomics.

Tian D, Shiiya H, Takahashi M, Terasaki Y, ... Sato M, Nakajima J
Background
Standardized uptake values (SUVs) derived from 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) are valuable but insufficient for detecting lung allograft rejection (AR). Using a rat lung transplantation (LTx) model, we investigated correlations of AR with the SUVmax and PET-derived radiomics and further evaluated the performance of machine learning (ML)-based radiomics for monitoring AR.
Methods
LTx was performed on 4 groups of rats: isograft, allograft-cyclosporinecontinuous (CsAcont), allograft-CsAdelayed, and allograft-CsA1week. Each rat underwent 18F-FDG PET at week 3 or 6. The SUVmax and radiomic features were extracted from the PET images. Least absolute shrinkage and selection operator regression was used to construct a radiomics score (Rad-score). Ten modeling algorithms with 7 feature selection methods were performed to develop 70 radiomics models (49 ML models and 21 logistic regression models) for monitoring AR, validated using the bootstrap method.
Results
In total, 837 radiomic features were extracted from each PET image. The SUVmax and Rad-score showed significant positive correlations with histopathology (p < .05). The area under the curve (AUC) of SUVmax for detecting AR was 0.783. The median AUC of ML models was 0.921, which was superior to that of logistic regression models (median AUC, 0.721). The optimal ML model using a random forest modeling algorithm with random forest feature selection method exhibited the highest AUC of 0.982 (95% confidence interval, 0.875-1.000) in all models.
Conclusions
SUVmax provided a good correlation with AR, but ML-based PET radiomics further strengthened the power of 18F-FDG PET functional imaging for monitoring AR in LTx.

Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 22 Mar 2022; epub ahead of print
Tian D, Shiiya H, Takahashi M, Terasaki Y, ... Sato M, Nakajima J
J Heart Lung Transplant: 22 Mar 2022; epub ahead of print | PMID: 35430149
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Impact:
Abstract

Recovery of left ventricular function is associated with improved outcomes in LVAD recipients.

Olsen C, Mandawat A, Sun JL, Triana T, Chiswell K, Karra R
Background
The significance of recovered left ventricular ejection fraction (LVEF) in LVAD recipients, outside of pump explantation, is unclear.
Methods
Patients undergoing first LVAD implantation at Duke University Hospital between 2006 and 2017 were evaluated for LVEF recovery up to 2 years following implant. Occurrence of gastrointestinal bleeding (GIB), hospitalization for heart failure (HF), pump thrombosis and death were assessed before and after LVEF recovery.
Results
Of 286 patients who met inclusion criteria, 9.8% reached a \"threshold\" of recovery with an LVEF ≥ 40%. 17.4% achieved \"relative\" recovery with an increase in LVEF ≥ 10% since LVAD implantation. For either definition, recovered patients had a lower incidence of a composite endpoint of GIB, HF hospitalization, pump thrombosis, or death compared to patients without recovery. Patients with \"threshold\" recovery had 4.7 events per 100 patient-years (95% CI, 0.7-33.6) compared to 48.8 events per 100 patient-years (95% CI, 39.5-60.3) without \"threshold\" recovery [p = .020]. Those with \"relative\" recovery had 14.1 events per 100 patient-years [95% CI, 5.9-33.8] versus 50.7 events per 100 patient-years (95% CI, 40.7-63.0) without \"relative\" recovery [p = 0.005]. However, improved outcomes in the \"relative\" recovery group were limited to those who also met the \"threshold\" definition. Importantly, among patients who achieved \"threshold\" recovery, the incidence of the composite endpoint declines in the postrecovery period, suggesting that LVEF recovery mechanistically results in improved outcomes.
Conclusions
An LVEF ≥ 40% associates with better outcomes in LVAD recipients. Methods to promote recovery could reduce morbidity and mortality related to LVAD support.

Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 17 Mar 2022; epub ahead of print
Olsen C, Mandawat A, Sun JL, Triana T, Chiswell K, Karra R
J Heart Lung Transplant: 17 Mar 2022; epub ahead of print | PMID: 35410822
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Abstract

Pathophysiological evaluations of initial plaque development after heart transplantation via serial multimodality imaging and cytokine assessments.

Shiraki T, Ichibori Y, Ohtani T, Mizote I, ... Sawa Y, Sakata Y
Background
Detailed morphological characteristics of de novo and donor-transmitted plaques and the association of serum T-lymphocyte cytokine levels with plaque progression of coronary allograft vasculopathy within 1 year after heart transplantation are unknown.
Methods
In this retrospective analysis of data in a prospectively maintained database, 40 heart transplant recipients were included. We performed serial 3 vessel optical coherence tomography and intravascular ultrasound analyses, at the 8 week (baseline) and 12 month post-transplantation follow-ups, and serum cytokine measurements (n = 23). The correlation between serum cytokines and Δplaque burden (between baseline and follow-up) was evaluated depending on plaque morphology.
Results
Thirteen de novo plaques (maximum intimal thickness ≥0.5 mm at the 12 month follow-up without plaques at baseline) were identified in 8 recipients, and 31 donor-transmitted plaques (maximum intimal thickness ≥0.5 mm at baseline) were detected in 17 recipients. Compared with donor-transmitted plaques, the Δplaque burden in the de novo plaques, with mainly fibrous morphology, was high (38.8% [29.6%-41.2%] vs 8.7% [1.33%-13.6%], p < 0.001). Stratification of the morphology of donor-transmitted plaques revealed that the Δplaque burden in fibrous plaques (10.6% [7.0%-18.0%]) was similar to that in fibroatheroma (10.3% [8.7%-23.8%]). Serum interleukin-31 levels at baseline correlated with fibrous plaque proliferation (r = 0.73, p = 0.007) even under immunosuppressive conditions, whereas other cytokines (interleukin-1β, interleukin-17, and interferon-gamma) were mostly undetectable.
Conclusions
Intimal fibrous proliferation contributed to the progression of donor-transmitted and de novo plaques. Serum interleukin-31 levels at baseline may contribute to intimal fibrous proliferation within 1 year after heart transplantation.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 16 Mar 2022; epub ahead of print
Shiraki T, Ichibori Y, Ohtani T, Mizote I, ... Sawa Y, Sakata Y
J Heart Lung Transplant: 16 Mar 2022; epub ahead of print | PMID: 35400587
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Impact:
Abstract

Oxygen Uptake During Activities of Daily Life in Patients Treated With a Left Ventricular Assist Device.

Mirza KK, Thomas B, Nordsborg NB, Rossing K, Boesgaard S, Gustafsson F
Introduction
Oxygen consumption during activities of daily life (ADL) is not described in recipients of left ventricular assist device (LVAD). We aimed to investigate the relation between oxygen consumption during predefined ADLs and measures of functional capacity (FC) in stable-phase LVAD recipients.
Methods
LVADs and controls were matched on gender, age, BMI, smoking status, and ethnicity. VO2 was measured using mobile equipment (K5, Cosmed, Rome, Italy) while putting on vest and LVAD equipment(1), folding towels(2), putting on socks and shoes(3), putting bottles in a cupboard(4), making a bed(5), walking on stairs without(6) and with extra weight(7), and sweeping the floor(8). Submaximal FC was tested by means of 6 minute walk test (6MWT) and peak oxygen uptake (pVO2) to test maximal FC.
Results
Fifteen LVAD patients and 16 controls were included; Patients were 61 ± 10years, all males with BMI 28 ± 5kg/m2 and implanted with Heartmate 3 (DT: 60%). PVO2 was 14.9 ± 2.2 ml/kg/min in patients and 39.6 ± 7.7 in controls (p < 0.001). Oxygen consumption expressed as percent of pVO2 for each task in patients vs controls was (%): ADL1: 41 ± 5 vs 21 ± 4, ADL2: 41 ± 6 vs 22 ± 5 %, ADL3: 50 ± 16 vs 24 ± 5%, ADL4: 45 ± 12 vs 22 ± 4, ADL5: 50 ± 8 vs 23 ± 4, ADL6: 66 ± 10 vs 30 ± 4, ADL7: 65 ± 10 vs 31 ± 5, ADL8: 75 ± 10 vs 39 ± 12, (p < 0.001 for all). During 6MWT LVAD patients used 96% ± 8 % of their pVO2.
Conclusion
Recipients of durable LVADs perform daily life activities at oxygen uptake levels much closer to their peak cardiopulmonary reserve than matched healthy controls.

Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 16 Mar 2022; epub ahead of print
Mirza KK, Thomas B, Nordsborg NB, Rossing K, Boesgaard S, Gustafsson F
J Heart Lung Transplant: 16 Mar 2022; epub ahead of print | PMID: 35400588
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Impact:
Abstract

ISHLT position paper on thoracic organ transplantation in controlled donation after circulatory determination of death (cDCD).

Holm AM, Courtwright A, Olland A, Zuckermann A, Van Raemdonck D
Controlled organ donation after circulatory determination of death is increasingly being used for the donation of organs also in thoracic transplantation. This document outlines the position of the International Society for Heart and Lung Transplantation on thoracic organ transplantation in circulatory determination of death. The document also includes a position regarding some of the methods applied to ensure the viability of Donation after Circulatory Death organs retrieved after certification of death.

Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 14 Mar 2022; epub ahead of print
Holm AM, Courtwright A, Olland A, Zuckermann A, Van Raemdonck D
J Heart Lung Transplant: 14 Mar 2022; epub ahead of print | PMID: 35370034
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Impact:
Abstract

The evolution of pediatric heart retransplantation over three decades: An analysis from the PHTS.

Vazquez Alvarez MDC, Cantor R, Koehl D, Nandi D, ... Allain-Rooney T, Dipchand AI
Background
Retransplantation is rare and associated with worse survival and more morbidity. The study aim is to describe an updated cohort of pediatric retransplants, determine if there has been an era effect on outcomes, and understand if identified trends are explained by changes in patient selection.
Methods
Pediatric Heart Transplant Society database analysis of retransplantation patients <18 years of age (Era 1: 1993-2001, Era 2: 2002-2010, Era 3: 2011-2018). Multivariate analysis identified risk factors for graft loss. Multiphase parametric hazard modeling was used to depict era and risk factor effect.
Results
Survival was lower (p < .0001) for retransplant (n = 222) compared to primary transplant (n = 6548) (median 9.3 vs 20.2 years). Median survival increased from Era 1 to 2 (4.8 vs 9.3 years; p < .0001) with no incremental change in Era 3. Era 2 and 3 retransplants had a longer inter-transplant interval (p < .0001), were less frequently for early graft failure (p = .0004) or acute rejection (p = .007), more frequently from a ventricular assist device (p = .0014), and less frequently from extracorporeal membrane oxygenation (p = .0024). Predictors of graft loss included Era 1 (HR 10.55, p = .001), congenital heart disease (HR 4.42, p = .01), inter-transplant interval <1 year (HR 5.34, p = .002), and mechanical support (ventricular assist device HR 7.47, p = .0042; extracorporeal membrane oxygenation HR 10.09, p < .0001). For each 1-year increase in inter-transplant interval, graft loss risk decreased by 1.15 (p = .0002). Retransplantation was associated with more rejection, infection, and allograft vasculopathy.
Conclusions
Graft survival has improved in pediatric retransplants making it a viable option in select patients. Retransplantation should be avoided in the setting of early graft failure especially requiring mechanical support.

Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 14 Mar 2022; epub ahead of print
Vazquez Alvarez MDC, Cantor R, Koehl D, Nandi D, ... Allain-Rooney T, Dipchand AI
J Heart Lung Transplant: 14 Mar 2022; epub ahead of print | PMID: 35400589
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Impact:
Abstract

Central venoarterial extracorporeal membrane oxygenation as a bridge to recovery after pulmonary endarterectomy in patients with decompensated right heart failure.

Abdelnour-Berchtold E, Donahoe L, McRae K, Asghar U, ... Granton J, de Perrot M
Introduction
Patients with chronic thromboembolic pulmonary hypertension (CTEPH) and decompensated right heart failure (DRHF) have worse outcomes after pulmonary endarterectomy (PEA). We reviewed the role of central veno-arterial extracorporeal membrane oxygenation (VA-ECMO) as a bridge to recovery after PEA in these patients.
Methods
Of 388 consecutive patients undergoing PEA, 40 (10.3%) were admitted with DRHF before PEA. This group was compared to the remaining 348 patients undergoing PEA (elective group). We also compared 2 periods: 2005-2013 (n = 120) and 2014-2019 (n = 268) after which early central VA-ECMO was introduced as a strategy to manage difficulty weaning from cardiopulmonary bypass (CPB).
Results
The proportion of patients with DRHF remained similar between the first and second period (13% vs 9%, p = .2). The number of VA-ECMO bridge to recovery increased from 0.8% in 2005-2013 to 6.3% in 2014-2019 (p = .02). In the second period, 29% of DRHF patients were transitioned intraoperatively from CPB to central VA-ECMO for a median duration of 3 (2-7) days. After the introduction of central VA-ECMO as a bridge to recovery, the hospital mortality in patients with DRHF dropped from 31% in 2005-2013 to 4% in 2014-2019 (p = .03). In the long-term, the functional recovery and survival after discharged from hospital was similar between the DRHF group and the elective group. However, at 5 years, DRHF patients more frequently required PH targeted medical therapy (45% vs 20% in the elective group, p = .002).
Conclusions
Central VA-ECMO as a bridge to recovery is an important treatment strategy that can decrease hospital mortality in patients with DRHF and lead to excellent long-term outcome.

Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 09 Mar 2022; epub ahead of print
Abdelnour-Berchtold E, Donahoe L, McRae K, Asghar U, ... Granton J, de Perrot M
J Heart Lung Transplant: 09 Mar 2022; epub ahead of print | PMID: 35370035
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Impact:
Abstract

Exercise invasive hemodynamics in adults post-fontan: A novel tool in understanding functional limitation and liver disease.

Miranda WR, Jain CC, Borlaug BA, Connolly HM, Egbe AC
Functional impairment is essentially universal among adults post-Fontan palliation. Cardiac catheterization is frequently performed in patients post-Fontan but normal resting Fontan and ventricular filling pressures are commonly recorded even in highly symptomatic individuals. Ascertaining the etiology of exertional symptoms in these individuals is further complicated by the prevalence of co-existent sarcopenia, abnormal skeletal muscle function, impaired respiratory mechanics, and deconditioning. Exercise right heart catheterization is increasingly used in acquired heart disease but the diagnostic yield of exercise at the time of cardiac catheterization in Fontan patients remains largely unknown. We report herein exercise catheterization findings in 4 consecutive adults post-Fontan referred to our laboratory. We believe this novel series illustrates several potential roles for exercise during catheterization of adults post-Fontan, with each patient having a unique constellation of hemodynamic findings to explain their clinical presentation and tailor their management.

Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 09 Mar 2022; epub ahead of print
Miranda WR, Jain CC, Borlaug BA, Connolly HM, Egbe AC
J Heart Lung Transplant: 09 Mar 2022; epub ahead of print | PMID: 35400586
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Impact:
Abstract

Post-transplant lymphoproliferative disorder presenting as supraglottitis following pediatric heart transplantation treated with EBV-specific cytotoxic T-lymphocytes.

Duignan S, O\'Marcaigh A, Russell J, Mehanna R, ... Fenton M, McMahon CJ
We present the case of a 4 year-old boy post heart transplantation who presented with signs and symptoms of critical airway obstruction and was initially diagnosed with infective supraglottitis. Following re-presentation and biopsy, this was confirmed as post-transplant lymphoproliferative disorder (PTLD) in an unusual site; laryngeal PTLD is rare. The patient failed standard therapy and ultimately was successfully treated with EBV-specific cytotoxic T lymphocytes (CTL). This case describes a rare presentation of PTLD which required a novel treatment approach including elective tracheostomy prior to CTL therapy. The treatment was successful and the patient was decannulated prior to discharge following 4 negative biopsies, the most recent 6 months following treatment completion. The case also highlights the importance of extra-vigilance in the post-transplant population and of a collaborative approach between multiple specialties across two separate countries including the transplant center and the referral center.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 06 Mar 2022; epub ahead of print
Duignan S, O'Marcaigh A, Russell J, Mehanna R, ... Fenton M, McMahon CJ
J Heart Lung Transplant: 06 Mar 2022; epub ahead of print | PMID: 35370033
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Impact:
Abstract

Stem cell therapy for pulmonary arterial hypertension: An update.

Sun QW, Sun Z
Pulmonary arterial hypertension (PAH) remains a deadly disease, and there currently is no cure for this life-threating medical problem. The average lifespan is about 5 to 7 years after diagnosis of PAH. Therefore, a conceptual breakthrough to develop new therapeutic strategies for PAH is urgently needed. Growing evidence shows that stem cells are emerging as a novel effective treatment, but the understanding of its underlying mechanisms is still limited. This review highlights the mechanisms through which stem cells successfully reverse pulmonary vascular endothelial dysfunction, pulmonary artery smooth muscle cell over-proliferation, and mitochondrial dysfunction in PAH patients and common rodent models used in PAH research. They can modulate common underlying pathways involved in PAH, including the nitric oxide synthase, mitochondrial regulators, microRNAs and STAT3-BMPR signaling. Genetic modifications further enhance the therapeutic effects of stem cells on PAH. Clinical trials showed promising therapeutic potential of mesenchymal stem cells and endothelial progenitor cells for PAH. Potential limitations and challenges are also discussed. The current findings support the need for further investigation and validation of stem cell therapy for PAH.

Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 06 Mar 2022; epub ahead of print
Sun QW, Sun Z
J Heart Lung Transplant: 06 Mar 2022; epub ahead of print | PMID: 35341679
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Impact:
Abstract

Residual mitral regurgitation in patients with left ventricular assist device support - An INTERMACS analysis.

Jain R, Truby LK, Topkara VK
Background
Left ventricular assist device (LVAD) placement frequently leads to a reduction in the severity of functional mitral regurgitation (MR). However, a significant number of LVAD supported patients have residual MR. We sought to assess the impact of residual MR in LVAD patient outcomes.
Methods
Patients in the INTERMACS registry who received a continuous flow LVAD between 2006 and 2017 without a prior mitral valve repair were included for analysis. Residual MR was defined as moderate or severe MR within the first 3 months device support. Baseline characteristics, echocardiographic and hemodynamic variables, and clinical outcomes were comparatively analyzed between those with or without residual MR.
Results
A total of 8,364 patients were included in the study, of which 18.8% demonstrated residual MR. Younger age, female gender, and non-ischemic heart failure were predictors of residual MR, as were increased LVEDD, RV dysfunction, severe baseline MR or TR, and elevated right heart pressures. Concomitant mitral valve repair reduced the risk of residual MR. Those with residual MR demonstrated worse LV remodeling, more right ventricular dysfunction, and higher right heart pressures at almost all time points analyzed. Residual MR was associated with increased risk of right heart failure and renal failure, and a trend toward increased mortality on LVAD support.
Conclusions
Residual MR is associated with worse clinical outcomes on LVAD support. Strategies to minimize MR including medical and device optimization as well as valve repair should be considered in LVAD patients with residual MR.

Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 05 Mar 2022; epub ahead of print
Jain R, Truby LK, Topkara VK
J Heart Lung Transplant: 05 Mar 2022; epub ahead of print | PMID: 35379546
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Impact:
Abstract

Incremental value of cardiopulmonary exercise testing in intermediate-risk pulmonary arterial hypertension.

Badagliacca R, Rischard F, Giudice FL, Howard L, ... Fedele F, Vizza CD
Background
Risk assessment in pulmonary arterial hypertension (PAH) is essential for prognostication. However, the majority of patients end-up in an intermediate risk status, offering insufficient guidance in clinical practice. The added value of cardiopulmonary exercise testing in this setting remains undefined.
Methods
Two independent cohorts with idiopathic PAH at intermediate risk were used to develop (n = 124) and externally validate (n = 143) the prognostic model. Cross-validation on the overall population was used to strengthen the results of the analysis. Risk assessment was based on the simplified version of the ESC/ERS guidelines score. Discrimination and calibration were assessed.
Results
A risk score was constructed based on the beta-coefficient of the cross-validated model, including the stroke volume index (SVI) and the peak oxygen uptake (VO2 peak). Patients were grouped based on cutoff values of the risk score allowing the highest discrimination in the overall cohort. Group 1, score ≤2 (101 patients) with VO2 peak ≥14 ml/kg/min and SVI >30 ml/m2; Group 2, score between 2 and 5 (112 patients) with VO2 peak between 9 and 14 ml/kg/min, and SVI between 20 and 50 ml/m2; Group 3, score >5 (46 patients) with VO2 peak <10 ml/kg/min and SVI <30 ml/m2. The event-free survival rates at 1, 2 and 3 years, were 96%, 83% and 79% for Group 1, respectively; 82%, 67% and 52% for Group 2; 69%, 50% and 41% for Group 3.
Conclusions
Combinations of VO2 peak and SVI may provide important information to further stratify intermediate-risk prevalent patients with idiopathic PAH.

Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 05 Mar 2022; epub ahead of print
Badagliacca R, Rischard F, Giudice FL, Howard L, ... Fedele F, Vizza CD
J Heart Lung Transplant: 05 Mar 2022; epub ahead of print | PMID: 35414469
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Impact:
Abstract

UNOS listing status-related changes in mechanical circulatory support utilization and outcomes in adult congenital heart disease patients.

Zhou AL, Menachem JN, Danford DA, Kutty S, Cedars AM
Background
The aim of this study was to investigate the impact of the new United Network for Organ Sharing (UNOS) listing criteria on mechanical circulatory support (MCS) utilization and outcomes in adult congenital heart disease (ACHD) patients.
Methods
We identified all ACHD and non-ACHD heart transplant candidates in the Scientific Registry of Transplant Recipients database listed during the 590 days prior to (historical cohort) or following (recent cohort) the UNOS allocation revision on October 18, 2018. Patients were grouped based on whether they received central temporary MCS (tMCS), peripheral tMCS, durable MCS, or no MCS.
Results
A total of 535 ACHD (242 historical, 293 recent) and 12,188 non-ACHD (6,258 historical, 5,930 recent) patients were included in our study. For ACHD patients, we found no differences in the historical versus recent cohort in utilization of central tMCS (3.31% vs 3.07%, p = .88) or durable MCS (3.31% vs 3.41%, p = .95), whereas the rate of peripheral tMCS increased (2.07% historical vs 6.83% recent, p = .009). Across both cohorts, ACHD patients supported with peripheral tMCS had shorter time-to-transplant than non-supported patients (25.7 vs 121.7 days, p = .002). ACHD patients supported with central tMCS had greater rates of post-transplant mortality relative to other ACHD patients (40.0% vs 12.6%, p = .006), while those supported with durable or peripheral temporary MCS had no differences in waitlist or post-transplant mortality compared to non-supported ACHD patients.
Conclusions
The 2018 UNOS allocation changes increased utilization of peripheral temporary MCS in ACHD patients, decreasing waitlist time without impact on post-transplant outcomes.

Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 05 Mar 2022; epub ahead of print
Zhou AL, Menachem JN, Danford DA, Kutty S, Cedars AM
J Heart Lung Transplant: 05 Mar 2022; epub ahead of print | PMID: 35397877
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Impact:
Abstract

Change in REVEAL Lite 2 risk score predicts outcomes in patients with pulmonary arterial hypertension in the PATENT study.

Benza RL, Boucly A, Farber HW, Frost AE, ... Meier C, Sitbon O
Background
Risk assessment is essential in pulmonary arterial hypertension (PAH) management. We investigated the effect of riociguat on REVEAL Lite 2 score, an abridged version of the REVEAL risk score, and its association with long-term outcomes in PATENT.
Methods
PATENT-1 was a randomized, double-blind study of riociguat vs placebo in patients with PAH. In the PATENT-2 open-label extension, all patients received riociguat up to 2.5 mg three times daily (n = 396). REVEAL Lite 2 scores were calculated at baseline, PATENT-1 Week 12, and PATENT-2 Week 12, with patients stratified as low- (1-5), intermediate- (6-7), or high-risk (≥8). Kaplan-Meier and Cox proportional hazards analyses assessed association of riociguat with survival and clinical worsening-free survival (CWFS).
Results
REVEAL Lite 2 score improved with riociguat 2.5 mg at PATENT-1 Week 12 (least-squares mean difference vs placebo: -0.8; p = 0.0004). More patients receiving riociguat 2.5 mg stabilized or improved risk stratum at PATENT-1 Week 12 vs placebo (p = 0.0005) and achieved low-risk status. REVEAL Lite 2 score at baseline and PATENT-1 Week 12 were associated with survival and CWFS (all p < 0.0001), as was change in score from baseline to Week 12 (p = 0.0002 and p < 0.0001, respectively). Survival and CWFS differed between risk strata at baseline (p < 0.0001) and PATENT-1 Week 12 (p < 0.0001).
Conclusions
This analysis confirms the risk-reduction benefits of riociguat in patients with PAH and further contributes to the validation of REVEAL Lite 2 in facilitating PAH risk assessment.

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

J Heart Lung Transplant: 27 Feb 2022; 41:411-420
Benza RL, Boucly A, Farber HW, Frost AE, ... Meier C, Sitbon O
J Heart Lung Transplant: 27 Feb 2022; 41:411-420 | PMID: 34848133
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Impact:
Abstract

Ex vivo treatment of cytomegalovirus in human donor lungs using a novel chemokine-based immunotoxin.

Ribeiro RVP, Ku T, Wang A, Pires L, ... Humar A, Cypel M
Background
Transmission of latent human cytomegalovirus (HCMV) via organ transplantation with post-transplant viral reactivation is extremely prevalent and results in substantial adverse impact on outcomes. Therapies targeting the latent reservoir within the allograft to mitigate viral transmission would represent a major advance. Here, we delivered an immunotoxin (F49A-FTP) that targets and kills latent HCMV aiming at reducing the HCMV reservoir from donor lungs using ex-vivo lung perfusion (EVLP).
Methods
HCMV seropositive human lungs were placed on EVLP alone or EVLP + 1mg/L of F49A-FTP for 6 hours (n = 6, each). CD14+ monocytes isolated from biopsies pre and post EVLP underwent HCMV reactivation assay designed to evaluate viral reactivation capacity. Off-target effects of F49A-FTP were studied evaluating cell death markers of CD34+ and CD14+ cells using flow cytometry. Lung function on EVLP and inflammatory cytokine production were evaluated as safety endpoints.
Results
We demonstrate that lungs treated ex-vivo with F49A-FTP had a significant reduction in HCMV reactivation compared to controls, suggesting successful targeting of latent virus (76% median reduction in F49A-FTP vs 15% increase in controls, p = 0.0087). Furthermore, there was comparable cell death rates of the targeted cells between both groups, suggesting no off-target effects. Ex-vivo lung function was stable over 6 hours and no differences in key inflammatory cytokines were observed demonstrating safety of this novel treatment.
Conclusions
Ex-vivo F49A-FTP treatment of human lungs targets and kills latent HCMV, markedly attenuating HCMV reactivation. This approach demonstrates the first experiments targeting latent HCMV in a donor organ with promising results towards clinical translation.

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

J Heart Lung Transplant: 27 Feb 2022; 41:287-297
Ribeiro RVP, Ku T, Wang A, Pires L, ... Humar A, Cypel M
J Heart Lung Transplant: 27 Feb 2022; 41:287-297 | PMID: 34802874
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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: 27 Feb 2022; 41:334-344
Halloran PF, Madill-Thomsen K, Aliabadi-Zuckermann AZ, Cadeiras M, ... Stehlik J, Zuckermann A
J Heart Lung Transplant: 27 Feb 2022; 41:334-344 | PMID: 34548198
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Impact:
Abstract

Twenty-four-hour blood pressure and heart rate variability are reduced in patients on left ventricular assist device support.

Castagna F, McDonnell BJ, Mondellini GM, Gaudig A, ... Parati G, Colombo PC
Background
Limited data exist on the circadian blood pressure (BP) and heart rate (HR) variations that occur in heart failure (HF) patients on left ventricular assist device (LVAD) support.
Methods
We prospectively recorded clinic and 24-hour ambulatory BP and HR data in patients on HeartMate II LVAD support. Results were compared to HF patients with ejection fraction ≤30% and controls with no history of cardiovascular disease. Physiologic nocturnal BP and HR dipping was defined as a ≥10% decline compared to daytime values.
Result
Twenty-nine LVAD patients (age 59 ± 15 years, 76% male, 38% ischemic etiology), 25 HF patients (age 64 ± 13 years, 84% male, 32% ischemic etiology) and 26 controls (age 56 ± 9 years, 62% male) were studied. Normal nocturnal BP dipping was less frequent in LVAD patients (10%) than in HF patients (28%) and controls (62%) and reversed BP dipping (BP increase at night) was more common in LVAD patients (24%), compared to HF (16%) and controls (8%), (p < 0.001, for all comparisons). Physiologic HR reduction was less frequent in LVAD patients (14%), compared to HF (16%) and controls (59%) (p < 0.001, for all comparisons). Among LVAD patients, 36% exhibited sustained hypertension over the 24-hours and 25% had white-coat hypertension.
Conclusions
Treatment of advanced HF with an LVAD does not restore physiologic circadian variability of BP and HR; additionally, BP was not adequately controlled in more than a third of LVAD patients, and a quarter of them exhibited white-coat hypertension. Future studies are warranted to confirm these findings and investigate prognostic and management implications in this population.

Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 27 Feb 2022; epub ahead of print
Castagna F, McDonnell BJ, Mondellini GM, Gaudig A, ... Parati G, Colombo PC
J Heart Lung Transplant: 27 Feb 2022; epub ahead of print | PMID: 35422348
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Impact:
Abstract

Impact of incorporating long-term survival for calculating transplant benefit in the US lung transplant allocation system.

Lehr CJ, Wey A, Skeans MA, Lease ED, Valapour M
Background
The lung allocation score prioritizes candidates for a lung transplant in the United States. As the country adopts the continuous distribution framework for organ allocation, we must reevaluate lung allocation score assumptions to maximize transplant benefit.
Methods
We used Scientific Registry of Transplant Recipients data to study the impact of these changes: (1) updating cohorts; (2) transitioning from 1- to 5-year posttransplant survival; (3) using time-varying effects for non-proportional hazards; and (4) weighting waitlist and posttransplant area under the curve differently. Models were compared using Spearman correlations and C-statistics. The thoracic simulation allocation model characterized transplant rates and proportions of recipient subgroups under the current and new systems.
Results
Posttransplant areas under the curve models were estimated with recipients aged ≥12 from January 1, 2014, to December 31, 2018. All models had similar C-statistics and Spearman correlations, indicating similar predictive performance and posttransplant area under the curve rankings. Five-year posttransplant area under the curve across age and diagnosis groups varied more than 1-year groups. Using the thoracic simulation allocation model, 1- and 5-year posttransplant model under the curve models showed similar transplant rates and recipient characteristics under the current system, but under continuous distribution, 5-year posttransplant area under the curve resulted in increased transplant rates with more recipients younger and in diagnosis groups B and C.
Conclusion
Incorporating equally weighted waitlist and posttransplant models using 5-year posttransplant survival detected the largest variability in survival under the continuous distribution system, which could improve long-term survival in the United States.

Copyright © 2022 International Society for Heart and Lung Transplantation. All rights reserved.

J Heart Lung Transplant: 26 Feb 2022; epub ahead of print
Lehr CJ, Wey A, Skeans MA, Lease ED, Valapour M
J Heart Lung Transplant: 26 Feb 2022; epub ahead of print | PMID: 35341678
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Impact:
Abstract

Defibrillator generator replacements in patients with left ventricular assist device support: The risks of hematoma and infection.

Eulert-Grehn JJ, Sterner I, Schoenrath F, Stein J, ... Potapov E, Starck C
Background
The majority (89%) of left ventricular assist device (LVAD) patients have an implantable cardioverter-defibrillator (ICD) in place. Due to the advances of modern-day LVAD therapy, more patients are on support for longer. This inevitably leads to more LVAD patients facing ICD generator battery depletion. Until now, there are insufficient data regarding periprocedural risks of generator replacements in a high-risk group like the LVAD cohort.
Methods
A retrospective, single-center analysis of pocket-related outcomes of all ICD generator replacements in LVAD and Non-LVAD patients between January 2014 and December 2018. The primary outcome was the combined endpoint of clinically significant pocket hematoma and/or cardiac implantable electronic device (CIED) infection in the first 6 months after ICD generator exchange. The clinically significant hematoma was defined as hematoma requiring reoperation, prolongation of hospitalization, or interruption of anticoagulation. The cumulative incidence function was calculated for the primary endpoint.
Results
Two hundred seventy-seven patients underwent ICD generator exchange in our clinic in this time. Of these, 251 patients had a complete 6-month follow-up regarding clinically significant pocket hematomas and pocket infections. One hundred ninety patients had no LVAD, and 61 patients were on LVAD support. The rate of the primary combined endpoint clinically significant pocket hematoma and/or CIED infection was 3.5 times higher in LVAD patients compared to the non-LVAD cohort (event rate 39.14 vs 11.07 per 100 patient-years, p = 0.048). Clinically significant pocket hematomas necessitating revision occurred nearly 4 times more often in the LVAD group (p = 0.042). Pocket device infection rates were around 16 times higher in LVAD patients compared to non-LVAD patients (p = 0.002).
Conclusions
Compared to Non-LVAD patients, LVAD patients exhibit a relevant higher rate of clinically significant pocket hematoma and CIED infection after ICD generator exchange. This information should additionally be considered in the decision-making process regarding the indication for ICD generator exchange.

Copyright © 2022 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 26 Feb 2022; epub ahead of print
Eulert-Grehn JJ, Sterner I, Schoenrath F, Stein J, ... Potapov E, Starck C
J Heart Lung Transplant: 26 Feb 2022; epub ahead of print | PMID: 35422347
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Impact:

This program is still in alpha version.