Journal: J Heart Lung Transplant

Sorted by: date / impact
Abstract

Kinetics of generic tacrolimus in heart transplantation: A cautionary note.

Il\'Giovine ZJ, Williams JB, Mason RP, Sherratt SCR, ... Mehra MR, Starling RC
Tacrolimus is a core component of immunosuppressive regimens. This study compared active pharmaceutical ingredient (API) and dissolution kinetics of branded tacrolimus and formulations from three generic manufacturers (Mylan, Dr. Reddy\'s, Intas) including samples from patients who suffered acute cardiac allograft rejection. Generic samples showed similar API content compared to branded samples with no major impurities. Capsules that underwent uniformity testing had consistent capsule-to-capsule API. Dissolution testing showed similar profiles between branded tacrolimus and Mylan, but notable differences with Dr. Reddy\'s and Intas. The approximate maximal inhibitory concentration (IC50) was highest in branded tacrolimus (29 minutes), followed by Mylan (26 minutes), Dr. Reddy\'s (19 minutes), and Intas (14 minutes) (Student-Newman-Keuls Multiple Comparisons Test; overall ANOVA: p = 0.0199, F = 6.469). This study suggests that the bioavailability of certain generic tacrolimus formulations peak significantly earlier than branded tacrolimus. Further study is needed to determine whether these differences are clinically relevant.

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

J Heart Lung Transplant: 16 Apr 2021; epub ahead of print
Il'Giovine ZJ, Williams JB, Mason RP, Sherratt SCR, ... Mehra MR, Starling RC
J Heart Lung Transplant: 16 Apr 2021; epub ahead of print | PMID: 33903017
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Venous or arterial thromboses after venoarterial extracorporeal membrane oxygenation support: Frequency and risk factors.

Bidar F, Lancelot A, Lebreton G, Pineton de Chambrun M, ... Bouglé A, Luyt CE
Background
Although venous thrombosis after venovenous-extracorporeal membrane oxygenation (ECMO) is well described, vascular complications occurring after venoarterial ECMO (VA-ECMO) removal have not yet been thoroughly described. Our aim was to evaluate the frequency of vascular (arterial and venous) complications after VA-ECMO removal and try to identify the risk factors associated with them.
Methods
Retrospective analysis of data prospectively collected in 2 intensive care units was performed. Consecutive patients successfully weaned off VA-ECMO during year 1 were screened for cannula-associated deep vein thrombosis (CaDVT) or arterial complications (arterial thrombosis/stenosis) using Doppler ultrasonography.
Results
From November 2018 to November 2019, a total of 107 patients with a median (interquartile range [IQR]) age of 54 (42-63) years and a median (IQR) ECMO support duration of 8 (2-5) days were successfully weaned off VA-ECMO and included. CaDVT occurred in 44 patients (41%), and arterial complications occurred in 15 (14%) (9 acute leg ischemia, 1 arteriovenous femoral fistula, and 5 late femoral stenosis). Multivariable analysis retained longer duration of ECMO support (odds ratio [OR]: 1.12 per day; 95% CI: 1.02-1.22) and infection occurring on ECMO (OR: 3.03; 95% CI: 1.14-8.03) as independent risk factors for CaDVT, whereas older age (OR: 0.97 per year; 95% CI: 0.94-0.99) and previous anti-coagulation use (OR: 0.21; 95% CI: 0.06-0.68) were protective factors for CaDVT. No risk factors for arterial complications were identified.
Conclusions
In patients requiring VA-ECMO support, vascular complications occurred frequently after its removal, especially CaDVT. Arterial complications, either early leg ischemia or late arterial stenosis, were observed less often. Strategies aimed at preventing CaDVT after VA-ECMO remain to be determined.

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

J Heart Lung Transplant: 30 Mar 2021; 40:307-315
Bidar F, Lancelot A, Lebreton G, Pineton de Chambrun M, ... Bouglé A, Luyt CE
J Heart Lung Transplant: 30 Mar 2021; 40:307-315 | PMID: 33422407
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Comparison of combined heart‒liver vs heart-only transplantation in pediatric and young adult Fontan recipients.

Sganga D, Hollander SA, Vaikunth S, Haeffele C, ... Bernstein D, Chen S
Background
Indications for a heart‒liver transplantation (HLT) for Fontan recipients are not well defined. We compared listing characteristics, post-operative complications, and post-transplant outcomes of Fontan recipients who underwent HLT with those of patients who underwent heart-only transplantation (HT). We hypothesized that patients who underwent HLT have increased post-operative complications but superior survival outcomes compared with patients who underwent HT.
Methods
We performed a retrospective review of Fontan recipients who underwent HLT or HT at a single institution. Characteristics at the time of listing, including the extent of liver disease determined by laboratory, imaging, and biopsy data, were compared. Post-operative complications were assessed, and the Kaplan‒Meier survival method was used to compare post-transplant survival. Univariate regression analyses were performed to identify the risk factors for increased mortality and morbidity among patients who underwent HT.
Results
A total of 47 patients (9 for HLT, 38 for HT) were included. Patients who underwent HLT were older, were more likely to be on dual inotrope therapy, and had evidence of worse liver disease. Whereas ischemic time was longer for the group who underwent HLT, post-operative complications were similar. Over a median post-transplant follow-up of 17 (interquartile range: 5-52) months, overall mortality for the cohort was 17%; only 1 patient who underwent HLT died (11%) vs 7 patients who underwent HT (18%) (p = 0.64). Among patients who underwent HT, cirrhosis on pre-transplant imaging was associated with worse outcomes.
Conclusions
Despite greater inotrope need and more severe liver disease at the time of listing, Fontan recipients undergoing HLT have post-transplant outcomes comparable with those of patients undergoing HT. HLT may offer a survival benefit for Fontan recipients with liver disease.

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

J Heart Lung Transplant: 30 Mar 2021; 40:298-306
Sganga D, Hollander SA, Vaikunth S, Haeffele C, ... Bernstein D, Chen S
J Heart Lung Transplant: 30 Mar 2021; 40:298-306 | PMID: 33485775
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Less invasive surgical implant strategy and right heart failure after LVAD implantation.

Saeed D, Muslem R, Rasheed M, Caliskan K, ... Houston BA, Tedford RJ
Background
Conventional median sternotomy (CMS) is still the standard technique utilized to implant left ventricular assist devices (LVADs). Recent studies suggest that less invasive surgery (LIS) may be beneficial; however, robust data on differences in right heart failure (RHF) are lacking. This study aimed to determine the impact of LIS compared with that of CMS on RHF outcomes after LVAD implantation.
Methods
An international multicenter retrospective cohort study was conducted across 5 centers. Patients were grouped according to their implantation technique (LIS vs CMS). Only centrifugal devices were included. RHF was defined as severe or severe acute RHF according to the 2013 Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) definition. Logistic multivariate regression and propensity score‒matched analyses were performed to account for confounding.
Results
Overall, 427 implantations occurred during the study period, with 305 patients implanted using CMS and 122 using LIS. Pre-operative extracorporeal membrane oxygenation (ECMO) and intra-aortic balloon pump (IABP) use was more common in the CMS group; off-pump implantation was more common in the LIS group. Other pre-implant variables, including age, creatinine, hemodynamics, and tricuspid regurgitation, did not differ between the 2 groups. Post-operative RHF was less common in the patients who underwent LIS than in those who underwent CMS as was post-operative right ventricular assist device (RVAD) use. LIS remained associated with less RHF in the multivariate analysis. After propensity score matching conditional for age, sex, INTERMACS profile, ECMO, and IABP use in a ratio of 2:1 (CMS to LIS), RHF (29.9% vs 18.6%, p = 0.001) and the need for post-operative RVAD (18.6% vs 8.2%; p = 0.009) remained more common in the CMS group than in the LIS group. There were no significant differences in survival up to 1 year between the groups.
Conclusions
LIS may be associated with less RHF after LVAD implantation compared with CMS. Despite the possible reduction in RHF, there was no difference in 1-year survival. LIS is an alternative to traditional CMS.

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

J Heart Lung Transplant: 30 Mar 2021; 40:289-297
Saeed D, Muslem R, Rasheed M, Caliskan K, ... Houston BA, Tedford RJ
J Heart Lung Transplant: 30 Mar 2021; 40:289-297 | PMID: 33509653
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Clinical features and prognosis of surgically proven constrictive pericarditis after orthotopic heart transplantation.

Lloyd JW, Oh JK, Daly RC, Frantz RR, ... Allen LS, Miranda WR
Constrictive pericarditis (CP) results in pericardial non-compliance and diastolic dysfunction. Definitive treatment is pericardiectomy, but data on CP after orthotopic heart transplantation (OHT) are limited. Accordingly, a retrospective review of 8 cases of surgically proven CP after OHT undergoing pericardiectomy was conducted. In this series, all patients were male. The median time to symptomatic CP after OHT was 1.7 years (range: 0.8-18.1 years). The echocardiographic assessment was diagnostic for CP in 3 cases (38%). Cross-sectional imaging was performed in 6 cases, revealing ≥ mild pericardial thickening in all. A total of 6 patients (75%) underwent cardiac catheterization, which revealed CP in 5 (83%). Post-pericardiectomy 30-day mortality was 13% (1 patient). The median survival after pericardiectomy was 2.3 years (range: 18 days-14.6 years) and 5-year survival was 29%. Overall, CP after OHT represents a subset of patients with CP with high morbidity and mortality, and multimodality assessment is essential for its diagnosis. Despite a relatively low surgical mortality, long-term survival is poor.

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

J Heart Lung Transplant: 30 Mar 2021; 40:241-246
Lloyd JW, Oh JK, Daly RC, Frantz RR, ... Allen LS, Miranda WR
J Heart Lung Transplant: 30 Mar 2021; 40:241-246 | PMID: 33546972
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Hyperbaric oxygen therapy to prevent central airway stenosis after lung transplantation.

Kraft BD, Mahmood K, Harlan NP, Hartwig MG, ... Suliman HB, Shofer SL
Background
Central airway stenosis (CAS) is a severe airway complication after lung transplantation associated with bronchial ischemia and necrosis. We sought to determine whether hyperbaric oxygen therapy (HBOT), an established treatment for tissue ischemia, attenuates post-transplant bronchial injury.
Methods
We performed a randomized, controlled trial comparing usual care with HBOT (2 atm absolute for 2 hours × 20 sessions) in subjects with extensive airway necrosis 4 weeks after transplantation. Endobronchial biopsies were collected at 4, 7, and 10 weeks after transplantation for a quantitative polymerase chain reaction. Coprimary outcomes were incidence of airway stenting and acute cellular rejection (ACR) at 1 year.
Results
The trial was stopped after enrolling 20 subjects (n = 10 per group) after a pre-planned interim analysis showed no difference between usual care and HBOT groups in stenting (both 40%), ACR (70% and 40%, respectively), or CAS (40% and 60%, respectively). Time to first stent placement (median [interquartile range]) was significantly shorter in the HBOT group (150 [73-150] vs 186 [167-206] days, p < 0.05). HIF gene expression was significantly increased in donor tissues at 4, 7, and 10 weeks after transplantation but was not altered by HBOT. Subjects who developed CAS or required stenting had significantly higher HMOX1 and VEGFA expression at 4 weeks (both p < 0.05). Subjects who developed ACR had significant FLT1, TIE2, and KDR expression at 4 weeks (all p < 0.05).
Conclusions
Incidence of CAS is high after severe, established airway necrosis after transplantation. HBOT does not reduce CAS severity or stenting. Elevated HMOX1 and VEGFA expressions appear to associate with airway complications.

Published by Elsevier Inc.

J Heart Lung Transplant: 30 Mar 2021; 40:269-278
Kraft BD, Mahmood K, Harlan NP, Hartwig MG, ... Suliman HB, Shofer SL
J Heart Lung Transplant: 30 Mar 2021; 40:269-278 | PMID: 33518452
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Patient and disease characteristics of the first 500 patients with pulmonary arterial hypertension treated with selexipag in real-world settings from SPHERE.

Kim NH, Hemnes AR, Chakinala MM, Highland KB, ... Narayan V, Farber HW
Background
Selexipag is a selective oral prostacyclin receptor agonist indicated for pulmonary arterial hypertension (PAH) treatment. SelexiPag: tHe usErs dRug rEgistry (SPHERE) (NCT03278002) is collecting data from selexipag-treated patients in real-world clinical practice to elucidate and describe the clinical characteristics, outcomes, and dosing/titration regimens of patients treated with selexipag in routine clinical practice.
Methods
SPHERE is a United States (US)-based, ongoing, multicenter, prospective observational study (target N = 800). This study enrolls patients who are either newly initiated on selexipag (≤60 days before enrollment) or were previously receiving selexipag with documentation of dose titration at study enrollment. Data collection for the study occurs at routine clinic visits. In this paper, we report on the first 500 patients enrolled.
Results
Median follow-up was 17.8 months; 77.6% of patients completed the planned 18 months follow-up, and 22.4% discontinued early from the study. At diagnosis, 94.8% of patients had PAH (World Health Organization [WHO] Group 1), most commonly idiopathic (49.2%) and connective tissue disease associated (26.4%). Most patients (72.4%) initiated selexipag more than 60 days before enrollment. At initiation, 31.0% of patients had WHO functional class (FC) II disease, and 49.6% had WHO FC II or III disease. In addition, 55.0% of patients were receiving double therapy (most commonly an endothelin receptor antagonist plus phosphodiesterase type 5 inhibitor [42.3%]), whereas 30.6% were receiving monotherapy. Despite most patients already receiving PAH-specific therapy, at selexipag initiation, 67.2% (336 of 500) were at intermediate risk, and 9.6% (48 of 500) were at high risk of 1-year mortality. Risk scores remained stable in ∼55% of patients and improved in ∼20% at the end of the study. In total, 72.2% of patients had at least 1 adverse event (AE), and 37.6% reported a serious AE. The median selexipag maintenance dose was 1,200 µg twice daily (interquartile range: 800-1,600 µg twice daily).
Conclusions
Real-world, US-based patients with PAH initiating selexipag typically have WHO FC II/III disease and are at intermediate risk, despite receiving PAH-specific treatment. Selexipag was prescribed as part of a combination regimen in most patients. The study identified no unexpected adverse effects.

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

J Heart Lung Transplant: 30 Mar 2021; 40:279-288
Kim NH, Hemnes AR, Chakinala MM, Highland KB, ... Narayan V, Farber HW
J Heart Lung Transplant: 30 Mar 2021; 40:279-288 | PMID: 33526303
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Mortality in patients with cardiogenic shock supported with VA ECMO: A systematic review and meta-analysis evaluating the impact of etiology on 29,289 patients.

Alba AC, Foroutan F, Buchan TA, Alvarez J, ... Rao V, Billia F
Background
Venoarterial extracorporeal membrane oxygenation (VA ECMO) is associated with variable outcomes. In this meta-analysis, we evaluated the mortality after VA ECMO across multiple etiologies of cardiogenic shock (CS).
Methods
In June 2019, we performed a systematic search selecting observational studies with ≥10 adult patients reporting on short-term mortality (30-day or mortality at discharge) after initiation of VA ECMO by CS etiology published after 2009. We performed meta-analyses using random effect models and used metaregression to evaluate mortality across CS etiology.
Results
We included 306 studies (29,289 patients): 25 studies on after heart transplantation (HTx) (771 patients), 13 on myocarditis (906 patients), 33 on decompensated heart failure (HF) (3,567 patients), 64 on after cardiotomy shock (8,231 patients), 10 on pulmonary embolism (PE) (221 patients), 80 on acute myocardial infarction (AMI) (7,774 patients), and 113 on after cardiac arrest [CA] (7,814 patients). With moderate certainty on effect estimates, we observed significantly different mortality estimates for various etiologies (p < 0.001), which is not explained by differences in age and sex across studies: 35% (95% CI: 29-42) for after HTx, 40% (95% CI: 33-46) for myocarditis, 53% (95% CI: 46-59) for HF, 52% (95% CI: 38-66) for PE, 59% (95% CI: 56-63) for cardiotomy, 60% (95% CI: 57-64) for AMI, 64% (95% CI: 59-69) for post‒in-hospital CA, and 76% (95% CI: 69-82) for post-out‒of-hospital CA. Univariable metaregression showed that variation in mortality estimates within etiology group was partially explained by population age, proportion of females, left ventricle venting, and CA.
Conclusions
Using an overall estimate of mortality for patients with CS requiring VA ECMO is inadequate given the differential outcomes by etiology. To further refine patient selection and management to improve outcomes, additional studies evaluating patient characteristics impacting outcomes by specific CS etiology are needed.

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

J Heart Lung Transplant: 30 Mar 2021; 40:260-268
Alba AC, Foroutan F, Buchan TA, Alvarez J, ... Rao V, Billia F
J Heart Lung Transplant: 30 Mar 2021; 40:260-268 | PMID: 33551227
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Safety of reduced anti-thrombotic strategy in patients with HeartMate 3 left ventricular assist device.

Marshall D, Sanchez J, Yuzefpolskaya M, Sayer GT, ... Uriel N, Topkara VK
There are limited safety data on reduced anti-thrombotic therapy (RT) in patients with HeartMate 3 (HM3) left ventricular assist device (LVAD). We conducted a single-center, retrospective study of patients with HM3 managed with RT from November 2014 through January 2020. We analyzed baseline characteristics, RT indications, and bleeding and thrombotic complications. We found that 50 of 161 patients with HM3 (31.1%) received RT starting at a median time of 90.5 days after LVAD implantation. Patients on RT were older and more likely to have ischemic heart failure than patients on standard anti-thrombotic therapy (ST). The most common indication for RT was gastrointestinal bleeding (29 patients [58.0%]). At 1-year follow-up, 5.0% of patients on RT developed a thrombotic event. Switching patients from ST to RT reduced the occurrence of major bleeding from 1.252 to 0.324 events per patient-year (p = 0.006). In our population of patients with HM3 LVAD, RT reduces bleeding without increasing the incidence of thrombosis. Our retrospective study suggests that an upfront RT strategy in patients with HM3 may be beneficial and should be prospectively studied.

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

J Heart Lung Transplant: 30 Mar 2021; 40:237-240
Marshall D, Sanchez J, Yuzefpolskaya M, Sayer GT, ... Uriel N, Topkara VK
J Heart Lung Transplant: 30 Mar 2021; 40:237-240 | PMID: 33551226
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Berlin Heart EXCOR and ACTION post-approval surveillance study report.

Zafar F, Conway J, Bleiweis MS, Al-Aklabi M, ... Villa C, ACTION Learning Network Investigators
Background
The Berlin Heart EXCOR Pediatric (EXCOR) ventricular assist device (VAD) was introduced in North America nearly 2 decades ago. The EXCOR was approved under Humanitarian Device Exemption status in 2011 and received post-market approval (PMA) in 2017 from Food and Drug Administration. Since the initial approval, the field of pediatric mechanical circulatory support has changed, specifically with regard to available devices, anticoagulation strategies, and the types of patients supported. This report summarizes the outcomes of patients supported with EXCOR from the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) registry. These data were part of the PMA surveillance study (PSS) required by the Food and Drug Administration.
Methods
ACTION is a learning collaborative of over 40 pediatric heart failure programs worldwide, which collects data for all VAD implantations as one of its initiatives. All patients in North America with EXCOR implants reported to ACTION from 2018 to 2020 (n = 72) who had met an outcome were included in the EXCOR PSS group. This was compared with a historical, previously reported Berlin Heart EXCOR study group (Berlin Heart study [BHS] group, n = 320, 2007‒2014).
Results
Patients in the PSS group were younger, were smaller in weight/body surface area, were more likely to have congenital heart disease, and were less likely to receive a bi-VAD than those in the BHS group. Patients in the PSS group were less likely to be in Interagency Registry for Mechanically Assisted Circulatory Support Profile 1 and were supported for a longer duration. The primary anticoagulation therapy for 92% of patients in the PSS group was bivalirudin. Success, defined as being transplanted, being weaned for recovery, or being alive on a device at 180 days after implantation, was 86% in the PSS group compared with 76% in the BHS group. Incidence of stroke was reduced by 44% and the frequency of pump exchange by 40% in the PSS group compared with those in the BHS group. Similarly, all other adverse events, including major bleeding, were reduced in the PSS group.
Conclusions
The PSS data, collected through ACTION, highlight the improvement in outcomes for patients supported with EXCOR compared with the outcomes in a historical cohort. These findings may be the result of changes in patient care practices over time and collaborative learning.

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

J Heart Lung Transplant: 30 Mar 2021; 40:251-259
Zafar F, Conway J, Bleiweis MS, Al-Aklabi M, ... Villa C, ACTION Learning Network Investigators
J Heart Lung Transplant: 30 Mar 2021; 40:251-259 | PMID: 33579597
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Retraction notice to ICAM-1 PROMOTES THE ABNORMAL ENDOTHELIAL CELL PHENOTYPE IN CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION.

Arthur Ataam J, Mercier O, Lamrani L, Amsallem M, ... Fadel E, Eddahibi S
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Authors. This request follows an examination by The Editors of the uncut gels provided by the authors, which led the Editors to conclude that data were compromised in the following western blot images: Figure 3C, Figure 5B and Figure 6B. Duplicated data for the beta actin images were found in Figures 5 and 6. Examination of the raw data used for the western blot quantification also revealed frequent duplicated data. The microscopy data in Figure 5A also has features compatible with compromised data although the raw data were not available to the Editors due to the regrettable death of Dr. Saadia Eddahibi. All of the remaining authors agree with the retraction and apologize to the Editors and the readers of The Journal for difficulties this issue has caused.

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

J Heart Lung Transplant: 30 Mar 2021; 40:318
Arthur Ataam J, Mercier O, Lamrani L, Amsallem M, ... Fadel E, Eddahibi S
J Heart Lung Transplant: 30 Mar 2021; 40:318 | PMID: 33810826
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Rotational thromboelastometry reduces blood loss and blood product usage after lung transplantation.

Durila M, Vajter J, Garaj M, Pollert L, ... Vymazal T, Lischke R
Background
The shortage of blood products has become a worldwide problem, especially during the COVID-19 Pandemic. Here, we investigated whether a point of care (POC) approach to perioperative bleeding and coagulopathy based on rotational thromboelastometry (ROTEM) results could decrease perioperative blood loss and the perioperative consumption of blood products during lung transplantation.
Methods
Patients undergoing bilateral lung transplantation were randomized into two groups: In the first group, designated the \"non POC\" group, the management of perioperative bleeding and coagulopathy was based on the clinical experience of the anesthesiologist; in the second group, designated the \"POC\" group, the management of perioperative bleeding, and coagulopathy was based on the ROTEM results.
Results
After performing an interim statistical analysis, the project was prematurely terminated as the results were significantly in favor of the POC approach. Data were analyzed for the period January 2018 until June 2020 when 67 patients were recruited into the study. There was significantly decreased perioperative blood loss in the POC group (n = 31 patients) with p = 0.013, decreased perioperative consumption of RBC with p = 0.009, and decreased perioperative consumption of fresh frozen plasma with p < 0.0001 (practically no fresh frozen plasma was used in the POC group) without deteriorating clot formation in secondary and primary hemostasis as compared to the non POC group (n = 36).
Conclusion
POC management of perioperative bleeding and coagulopathy based on ROTEM results is a promising strategy to decrease perioperative blood loss and the consumption of blood products in lung transplantation.

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

J Heart Lung Transplant: 28 Mar 2021; epub ahead of print
Durila M, Vajter J, Garaj M, Pollert L, ... Vymazal T, Lischke R
J Heart Lung Transplant: 28 Mar 2021; epub ahead of print | PMID: 33934981
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Lung and heart-lung transplantation for children with PAH: Dramatic benefits from the implementation of a high-priority allocation program in France.

Jérôme LP, Séverine F, Olaf M, Pauline P, ... Marc H, Elie F
Purpose
Pulmonary arterial hypertension (PAH) is rare but remains fatal in infants and children despite the advance of targeted therapies. Lung transplantation (LTx), first performed in pediatric patients in the 1980s, is, with the Potts shunt, the only potentially life-extending option in patients with end-stage PAH but is possible only in tightly selected patients. Size-matching challenges severely restrict the donor organ pool, resulting-together with peculiarities of PAH in infants-in high waitlist mortality. We aimed to investigate survival when using a high-priority allocation program (HPAP) in children with PAH listed for double-LTx or heart-LTx.
Methods
We conducted a single-center, retrospective, before-after study of consecutive children with severe Group 1 PAH listed for double-LTx or heart-LTx between 1988 and 2019. The HPAP was implemented in France in 2006 and 2007 for heart-LTx and double-LTx, respectively.
Results
Fifty-five children with PAH were listed for transplantation. Mean age at transplantation was 15.8±2.8 years and 72% had heart-lung transplantation. PAH was usually idiopathic (65%) or due to congenital heart disease (25%). HPAP implementation resulted in the following significant benefits: Decreased cumulative incidence of waitlist death within 1 and 2 years (p < 0.0001); increased cumulative incidence of transplantation within 6 months, from 44% to 67% (p < 0.01); and improved survival after listing (at 1, 3, and 5 years: 61%, 50%, and 44% vs. 92%, 84%, and 72% before and after HPAP implementation, respectively; p = 0.02).
Conclusion
HPAP implementation was associated with significant improvements in access to transplantation and in survival after listing in children with end-stage PAH.

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

J Heart Lung Transplant: 25 Mar 2021; epub ahead of print
Jérôme LP, Séverine F, Olaf M, Pauline P, ... Marc H, Elie F
J Heart Lung Transplant: 25 Mar 2021; epub ahead of print | PMID: 33849770
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Percutaneous RVAD with the Protek Duo for severe right ventricular primary graft dysfunction after heart transplant.

Carrozzini M, Merlanti B, Olivieri GM, Lanfranconi M, ... Mondino M, Russo CF
Right ventricular primary graft dysfunction after heart transplant is a serious life-threatening condition. The severe form, refractory to maximal medical therapy, has traditionally required temporary mechanical support through veno-arterial extracorporeal membrane oxygenation or central right ventricular support. The Protek Duo is a dual lumen cannula recently introduced in the market, which allows for the institution of a percutaneous right ventricular support. We present the first promising case series of the use of this novel support in patients with right ventricular primary graft dysfunction after heart transplant.

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

J Heart Lung Transplant: 24 Mar 2021; epub ahead of print
Carrozzini M, Merlanti B, Olivieri GM, Lanfranconi M, ... Mondino M, Russo CF
J Heart Lung Transplant: 24 Mar 2021; epub ahead of print | PMID: 33879383
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Cell-free DNA beyond a biomarker for rejection: Biological trigger of tissue injury and potential therapeutics.

Tsuji N, Agbor-Enoh S
Cell-free DNA, measured as donor-derived cell-free DNA is developed as a non-specific biomarker for allograft injury and transplant rejection. However, cell-free DNA characteristics are more specific, its fragment length, nucleotide content, and composition, as well as the tissue source of origin, are intrinsically linked to the underlying disease pathogenesis, showing distinct features in acute cellular rejection and antibody-mediated rejection for example. Further, cell-free DNA and cell-free mitochondrial DNA can directly trigger tissue injury as damage-associated molecular patterns through three major intracellular receptors, toll-like receptor 9 , cyclic guanosine monophosphate-adenosine monophosphate synthase, and inflammasomes (i.e., absent in melanoma 2: AIM2). Therefore, in addition to its role as a non-specific marker for allograft injury, cell-free DNA analysis may be used to phenotype transplant rejection, and to non-invasively point the underlying molecular mechanisms with allograft injury. Novel treatment approaches targeting these cell-free DNA pathways may be useful to treat transplant rejection and prevent end-organ dysfunction. In this review, we discuss the link between cell-free DNA characteristics and disease, the role of cell-free DNA as a damage-associated molecular pattern, and novel therapeutics targeting these cell-free DNA molecular pathways and their potential utility to treat transplant rejection.

Published by Elsevier Inc.

J Heart Lung Transplant: 23 Mar 2021; epub ahead of print
Tsuji N, Agbor-Enoh S
J Heart Lung Transplant: 23 Mar 2021; epub ahead of print | PMID: 33926787
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Heart transplant in Jehovah\'s Witness patients: A case-control study.

Sander S, Singer-Englar T, Nishihara K, Esmailian F, ... Kobashigawa JA, Kittleson MM
Heart transplantation (HTx) improves quality of life and survival in patients with advanced heart failure. Jehovah\'s Witnesses (JW) patients decline blood transfusion (including red cells, plasma and platelets) and are prohibited from heart transplantation at many centers. We report our experience with 20 consecutive JW patients with advanced heart failure who declined blood products referred to our center for HTx consideration. Of these, 7 were declined for transplant due to prior sternotomy, need for multi-organ transplant, or being too well. Of 13 JW patients accepted for heart transplant listing, 8 underwent HTx at our center. Compared to non-JW controls without prior cardiac surgery matched for age and listing status, JW HTx recipients had comparable incidence of primary graft dysfunction, rejection, allograft vasculopathy, and survival and hemoglobin up to 1 year. With appropriate selection, patients who are JW and decline blood products may successfully undergo heart transplantation.

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

J Heart Lung Transplant: 20 Mar 2021; epub ahead of print
Sander S, Singer-Englar T, Nishihara K, Esmailian F, ... Kobashigawa JA, Kittleson MM
J Heart Lung Transplant: 20 Mar 2021; epub ahead of print | PMID: 33839007
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Incidence and impact of primary graft dysfunction in adult heart transplant recipients: A systematic review and meta-analysis.

Buchan TA, Moayedi Y, Truby LK, Guyatt G, ... Alba AC, Foroutan F
Purpose
Primary graft dysfunction (PGD) is a leading cause of early mortality after heart transplant (HTx). To identify PGD incidence and impact on mortality, and to elucidate risk factors for PGD, we systematically reviewed studies using the ISHLT 2014 Consensus Report definition and reporting the incidence of PGD in adult HTx recipients.
Methods
We conducted a systematic search in January 2020 including studies reporting the incidence of PGD in adult HTx recipients. We used a random effects model to pool the incidence of PGD among HTx recipients and, for each PGD severity, the mortality rate among those who developed PGD. For prognostic factors evaluated in ≥2 studies, we used random effects meta-analyses to pool the adjusted odds ratios for development of PGD. The GRADE framework informed our certainty in the evidence.
Results
Of 148 publications identified, 36 observational studies proved eligible. With moderate certainty, we observed pooled incidences of 3.5%, 6.6%, 7.7%, and 1.6% and 1-year mortality rates of 15%, 21%, 41%, and 35% for mild, moderate, severe and isolated right ventricular-PGD, respectively. Donor factors (female sex, and undersized), recipient factors (creatinine, and pre-HTx use of amiodarone, and temporary or durable mechanical support), and prolonged ischemic time proved associated with PGD post-HTx.
Conclusion
Our review suggests that the incidence of PGD may be low but its risk of mortality high, increasing with PGD severity. Prognostic factors, including undersized donor, recipient use of amiodarone pre-HTx and recipient creatinine may guide future studies in exploring donor and/or recipient selection and risk mitigation strategies.

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

J Heart Lung Transplant: 19 Mar 2021; epub ahead of print
Buchan TA, Moayedi Y, Truby LK, Guyatt G, ... Alba AC, Foroutan F
J Heart Lung Transplant: 19 Mar 2021; epub ahead of print | PMID: 33947602
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Bone marrow-derived AXL tyrosine kinase promotes mitogenic crosstalk and cardiac allograft vasculopathy.

Glinton K, DeBerge M, Fisher E, Schroth S, ... Luo X, Thorp EB
Cardiac Allograft Vasculopathy (CAV) is a leading contributor to late transplant rejection. Although implicated, the mechanisms by which bone marrow-derived cells promote CAV remain unclear. Emerging evidence implicates the cell surface receptor tyrosine kinase AXL to be elevated in rejecting human allografts. AXL protein is found on multiple cell types, including bone marrow-derived myeloid cells. The causal role of AXL from this compartment and during transplant is largely unknown. This is important because AXL is a key regulator of myeloid inflammation. Utilizing experimental chimeras deficient in the bone marrow-derived Axl gene, we report that Axl antagonizes cardiac allograft survival and promotes CAV. Flow cytometric and histologic analyses of Axl-deficient transplant recipients revealed reductions in both allograft immune cell accumulation and vascular intimal thickness. Co-culture experiments designed to identify cell-intrinsic functions of Axl uncovered complementary cell-proliferative pathways by which Axl promotes CAV-associated inflammation. Specifically, Axl-deficient myeloid cells were less efficient at increasing the replication of both antigen-specific T cells and vascular smooth muscle cells (VSMCs), the latter a key hallmark of CAV. For the latter, we discovered that Axl-was required to amass the VSMC mitogen Platelet-Derived Growth Factor. Taken together, our studies reveal a new role for myeloid Axl in the progression of CAV and mitogenic crosstalk. Inhibition of AXL-protein, in combination with current standards of care, is a candidate strategy to prolong cardiac allograft survival.

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

J Heart Lung Transplant: 12 Mar 2021; epub ahead of print
Glinton K, DeBerge M, Fisher E, Schroth S, ... Luo X, Thorp EB
J Heart Lung Transplant: 12 Mar 2021; epub ahead of print | PMID: 33846079
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Stroke in pediatric ventricular assist device patients-a pedimacs registry analysis.

Niebler RA, Amdani S, Blume B, Cantor RS, ... Rosenthal DN, Ghanayem NS
Background
Cerebralvascular accidents (CVA) are common complications of pediatric ventricular assist devices (VADs). We employed the Pediatric Interagency Registry for Mechanical Circulatory Support (Pedimacs) to investigate rates, risk factors, and outcomes of CVA in pediatric patients supported on VAD.
Methods
Analysis of Pedimacs (September 2012-June 2019) data to determine rates of all neurologic events and specifically CVA. Risk factors were determined by a multiphase parametric hazard model. Outcomes of patients with CVA were compared with patients without CVA.
Results
We included 662 patients in our analysis. In total, 87 CVA events occurred in 71 patients (10.7%). The proportion of patients with CVA was highest in the paracorporeal pulsatile group (16.9%) followed by the paracorporeal continuous group (10.4%). However, the rate of CVA was lower in the paracorporeal pulsatile group compared to the paracorporeal continuous group (6.4 vs 11.1 events/100 patient months), which reflects differences in support duration. Ascites, higher patient profile groups, and implants within small volume centers were associated with the occurrence of CVA. Our analysis found that the recent era (i.e., June 2017), and intracorporeal continuous implants were protective. Mortality was higher in patients following a CVA diagnosis compared to those without a CVA diagnosis.
Conclusions
CVA continues to be a problem in pediatric VAD support, though the overall percent is now <11%. Data from the most recent era are encouraging, but CVA is still significantly associated with mortality. Future efforts should focus on pre-implant and early support periods.

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

J Heart Lung Transplant: 11 Mar 2021; epub ahead of print
Niebler RA, Amdani S, Blume B, Cantor RS, ... Rosenthal DN, Ghanayem NS
J Heart Lung Transplant: 11 Mar 2021; epub ahead of print | PMID: 33824064
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Prediction of donor related lung injury in clinical lung transplantation using a validated ex vivo lung perfusion inflammation score.

Sage AT, Richard-Greenblatt M, Zhong K, Bai XH, ... Kain KC, Keshavjee S
Background
Ex vivo lung perfusion (EVLP) is an isolated organ assessment technique that has revolutionized the field of lung transplantation and enabled a safe increase in the number of organs transplanted. The objective of this study was to develop a protein-based assay that would provide a precision medicine approach to lung injury assessment during EVLP.
Methods
Perfusate samples collected from clinical EVLP cases performed from 2009 to 2019 were separated into development (n = 281) and validation (n = 57) sets to derive and validate an inflammation score based on IL-6 and IL-8 protein levels in perfusate. The ability of an inflammation score to predict lungs suitable for transplantation and likely to produce excellent recipient outcomes (time on ventilator ≤ 3 days) was assessed. Inflammation scores were compared to conventional clinical EVLP assessment parameters and associated with outcomes, including primary graft dysfunction and patient care in the ICU.
Results
An inflammation score accurately predicted the decision to transplant (AUROC 68% [95% CI 62-74]) at the end of EVLP and those transplants associated with short ventilator times (AUROC 73% [95% CI 66-80]). The score identified lungs more likely to develop primary graft dysfunction at 72-hours post-transplant (OR 4.0, p = 0.03). A model comprised of the inflammation score and ∆PO2 was able to determine EVLP transplants that were likely to have excellent recipient outcomes, with an accuracy of 87% [95% CI 83-92].
Conclusions
The adoption of an inflammation score will improve accuracy of EVLP decision-making and increase confidence of surgical teams to determine lungs that are suitable for transplantation, thereby improving organ utilization rates and patient outcomes.

Copyright © 2021. Published by Elsevier Inc.

J Heart Lung Transplant: 04 Mar 2021; epub ahead of print
Sage AT, Richard-Greenblatt M, Zhong K, Bai XH, ... Kain KC, Keshavjee S
J Heart Lung Transplant: 04 Mar 2021; epub ahead of print | PMID: 33781664
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Impact of carfilzomib-based desensitization on heart transplantation of sensitized candidates.

Sriwattanakomen R, Xu Q, Demehin M, Shullo MA, ... Keebler ME, Zeevi A
Background
Allosensitization in heart transplant candidates is associated with longer transplant wait times and post-transplant complications. We summarize our experience with desensitization using carfilzomib, an irreversible proteasome inhibitor that causes plasma cell apoptosis.
Methods
One cycle of desensitization consisted of plasmapheresis and carfilzomib 20 mg/m2 on days 1, 2, 8, 9, 15, and 16 with intravenous immune globulin 2 g/kg after carfilzomib on day 16. Patients underwent repeat cycles as indicated. We compare calculated panel-reactive antibody (cPRA) for neat combined Class I and II IgG and C1q pre- and post-treatment using a cutoff for cPRA entry of ≥ 4000 and 500 MFI, respectively.
Results
From June 2013 to October 2019, 9 patients underwent 20 cycles of carfilzomib-based desensitization. Each cycle resulted in an average cPRA decrease of 24% (95% CI: 6-42) for IgG and 36% (95% CI: 17-55) for C1q. From treatment start to finish, mean cPRA fell from 76% to 40% (p = 0.01) for IgG and 56% to 4% (p = 0.017) for C1q. Six of 9 patients have been transplanted with 5 of the transplanted hearts crossing preoperative donor-specific antibodies. During a median follow-up of 35.1 months, all transplanted patients have survived with only 1 occurrence of treated rejection. Side effects of desensitization included acute kidney injury (67%) and thrombocytopenia (33%) with all episodes self-resolving.
Conclusions
A carfilzomib-based desensitization strategy among heart transplant candidates reduces the level of HLA antibodies and complement binding, facilitates successful transplantation, and is associated with excellent outcomes at 3 years.

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

J Heart Lung Transplant: 04 Mar 2021; epub ahead of print
Sriwattanakomen R, Xu Q, Demehin M, Shullo MA, ... Keebler ME, Zeevi A
J Heart Lung Transplant: 04 Mar 2021; epub ahead of print | PMID: 33785250
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

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

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

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

J Heart Lung Transplant: 04 Mar 2021; epub ahead of print
Girgis RE, Hoeper MM
J Heart Lung Transplant: 04 Mar 2021; epub ahead of print | PMID: 33832831
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Factors contributing to exercise capacity in chronic thromboembolic pulmonary hypertension with near-normal hemodynamics.

Tobita K, Goda A, Nishida Y, Takeuchi K, ... Soejima K, Satoh T
Background
Despite improved survival for patients with chronic thromboembolic pulmonary hypertension (CTEPH) due to progressive medical and interventional treatment, impaired exercise capacity remains common due to poorly understood mechanisms. We aimed to clarify the exercise capacity of CTEPH patients with near-normal pulmonary hemodynamics and evaluate its determinants among the hemodynamic, peripheral (e.g., oxygen use by the peripheral tissues), and muscular (e.g., skeletal muscle strength) factors.
Methods
Three hundred and twenty-nine patients with CTEPH (mean age, 63 ± 12 years; men/women, 73/256) with a near-normal mean pulmonary artery pressure (≤30 mm Hg) at rest were enrolled. We assessed exercise capacity by peak oxygen consumption (peak VO2) using cardiopulmonary exercise testing with a right heart catheter. We also measured the 6-minute walk distance (6MWD) and quadriceps muscle strength.
Results
The mean pulmonary artery pressure was 19 ± 4 mmHg and mean cardiac output was 4.8 ± 1.5 L/min at rest. The mean 6MWD was 444 ± 101 m, while the mean peak VO2 was 14.4 ± 3.9 mL/min/kg. A multivariate model that predicted 6MWD included quadriceps strength (β = 0.45, p < 0.001) and peak arterial venous oxygen difference (β = 0.29, p < 0.001). In contrast, the peak VO2 was best correlated with mPAP-CO slope (β = -0.30, p < 0.001), followed by quadriceps strength and peak arterial venous oxygen difference.
Conclusions
The 6MWD performance may be significantly influenced by peripheral oxygen use and muscular factors, while peak VO2 is influenced by hemodynamic and peripheral factors in CTEPH patients with near-normal hemodynamics.

Copyright © 2021. Published by Elsevier Inc.

J Heart Lung Transplant: 04 Mar 2021; epub ahead of print
Tobita K, Goda A, Nishida Y, Takeuchi K, ... Soejima K, Satoh T
J Heart Lung Transplant: 04 Mar 2021; epub ahead of print | PMID: 33879384
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Association between digoxin use and gastrointestinal bleeding in contemporary continuous flow left ventricular assist device support.

El Rafei A, Trachtenberg BH, Schultz J, John R, ... Goodwin K, Cogswell R
Background
Assess the association between digoxin use and gastrointestinal bleeding (GIB) in a multicenter continuous flow left ventricular assist device (LVAD) cohort.
Methods
Patients implanted with continuous flow LVADs with data on GIB and digoxin use from two centers were included in the analysis (n = 649). GIB events were captured up to 2 years of follow-up. Digoxin use was defined as digoxin prescribed at discharge or within the first 3 months after LVAD implantation. A negative binomial regression model was performed to determine the association between digoxin use and number of GIB events over the follow-up period.
Results
Mean age of the cohort was 57 years (±14) and 45% (293/649) were bridge to transplant (BTT). Digoxin was prescribed in 33% of patients. Digoxin use was associated with an unadjusted 32% reduction in the incidence of rate of all cause GIB (IRR 0.68, 95% CI 0.46-0.99, p = 0.049). After adjusting for age, sex, Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile, renal function, and implanting center there was still a 34% reduction in the incidence rate (IRR 0.67, 95% CI 0.45-0.99, p = 0.048). When limiting the analysis to those with likely arteriovenous malformation associated GIB, the association strengthened (unadjusted: IRR 0.48, 95 % CI 0.26-0.89, p = 0.02, adjusted: IRR 0.47, 95 % CI 0.25-0.9, p = 0.022).
Conclusions
In this multicenter study, inclusive of contemporary devices, digoxin use was associated with reduced GIB events. Prospective data will be required to confirm this association.

Copyright © 2021. Published by Elsevier Inc.

J Heart Lung Transplant: 03 Mar 2021; epub ahead of print
El Rafei A, Trachtenberg BH, Schultz J, John R, ... Goodwin K, Cogswell R
J Heart Lung Transplant: 03 Mar 2021; epub ahead of print | PMID: 33875331
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

N-myc-interactor mediates microbiome induced epithelial to mesenchymal transition and is associated with chronic lung allograft dysfunction.

Banday MM, Kumar A, Vestal G, Sethi J, ... Seyfang A, Sharma NS
Background
Recent evidence suggests a role for lung microbiome in occurrence of chronic lung allograft dysfunction (CLAD). However, the mechanisms linking the microbiome to CLAD are poorly delineated. We investigated a possible mechanism involved in microbial modulation of mucosal response leading to CLAD with the hypothesis that a Proteobacteria dominant lung microbiome would inhibit N-myc-interactor (NMI) expression and induce epithelial to mesenchymal transition (EMT).
Methods
Explant CLAD, non-CLAD, and healthy nontransplant lung tissue were collected, as well as bronchoalveolar lavage from 14 CLAD and matched non-CLAD subjects, which were followed by 16S rRNA amplicon sequencing and quantitative polymerase chain reaction (PCR) analysis. Pseudomonas aeruginosa (PsA) or PsA-lipopolysaccharide was cocultured with primary human bronchial epithelial cells (PBEC). Western blot analysis and quantitative reverse transcription (qRT) PCR was performed to evaluate NMI expression and EMT in explants and in PsA-exposed PBECs. These experiments were repeated after siRNA silencing and upregulation (plasmid vector) of EMT regulator NMI.
Results
16S rRNA amplicon analyses revealed that CLAD patients have a higher abundance of phyla Proteobacteria and reduced abundance of the phyla Bacteroidetes. At the genera level, CLAD subjects had an increased abundance of genera Pseudomonas and reduced Prevotella. Human CLAD airway cells showed a downregulation of the N-myc-interactor gene and presence of EMT. Furthermore, exposure of human primary bronchial epithelial cells to PsA resulted in downregulation of NMI and induction of an EMT phenotype while NMI upregulation resulted in attenuation of this PsA-induced EMT response.
Conclusions
CLAD is associated with increased bacterial biomass and a Proteobacteria enriched airway microbiome and EMT. Proteobacteria such as PsA induces EMT in human bronchial epithelial cells via NMI, demonstrating a newly uncovered mechanism by which the microbiome induces cellular metaplasia.

Published by Elsevier Inc.

J Heart Lung Transplant: 01 Mar 2021; epub ahead of print
Banday MM, Kumar A, Vestal G, Sethi J, ... Seyfang A, Sharma NS
J Heart Lung Transplant: 01 Mar 2021; epub ahead of print | PMID: 33781665
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Methane supplementation improves graft function in experimental heart transplantation.

Benke K, Jász DK, Szilágyi ÁL, Baráth B, ... Hartmann P, Boros M
Background
Maintenance of cell viability during cold storage is a key issue in organ transplantation. Methane (CH4) bioactivity has recently been recognized in ischemia/reperfusion conditions; we therefore hypothesized that cold storage in CH4-enriched preservation solution can provide an increased defense against organ dysfunction during experimental heart transplantation (HTX).
Methods
The hearts of donor Lewis rats were stored for 60 minutes in cold histidine-tryptophan-ketoglutarate (Custodiol [CS]) or CH4-saturated CS solution (CS-CH4) (n = 12 each). Standard heterotopic HTX was performed, and 60 minutes later, the left ventricular (LV) pressure-volume relationships LV systolic pressure (LVSP), systolic pressure increment (dP/dtmax), diastolic pressure decrement, and coronary blood flow (CBF) were measured. Tissue samples were taken to detect proinflammatory parameters, structural damage (by light microscopy), endoplasmic reticulum (ER) stress, and apoptosis markers (CCAAT/enhancer binding protein [C/EBP] homologous protein, GRP78, glycogen synthase kinase-3β, very low-density lipoprotein receptor, caspase 3 and 9, B-cell lymphoma 2, and bcl-2-like protein 4), whereas mitochondrial functional changes were analyzed by high-resolution respirometry.
Results
LVSP and dP/dtmax increased significantly at the largest pre-load volumes in CS-CH4 grafts as compared with the CS group (114.5 ± 16.6 mm Hg vs 82.8 ± 4.6 mm Hg and 3,133 ± 430 mm Hg/s vs 1,739 ± 169 mm Hg/s, respectively); the diastolic function and CBF (2.4 ± 0.4 ml/min/g vs 1.3 ± 0.3 ml/min/g) also improved. Mitochondrial oxidative phosphorylation capacity was more preserved (58.5 ± 9.4 pmol/s/ml vs 27.7 ± 6.6 pmol/s/ml), and cytochrome c release was reduced in CS-CH4 storage. Signs of HTX-caused myocardial damage, level of ER stress, and the transcription of proapoptotic proteins were significantly lower in CS-CH4 grafts.
Conclusion
The addition of CH4 during 1 hour of cold storage improved early in vitro graft function and reduced mitochondrial dysfunction and activation of inflammation. Evidence shows that CH4 reduced ER stress-linked proapoptotic signaling.

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

J Heart Lung Transplant: 27 Feb 2021; 40:183-192
Benke K, Jász DK, Szilágyi ÁL, Baráth B, ... Hartmann P, Boros M
J Heart Lung Transplant: 27 Feb 2021; 40:183-192 | PMID: 33277170
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The impact of gastrointestinal dysmotility on the aerodigestive microbiome of pediatric lung transplant recipients.

Lötstedt B, Boyer D, Visner G, Freiberger D, ... Alm E, Rosen R
Background
Delayed gastric emptying has been associated with increased graft rejection, although the mechanism of this association is not known. This study aims to investigate the interrelationship between delays in gastrointestinal motility and the diversity and composition of gastric, oropharyngeal, and lung microbiomes in pediatric lung transplant recipients.
Methods
We prospectively recruited 23 pediatric lung transplant recipients and 98 pediatric patients with respiratory symptoms undergoing combined endoscopy and bronchoscopy. Gastric, oropharyngeal, and bronchoalveolar lavage samples were collected for 16S sequencing. Gastric samples were also analyzed for bile composition using liquid chromatography.
Results
Patients who underwent lung transplantation had significantly reduced alpha diversity in gastric and oropharyngeal sites compared with patients with respiratory symptoms. This reduction in alpha diversity was especially evident in gastric samples in patients with delayed gastric emptying defined as abnormal gastric emptying on nuclear scintigraphy or as an elevation in gastric bile concentration (p ≤ 0.05). Whereas monocolonies were seen in the lungs of patients who underwent transplantation, these were not the same microbes seen in the stomach; the microbial overlap between lung and gastric samples within patients was low, and data indicated high individual variation between lung transplant recipients. Other contributors to reduced alpha diversity included antibiotics in combination with proton pump inhibitors, especially in gastric and oropharyngeal samples.
Conclusions
Lung transplant recipients have reduced microbial diversity in gastric fluid (GF) and oropharynx compared with patients who did not undergo lung transplantation. The decreased alpha diversity in GF may be associated with dysmotility.

Copyright © 2020. Published by Elsevier Inc.

J Heart Lung Transplant: 27 Feb 2021; 40:210-219
Lötstedt B, Boyer D, Visner G, Freiberger D, ... Alm E, Rosen R
J Heart Lung Transplant: 27 Feb 2021; 40:210-219 | PMID: 33349521
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Outcomes after heart transplantation and total artificial heart implantation: A multicenter study.

Carrier M, Moriguchi J, Shah KB, Anyanwu AC, ... Cossette M, Noly PE
Background
We sought to assess the outcomes after heart transplantation (HT) of patients supported with a temporary total artificial heart (t-TAH) as a bridge to transplantation in high-volume centers.
Methods
A retrospective analysis of 217 consecutive patients who underwent t-TAH (SynCardia Systems, Tucson, Arizona) implantation between January 2014 and May 2019 in 6 high-volume North American centers was performed. End points included survival and adverse events after t-TAH and HT.
Results
The mean age of patients was 49 ± 12 years, and heart failure etiologies were non-ischemic dilated cardiomyopathy (36%), ischemic (25%), restrictive (12%), and cardiac graft failure (9%). A total of 101 (48%) patients had Interagency Registry for Mechanically Assisted Circulatory Support patient profile 1, and 65 (31%) had Interagency Registry for Mechanically Assisted Circulatory Support patient profile 2. At the end of the study period, 138 of 217 (63.5%) patients had undergone HT, and 75 (34.5%) patients died before HT. The mean time between t-TAH implantation and HT averaged 181 ± 179 days (range: 0-849) and the mean follow-up after HT was 35 ± 25 months. The overall survival in the entire cohort was 75%, 64%, and 58% at 1, 2, and 5 years, respectively. Post-transplant survival was 88%, 84%, 79%, and 74% at 6 months, 1 year, 2 years, and 5 years, respectively. Among the 32 patients (23%) who died after HT, the main causes of death were chronic allograft vasculopathy (25%), multiorgan failure (21.8%), sepsis (15.6%), and stroke (9%).
Conclusion
In this multicenter study, almost two thirds of patients implanted with a t-TAH could be transplanted. The overall and post-transplantation survival after t-TAH was satisfactory in these critically ill patients.

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

J Heart Lung Transplant: 27 Feb 2021; 40:220-228
Carrier M, Moriguchi J, Shah KB, Anyanwu AC, ... Cossette M, Noly PE
J Heart Lung Transplant: 27 Feb 2021; 40:220-228 | PMID: 33341359
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Bridging the survival gap in cystic fibrosis: An investigation of lung transplant outcomes in Canada and the United States.

Stephenson AL, Ramos KJ, Sykes J, Ma X, ... Chaparro C, Goss CH
Background
Previous literature in cystic fibrosis (CF) has shown a 10-year survival gap between Canada and the United States (US). We hypothesized that differential access to and survival after lung transplantation may contribute to the observed gap. The objectives of this study were to compare CF transplant outcomes between Canada and the US and estimate the potential contribution of transplantation to the survival gap.
Methods
Data from the Canadian CF Registry and the US Cystic Fibrosis Foundation Patient Registry supplemented with data from United Network for Organ Sharing were used. The probability of surviving after transplantation between 2005 and 2016 was calculated using the Kaplan‒Meier method. Survival by insurance status at the time of transplantation and transplant center volume in the US were compared with those in Canada using Cox proportional hazard models. Simulations were used to estimate the contribution of transplantation to the survival gap.
Results
Between 2005 and 2016, there were 2,653 patients in the US and 470 in Canada who underwent lung transplantation for CF. The 1-, 3-, and 5-year survival rates were 88.3%, 71.8%, and 60.3%, respectively, in the US compared with 90.5%, 79.9%, and 69.7%, respectively, in Canada. Patients in the US were also more likely to die on the waitlist (p < 0.01) than patients in Canada. If the proportion of who underwent transplantation and post-transplant survival in the US were to increase to those observed in Canada, we estimate that the survival gap would decrease from 10.8 years to 7.5 years.
Conclusions
Differences in waitlist mortality and post-transplant survival can explain up to a third of the survival gap observed between the US and Canada.

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

J Heart Lung Transplant: 27 Feb 2021; 40:201-209
Stephenson AL, Ramos KJ, Sykes J, Ma X, ... Chaparro C, Goss CH
J Heart Lung Transplant: 27 Feb 2021; 40:201-209 | PMID: 33386232
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

The results of a single-center experience with HeartMate 3 in a biventricular configuration.

McGiffin D, Kure C, McLean J, Marasco S, ... Taylor A, Kaye D
Background
Right ventricular (RV) failure after left ventricular assist device (VAD) implantation is a difficult problem. One solution is the implantation of continuous-flow VADs in a biventricular configuration. Disappointing survival and a concerning incidence of right-sided pump thrombosis have been previously reported.
Methods
From May 2017 to April 2020, a total of 12 patients underwent implantation of HeartMate 3 (HM3) biventricular VADs (BiVADs) as a bridge to cardiac transplantation. The right-sided pump was implanted in the right atrium in all cases. Adverse events and patient outcomes were determined.
Results
Patients were male, and the mean age was 44 years. The etiology was dilated cardiomyopathy (6 patients), sarcoid heart disease (2 patients), ischemic cardiomyopathy (1 patient), anthracycline cardiomyopathy (1 patient), non-compaction cardiomyopathy (1 patient), and arrhythmogenic RV cardiomyopathy with biventricular involvement (1 patient). There was 1 death from multisystem failure. There were 3 episodes of right VAD thrombus (thrombosis or clot ingestion); 1 managed medically, 1 recognized intraoperatively treated with clot retrieval, and 1 requiring pump exchange. There were 3 driveline infections. At 18 months after the procedure, 5 patients (41.7%) had undergone cardiac transplantation, 5 patients (41.7%) were alive and on biventricular support, 1 patient had died (8.3%), and 1 patient had VAD explantation for myocardial recovery (8.3%). Actuarial survival at 18 months was 91.7%.
Conclusions
In this small study, HM3 BiVAD in these critically ill patients was used with low mortality. This suggests that the timely deployment of biventricular support with HM3 can be associated with favorable outcomes.

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

J Heart Lung Transplant: 27 Feb 2021; 40:193-200
McGiffin D, Kure C, McLean J, Marasco S, ... Taylor A, Kaye D
J Heart Lung Transplant: 27 Feb 2021; 40:193-200 | PMID: 33423854
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Right ventricular adaptation to pressure-overload: Differences between chronic thromboembolic pulmonary hypertension and idiopathic pulmonary arterial hypertension.

Braams NJ, van Leeuwen JW, Vonk Noordegraaf A, Nossent EJ, ... Meijboom LJ, de Man FS
Background
Chronic thromboembolic pulmonary hypertension (CTEPH) and idiopathic pulmonary arterial hypertension (iPAH) are both associated with right ventricular (RV) failure and mortality. However, CTEPH patients are older, more often male and usually have more co-morbidities than iPAH patients, including a history of venous thromboembolism. Therefore, RV adaptation to pressure-overload in CTEPH may be different than in iPAH.
Methods
We included all treatment-naive CTEPH and iPAH patients diagnosed in the Amsterdam UMC between 2000 and 2019 if cardiac magnetic resonance imaging (CMR) and a right heart catheterization were performed at time of diagnosis. Load-dependent RV volumes and mass were assessed with CMR. Load-independent RV contractility, afterload and diastolic stiffness in relation to afterload were obtained using single beat pressure-volume loop analysis. Differences in RV characteristics between CTEPH and iPAH were analyzed using multiple linear regression with interaction testing after correcting for confounders.
Results
We included 235 patients in this study and performed pressure-volume loop analysis in 136 patients. In addition to being older and more often male, CTEPH patients had a lower pulmonary vascular resistance than iPAH patients at the time of diagnosis. After correcting for these confounders, CTEPH patients had a somewhat higher RV end-diastolic volume index (87 ± 27 ml vs 82 ± 25 ml; p < .01), and a lower RV relative wall thickness (0.6 ± 0,1 g/ml vs 0.7 ± 0,2 g/ml; p < .01). The correlation coefficient of RV diastolic stiffness to afterload was higher in CTEPH compared to iPAH (p < .05; independent of age and gender).
Conclusions
Despite differences in patient characteristics, disease etiology and physiology, RV functional parameters in CTEPH and iPAH are mostly similar. The right ventricle in CTEPH is marginally more dilated, stiffer and less hypertrophic than in iPAH.

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

J Heart Lung Transplant: 27 Feb 2021; epub ahead of print
Braams NJ, van Leeuwen JW, Vonk Noordegraaf A, Nossent EJ, ... Meijboom LJ, de Man FS
J Heart Lung Transplant: 27 Feb 2021; epub ahead of print | PMID: 33745783
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Once daily tacrolimus conversion in lung transplantation: A prospective study on safety and medication adherence.

Godinas L, Dobbels F, Hulst L, Verbeeck I, ... Verleden GM, Vos R
Background
Lung transplantation (LTx) requires a calcineurin inhibitor-based immunosuppressive regimen. A once daily (QD) tacrolimus regimen was developed to increase medication adherence. However, data concerning its safety and efficacy in LTx are lacking.
Methods
In this prospective study, stable LTx patients were consecutively converted from twice daily (BID) tacrolimus to QD tacrolimus on a 1 mg:1 mg basis. Trough level (Cmin), renal function, cholesterol, fasting glucose, potassium and lung function were monitored six months before and up to one year after conversion. Adherence and its barriers were assessed by self-reported questionnaires (Basel Assessment of Adherence to Immunosuppressive Medications Scale (BAASIS) and Identification of Medication Adherence Barriers questionnaire (IMAB)) and blood-based assays (mean Cmin and coefficient of variation (CV)).
Results
We included 372 patients, in whom we observed a decrease in tacrolimus Cmin of 18.5% (p < 0.0001) post-conversion, requiring subsequent daily dose adaptations in both cystic fibrosis (CF) (n = 72) and non-CF patients (n = 300). We observed a small decrease in eGFR one year post-conversion (p = 0.024). No significant changes in blood creatinine, potassium, fasting glucose, cholesterol or rate of lung function decline were observed. In a subgroup of 166 patients, significantly fewer patients missed doses (8.4% vs. 19.3%, p = 0.016) or had irregular intake post-conversion (19.3% vs. 32.5%, p = 0.019). Mean Cmin and CV, as well as the total number of barriers, also decreased significantly post-conversion.
Conclusions
In LTx, conversion from BID to QD tacrolimus (1 mg:1 mg) requires close monitoring of tacrolimus Cmin. QD tacrolimus after transplantation is safe with respect to renal function, metabolic parameters and allograft function and improves LTx recipient adherence.

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

J Heart Lung Transplant: 26 Feb 2021; epub ahead of print
Godinas L, Dobbels F, Hulst L, Verbeeck I, ... Verleden GM, Vos R
J Heart Lung Transplant: 26 Feb 2021; epub ahead of print | PMID: 33840608
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Machine learning, artificial intelligence and mechanical circulatory support: A primer for clinicians.

Kanwar MK, Kilic A, Mehra MR
Artificial intelligence (AI) refers to the ability of machines to perform intelligent tasks, and machine learning (ML) is a subset of AI describing the ability of machines to learn independently and make accurate predictions. The application of AI combined with \"big data\" from the electronic health records, is poised to impact how we take care of patients. In recent years, an expanding body of literature has been published using ML in cardiovascular health care, including mechanical circulatory support (MCS). This primer article provides an overview for clinicians on relevant concepts of ML and AI, reviews predictive modeling concepts in ML and provides contextual reference to how AI is being adapted in the field of MCS. Lastly, it explains how these methods could be incorporated in the practices of medicine to improve patient outcomes.

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

J Heart Lung Transplant: 26 Feb 2021; epub ahead of print
Kanwar MK, Kilic A, Mehra MR
J Heart Lung Transplant: 26 Feb 2021; epub ahead of print | PMID: 33775520
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Monitoring of perfusion quality and prediction of donor heart function during ex-vivo machine perfusion by myocardial microcirculation versus surrogate parameters.

Saemann L, Wenzel F, Kohl M, Korkmaz-Icöz S, ... Karck M, Szabó G
Currently, lactate (Lac) is used to evaluate machine perfusion (MP) of hearts, donated after circulatory death (DCD). We hypothesize that monitoring of myocardial microcirculation (mLDP) by Laser-Doppler-Perfusion is superior to Lac to evaluate perfusion and predict contractility. In a pig model, DCD-hearts were perfused 4 hours followed by reperfusion and left ventricular contractility measurement. Lac and mLDP were measured every 30 min in successfully (N = 9) and unsuccessfully (N = 7) maintained hearts. Successfully maintained hearts showed decreasing Lac (5.6 to 2.8 mmol/L) and slightly downregulated (92%) mLDP. In unsuccessfully maintained hearts Lac first decreased (5.1 to 3.8 mmol/L) followed by increase and mLDP dropped to 39%. In a single-variable regression only mLDP showed a significant r² for systolic (0.514, p = 0.045) and diastolic (0.501, p = 0.049) parameters. The combination of mLDP and Lac (r2 = 0.876, p = 0.005) showed best results. mLDP seems to be superior to Lac to show perfusion disorders and predict DCD-heart contractility.

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

J Heart Lung Transplant: 21 Feb 2021; epub ahead of print
Saemann L, Wenzel F, Kohl M, Korkmaz-Icöz S, ... Karck M, Szabó G
J Heart Lung Transplant: 21 Feb 2021; epub ahead of print | PMID: 33726982
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Effects of GLP-1 receptor agonists and SGLT-2 inhibitors in heart transplant patients with type 2 diabetes: Initial report from a cardiometabolic center of excellence.

Sammour Y, Nassif M, Magwire M, Thomas M, ... O\'Keefe J, Kosiborod M
Type 2 diabetes mellitus (T2D) is a common comorbidity among patients who have undergone heart transplantation. Recently two classes of glucose-lowering medications (sodium-glucose cotransporter type-2 inhibitors [SGLT-2Is] and glucagon-like-peptide-1 receptor agonists [GLP-1RAs]), have been shown to significantly improve cardiovascular outcomes. There is a paucity of data regarding their use in immunosuppressed patients, with many studies specifically excluding this population. We retrospectively evaluated the safety and efficacy of GLP-1RAs and SGLT-2Is in patients who had undergone orthotopic heart transplant at a high-volume center. Among 21 patients, we found significant weight loss, reductions in insulin use, hemoglobin A1c, and low-density lipoprotein-cholesterol. Moreover, both SGLT-2Is and GLP-1RAs were well tolerated with no adverse events leading to discontinuation of either therapy. While larger studies of patients after solid organ transplant are needed, this small hypothesis-generating study demonstrates that SGLT-2Is and GLP-1RAs appear safe and effective therapies among patients with T2D after heart transplant.

Copyright © 2021. Published by Elsevier Inc.

J Heart Lung Transplant: 21 Feb 2021; epub ahead of print
Sammour Y, Nassif M, Magwire M, Thomas M, ... O'Keefe J, Kosiborod M
J Heart Lung Transplant: 21 Feb 2021; epub ahead of print | PMID: 33745782
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Resource utilization in children with paracorporeal continuous-flow ventricular assist devices.

Burstein DS, Griffis H, Zhang X, Cantor RS, ... Kirklin JK, Rossano JW
Background
Paracorporeal continuous-flow ventricular assist devices (PCF VAD) are increasingly used in pediatrics, yet PCF VAD resource utilization has not been reported to date.
Methods
Pediatric Interagency Registry for Mechanically Assisted Circulatory Support (PediMACS), a national registry of VADs in children, and Pediatric Health Information System (PHIS), an administrative database of children\'s hospitals, were merged to assess VAD implants from 19 centers between 2012 and 2016. Resource utilization, including hospital and intensive care unit length of stay (LOS), and costs are analyzed for PCF VAD, durable VAD (DVAD), and combined PCF-DVAD support.
Results
Of 177 children (20% PCF VAD, 14% PCF-DVAD, 66% DVAD), those with PCF VAD or PCF-DVAD are younger (median age 4 [IQR 0-10] years and 3 [IQR 0-9] years, respectively) and more often have congenital heart disease (44%; 28%, respectively) compared to DVAD (11 [IQR 3-17] years; 14% CHD); p < 0.01 for both. Median post-VAD LOS is prolonged ranging from 43 (IQR 15-82) days in PCF VAD to 72 (IQR 55-107) days in PCF-DVAD, with significant hospitalization costs (PCF VAD $450,000 [IQR $210,000-$780,000]; PCF-DVAD $770,000 [IQR $510,000-$1,000,000]). After adjusting for patient-level factors, greater post-VAD hospital costs are associated with LOS, ECMO pre-VAD, greater chronic complex conditions, and major adverse events (p < 0.05 for all). VAD strategy and underlying cardiac disease are not associated with LOS or overall costs, although PCF VAD is associated with higher daily-level costs driven by increased pharmacy, laboratory, imaging, and clinical services costs.
Conclusion
Pediatric PCF VAD resource utilization is staggeringly high with costs primarily driven by pre-implantation patient illness, hospital LOS, and clinical care costs.

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

J Heart Lung Transplant: 21 Feb 2021; epub ahead of print
Burstein DS, Griffis H, Zhang X, Cantor RS, ... Kirklin JK, Rossano JW
J Heart Lung Transplant: 21 Feb 2021; epub ahead of print | PMID: 33744087
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Clinical outcomes and healthcare expenditures in the real world with left ventricular assist devices - The CLEAR-LVAD study.

Pagani FD, Mehra MR, Cowger JA, Horstmanshof DA, ... Kormos RL, Rogers JG
Background
Several distinctly engineered left ventricular assist devices (LVADs) are in clinical use. However, contemporaneous real world comparisons have not been conducted, and clinical trials were not powered to evaluate differential survival outcomes across devices.
Objectives
Determine real world survival outcomes and healthcare expenditures for commercially available durable LVADs.
Methods
Using a retrospective observational cohort design, Medicare claims files were linked to manufacturer device registration data to identify de-novo, durable LVAD implants performed between January 2014 and December 2018, with follow-up through December 2019. Survival outcomes were compared using a Cox proportional hazards model stratified by LVAD type and validated using propensity score matching. Healthcare resource utilization was analyzed across device types by using nonparametric bootstrap analysis methodology. Primary outcome was survival at 1-year and total Part A Medicare payments.
Results
A total of 4,195 de-novo LVAD implants were identified in fee-for-service Medicare beneficiaries (821 HeartMate 3; 1,840 HeartMate II; and 1,534 Other-VADs). The adjusted hazard ratio for mortality at 1-year (confirmed in a propensity score matched analysis) for the HeartMate 3 vs HeartMate II was 0.64 (95% CI; 0.52-0.79, p< 0.001) and for the HeartMate 3 vs Other-VADs was 0.51 (95% CI; 0.42-0.63, p < 0.001). The HeartMate 3 cohort experienced fewer hospitalizations per patient-year vs Other-VADs (respectively, 2.8 vs 3.2 EPPY hospitalizations, p < 0.01) and 6.1 fewer hospital days on average (respectively, 25.2 vs 31.3 days, p < 0.01). The difference in Medicare expenditures, conditional on survival, for HeartMate 3 vs HeartMate II was -$10,722, p < 0.001 (17.4% reduction) and for HeartMate 3 vs Other-VADs was -$17,947, p < 0.001 (26.1% reduction).
Conclusions
In this analysis of a large, real world, United States. administrative dataset of durable LVADs, we observed that the HeartMate 3 had superior survival, reduced healthcare resource use, and lower healthcare expenditure compared to other contemporary commercially available LVADs.

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

J Heart Lung Transplant: 21 Feb 2021; epub ahead of print
Pagani FD, Mehra MR, Cowger JA, Horstmanshof DA, ... Kormos RL, Rogers JG
J Heart Lung Transplant: 21 Feb 2021; epub ahead of print | PMID: 33744086
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Use of donor-derived-cell-free DNA as a marker of early allograft injury in primary graft dysfunction (PGD) to predict the risk of chronic lung allograft dysfunction (CLAD).

Keller M, Bush E, Diamond JM, Shah P, ... Jang M, Agbor-Enoh S
Background
Primary graft dysfunction (PGD) is a risk factor for chronic lung allograft dysfunction (CLAD). However, the association between PGD and degree of allograft injury remains poorly defined. In this study, we leverage a novel biomarker for allograft injury, percentage donor-derived cell-free DNA (%ddcfDNA), to study the association between PGD, degree of allograft injury, and the development of CLAD.
Methods
This prospective cohort study recruited 99 lung transplant recipients and collected plasma samples on days 1, 3, and 7 for %ddcfDNA measurements. Clinical data on day 3 was used to adjudicate for PGD. %ddcfDNA levels were compared between PGD grades. In PGD patients, %ddcfDNA was compared between those who developed CLAD and those who did not.
Results
On posttransplant day 3, %ddcfDNA was higher in PGD than in non-PGD patients (median [IQR]: 12.2% [8.2, 22.0] vs 8.5% [5.6, 13.2] p = 0.01). %ddcfDNA correlated with the severity grade of PGD (r = 0.24, p = 0.02). Within the PGD group, higher levels of %ddcfDNA correlated with increased risk of developing CLAD (log OR(SE) 1.38 (0.53), p = 0.009). PGD patients who developed CLAD showed ∼2-times higher %ddcfDNA levels than patients who did not develop CLAD (median [IQR]: 22.4% [11.8, 27.6] vs 9.9% [6.7, 14.9], p = 0.007).
Conclusion
PGD patients demonstrated increased early posttransplant allograft injury, as measured by %ddcfDNA, in comparison to non-PGD patients, and these high %ddcfDNA levels were associated with subsequent development of CLAD. This study suggests that %ddcfDNA identifies PGD patients at greater risk of CLAD than PGD alone.

Published by Elsevier Inc.

J Heart Lung Transplant: 19 Feb 2021; epub ahead of print
Keller M, Bush E, Diamond JM, Shah P, ... Jang M, Agbor-Enoh S
J Heart Lung Transplant: 19 Feb 2021; epub ahead of print | PMID: 33814284
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Impact of lung morphology on clinical outcomes with riociguat in patients with pulmonary hypertension and idiopathic interstitial pneumonia: A post hoc subgroup analysis of the RISE-IIP study.

Nathan SD, Cottin V, Behr J, Hoeper MM, ... Nikkho S, Wells AU
Background
Riociguat in Patients with Symptomatic Pulmonary Hypertension associated with Idiopathic Interstitial Pneumonias (RISE-IIP), a randomized, controlled, phase 2b trial of riociguat for pulmonary hypertension associated with idiopathic interstitial pneumonia, was terminated early due to increased mortality in riociguat-treated patients. Baseline characteristics of enrolled patients demonstrated a low diffusing capacity of the lung for carbon monoxide (DLCO) with preserved lung volumes at baseline, suggesting the presence of combined pulmonary fibrosis and emphysema (CPFE) in some patients. This post hoc analysis of RISE-IIP was undertaken to explore lung morphology, assessed by high-resolution computed tomography, and associated clinical outcomes.
Methods
Available baseline/pre-baseline high-resolution computed tomography scans were reviewed centrally by 2 radiologists. The extent of emphysema and fibrosis was retrospectively scored and combined to provide the total CPFE score.
Results
Data were available for 65/147 patients (44%), including 15/27 fatal cases (56%). Of these, 41/65 patients (63%) had CPFE. Mortality was higher in patients with CPFE (12/41; 29%) than those without (3/24; 13%). Fourteen patients with CPFE had emphysema > fibrosis (4 died). No relationship was observed between CPFE score, survival status, and treatment assignment. A low DLCO, short 6-min walking distance, and high forced vital capacity:DLCO ratio at baseline also appeared to be risk factors for mortality.
Conclusions
High parenchymal lung disease burden and the presence of more emphysema than fibrosis might have predisposed patients with pulmonary hypertension associated with idiopathic interstitial pneumonia to poor outcomes in RISE-IIP. Future studies of therapy for group 3 pulmonary hypertension should include centrally adjudicated imaging for morphologic phenotyping and disease burden evaluation during screening.

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

J Heart Lung Transplant: 18 Feb 2021; epub ahead of print
Nathan SD, Cottin V, Behr J, Hoeper MM, ... Nikkho S, Wells AU
J Heart Lung Transplant: 18 Feb 2021; epub ahead of print | PMID: 33744088
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Exercise right ventricular ejection fraction predicts right ventricular contractile reserve.

Ireland CG, Damico RL, Kolb TM, Mathai SC, ... Tedford RJ, Hsu S
Background
Right ventricular (RV) contractile reserve shows promise as an indicator of occult RV dysfunction in pulmonary vascular disease. We investigated which measure of RV contractile reserve during exercise best predicts occult RV dysfunction and clinical outcomes.
Methods
We prospectively studied RV contractile reserve in 35 human subjects referred for right heart catheterization for known or suspected pulmonary hypertension. All underwent cardiac magnetic resonance imaging, echocardiography, and supine invasive cardiopulmonary exercise testing with concomitant RV pressure-volume catheterization. Event-free survival was prospectively adjudicated from time of right heart catheterization for a 4-year follow-up period.
Results
RV contractile reserve during exercise, as measured by a positive change in end-systolic elastance (Ees) during exertion, was associated with elevation in pulmonary pressures but preservation of RV volumes. Lack of RV reserve, on the other hand, was tightly coupled with acute RV dilation during exertion (R2 = 0.76, p< 0.001). RV Ees and dilation changes each predicted resting RV-PA dysfunction. RV ejection fraction during exercise, which captured exertional changes in both RV Ees and RV dilation, proved to be a robust surrogate for RV contractile reserve. Reduced exercise RV ejection fraction best predicted occult RV dysfunction among a variety of resting and exercise RV measures, and was also associated with clinical worsening.
Conclusions
RV ejection fraction during exercise, as an index of RV contractile reserve, allows for excellent identification of occult RV dysfunction, more so than resting measures of RV function, and may predict clinical outcomes as well.

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

J Heart Lung Transplant: 16 Feb 2021; epub ahead of print
Ireland CG, Damico RL, Kolb TM, Mathai SC, ... Tedford RJ, Hsu S
J Heart Lung Transplant: 16 Feb 2021; epub ahead of print | PMID: 33752973
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Survival implications of prescription opioid and benzodiazepine use in lung transplant recipients: Analysis of linked transplant registry and pharmacy fill records.

Lentine KL, Salvalaggio PR, Caliskan Y, Lam NN, ... Kasiske BL, Schnitzler MA
Background
Prescription opioid and benzodiazepine use have been associated with morbidity and mortality among some groups of solid organ transplant recipients, but implications for outcomes among lung transplant patients are not well described.
Methods
We conducted a retrospective cohort study using linked national transplant registry and pharmaceutical records to characterize the associations between benzodiazepine and opioid prescription fills in the years before and after lung transplant (2006-2017), with risk-adjusted posttransplant survival (adjusted hazard ratio, LCLaHRUCL).
Results
Among 11,568 recipients, 33.7% filled an opioid prescription, and 25.8% filled a benzodiazepine prescription before transplant. Compared to patients without prescriptions, those who filled both short- and long-acting benzodiazepine prescriptions before transplant had 2-fold higher mortality in the first year posttransplant (aHR, 1.392.123.21), after adjustment for baseline factors and opioid fills, while pretransplant opioid fills were not associated with posttransplant mortality after adjustment for benzodiazepine fills. Pretransplant opioid and benzodiazepine use strongly predicted more use after transplant. Fills of both short- and long-acting benzodiazepines in the first year posttransplant were associated with 77% increased mortality >1-to-2 years posttransplant (aHR, 1.061.772.96). Compared with no posttransplant opioid fills, there was a dose-dependent association between first-year opioid fills and subsequent adjusted mortality risk (level 2: aHR, 1.171.501.92 to level 4: aHR, 1.562.012.59). These effects were independent, and interactions were not detected.
Conclusions
Benzodiazepine prescription fills before and after lung transplant, and opioid fills after transplant, are independently associated with posttransplant mortality. Review of benzodiazepine and opioid use history is relevant to risk-stratifying patients before and after lung transplant.

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

J Heart Lung Transplant: 16 Feb 2021; epub ahead of print
Lentine KL, Salvalaggio PR, Caliskan Y, Lam NN, ... Kasiske BL, Schnitzler MA
J Heart Lung Transplant: 16 Feb 2021; epub ahead of print | PMID: 33846078
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Use of metabolomics to identify strategies to improve and prolong ex vivo lung perfusion for lung transplants.

Shin J, Hsin MK, Baciu C, Chen Y, ... Keshavjee S, Liu M
Background
Normothermic ex vivo lung perfusion (EVLP) allows for functional assessment of donor lungs; thus has increased the use of marginal lungs for transplantation. To extend EVLP for advanced organ reconditioning and regenerative interventions, cellular metabolic changes need to be understood. We sought to comprehensively characterize the dynamic metabolic changes of the lungs during EVLP, and to identify strategies to improve EVLP.
Methods
Human donor lungs (n = 50) were assessed under a 4-hour Toronto EVLP protocol. EVLP perfusate was sampled at first (EVLP-1h) and fourth hour (EVLP-4h) of perfusion and were submitted for mass spectrometry-based untargeted metabolic profiling. Differentially expressed metabolites between the 2 timepoints were identified and analyzed from the samples of lungs transplanted post-EVLP (n = 42) to determine the underlying molecular mechanisms.
Results
Of the total 312 detected metabolites, 84 were up-regulated and 103 were down-regulated at EVLP-4h relative to 1h (FDR adjusted p < .05, fold change ≥ |1.1|). At EVLP-4h, markedly decreased energy substrates were observed, accompanied by the increase in fatty acid β-oxidation. Concurrently, accumulation of amino acids and nucleic acids was evident, indicative of increased protein and nucleotide catabolism. The uniform decrease in free lysophospholipids and polyunsaturated fatty acids at EVLP-4h suggests cell membrane remodeling.
Conclusions
Untargeted metabolomics revealed signs of energy substrate consumption and metabolic by-product accumulation under current EVLP protocols. Strategies to supplement nutrients and to maintain homeostasis will be vital in improving the current clinical practice and prolonging organ perfusion for therapeutic application to further enhance donor lung utilization.

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

J Heart Lung Transplant: 16 Feb 2021; epub ahead of print
Shin J, Hsin MK, Baciu C, Chen Y, ... Keshavjee S, Liu M
J Heart Lung Transplant: 16 Feb 2021; epub ahead of print | PMID: 33849769
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Operating room extubation: A predictive factor for 1-year survival after double-lung transplantation.

Fessler J, Fischler M, Sage E, Ouattara J, ... Vallee A, Le Guen M
Background
Operating room (OR) extubation has been reported after lung transplantation (LT) in small cohorts. This study aimed to evaluate the prognosis of OR-extubated patients. The secondary objectives were to evaluate the safety of this approach and to identify its predictive factors.
Methods
This retrospective single-center cohort study included patients undergoing double lung transplantation (DLT) from January 2012 to June 2019. Patients undergoing multiorgan transplantation, repeat transplantation, or cardiopulmonary bypass during the study period were excluded. OR-extubated patients were compared with intensive care unit (ICU)-extubated patients.
Results
Among the 450 patients included in the analysis, 161 (35.8%) were extubated in the OR, and 4 were reintubated within 24 hours. Predictive factors for OR extubation were chronic obstructive pulmonary disease (COPD)/emphysema (p = .002) and cystic fibrosis (p = .005), recipient body mass index (p = .048), and the PaO2/FiO2 ratio 10 minutes after second graft implantation (p < .001). OR-extubated patients had a lower prevalence of grade 3 primary graft dysfunction at day 3 (p < .001). Eight (5.0%) patients died within the first year after OR extubation, and 49 (13.5%) patients died after ICU extubation (log-rank test; p = .005). After adjustment for OR extubation predictive factors, the multivariate Cox regression model showed that OR extubation was associated with greater one-year survival (adjusted hazard ratio = 0.40 [0.16-0.91], p = .028).
Conclusions
OR extubation was associated with a favorable prognosis after DLT, but the association should not be interpreted as causality. This fast-track protocol was made possible by a team committed to developing a comprehensive strategy to enhance recovery.

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

J Heart Lung Transplant: 04 Feb 2021; epub ahead of print
Fessler J, Fischler M, Sage E, Ouattara J, ... Vallee A, Le Guen M
J Heart Lung Transplant: 04 Feb 2021; epub ahead of print | PMID: 33632637
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Assessing hemodynamic response to submaximal exercise in pulmonary arterial hypertension patients using an implantable hemodynamic monitor.

Airhart S, Badie N, Doyle M, Correa-Jacque P, Daniels C, Benza R
Pulmonary arterial hypertension (PAH) is a chronic, progressive disease that is incurable, even with effective therapy. Long-term outcome in PAH is best preserved by targeting hemodynamic improvements to reduce risk of subsequent right ventricular (RV) failure. Methods that can assess RV adaptation to stress have important implications to better understand an individual\'s physiology and may play a pivotal role in guiding therapy in PAH. In this novel pilot study, we evaluate the feasibility of monitoring hemodynamic response to 6-minute walk distance in patients with PAH using the CardioMEMS HF System.

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

J Heart Lung Transplant: 04 Feb 2021; epub ahead of print
Airhart S, Badie N, Doyle M, Correa-Jacque P, Daniels C, Benza R
J Heart Lung Transplant: 04 Feb 2021; epub ahead of print | PMID: 33752972
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Abstract

Clinical utility of donor-derived cell-free DNA testing in cardiac transplantation.

Khush KK
Surveillance of allograft health after transplantation has traditionally relied on biopsy procedures that enable pathologic assessment for acute rejection. Noninvasive methods to assess for graft injury have been developed and tested over the past decade, and now offer a convenient way to reduce reliance on invasive testing and improve patient satisfaction. Emerging evidence suggests that detection of allograft injury via donor-derived cell-free DNA (dd-cfDNA) may, in fact, have better sensitivity compared to traditional biopsy-based strategies. This state-of-the-art review describes the development, testing, and current use of dd-cfDNA assays for acute rejection monitoring after heart transplantation, and discusses innovative ways that such assays can be used for personalized patient management.

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

J Heart Lung Transplant: 03 Feb 2021; epub ahead of print
Khush KK
J Heart Lung Transplant: 03 Feb 2021; epub ahead of print | PMID: 33610430
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:

This program is still in alpha version.