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The Journal of Heart and Lung Transplantation
International Society for Heart and Lung Transplantation.

Full recovery of right ventricular systolic function in children undergoing bilateral lung transplantation for severe PAH

Open AccessPublished:October 29, 2021DOI:https://doi.org/10.1016/j.healun.2021.10.014

      Background

      We investigated whether RV function recovers in children with pulmonary arterial hypertension (PAH) and RV failure undergoing lung transplantation (LuTx).

      Methods

      Prospective observational study of 15 consecutive children, 1.9 to 17.6 years old, with PAH undergoing bilateral LuTx. We performed advanced echocardiography (Echo) and cardiac magnetic resonance imaging (MRI), followed by conventional and strain analysis, pre- and ∼6 weeks post-LuTx.

      Results

      After LuTx, RV/LV end-systolic diameter ratio (Echo), RV volumes and systolic RV function (RVEF 63 vs 30 %; p < 0.05) by MRI completely normalized, even in children with severe RV failure (RVEF < 40%). The echocardiographic end-systolic LV eccentricity index nearly normalized post-LuTx (1.0 vs 2.0, p < 0.0001) while RV hypertrophy regressed more slowly and was still evident. We found especially the end-systolic RV/LV ratios by Echo (diameter: 0.6 vs 2.6) or MRI (volumes: 0.8 vs 3.4) excellent diagnostic tools (p < 0.05): Together with RVEF by MRI, these ratios were superior to tricuspid annular plane systolic excursion (TAPSE; p = 0.4551) in assessing global systolic RV dysfunction. Moreover, children with severe PAH had reduced RV 2D longitudinal strain (Echo, MRI; p = 0.0450) and decreased RV 2D radial and circumferential strain (MRI; p = 0.0026 and p = 0.0036 respectively), all of which greatly improved following LuTx.

      Conclusion

      We demonstrate full recovery of RV systolic function in children within two months after LuTx for severe PAH, independently of the patients’ age, weight, and hemodynamic compromise preceding the LuTx. Even in end-stage pediatric PAH with poor RV function and low cardiac output, LuTx should be preferred over heart-lung transplantation.

      KEYWORDS

      Abbreviations:

      CPB (cardiopulmonary bypass), CI (cardiac index, syn, Qsi, systemic blood flow index (Qs indexed to body surface area)), HLTx (combined heart and lung transplantation), IPAH/HPAH (idiopathic/heritable pulmonary arterial hypertension), LuTx (lung transplantation, LV, left ventricle), LVES EI (left ventricular end-systolic eccentricity index), LVESV (left ventricular end-systolic volume), LVLS (left ventricular longitudinal strain), PAH-CHD (pulmonary arterial hypertension associated with congenital heart disease), PVD (pulmonary vascular disease), PVOD/PCH (pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis), RV (right ventricle), RVAWD (right ventricular anterior wall diameter (in diastole)), RVEDD (right ventricular end-diastolic diameter), RVH (right ventricular hypertrophy), RV/LV (end-systolic ratio, ratios of inner diameters of RV over LV in end-systole), RV mass index (right ventricular mass index), RVEDV index (right ventricular end-diastolic volume (indexed to body surface area)), RVEF (right ventricular ejection fraction), RVES RI (right ventricular end-systolic remodeling index), RVLS (right ventricular longitudinal strain), RVRS (right ventricular radial strain), RVCS (right ventricular circumferential strain), RVCSR (right ventricular circumferential strain rate), TAPSE (tricuspid annular plane systolic excursion), VA-ECMO (veno-arterial extracorporeal membrane oxygenation)
      The hallmarks of progressive pulmonary arterial hypertension (PAH) are pulmonary vascular remodeling, greatly elevated pulmonary arterial pressure (PAP), right ventricular (RV) dysfunction, underfilling/compression of the left ventricle (LV), and ultimately fatal heart failure.
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      The mortality of incident precapillary pulmonary hypertension (PH) has decreased over the last two decades in children
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      and adults,
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      2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
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      but still remains high. According to the REVEAL registry (2006-2010), one in four children with idiopathic/heritable PAH (IPAH/HPAH) or congenital heart disease-associated PAH (PAH-CHD) dies within five years of diagnosis.
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      Consequently, transplant-free survival with various forms of PAH, especially when not responding to early combinatory drug therapy, is poor.
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      2019 updated consensus statement on the diagnosis and treatment of pediatric pulmonary hypertension: The European Pediatric Pulmonary Vascular Disease Network (EPPVDN), endorsed by AEPC, ESPR and ISHLT.
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      • Kaestner M
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      Pulmonary hypertension in the intensive care unit. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      Despite further improvements in pharmacotherapy
      • Hansmann G
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      • Alastalo TP
      • et al.
      2019 updated consensus statement on the diagnosis and treatment of pediatric pulmonary hypertension: The European Pediatric Pulmonary Vascular Disease Network (EPPVDN), endorsed by AEPC, ESPR and ISHLT.
      ,
      • Galie N
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      • Frantz RP
      • et al.
      Risk stratification and medical therapy of pulmonary arterial hypertension.
      ,
      • Hansmann G
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      Treatment of children with pulmonary hypertension. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      • Hansmann G
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      Selexipag for the treatment of children with pulmonary arterial hypertension: First multicenter experience in drug safety and efficacy.
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      and survival at expert PH centers over the last decade,
      • Hansmann G
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      ,
      • Hansmann G
      • Koestenberger M
      • Alastalo TP
      • et al.
      2019 updated consensus statement on the diagnosis and treatment of pediatric pulmonary hypertension: The European Pediatric Pulmonary Vascular Disease Network (EPPVDN), endorsed by AEPC, ESPR and ISHLT.
      ,
      • Rosenzweig EB
      • Abman SH
      • Adatia I
      • et al.
      Paediatric pulmonary arterial hypertension: updates on definition, classification, diagnostics and management.
      bilateral lung transplantation (LuTx) or combined heart-lung-Tx (HLTx) remains the only established treatment option for patients with end-stage PAH.
      • Hansmann G
      Pulmonary hypertension in infants, children, and young adults.
      • Frank BS
      • Ivy DD
      Diagnosis, ealuation and treatment of pulmonary arterial hypertension in children.
      • Hansmann G
      • Koestenberger M
      • Alastalo TP
      • et al.
      2019 updated consensus statement on the diagnosis and treatment of pediatric pulmonary hypertension: The European Pediatric Pulmonary Vascular Disease Network (EPPVDN), endorsed by AEPC, ESPR and ISHLT.
      • Galie N
      • Humbert M
      • Vachiery JL
      • et al.
      2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT).
      • Galie N
      • Channick RN
      • Frantz RP
      • et al.
      Risk stratification and medical therapy of pulmonary arterial hypertension.
      ,
      • Rosenzweig EB
      • Abman SH
      • Adatia I
      • et al.
      Paediatric pulmonary arterial hypertension: updates on definition, classification, diagnostics and management.
      In the overall pediatric thoracic transplant population, post-LuTx outcomes for IPAH appear to be similar to those of children transplanted for other indications in both the International Society for Heart and Lung Transplantation (ISHLT) registry (2000-2017; n = 178 IPAH-LuTx)
      • Goldfarb SB
      • Hayes Jr., D
      • Levvey BJ
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      The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Twenty-first Pediatric Lung and HeartLung Transplantation Report-2018; Focus Theme: Multiorgan Transplantation.
      and the United Network for Organ Sharing (UNOS) registry (2005-2015; n = 65 PH-LuTx, age 10 ± 6 years).
      • Hubbard R
      • Miller R
      • Tumin D
      • Tobias JD
      • Hayes Jr., D
      Transplant outcomes for idiopathic pulmonary hypertension in children.
      The latter analysis demonstrated 5-year survival rates of 61% for LuTx (n = 47), and only 48% for HLTx (n = 18), although this difference did not reach statistical significance.
      • Hubbard R
      • Miller R
      • Tumin D
      • Tobias JD
      • Hayes Jr., D
      Transplant outcomes for idiopathic pulmonary hypertension in children.
      Similarly, previous analyses of small pediatric PH cohorts post-LuTx suggested a 3- and 5-year survival of 84%
      • Schaellibaum G
      • Lammers AE
      • Faro A
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      Bilateral lung transplantation for pediatric idiopathic pulmonary arterial hypertension: a multi-center experience.
      and 61%,
      • Goldstein BS
      • Sweet SC
      • Mao J
      • Huddleston CB
      • Grady RM
      Lung transplantation in children with idiopathic pulmonary arterial hypertension: an 18-year experience.
      respectively.
      Since (young) children with near-systemic PH typically have preserved cardiac index (CI) and exercise tolerance even with advanced pulmonary vascular disease (PVD),
      • Melicoff E
      • Hayes Jr., D
      • Benden C
      Lung transplantation as an intervention for pediatric pulmonary hypertension.
      and frequently do not meet the 2015 ISHLT criteria for listing of adults,
      • Weill D
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      • Corris PA
      • et al.
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      the optimal timing of listing treatment-resistant PAH children for transplantation remains challenging. As a consequence, pediatric candidates with severe PH are referred late for LuTx or HLTx transplantation, often requiring immediate intensive care treatment of acute or acute-on-chronic RV failure, including veno-arterial ECMO.
      • Hansmann G
      • Koestenberger M
      • Alastalo TP
      • et al.
      2019 updated consensus statement on the diagnosis and treatment of pediatric pulmonary hypertension: The European Pediatric Pulmonary Vascular Disease Network (EPPVDN), endorsed by AEPC, ESPR and ISHLT.
      ,
      • Kaestner M
      • Schranz D
      • Warnecke G
      • Apitz C
      • Hansmann G
      • Miera O
      Pulmonary hypertension in the intensive care unit. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      ,
      • Puri V
      • Epstein D
      • Raithel SC
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      Extracorporeal membrane oxygenation in pediatric lung transplantation.
      On the other hand, an unknown number of end-stage PH children are not referred to pediatric LuTx centers because of the common beliefs: (1) an RV with very poor function could not recover even with LuTx, or (2) the young age/low body weight would prevent technical transplant success. Although PAH is the second most common indication for LuTx in children, (1) how completely and (2) how quickly the ventricular-ventricular interaction
      • Friedberg MK
      Imaging right-left ventricular interactions.
      and RV function recover after LuTx in severe PAH with RV failure, has not been comprehensively investigated. We hypothesized that such RV recovery would be complete and evident prior to hospital discharge, irrespective of the hemodynamic compromise at the time of LuTx. In this prospective observational study, we applied advanced echocardiography and cardiac magnetic resonance imaging (MRI) pre- and post-LuTx, and investigated RV systolic function within ∼2 months of LuTx in children with severe PAH and RV failure.

      Methods

      Patient population

      This was a prospective observational study of 15 consecutive children (age range: 1.9-17.6 years) with severe PAH who underwent bilateral lung transplantation at Hannover Medical School between December 2013 and January 2021 (Table 1, Table S2). PAH was defined according to the World Symposium of PH (WSPH, 2018):
      • Rosenzweig EB
      • Abman SH
      • Adatia I
      • et al.
      Paediatric pulmonary arterial hypertension: updates on definition, classification, diagnostics and management.
      ,
      • Simonneau G
      • Montani D
      • Celermajer DS
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      mPAP >20 mmHg, PAWP ≤15 mm Hg, and pulmonary vascular resistance (PVR) index ≥3 WU·m2 when >3 months old, at sea level.
      • Hansmann G
      • Koestenberger M
      • Alastalo TP
      • et al.
      2019 updated consensus statement on the diagnosis and treatment of pediatric pulmonary hypertension: The European Pediatric Pulmonary Vascular Disease Network (EPPVDN), endorsed by AEPC, ESPR and ISHLT.
      We consecutively enrolled children in WSPH diagnosis group 1 PH, and excluded LuTx patients primarily in WSPH diagnosis group 2 to 5 PH (“secondary PH”, Table S1). The EPPVDN pediatric PH risk score,
      • Frank BS
      • Ivy DD
      Diagnosis, ealuation and treatment of pulmonary arterial hypertension in children.
      consisting of 17 clinical, echocardiographic and hemodynamic variables, was calculated to judge the patients’ condition prior to transplant.
      Table 1Characteristics of all 15 PAH Patients Undergoing Bilateral Lung Transplantation.
      Patients #1-15Pre-LuTx n = 15Post-LuTx n = 15
      Demographics
       Age – years (range)10.7 ± 1.3 (1.9-17.6)10.9 ± 1.3 (2.1-17.8)
       Sex, Female – n (%)12 (80%)12 (80%)
       Height – m1.4 ± 0.11.4 ± 0.1
       Weight – kg32.3 ± 4.031.5 ± 3.9
       BSA – m21.1 ± 0.11.1 ± 0.1
      Clinical Diagnosis
       PH Group – n
       PH Group 1
       1.1 IPAH6
       1.2 HPAH (BMPR2, n = 3; TBX4, n = 1)4
       1.4.4 PAH-CHD2
       1.6 PVOD/PCH3
      Co-morbidities – n
       Hereditary thrombophilia1
       HHT (Osler's disease)1
       Type 1 diabetes1
       von Willebrand disease6 confirmed
      Functional Status
       WHO Functional Class3.7 ± 0.1
       6 MWD (0 m for ECMO)* – m, n = 13208 ± 52
       6 MWD (last before LuTx) – m, n = 13264 ± 48
      NTproBNP – ng/l, n = 73093.7 ± 1647.3945.6 ± 262.2
      Key Hemodynamics
       mRAP – mm Hg, n = 129.3 ± 1.1
       RVEDP – mm Hg, n = 1112.7 ± 0.9
       mPAP/mSAP, n = 121.2 ± 0.04
       PVRi – WU·m2, n = 1226.2 ± 2.5
       PVR/SVR, n = 121.4 ± 0.1
       Qsi – L/min/m2, n = 122.9 ± 0.3
      Risk Stratification (EPPVDN)
       Patients total – n

       Noninvasive Risk – n
      15

      Higher Risk – 9

      Intermediate Risk – 6


         Higher Risk Score, max. 15 (decimal)10.2/15 (0.68 ± 0.04)
         Lower Risk Score, max. 14 (decimal)1.9/14 (0.14 ± 0.02)
       Patients with cath 0-12 months pre-LuTx – n

       Invasive Risk – n
      12

      Higher Risk – 8

      Intermediate Risk – 4
         Higher Risk Score, max. 21 (decimal)13.3/21 (0.63 ± 0.05)
         Lower Risk Score, max. 20 (decimal)3.3/20 (0.16 ± 0.03)
      Pre-/Post-LuTx Imaging Intervals
       Interval Echo to Tx / Tx to Echo – days (range), n = 1528 ± 6 (0-75)41 ± 5 (9-76)
       Interval MRI to Tx / Tx to MRI – days (range), n = 661 ± 31 (15-203)43 ± 4 (31-56)
      Values are presented as mean ± SEM. The indicated serum N-terminal prohormone of brain natriuretic peptide (NTproBNP) concentrations were the last measurements prior to LuTx and determined ± 14 days around the post-LuTx echo. Only catheterization data within the preceding 12 months pre-LuTx are shown and taken into account for the risk scores. For risk stratification, see the new 2019 EPPVDN risk score. Of note, the mean EPPVDN pediatric PH higher risk score at the time of lung transplantation was 0.63 (invasive) and 0.68 (noninvasive), respectively.
      * Three patients were supported with VA-ECMO for 1-12 days preceding LuTx. Abbreviations: 6 MWD, 6-min walk distance; BMPR2, bone morphogenetic protein receptor 2 (mutation); BSA, body surface area; cath, catheterization; CHD, congenital heart disease; ECMO, extracorporeal membrane oxygenation; EPPVDN, European Pediatric Pulmonary Vascular Disease Network; HHT, hereditary hemorrhagic telangiectasia; HPAH, heritable PAH; IPAH, idiopathic PAH; LuTx, lung transplantation; mPAP, mean pulmonary arterial pressure; mRAP, mean right atrial pressure; mSAP, mean systemic arterial pressure; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PAH, pulmonary arterial hypertension; PCH, pulmonary capillary hemangiomatosis; PVOD, pulmonary venoocclusive disease; PVR, pulmonary vascular resistance; PVRi, pulmonary vascular resistance index; Qsi, systemic flow index; RVEDP, right ventricular end-diastolic pressure; SVR, systemic vascular resistance; TBX4, T-box transcription factor 4 (mutation); vWD, von Willebrand disease; WHO, World Health Organisation.

      Bilateral lung transplantation

      Three patients underwent bilateral LuTx on cardiopulmonary bypass (CPB; age 2.3-6.1 years, 8.9-16.8 kg), and 12 patients (age 1.9-17.6 years, 8.2-57.0 kg) were transplanted on veno-arterial extracorporeal membrane oxygenation (VA-ECMO).

      Non-invasive imaging (Echocardiography, cardiac MRI)

      Details on the imaging methods (conventional, biventricular tissue tracking/strain analysis)
      • Koestenberger M
      • Friedberg MK
      • Ravekes W
      • Nestaas E
      • Hansmann G
      Non-invasive imaging for congenital heart disease: recent innovations in transthoracic echocardiography.
      • Truong U
      • Meinel K
      • Haddad F
      • et al.
      Update on noninvasive imaging of right ventricle dysfunction in pulmonary hypertension.
      • Latus H
      • Kuehne T
      • Beerbaum P
      • et al.
      Cardiac MR and CT imaging in children with suspected or confirmed pulmonary hypertension/pulmonary hypertensive vascular disease. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK.
      are given in the Online Supplement. All patients underwent echocardiography at both time points (pre- and post-LuTx). Cardiac MRI could not be performed in 9/15 children because they either required general anesthesia or were too sick to undergo MRI safely.

      Statistical analysis

      The statistical analysis was based on hemodynamic data sets (echocardiography, cardiac magnetic resonance imaging; conventional, Table S4, and strain, Table S5). Either the Wilcoxon signed-rank test or paired two-tailed t-test was used to make pairwise-comparisons for data collected pre-LuTx and post-LuTx depending on the outcome of normality testing of the difference between the pairs. The pair differences were considered normally distributed if they passed all applied normality tests (p-value > 0.05): D'agostino-Pearson (not used with the MRI samples due to the small sample size), Shapiro-Wilk, and Kolmogorov-Smirnov. All statistical analysis was performed in GraphPad Prism. The changes in the examined variables (Figure 1, Figure 2, Figure 3) were visualized using R and GraphPad Prism software. Details on the methodology, imaging, and outcome variables can be found in the Online Supplement and the figure legends.
      Figure 1
      Figure 1Pressure unloading after bilateral lung transplantation (LuTx) leads to echocardiographic regression of RV hypertrophy, rapid normalization of RV dilation, and improvement of RV-LV interaction within 6 weeks post-LuTx. The direction of changes in echocardiographic variables between the time points before and after the lung transplantation indicate positive response in all patients. All patients with echocardiographic data pre-LuTx and post-LuTx (N = 15) are shown. There were 28 ± 6 days between pre-LuTx Echo and LuTx, and 41 ± 5 days between LuTx and scheduled post-LuTx Echo. All echocardiographic variables except TAPSE demonstrated significant improvement. Note the highly variable TAPSE values pre-LuTx and inconsistent changes post-LuTx (see main text). Either the Wilcoxon signed-rank test or paired two-tailed t-test was used. ⁎⁎⁎⁎p < 0.0001, n = 15. The box and whisker plots (third column) show the median, interquartile range (IQR), and 10-90th percentile. The scatter plots (fourth column) show the 95% confidence interval for the median. Abbreviations: RV, right ventricle; RVAWD, RV anterior wall diameter; RVEDD, RV end-diastolic diameter; LV, left ventricle; TAPSE, tricuspid annular plane systolic excursion.

      Ethics statement

      This study does not fulfil all criteria of a clinical trial (variable imaging intervals, participant N <20). All cardiac catheterizations were clinically indicated. All clinical data were anonymized. Informed consent was obtained from the legal caregivers according to the principles expressed in the Declaration of Helsinki (IRB approval #2200).

      Results

      Demographic and clinical characteristics at baseline

      Demographic and clinical characteristics of the 15 children with WSPH group 1 PH are summarized in Table 1, and are shown individually in Table S2. Age at transplantation was 23 months to 17 years (mean 10.8 years). Nine patients were under 12 years old (LAS exemption), two of which had body surface area and weight below 0.5 m2 and 9 kg, respectively (range: 0.42-1.70m2; 8.2-57.0 kg). All patients were in WSPH diagnosis group 1 PH (Tables S1, S2): 6 IPAH; 4 HPAH; 2 PAH-congenital heart disease (PAH-CHD); 2 pulmonary veno-occlusive disease (PVOD); 1 pulmonary capillary hemangiomatosis (PCH). All patients were symptomatic, in WHO functional class 3 or 4, with a mean 6-minute-walk distance of 208 ± 52 meters (n = 13; Table 1, Table S2). In the 7-year study period, no PAH patients died on the waiting list or during evaluation for LuTx in our center.

      Early post-operative course after LuTx for severe PAH and RV failure in children

      Six patients had confirmed von Willebrand disease type 2 and received F. VIII supplementation during VA-ECMO pre- and post-LuTx. Two major complications occurred on VA-ECMO: pre-LuTx ECMO cannula dislocation and hematothorax requiring thoracotomy, and post-LuTx subtotal middle cerebral artery infarction in a patient with prothrombin mutation. A detailed analysis of the clinical course and outcome up to one year post-LuTx was not performed for this study. All 15 PH-LuTx patients are alive, as of March 31, 2021 (mean follow-up post-LuTx: 39 months; range 2 months-7 years). See Online Supplement.

      Systolic RV function fully recovers within 2 months after LuTx for severe PAH

      We report full recovery of RV systolic function in 15 children after bilateral LuTx, in association with regression of RV hypertrophy (RVH), and normalization of RV volumes, by means of transthoracic echocardiography (Echo, n = 15) and cardiac MR imaging (MRI, n = 6; Table S3).
      Transthoracic echocardiography (B-mode, M-mode, Doppler; Figure 1, Table S4). Intervals were 28±6 days between pre-LuTx Echo and LuTx, and 41±5 days between LuTx and scheduled post-LuTx Echo. The RV anterior wall diameter (RVAWD), as a 2-dimensional indicator of RVH, decreased in all 15 patients (by 20% to 40% in most patients, p < 0.0001; median change -31%; Figure 1A,B). However, RVH persisted beyond 2 months post-LuTx by non-invasive imaging and EKG criteria.
      The RV end-diastolic diameter (RVEDD, M-mode), a surrogate of RV dilation, shortened in all patients and normalized in most patients after LuTx (p < 0.0001; median change -50%; Figure 1C,D). The RV/LV end-systolic diameter ratio (Figure 1E,F) and the LV end-systolic eccentricity index (LVES EI, Figure 1G,F; normal reference <1 for both) were greatly abnormal pre-LuTx, with median values of 2.6 and 2.0, respectively. In contrast to RVAWD and RVEDD that showed similar relative diameter reduction post-LuTx in most patients (Figure 1A-D), the RV/LV end-systolic diameter ratio and LV end-systolic eccentricity index (LVES EI) had a “hand fan” type reduction pattern: even PAH patients with very high ratios (RV dilation, LV compression/underfilling+++) pre-LuTx rapidly normalized both indices post-LuTx to indices of 0.62 and 1.0, respectively (Figure 1E-H).
      For tricuspid annular plane systolic excursion (TAPSE), a conventional marker for longitudinal systolic RV function, we found very high variance for absolute values and the direction and magnitude of change post-LuTx (Figure 1I,J). In fact, there was no significant difference in TAPSE pre- and post-LuTx (p = 0.4551; Figure 1J). We also calculated the RV end-systolic remodeling index (RVES RI), defined as the ratio of end-systolic RV free wall longitudinal length over septal length, as an easily obtainable, comprehensive indicator of RV volume and shortening: RVES RI was greatly abnormal pre-LuTx (1.53 ± 0.03) and decreased post-LuTx in all patients to a median of 1.27 ± 0.04 (normal < 1.2), with high variance of the relative change in the individual patients (Figure S1).

      Cardiac MR imaging (cine)

      There were 61 ± 31 days between pre-LuTx MRI and LuTx, and 43 ± 4 days between LuTx and scheduled post-LuTx MRI (n = 6) (Table S4). The major echocardiographic findings on RV hypertrophy and dilation were confirmed by the gold standard method, MRI (Figure S2; Movie S1A, S1B): The RV mass index decreased in all 6 patients (p < 0.05; median change -35%; Figure 2A,B). The RV end-diastolic volume index (RVEDV index) decreased and normalized in all patients post-LuTx (p < 0.05; median change -61%; Figure 2C,D). The novel RV/LV end-systolic volume ratio (Figure 2E,F), as indicator of both pressure-overload induced RV dilation and LV underfilling, was 3.4 (median), and had the largest effect size for LuTx in declining to normal values (<1) in all patients (median change -76%, p < 0.05; Figure 2E,F). Most importantly, RV pressure unloading by LuTx resulted in complete normalization of systolic RV function, by means of RV ejection fraction, improving from 30% to 63% (p < 0.05; RVEF median change +110%; Figure 2G,H). In contrast, the cardiac index-based MR-quantified stroke volume and cardiac index showed very high variance for absolute values, and changed with LuTx (n.s., p = 0.4565; Figure 2I,J), similarly to Echo-based TAPSE (Figure 1I,J).
      Figure 2
      Figure 2Cardiac magnetic resonance imaging demonstrates bilateral lung transplantation (LuTx) leads to reduction of RV mass, rapid normalization of RV and LV volumes, full recovery of RV systolic function within 6 weeks post-LuTx. The direction of changes in cardiac MR variables between the time points before and after the lung transplantation indicate positive response in all patients. All patients with cardiac MR data pre-LuTx and post-LuTx (N = 6) are shown. There were 61 ± 31 days between pre-LuTx MRI and LuTx, and 43 ± 4 days between LuTx and scheduled post-LuTx MRI. All cardiac MR variables except Qsi, as calculated by LV stroke volume multiplied by heart rate, showed significant improvement after LuTx. Note the high variability and inconsistent changes in cardiac index (Qsi) post-LuTx (see main text). Either the Wilcoxon signed-rank test or paired two-tailed t-test was used. *p < 0.05, ***p < 0.001, n = 6. The box and whisker plots (third column) show the median, interquartile range (IQR), and 10-90th percentile. The scatter plots (fourth column) show the 95% confidence interval for the median. Abbreviations: MR, magnetic resonance; RV, right ventricle; RVEDV, RV end-diastolic volume; RVESV, RV end-systolic volume; LVESV, left ventricular end-systolic volume; RVEF, RV ejection fraction; Qsi, cardiac index.

      Echocardiographic 2D-speckle tracking (longitudinal RV and LV strain)

      To study modest alterations of RV myocardial contractility with pressure loading (pre-LuTx) and unloading (post-LuTx), we performed biventricular echocardiographic 2D-speckle tracking and subsequent longitudinal strain analysis (2D LS) in 13 of 15 patients with severe PAH (2/15 patients had insufficient 4-chamber view Echo windows post-LuTx) (Table S5). Figure 3 shows representative original still frames and longitudinal strain analysis of the RV (Figure 3 A,B) and LV (Figure 3 C,D) in a child with IPAH, pre- and post-LuTx. RV longitudinal strain (RV 4CSL) was greatly abnormal in PAH patients pre-LuTx (mean -12.60 ± 1.75 %), and recovered to commonly accepted normal values (green zone) two months post-LuTx (mean -22.07 ± 2.34 %; Figure 3E,F). Consistent changes in the segmental and average RV longitudinal strain are shown in Figure S3. In contrast, LV longitudinal strain (LV 4CSL) was low normal in PAH pre-LuTx (mean -20.41±2.01 %) and increased to higher values in approximately half of the PAH patients post-LuTx (Figure 3 G,H). These findings are consistent with reversal of the underlying pathophysiology, that is, RV pressure overload and RV failure. Consistent changes in the segmental and average RV longitudinal strain are shown in Figure S3.
      Figure 3
      Figure 3Echocardiographic 2D-speckle tracking (longitudinal RV and LV strain). Figures 3 A-D show representative frames and longitudinal strain analysis of the RV and LV of patient No. 15 with IPAH, pre- and post-LuTx. Figures 3 E-H show the results of 2 D strain analysis of the 13 patients with accessible cardiac strain data pre- and post-LuTx. RV longitudinal strain (RV 4CSL) was abnormal in almost all PAH patients pre-LuTx (mean -12.60 ± 1.75%), and recovered to commonly accepted normal values within 2 months post-LuTx. The paired two-tailed t-test was used reaching statistical significance for RV 4CLS strain changes pre- and post-LuTx (***p < 0.001, n = 13). Figure 3 E+G show the individual changes of each of the thirteen patients with sufficient 2D-speckle tracking data pre- and post-LuTx (percentage change). The box and whisker plots (Figure 3 F+H) show the median, interquartile range (IQR), and 10-90th percentile. Changes were also evident for LV strain analysis (LV 4CSL), not reaching statistical significance. Abbreviations: RV, right ventricle; RV 4CSL, RV 4-chaber longitudinal strain; LV, left ventricle; LV 4CSL, LV 4-chamber longitudinal strain.

      Cardiac MR-based RV and LV tissue tracking (TT strain analysis)

      To assess not only biventricular longitudinal, but also radial and circumferential strain, independently of the limited echocardiographic windows especially post-LuTx, we conducted cardiac MR tissue tracking and strain analysis in six end-stage PAH patients pre- and post-LuTx. Figure 4 shows an exemplary original 4-chamber MR cine image, the corresponding tissue tracking (Figure 4A) and RV longitudinal strain analysis (Figure 4B). MR-based RV radial strain (RVRS) increased from a mean of 10.25% ± 1.37 % pre-LuTx, to 20.85% ± 1.32 % post-LuTx (Figure 4C). Likewise, MR-based RV circumferential strain (Figure 4E,F) and circumferential strain rate (Figure 4G,H) approximately doubled after RV pressure unloading post-LuTx. Finally, consistently with the 2D-echocardiographical strain data, the MR-based RV longitudinal strain improved from 10.22 ± 1.14 % pre-LuTx by approx. 73% to -17.7% ± 3.12% post-LuTx (Figure 4I,J). In contrast to the aforementioned significant changes in RV strain by MR-tissue tracking, neither the LV radial, circumferential nor longitudinal strain changed significantly post- vs pre-LuTx (Table S5).
      Figure 4
      Figure 4Cardiac magnetic resonance tissue tracking and right ventricular strain analysis. Figure 4A presents the tissue tracking along the endocardial and epicardial border for subsequent biventricular longitudinal strain analysis. Figure 4B shows a representative RV longitudinal strain curve taken from the 4-chamber RV. Figures 4C-J demonstrate the rapid improvement (normalization) of RV radial strain (C, D), RV circumferential strain (E, F) and strain rate (G, H), and RV longitudinal strain (I, J) approx. 6-8 weeks after bilateral lung transplantation (LuTx). The individual patients with patient IDs and individual percent changes are shown in C, E, G, I. The according quantification of strain, strain rate and change thereof, are represented in the bar graphs on the right in D, F, H, and J. Either the Wilcoxon signed-rank test or paired two-tailed t-test was used. *p < 0.05, **p < 0.01, n = 6. The box and whisker plots (third column) show the median, interquartile range (IQR), and 10-90th percentile. The scatter plots (fourth column) show the 95% confidence interval for the median. Abbreviations: 4C, 4-chamber; RV, right ventricle; RVRS, RV radial strain; RVCS, RV circumferential strain; RVCSR, RV circumferential strain rate; RVLS, RV longitudinal strain.

      Discussion

      The clinical course of severe PAH in young patients is frequently characterized by late diagnosis, a biphasic treatment response, rapid progression of PVD, and a late but sharp decline of RV performance.
      • Hansmann G
      Pulmonary hypertension in infants, children, and young adults.
      ,
      • Hansmann G
      • Koestenberger M
      • Alastalo TP
      • et al.
      2019 updated consensus statement on the diagnosis and treatment of pediatric pulmonary hypertension: The European Pediatric Pulmonary Vascular Disease Network (EPPVDN), endorsed by AEPC, ESPR and ISHLT.
      Thus, pediatric patients with severe PH and RV dysfunction should be referred early for LuTx evaluation, even if they do not meet the 2015 criteria for listing of primarily adults by the ISHLT
      • Weill D
      • Benden C
      • Corris PA
      • et al.
      A consensus document for the selection of lung transplant candidates: 2014–an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation.
      (NYHA functional class 3 or 4 without improvement, cardiac index <2 L/min/m2, and mean right atrial pressure of >15 mm Hg).
      The major finding of this prospective observational imaging study is the demonstration of rapid and full recovery of RV systolic function within ∼6 weeks in children undergoing LuTx for severe PAH, irrespective of the severity of RV dysfunction, need for VA-ECMO pre-LuTx, age, or weight. RV pressure unloading following LuTx resulted in complete normalization of RV ejection fraction, improving from 30% to 63%, as determined by cardiac MRI (Figure 2G,H). In contrast to the persistently increased RV mass, RV volumes rapidly normalized within 6 weeks after LuTx. We introduced the MRI-based RV/LV end-systolic volume ratio that is an indicator of all, pressure-overload induced RV dilation, systolic leftward septal shift, and LV underfilling. The MRI-based RV/LV end-systolic volume ratio appeared superior to the classical RVEDV indexed to BSA in our cohort.
      Our data demonstrate that readily available transthoracic echocardiography
      • Koestenberger M
      • Friedberg MK
      • Ravekes W
      • Nestaas E
      • Hansmann G
      Non-invasive imaging for congenital heart disease: recent innovations in transthoracic echocardiography.
      ,
      • Koestenberger M
      • Apitz C
      • Abdul-Khaliq H
      • Hansmann G
      Transthoracic echocardiography for the evaluation of children and adolescents with suspected or confirmed pulmonary hypertension. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and D6PK.
      can sufficiently document the post-LuTx improvements of RVH, RV dilation, and LV filling. In this regard, we unraveled the RV/LV end-systolic diameter ratio,
      • Koestenberger M
      • Sallmon H
      • Avian A
      • et al.
      Ventricular-ventricular interaction variables correlate with surrogate variables of clinical outcome in children with pulmonary hypertension.
      ,
      • Koestenberger M
      • Friedberg MK
      • Nestaas E
      • Michel-Behnke I
      • Hansmann G
      Transthoracic echocardiography in the evaluation of pediatric pulmonary hypertension and ventricular dysfunction.
      LV end-systolic eccentricity index (LVES EI),
      • Burkett DA
      • Patel SS
      • Mertens L
      • Friedberg MK
      • Ivy DD
      Relationship between left ventricular geometry and invasive hemodynamics in pediatric pulmonary hypertension.
      ,
      • Koestenberger M
      • Hansmann G
      Left ventricular geometry and near-simultaneous invasive hemodynamics in pediatric pulmonary hypertension.
      and RV end-systolic remodeling index (RVES RI)
      • Koestenberger M
      • Avian A
      • Chouvarine P
      • et al.
      Right ventricular end-systolic remodeling index in the assessment of pediatric pulmonary arterial hypertension. The European Pediatric Pulmonary Vascular Disease Network (EPPVDN).
      as the most robust and useful echocardiographic markers.
      • Koestenberger M
      • Friedberg MK
      • Ravekes W
      • Nestaas E
      • Hansmann G
      Non-invasive imaging for congenital heart disease: recent innovations in transthoracic echocardiography.
      ,
      • Koestenberger M
      • Apitz C
      • Abdul-Khaliq H
      • Hansmann G
      Transthoracic echocardiography for the evaluation of children and adolescents with suspected or confirmed pulmonary hypertension. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and D6PK.
      ,
      • Koestenberger M
      • Friedberg MK
      • Nestaas E
      • Michel-Behnke I
      • Hansmann G
      Transthoracic echocardiography in the evaluation of pediatric pulmonary hypertension and ventricular dysfunction.
      ,
      • Meinel K
      • Koestenberger M
      • Sallmon H
      • Hansmann G
      • Pieles GE
      Echocardiography for the assessment of pulmonary hypertension and congenital heart disease in the young.
      We
      • Koestenberger M
      • Sallmon H
      • Avian A
      • et al.
      Ventricular-ventricular interaction variables correlate with surrogate variables of clinical outcome in children with pulmonary hypertension.
      and others
      • Burkett DA
      • Patel SS
      • Mertens L
      • Friedberg MK
      • Ivy DD
      Relationship between left ventricular geometry and invasive hemodynamics in pediatric pulmonary hypertension.
      ,
      • Jone PN
      • Hinzman J
      • Wagner BD
      • Ivy DD
      • Younoszai A
      Right ventricular to left ventricular diameter ratio at end-systole in evaluating outcomes in children with pulmonary hypertension.
      showed that children with more than mild PH had increased RV/LV end-systolic dimension ratio (>1) that reached a grossly abnormal ratio of 2.6 pre-LuTx in the end-stage PAH children of the current study (Figure 1E,F). Both, the RV/LV end-systolic diameter ratio and the LVES EI correlate with invasive hemodynamics and outcome measures; a LVES EI of 1.42 and 1.94 best identified half-systemic and systemic pediatric PH, respectively.
      • Burkett DA
      • Patel SS
      • Mertens L
      • Friedberg MK
      • Ivy DD
      Relationship between left ventricular geometry and invasive hemodynamics in pediatric pulmonary hypertension.
      The RVES RI was increased in 2 pediatric cohorts with mild to moderate PH (1.45 ± 0.16; 1.50 ± 0.29) vs healthy controls (1.16 ± 0.06),
      • Koestenberger M
      • Avian A
      • Chouvarine P
      • et al.
      Right ventricular end-systolic remodeling index in the assessment of pediatric pulmonary arterial hypertension. The European Pediatric Pulmonary Vascular Disease Network (EPPVDN).
      and strongly predicted outcome in adults with PAH.
      • Amsallem M
      • Sweatt AJ
      • Aymami MC
      • et al.
      Right heart end-systolic remodeling index strongly predicts outcomes in pulmonary arterial hypertension: comparison with validated models.
      In the current study, RVES RI was greatly abnormal before LuTx (1.53), and decreased after LuTx in all PH patients to a median of 1.27 (normal <1.2; Figure S1), outperforming TAPSE as a marker of RV longitudinal shortening and systolic-diastolic volume change. TAPSE data had very high variability pre- and post-LuTx (Figure 1I,J). Indeed, we found a decline in TAPSE after LuTx in about half of the transplanted PH patients, probably due to RV rotation after pressure unloading and, consecutively, a major change in the angle of M-mode interrogation. PAH outpatients may have advanced disease but normal TAPSE z-scores,
      • Koestenberger M
      • Ravekes W
      • Nagel B
      • et al.
      Reference values of the right ventricular outflow tract systolic excursion in 711 healthy children and calculation of z-score values.
      and, indeed, several of the 15 PH children in the current study were transplanted with “normal” TAPSE values. Thus, we question the usefulness of conventional TAPSE to monitor deteriorating or recovering global RV systolic function in the setting of pressure (un)loading. Therefore, we suggest that global systolic function may be best determined by the Echo-derived RV/LV end-systolic diameter ratio, LV end-systolic eccentricity index, and RV end-systolic remodeling index, as well as, the MRI-based RVEF (gold standard) and RV/LV end-systolic volume ratio.
      In addition to the above standard-of-care diagnostics, we conducted echocardiographic 2D speckle tracking (4-chamber longitudinal strain, 4CSL) and MR Tissue Tracking (MR-derived longitudinal, radial, and circumferential strain) analysis pre- and post-LuTx. We chose echocardiographic 2D 4CSL because of its reported superiority in adult PAH over circumferential and radial strain, and even conventional RV function variables, in terms of sensitivity and its ability to predict adverse clinical outcomes.
      • Li Y
      • Wang T
      • Haines P
      • et al.
      Prognostic value of right ventricular two-dimensional and three-dimensional speckle-tracking strain in pulmonary arterial hypertension: superiority of longitudinal strain over circumferential and radial strain.
      Here, we demonstrate much improved longitudinal contractility of the RV (2D 4CSL) after LuTx in PAH children, whereas LV strain remained stable or only slightly increased (Figure 3H). Echo-based RV 4CSL can aid in the echocardiographic judgement of pediatric PAH treatment response as it relates to RV performance. In a subgroup of six pediatric patients, we conducted advanced MRI-based tissue tracking/strain analysis, confirmed the echocardiographic 4CSL findings on much improved RV longitudinal contractility, and unraveled an even more improved MR-derived radial as well as circumferential strain and strain rate after complete RV unloading post-LuTx.
      The ISHLT Thoracic Transplant registry (2000-2017) reported a total of 178 pediatric LuTx for IPAH and 78 pediatric LuTx for PH non-IPAH.
      • Goldfarb SB
      • Hayes Jr., D
      • Levvey BJ
      • et al.
      The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Twenty-first Pediatric Lung and HeartLung Transplantation Report-2018; Focus Theme: Multiorgan Transplantation.
      The combined PH group was the most frequent indication for LuTx in children 0-5 years old.
      • Goldfarb SB
      • Hayes Jr., D
      • Levvey BJ
      • et al.
      The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Twenty-first Pediatric Lung and HeartLung Transplantation Report-2018; Focus Theme: Multiorgan Transplantation.
      Given all, (1) the shortage of heart-lung blocs in N. America and Europe, as evidenced by less than eight pediatric HLTx/year for the last 10 years in the UNOS registry,
      • Melicoff E
      • Hayes Jr., D
      • Benden C
      Lung transplantation as an intervention for pediatric pulmonary hypertension.
      (2) the surgical complexity of HLTx in comparison to LuTx, (3) the rapid recovery of RV systolic function after LuTx, as demonstrated in the current study, and (4) excellent midterm outcomes after LuTx for PAH in high volume centers,
      • Melicoff E
      • Hayes Jr., D
      • Benden C
      Lung transplantation as an intervention for pediatric pulmonary hypertension.
      HLTx appears an obsolete treatment option for end-stage group 1 PH (PAH), at least in children >2 years of age,
      • Gorler H
      • Struber M
      • Ballmann M
      • et al.
      Lung and heart-lung transplantation in children and adolescents: a long-term single-center experience.
      in the absence of complex CHD
      • Brouckaert J
      • Verleden SE
      • Verbelen T
      • et al.
      Double-lung versus heart-lung transplantation for precapillary pulmonary arterial hypertension: a 24-year single-center retrospective study.
      or other rare circumstances (see below).
      Combined heart-lung transplantation rather than LuTx is considered in patients with postcapillary PH due to persistent LV dysfunction (e.g., cardiomyopathy), in precapillary PH and additional LV dysfunction that cannot be explained by PAH-related ventricular-ventricular interaction, in complex CHD, or after surgical correction of multiple pulmonary vein stenoses. Other circumstances that would make a patient not a good candidate for LuTx include severe concerns regarding parental compliance, language barrier, severe dystrophy etc. (see 2021 ISHLT consensus document).
      • Leard LE
      • Holm AM
      • Valapour M
      • et al.
      Consensus document for the selection of lung transplant candidates: An update from the International Society for Heart and Lung Transplantation.
      Our current study is limited by the low number of patients enrolled and wide age range. While these are typical limitations in pediatric studies on a rare and fatal disease, we feel our data collection and analysis still provides very valuable information on the timing and magnitude of RV recovery after pressure unloading for severe PH. To minimize selection bias and heterogeneity of PH etiology, we enrolled the subjects consecutively and only those with WSPH group 1 PH (IPAH/HPAH, PAH-CHD, PVOD/PCH).

      Conclusions

      Six weeks after bilateral LuTx for severe PAH and RV failure, RV volumes and systolic RV function completely normalize, even in children with severe RV failure (RVEF <40%). Therefore, in end-stage pediatric PAH with poor RV function and low cardiac output, LuTx should be preferred over heart-lung transplantation. We propose that the RV/LV end-systolic ratios by Echo (diameter) and MRI (volumes) are excellent diagnostic tools for pediatric PAH outpatient follow up. In our prospective observational study, MR-based RVEF and tissue tracking (longitudinal, radial, circumferential strain) were superior to echocardiographic TAPSE in the evaluation of clinically relevant global systolic RV dysfunction in both the pressure loaded and unloaded RV. In addition, children with PAH have reduced RV 2D longitudinal strain that improves following LuTx. Perspectively, easily obtainable RV/LV end-systolic ratios and echocardiographic 2D RV longitudinal strain can likely track clinical improvement in pediatric PAH and may provide valuable prognostic information beyond LuTx, for example, the response to add-on PAH-targeted pharmacotherapy.

      Author contributions

      G.H. conceptualized, designed and supervised the study, and wrote the manuscript. F.D. provided clinical data, performed statistical analysis and produced display items. P.C. performed advanced statistical analysis and produced display items. F.I. provided clinical data. T.J., T.A., D.H. and G.H. performed quantitative imaging analysis. All authors reviewed and revised the manuscript for important intellectual content.

      Disclosure statement

      All authors declare they have no conflict of interest related to the content of this work.
      This study was supported by the German Research Foundation (DFG KFO311; HA4348/6-2 to G.H.) and the European Pediatric Pulmonary Vascular Disease Network (www.pvdnetwork.org). Dr. Hansmann receives additional funding from the Federal Ministry of Education and Research (BMBF ViP+ program 03VP08053; BMBF 01KC2001B).

      Acknowledgment

      The authors thank Holger Schürmann (Philipps, Hamburg, Germany), Angelos Patogiannes and Daniel Röbke (both TomTec, Unterschleissheim, Germany) for their assistance with the echocardiographic 2D strain analysis software.

      Appendix. Supplementary materials

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      Related Podcast

      JHLT: The Podcast Episode 14: February 2022

      Join Daniel R. Goldstein, MD, Editor-in-Chief of JHLT, and the JHLT Digital Media Editors for two interviews with authors from the February issue of The Journal of Heart and Lung Transplantation.

      First, the editors speak with Georg Hansmann, MD, PhD, Associate Professor of Pediatrics at Hannover Medical School. Dr. Hansmann is the lead author on a paper entitled “Full recovery of right ventricular systolic function in children undergoing bilateral lung transplantation for severe PAH.” Beginning at 1:37, Erika Lease, MD, interviews Dr. Hansmann about the findings of the study, follow up recommendations, and potential practice changes in clinical settings.

      Starting at 14:27, Marty Tam, MD, is in conversation with Jan Griffin, MD, Assistant Professor of Medicine at Columbia University Irving Medical Center, about her study from the February issue: “Surveillance for disease progression of transthyretin amyloidosis (ATTR) post heart transplantation in the era of novel disease modifying therapies.” Dr. Griffin discusses her team’s work on transplanting patients with TTR cardiac amyloidosis, a structured surveillance program, and disease modifying agents post-transplant.