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Guignabert C, Alvira CM, Alastalo T-P, Sawada H, Hansmann G, Zhao M, Wang L, El-Bizri N, Rabinovitch M. Tie2-mediated loss of peroxisome proliferator-activated receptor-[gamma] in mice causes PDGF receptor-[beta]-dependent pulmonary arterial muscularization. Am J Physiol Lung Cell Mol Physiol 297: L1082-L1090, 2009. First published October 2, 2009; doi: 10.1152/ajplung.00199.2009.--Peroxisome proliferator-activated receptor (PPAR)-[gamma] is reduced in pulmonary arteries (PAs) of patients with PA hypertension (PAH), and we reported that deletion of PPAR[gamma] in smooth muscle cells (SMCs) of transgenic mice results in PAH. However, the sequelae of loss of PPAR[gamma] in PA endothelial cells (ECs) are unknown. Therefore, we bred Tie2-Cre mice with PPAR[[gamma].sup.flox/flox] mice to induce EC loss of PPAR[gamma] (Tie2 PPAR[[gamma].sup.-/-]), and we assessed PAH by right ventricular systolic pressure (RVSP), RV hypertrophy (RVH), and muscularized distal PAs in room air (RA), after chronic hypoxia (CH), and after 4 wk of recovery in RA (Rec-RA). The Tie2 PPAR[[gamma].sup.-/-] mice developed spontaneous PAH in RA with increased RVSP, RVH, and muscularized PAs vs. wild type (WT); both genotypes exhibited a similar degree of PAH following chronic hypoxia, but Tie2 PPAR[[gamma].sup.-/-] mice had more residual PAH compared with WT mice after Rec-RA. The Tie2 PPAR[[gamma].sup.-/-] vs. WT mice in RA had increased platelet-derived growth factor receptor-[beta] (PDGF-R[beta]) expression and signaling, despite an elevation in the PPAR[gamma] target apolipoprotein E, an inhibitor of PDGF signaling. Inhibition of PDGF-R[beta] signaling with imatinib, however, was sufficient to reverse the PAH observed in the Tie2 PPAR[[gamma.sup.-/-] mice. Thus the disruption of PPAR[gamma] signaling in EC is sufficient to cause mild PAH and to impair recovery from CH-induced PAH. Inhibition of heightened PDGF-R[beta] signaling is sufficient to reverse PAH in this genetic model. endothelial cells; platelet-derived growth factor receptor-[beta]; pulmonary remodeling; smooth muscle cell; platelet-derived growth factor doi: 10.1152/ajplung.00199.2009

Peroxisome proliferator-activated receptor (PPAR)-γ is reduced in pulmonary arteries (PAs) of patients with PA hypertension (PAH), and we reported that deletion of PPAR-y in smooth muscle cells (SMCs) of transgenic mice results in PAH. However, the sequelae of loss of PPAR-γ in PA endothelial cells (ECs) are unknown. Therefore, we bred Tie2-Cre mice with PPARγflox/flox mice to induce EC loss of PPARγ (Tie2 PPAR-γ-/-), and we assessed PAH by right ventricular systolic pressure (RVSP), RV hypertrophy (RVH), and muscularized distal PAs in room air (RA), after chronic hypoxia (CH), and after 4 wk of recovery in RA (Rec-RA). The Tie2 PPARγ-/- mice developed spontaneous PAH in RA with increased RVSP, RVH, and muscularized PAs vs. wild type (WT); both genotypes exhibited a similar degree of PAH following chronic hypoxia, but Tie2 PPARγ-/- mice had more residual PAH compared with WT mice after Rec-RA. The Tie2 PPARγ-/- vs. WT mice in RA had increased platelet-derived growth factor receptor-β (PDGF-Rβ) expression and signaling, despite an elevation in the PPARγ target apolipoprotein E, an inhibitor of PDGF signaling. Inhibition of PDGF-Rγ signaling with imatinib, however, was sufficient to reverse the PAH observed in the Tie2 PPARγ-/- mice. Thus the disruption of PPARγ signaling in EC is sufficient to cause mild PAH and to impair recovery from CH-induced PAH. Inhibition of heightened PDGF-Rβ signaling is sufficient to reverse PAH in this genetic model. [ABSTRACT FROM AUTHOR]

Ozone oxidation is proven to be an effective solution for the degradation of selected oestrogenic active substances detected in secondary wastewaters such as β-oestradiol, oestrone, oestriol, 17-α-ethinyloestradiol, mestranol, daidzeine, β-sitosterol, bisphenol A, norethisterone, 4-tertoctylphenol and 4-iso-nonylphenol, up to their limit of detection. The matrix-effect of wastewater was investigated performing ozone experiments under batch mode and continuous mode using drinking water and a wastewater issued from a local plant both spiked with the non-detected substances. The results obtained indicate that the wastewater matrix greatly affects the kinetics of ozone reaction with these substances but does not really change the related reactivity scale. The ozone dose corresponding to the full conversion of target EDCs consequently increases as their oxidation takes place competing with reactions of background pollutants represented by the COD and DOC content. However, a usual dose close to 12 mg/L was found sufficient to provide high degradation yields for all substances studied while 35% of COD was removed. This is a contribution to the numerous current works focused on technologies able to improve the quality of water discharged from wastewater treatment plants, both considering conventional parameters and emerging contaminants. [ABSTRACT FROM AUTHOR]

Children with left heart disease are at risk for developing pulmonary hypertension, initially secondary to pulmonary venous hypertension that can progress to include elevated pulmonary vascular resistance, known as combined pre- and postcapillary pulmonary hypertension. Elevated pulmonary vascular resistance may pose a risk to the right ventricle of a newly transplanted heart because of increased afterload and is an important consideration for heart transplant eligibility. However, the epidemiology, pathophysiology, optimal diagnostic and treatment approaches, and thresholds for pulmonary vascular resistance in pulmonary hypertension associated with left heart disease remain unclear because of lack of evidence, particularly in pediatrics. The result is heterogeneity with respect to hemodynamic assessment, use of pulmonary vasodilator therapies, and heart transplant listing. This scientific statement aims to synthesize the available data and highlight areas of general consensus as well as important knowledge gaps.

Cardiovascular magnetic resonance (CMR) imaging is recommended in patients with congenital heart disease (CHD) in clinical practice guidelines as the imaging standard for a large variety of diseases. As CMR is evolving, novel techniques are becoming available. Some of them are already used clinically, whereas others still need further evaluation. In this statement, the authors give an overview of relevant new CMR techniques for the assessment of CHD. Studies with reference values for these new techniques are listed in the Supplementary data online, supplement., Competing Interests: Conflict of interest: The authors have nothing to Disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Objectives:  Patients with congenital heart disease frequently require surgical or percutaneous interventional valve replacement after initial congenital heart defect (CHD) repair. In some of these patients, simultaneous replacement of both semilunar valves is necessary, resulting in increased procedural complexity, morbidity, and mortality. In this study, we analyze the outcomes of simultaneous aortic and pulmonary valve replacements following multiple surgical interventions for CHD., Methods:  This was a retrospective study of 24 patients who after initial repair of CHD underwent single-stage aortic and pulmonary valve replacement at our institution between 2003 and 2021., Results:  The mean age of the patients was 28 ± 13 years; the mean time since the last surgery was 15 ± 11 years. Decellularized valved homografts (DVHs) were used in nine patients, and mechanical valves were implanted in seven others. In eight patients, DVHs, biological, and mechanical valves were implanted in various combinations. The mean cardiopulmonary bypass time was 303 ± 104 minutes, and aortic cross-clamp time was 152 ± 73 minutes. Two patients died at 12 and 16 days postoperatively. At a maximum follow-up time of 17 years (mean 7 ± 5 years), 95% of the surviving patients were categorized as New York Heart Association heart failure class I., Conclusion:  Single-stage aortic and pulmonary valve replacement after initial repair of CHD remains challenging with substantial perioperative mortality (8.3%). Nevertheless, long-term survival and clinical status at the latest follow-up were excellent. The valve type had no relevant impact on the postoperative course. The selection of the valves for implantation should take into account operation-specific factors-in particular reoperability-as well as the patients' wishes., Competing Interests: A.H. holds shares in Corlife oHG, the company providing the patented service of processing decellularized allografts used in this study. All other authors declared no potential conflict of interest with respect to the study, authorship, and publication of this article., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

The serotonin pathway has long been proposed as a promising target for pulmonary arterial hypertension (PAH)-a progressive and uncurable disease. We developed a highly specific inhibitor of the serotonin synthesizing enzyme tryptophan hydroxylase 1 (TPH1), TPT-001 (TPHi). In this study, the authors sought to treat severe PAH in the Sugen/hypoxia (SuHx) rat model with the oral TPHi TPT-001. Male Sprague Dawley rats were divided into 3 groups: 1) ConNx, control animals; 2) SuHx, injected subcutaneously with SU5416 and exposed to chronic hypoxia for 3 weeks, followed by 6 weeks in room air; and 3) SuHx+TPHi, SuHx animals treated orally with TPHi for 5 weeks. Closed-chest right- and left heart catheterization and echocardiography were performed. Lungs were subject to histologic and mRNA sequencing analyses. Compared with SuHx-exposed rats, which developed severe PAH and right ventricular (RV) dysfunction, TPHi-treated SuHx rats had greatly lowered RV systolic (mean ± SEM: 41 ± 2.3 mm Hg vs 86 ± 6.5 mm Hg; P  < 0.001) and end-diastolic (mean ± SEM: 4 ± 0.7 mm Hg vs 14 ± 1.7 mm Hg; P  < 0.001) pressures, decreased RV hypertrophy and dilation (all not significantly different from control rats), and reversed pulmonary vascular remodeling. We identified perivascular infiltration of CD3 + T cells and proinflammatory F4/80 + and CD68 + macrophages and proliferating cell nuclear antigen-positive alveolar epithelial cells all suppressed by TPHi treatment. Whole-lung mRNA sequencing in SuHx rats showed distinct gene expression patterns related to pulmonary arterial smooth muscle cell proliferation (Rpph1, Lgals3, Gata4), reactive oxygen species, inflammation (Tnfsrf17, iNOS), and vasodilation (Pde1b, Kng1), which reversed expression with TPHi treatment. Inhibition of TPH1 with a new class of drugs (here, TPT-001) has the potential to attenuate or even reverse severe PAH and associated RV dysfunction in vivo by blocking the serotonin pathway., Competing Interests: This study was funded by the Federal Ministry of Education and Research (01KC2001B and 03VP08053 to Dr Hansmann; 01KC2001A, 03VP08051, and 16GW0298 to Dr Bader). Dr Hansmann also receives funding from the German Research Foundation (DFG KFO311 grant HA4348/6-2) and the European Pediatric Pulmonary Vascular Disease Network. Dr Nazaré has received funding from the Federal Ministry of Economic Affairs (ZIM grant 16KN073251). Drs Specker, Nazaré, Matthes, and Bader hold patents on the novel class of TPHi. Drs Specker, Wesolowski, and Bader are founders of Trypto Therapeutics GmbH. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Post-COVID syndrome (PCS) can adversely affect the quality of life of patients and their families. In particular, the degree of cardiac impairment in children with PCS is unknown., Objective: The aim of this study was to identify potential cardiac inflammatory sequelae in children with PCS compared with healthy controls., Methods: This single-center, prospective, intraindividual, observational study assesses cardiac function, global and segment-based strains, and tissue characterization in 29 age- and sex-matched children with PCS and healthy children using a 3 T magnetic resonance imaging (MRI)., Results: Cardiac MRI was carried out over 36.4 ± 24.9 weeks post-COVID infection. The study cohort has an average age of 14.0 ± 2.8 years, for which the majority of individuals experience from fatigue, concentration disorders, dyspnea, dizziness, and muscle ache. Children with PSC in contrast to the control group exhibited elevated heart rate (83.7 ± 18.1 beats per minute vs 75.2 ± 11.2 beats per minute, P = 0.019), increased indexed right ventricular end-diastolic volume (95.2 ± 19.2 mlm -2 vs 82.0 ± 21.5 mlm -2 , P = 0.018) and end-systolic volume (40.3 ± 7.9 mlm -2 vs 34.8 ± 6.2 mlm -2 , P = 0.005), and elevated basal and midventricular T1 and T2 relaxation times ( P < 0.001 to P = 0.013). Based on the updated Lake Louise Criteria, myocardial inflammation is present in 20 (69%) children with PCS. No statistically significant difference was observed for global strains., Conclusions: Cardiac MRI revealed altered right ventricular volumetrics and elevated T1 and T2 mapping values in children with PCS, suggestive for a diffuse myocardial inflammation, which may be useful for the diagnostic workup of PCS in children., Competing Interests: Conflicts of interest and sources of funding: Ministry for Science and Culture of Lower Saxony in Germany (grant number: ZN3894); Radiological Cooperative Network (RACOON) of the Network University Medicine (NUM) under the BMBF grant numbers 01KX2021 and 01KX2121., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Alveolar hypoxia is protective in the context of cardiovascular and ischemic heart disease; however, the underlying mechanisms are incompletely understood. The present study sought to test the hypothesis that hypoxia is cardioprotective in left ventricular pressure overload (LVPO)-induced heart failure. We furthermore aimed to test that overlapping mechanisms promote cardiac recovery in heart failure patients following left ventricular assist device-mediated mechanical unloading and circulatory support., Methods and Results: We established a novel murine model of combined chronic alveolar hypoxia and LVPO following transverse aortic constriction (HxTAC). The HxTAC model is resistant to cardiac hypertrophy and the development of heart failure. The cardioprotective mechanisms identified in our HxTAC model include increased activation of HIF (hypoxia-inducible factor)-1α-mediated angiogenesis, attenuated induction of genes associated with pathological remodeling, and preserved metabolic gene expression as identified by RNA sequencing. Furthermore, LVPO decreased Tbx5 and increased Hsd11b1 mRNA expression under normoxic conditions, which was attenuated under hypoxic conditions and may induce additional hypoxia-mediated cardioprotective effects. Analysis of samples from patients with advanced heart failure that demonstrated left ventricular assist device-mediated myocardial recovery revealed a similar expression pattern for TBX5 and HSD11B1 as observed in HxTAC hearts., Conclusions: Hypoxia attenuates LVPO-induced heart failure. Cardioprotective pathways identified in the HxTAC model might also contribute to cardiac recovery following left ventricular assist device support. These data highlight the potential of our novel HxTAC model to identify hypoxia-mediated cardioprotective mechanisms and therapeutic targets that attenuate LVPO-induced heart failure and mediate cardiac recovery following mechanical circulatory support.

Pulmonary hypertension (PH) is the most severe complication in preterm infants with bronchopulmonary dysplasia (BPD) and associated with significant mortality. Diagnostic and treatment strategies, however, still lack standardization. By the use of a survey study (PH in BPD), we assessed clinical practice (diagnosis, treatment, follow-up) in preterm infants with early postnatal persistent pulmonary hypertension of the newborn (PPHN) as well as at risk for or with established BPD-associated PH between 06/2018 and 10/2020 in two-thirds of all German perinatal centers with >70 very low birthweight infants/year including their cardiology departments and outpatient units. Data were analyzed descriptively by measures of locations and distributional shares. In routine postnatal care, clinical presentation and echocardiography were reported as the main diagnostic modalities to screen for PPHN in preterm infants, whereas biomarkers brain natriuretic peptide/N-terminal pro b-type natriuretic peptide were infrequently used. For PPHN treatment, inhaled nitric oxide was used in varying frequency. The majority of participants agreed to prescribe diuretics and steroids (systemic/inhaled) for infants at risk for or with established BPD-associated PH and strongly agreed on recommending respiratory syncytial virus immunization and the use of home monitoring upon discharge. Reported oxygen saturation targets, however, varied in these patients in in- and outpatient care. The survey reveals shared practices in diagnostic and therapeutic strategies for preterms with PPHN and BPD-associated PH in Germany. Future studies are needed to agree on detailed echo parameters and biomarkers to diagnose and monitor disease next to a much-needed agreement on the use of pulmonary vasodilators, steroids, and diuretics as well as target oxygen saturation levels., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Excessive renal TGF-β production and pro-fibrotic miRNAs are important drivers of kidney fibrosis that lack any efficient treatment. Dysfunctional autophagy might play an important role in the pathogenesis. We aimed to study the yet unknown effects of peroxisome proliferator-activated receptor-γ (PPARγ) agonist pioglitazone (Pio) on renal autophagy and miRNA dysregulation during fibrosis. Mouse primary tubular epithelial cells (PTEC) were isolated, pre-treated with 5 µM pioglitazone, and then stimulated with 10 ng/mL TGF-β1 for 24 h. Male 10-week-old C57Bl6 control (CTL) and TGF-β overexpressing mice were fed with regular chow (TGF) or Pio-containing chow (20 mg/kg/day) for 5 weeks (TGF + Pio). PTEC and kidneys were evaluated for mRNA and protein expression. In PTEC, pioglitazone attenuated ( p < 0.05) the TGF-β-induced up-regulation of Col1a1 (1.4-fold), Tgfb1 (2.2-fold), Ctgf (1.5-fold), Egr2 (2.5-fold) mRNAs, miR-130a (1.6-fold), and miR-199a (1.5-fold), inhibited epithelial-to-mesenchymal transition, and rescued autophagy function. In TGF mice, pioglitazone greatly improved kidney fibrosis and related dysfunctional autophagy (increased LC3-II/I ratio and reduced SQSTM1 protein content ( p < 0.05)). These were accompanied by 5-fold, 3-fold, 12-fold, and 2-fold suppression ( p < 0.05) of renal Ccl2, Il6, C3, and Lgals3 mRNA expression, respectively. Our results implicate that pioglitazone counteracts multiple pro-fibrotic processes in the kidney, including autophagy dysfunction and miRNA dysregulation.

Background: Bilateral lung transplantation (LuTx) remains the only established treatment for children with end-stage pulmonary arterial hypertension (PAH). Although PAH is the second most common indication for LuTx, little is known about optimal perioperative management and midterm clinical outcomes., Methods: Prospective observational study on consecutive children with PAH who underwent LuTx with scheduled postoperative VA-ECMO support at Hannover Medical School from December 2013 to June 2020., Results: Twelve patients with PAH underwent LuTx (mean age 11.9 years; age range 1.9-17.8). Underlying diagnoses included idiopathic ( n  = 4) or heritable PAH ( n  = 4), PAH associated with congenital heart disease ( n  = 2), pulmonary veno-occlusive disease ( n  = 1), and pulmonary capillary hemangiomatosis ( n  = 1). The mean waiting time was 58.5 days (range 1-220d). Three patients were bridged to LuTx on VA-ECMO. Intraoperative VA-ECMO/cardiopulmonary bypass was applied and VA-ECMO was continued postoperatively in all patients (mean ECMO-duration 185 h; range 73-363 h; early extubation). The median postoperative ventilation time was 28 h (range 17-145 h). Echocardiographic conventional and strain analysis showed that 12 months after LuTx, all patients had normal biventricular systolic function. All PAH patients are alive 2 years after LuTx (median follow-up 53 months, range 26-104 months)., Conclusion: LuTx in children with end-stage PAH resulted in excellent midterm outcomes (100% survival 2 years post-LuTx). Postoperative VA-ECMO facilitates early extubation with rapid gain of allograft function and sustained biventricular reverse-remodeling and systolic function after RV pressure unloading and LV volume loading., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor SM declared a shared committee working group lung transplantation with the author FI at the time of review., (© 2023 Jack, Carlens, Diekmann, Hasan, Chouvarine, Schwerk, Müller, Wieland, Tudorache, Warnecke, Avsar, Horke, Ius, Bobylev and Hansmann.)

Background: Critical coarctation of the aorta (CoA) is a life-threatening condition in newborns that is associated with biventricular dysfunction., Objectives: The purpose of this study was to examine clinical outcome and echocardiographic changes in isthmus diameter and biventricular function in newborns with critical CoA treated with balloon dilation/stent placement or surgery., Methods: This is a retrospective single-center cohort study of 26 consecutive neonates with isolated critical CoA, who underwent transcatheter intervention (balloon angioplasty/stent; n = 10) or surgical CoA-repair (n = 16) (2012-2021). Isthmus dimensions and biventricular function at baseline and at hospital discharge were examined by echocardiography, including strain analysis of systolic and diastolic function using 2-dimensional speckle tracking., Results: Cardiogenic shock at hospital admission was more frequent in the interventional vs the surgical cohort (50% vs 25% of neonates). Echocardiographic isthmus diameter increased with therapy by 0.9 ± 0.1 mm and 1.0 ± 0.1 mm, respectively. Severe systolic left ventricular (LV) dysfunction was more common in interventional patients pre-therapy (LV ejection fraction <50% in 90% vs 38% of surgical patients), resulting in strongly reduced longitudinal strain (LV: -12.3% vs -16.3%; right ventricle:-13.8% vs -16.1% in the interventional and surgical patients, respectively). Prior to hospital discharge, all 26 patients had full recovery of biventricular systolic function, including normalization of longitudinal, radial, and circumferential LV strain and longitudinal right ventricular free wall strain. Improvement of LV diastolic function by strain analysis was evident in both cohorts pre-hospital discharge., Conclusions: Initial treatment of isolated CoA by percutaneous transcatheter intervention or surgical repair results in recovery of biventricular systolic function, making transcatheter treatment particularly suitable as rescue therapy for neonates with critical CoA., Competing Interests: This study was supported by the 10.13039/501100001659German Research Foundation DFG KFO 311 “Pre-Terminal Heart and Lung Failure–Unloading and Repair” (HA4348/6-2 to G.H.). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2023 The Authors.)

Competing Interests: S. Y. C. is a director, officer, and shareholder of Synhale Therapeutics. The remaining authors declare no conflict of interest.

Background and Objectives: Emerging evidence suggests that increased degradation of von Willebrand factor and decrease in high molecular weight multimers occurs in patients with pulmonary hypertension (PH). However, the link between acquired von Willebrand Syndrome (AVWS) type 2 and PH remains poorly understood., Material and Methods: We retrospectively evaluated the charts of 20 children with PH who underwent bilateral lung transplantation (LuTx) between 2013 and 2022. Von Willebrand variables were determined in 14 of these patients; 11 patients had complete diagnostics including multimer analysis., Results: We confirmed AVWS in 82% of the children studied (9 of 11 patients by multimer analysis). The two remaining patients had suspected AVWS type 2 because of a VWF:Ac/VWF:Ag ratio of <0.7. Platelet dysfunction or suspicion of VWD type 1 were found in two separate patients. All but one of the 14 children with severe PH had a coagulation disorder. Most patients (9 proven, 2 suspected) had AVWS type 2. Notably, 3 of 5 patients (60%) with normal VWF:Ac/VWF:Ag ratio >0.7 had abnormal VWF multimers, indicating AVWS type 2. Hemostatic complications were observed in 4 of 12 (33%) patients with VWS and 3 of 6 (50%) patients without diagnostics and therapy., Conclusion: For children with moderate to severe PH, we recommend systematic analysis of von Willebrand variables, including multimer analysis, PFA-100 and platelet function testing. Awareness of the diagnosis "AVWS" and adequate therapy may help to prevent these patients from bleeding complications in case of surgical interventions or trauma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Wieland, Diekmann, Carlens, Hinze, Lambeck, Jack and Hansmann.)

Objectives: In 2019, the European Paediatric Pulmonary Vascular Disease Network (EPPVDN) developed a PH risk score to assess the risk and severity of pulmonary hypertension (PH) in children and young adults. We conducted a prospective observational study to validate the EPPVDN paediatric PH risk score by means of cardiac magnetic resonance imaging (CMR) and echocardiography., Methods: During the same inpatient stay, the invasive and noninvasive EPPVDN PH risk scores were determined, and a protocol-driven CMR study was performed on 20 PAH children. Subsequently, we correlated the risk scores with imaging variables derived from CMR and echocardiography, including strain. Further, we applied the risk score to nine children with PAH who received add-on selexipag therapy. Before and approximately six months after selexipag start, the risk score and echocardiographic RV strain were determined and delta changes of both were correlated., Results: We found strong correlations of conventional CMR (r = 0.69-0.88), CMR strain (r = 0.71-0.88), advanced echocardiographic (r = 0.65-0.88) and echocardiographic strain variables (r = 0.67-0.86) with the EPPVDN PH risk scores (p < .006). In the selexipag cohort, the change in echo-derived RV free wall strain correlated well with the change in the invasive higher risk score (r = 0.72, p = .028)., Conclusions: We demonstrate strong correlations of outcome-relevant CMR and echocardiographic variables with the EPPVDN PH risk scores, and thus validated the score via independent methods. To achieve broad and easy access, we developed a calculator for the risk score as a web application (www.pvdnetwork.org/pedphriskscore). The novel EPPVDN PH risk score will be useful in routine clinical care and can now be applied in larger paediatric PH studies., (© 2022 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Chronic pulmonary hypertension of infancy (cPHi) is a heterogeneous disease process that contributes to morbidity and mortality in preterm infants. cPHi is most commonly associated with chronic lung disease of prematurity and represents a unique phenotype of bronchopulmonary dysplasia. It is characterized by persistently elevated or newly rising pulmonary vascular resistance and pulmonary artery pressure beyond the first weeks of age. The high-pressure afterload on the right ventricle may or may not be tolerated, depending upon additional cardiovascular shunting and co-morbidities. A comprehensive clinical evaluation combined with advanced hemodynamic assessment by echocardiography and other cardiac imaging modalities help decipher the etiopathologies of disease, identify cardiopulmonary compromise earlier and guide individualized therapeutic intervention tailored by the phenotype. This review summarizes the underlying etiologies, risk factors for development, hemodynamic assessment, management, and follow-up of cPHi in preterm infants. We offer an algorithm for early detection of cPHi and outline research priorities., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: An accurate assessment of the right and left ventricle and their interaction is important in pediatric pulmonary hypertension (PH). Our objective was to provide normal reference values for the right ventricular to left ventricular endsystolic (RV/LVes) ratio and the LV endsystolic eccentricity index (LVes EI) in healthy children and in children with PH., Methods: We conducted an echocardiographic study in 769 healthy children (median age: 3.36 years; range: 1 day-18 years) and validated abnormal values in 44 children with PH (median age: 2.1 years; range: 0.1 months-17.7 years). We determined the effects of gender, age, body length, body weight, and body surface area (BSA) on RV/LVes ratio and LVes EI values. The RV/LVes ratio and LVes EI were measured from the parasternal short axis view between papillary muscle from the endocardial to endocardial surfaces., Results: Both, the RV/LVes ratio and the LVes EI were highly age-dependent: (i) neonates RV/LVes ratio [median 0.83 (range 0.53-1.37)], LVes EI [1.21 (0.92-1.45)]; (ii) 12-24 months old: RV/LVes ratio: [0.55 (0.35-0.80)], LVes EI: [1.0 (0.88-1.13)]; iii) 18th year of life RV/LVes ratio: [0.53 (0.32-0.74)], LVes EI: [1.0 (0.97-1.07)]. Healthy neonates had high LVes EI and RV/LVes ratios, both gradually decreased within the first year of life and until BSA values of about 0.5 m 2 , body weight to about 15 kg and body length to about 75 cm, but were almost constant thereafter. Children (>1 year) and adolescents with PH had significantly higher RV/LVes ratio (no PH: median 0.55, IQR 0.49-0.60; PH: 1.02, 0.87-1.26; p < 0.001) and higher LVes EI values (no PH: 1.00, 0.98-1.00; PH: 1.53, 1.26-1.71; p < 0.001) compared to those without PH. To predict the presence of PH in children > 1 year, we found the following best cutoff values: RV/LVes ratio ≥ 0.67 (sensitivity: 1.00, specificity: 0.95) and LVes EI ≥ 1.06 (sensitivity: 1.00, specificity: 0.97)., Conclusion: We provide normal echocardiographic reference values of the RV/LVes ratio and LVes EI in healthy children, as well as statistically determined cutoffs for the increased values in children with PH., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schweintzger, Kurath-Koller, Burmas, Grangl, Fandl, Noessler, Avian, Gamillscheg, Chouvarine, Hansmann and Koestenberger.)

Here we report application of human umbilical cord mesenchymal stem cell (HUCMSC)-derived therapy for pulmonary arterial hypertension (PAH). A 3-year-old female presented with heritable PAH associated with hereditary hemorrhagic telangiectasia and was treated for 6 months with serial intravascular infusions of conditioned media (CM) from allogenic HUCMSCs. The treatment markedly improved clinical and hemodynamic parameters and decreased blood plasma markers of vascular fibrosis, injury and inflammation. A comparative analysis of single-cell RNA sequencing data collected from three HUCMSCs and two human umbilical vein endothelial cell (HUVEC) controls identified eight common cell clusters, all of which indicated regenerative potential specific for HUCMSCs. The properties of HUCMSCs were validated by untargeted label-free quantitation of the cell and CM proteome, suggesting increased activity of regeneration, autophagy and anti-inflammation pathways and mitochondrial function. Prostaglandin analysis demonstrated increased HUCMSC secretion of prostaglandin E2, known for its regenerative capacity. Additional prospective clinical studies are warranted to confirm and further explore the benefits of HUCMSC-derived therapy for PAH., (© 2022. The Author(s).)

Objective: Extremely low gestational age newborns (ELGANs) represent an especially vulnerable population. Herein, we aimed to determine incidence and severity of pulmonary hypertension associated with bronchopulmonary dysplasia (BPD-PH) in extremely immature ELGANs (gestational age: 23 0/6 -25 6/7 weeks)., Methods: In this prospective observational cohort study, we assessed BPD-PH by means of several echocardiography markers and serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels at 3 and 12 months of chronological age. In addition, we analyzed incidence and efficacy of pharmacologic treatment for BPD-PH., Results: At 3 months 15/34 ELGANs had echocardiographic evidence of BPD-PH, while at 12 months of age 6/34 still had PH. PH-targeted therapy consisted of sildenafil monotherapy in 11 and dual oral combination therapy (sildenafil and macitentan) in four ELGANs at 3 and 12 months., Conclusion: 44% (15/34) of ELGANs developed BPD-PH. All received PH-targeted pharmacotherapy at 3 months, leading to hemodynamic improvements at 12 months in most infants., (© 2022. The Author(s).)

Hepatic congestion occurs in patients with right heart failure and can ultimately lead to liver fibrosis or cardiac cirrhosis. Elevated pulmonary arterial pressure is found in patients with hepatic congestion. However, whether pulmonary arterial hypertension (PAH) can be a cause of liver fibrosis is unknown. The aim of this study was to investigate whether rats in the SuHx model with severe PAH develop liver fibrosis and to explore the mechanisms of congestive hepatic fibrosis both in rats and humans. To achieve this, PAH was induced in six to eight-week old male Sprague Dawley rats by a single subcutaneous injection of the VEGFR 2 inhibitor SU5416 and subsequent hypoxia for 3 weeks, followed by a 6-week period in room air. SuHx-exposed rats developed severe PAH, right ventricular hypertrophy (RVH), and consecutive right ventricular failure. Cardiac magnetic resonance imaging (MRI) and histological analysis revealed that PAH rats developed both hepatic congestion and liver fibrosis. Gene set enrichment analysis (GSEA) of whole liver RNA sequencing data identified a hepatic stellate cell specific gene signature in PAH rats. Consistently, tissue microarray from liver of patients with histological evidence of hepatic congestion and underlying heart disease revealed similar fibrogenic gene expression patterns and signaling pathways. In conclusion, severe PAH with concomitant right heart failure leads to hepatic congestion and liver fibrosis in the SU5416/hypoxia rat PAH model. Patients with PAH should therefore be screened for unrecognized liver fibrosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hamberger, Legchenko, Chouvarine, Mederacke, Taubert, Meier, Jonigk, Hansmann and Mederacke.)