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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.)

The low-density lipoprotein receptor (LDLR) gene family includes LDLR, very LDLR, and LDL receptor-related proteins (LRPs) such as LRP1, LRP1b (aka LRP-DIT), LRP2 (aka megalin), LRP4, and LRP5/6, and LRP8 (aka ApoER2). LDLR family members constitute a class of closely related multifunctional, transmembrane receptors, with diverse functions, from embryonic development to cancer, lipid metabolism, and cardiovascular homeostasis. While LDLR family members have been studied extensively in the systemic circulation in the context of atherosclerosis, their roles in pulmonary arterial hypertension (PAH) are understudied and largely unknown. Endothelial dysfunction, tissue infiltration of monocytes, and proliferation of pulmonary artery smooth muscle cells are hallmarks of PAH, leading to vascular remodeling, obliteration, increased pulmonary vascular resistance, heart failure, and death. LDLR family members are entangled with the aforementioned detrimental processes by controlling many pathways that are dysregulated in PAH; these include lipid metabolism and oxidation, but also platelet-derived growth factor, transforming growth factor β1, Wnt, apolipoprotein E, bone morpohogenetic proteins, and peroxisome proliferator-activated receptor gamma. In this paper, we discuss the current knowledge on LDLR family members in PAH. We also review mechanisms and drugs discovered in biological contexts and diseases other than PAH that are likely very relevant in the hypertensive pulmonary vasculature and the future care of patients with PAH or other chronic, progressive, debilitating cardiovascular diseases., Competing Interests: Dr Herz was supported by grants from the National Heart, Lung, and Blood Institute (R37 HL063762), the National Institute on Aging (RF AG053391), the National Institute on Neurological Disorders and Stroke and National Institute on Aging (R01 NS093382), and BrightFocus (A2016396S); the Bluefield Project to Cure FTD; and a Harrington Scholar Innovator Award (2019). Dr Hansmann has received financial support from the German Research Foundation (HA4348/2-2 and HA4348/6-2 KFO311), the Federal Ministry of Education and Research (BMBF ViP+ program-03VP08053; BMBF 01KC2001B), and the European Pediatric Pulmonary Vascular Disease Network. Dr Calvier and Dr Herz are shareholders of Reelin Therapeutics and co-inventors of a patent related to anti-Reelin strategies (application number 15/763,047 and publication number 20180273637). Dr Hansmann has reported that he has no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Objective: Paediatric lung transplantation poses unique management challenges. Experience regarding indications and outcome is scarce, especially in younger children. The primary aim of this study was to investigate outcome after first lung transplantation in children <12 years of age in comparison to adolescents (12-17 years old)., Methods: Records of patients <18 years who underwent first lung transplantation between 01/2005 and 01/2021 were retrospectively reviewed, and compared between children <12 years old and adolescents. Median (IQR) follow-up was 51 (23-91) months., Results: Of the 117 patients underwent first lung transplantation at our institution, of whom 42 (35.8%) patients were <12 years and 75 (64.2%) ≥12 years old. Compared to adolescents, children were more often transplanted for interstitial lung disease (33.3% vs 12%, p = 0.005) and precapillary pulmonary hypertension (28.6% vs 12%, p = 0.025), and required more often intraoperative cardiopulmonary bypass (31% vs 14.7%, p = 0.036) and postoperative ECMO support (47.6% vs 13.3%, p < 0.001). Postoperatively, children required longer ventilation times (78 vs 18 hours, p = 0.009) and longer ICU stay (9.5 vs 3 days, p < 0.001) compared to their older counterparts. Primary graft dysfunction grade 3 at 72 hours (9.5% vs 9.3%, p = 0.999), in-hospital mortality (2.4% vs 6.7%, p = 0.418), graft survival (80% vs 62%, p = 0.479) and freedom from chronic lung allograft dysfunction (76% vs 59%, p = 0.41) at 8-year follow-up did not differ between groups., Conclusions: Lung transplantation in children under 12 years is challenging due to underlying medical conditions and operative complexity. Nevertheless, outcomes are comparable to those in older children., Competing Interests: Disclosure statement Fabio Ius declares a consulting contract with Biotest AG, outside the submitted work. Funding not to be declared., (Copyright © 2021 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Objectives: Interleukin-7 (IL-7) secures B cell maturation, regulatory T and natural killer (NK) cell survival, and homeostasis, all of which are important for beneficial immunomodulation in pulmonary arterial hypertension (PAH). However, the role and potential impact of IL-7, VEGF-C and the vascular injury markers ICAM-1, and VCAM-1 on the pathobiology and severity of PAH is unknown. Methods: EDTA blood was collected during cardiac catheterization from the superior vena cava (SVC), pulmonary artery (PA), and ascending aorta (AAO) in children with pulmonary hypertension (PH) [ n = 10; 9.1 (3.9-18.5) years] and non-PH controls [ n = 10; 10.5 (2.0-17.3) years]. Compartment-specific plasma concentrations of IL-7, VEGF-C, aldosterone, ICAM-1, and VCAM-1 were determined using Meso Scale Discovery's multi array technology and the LIAISON Aldosterone Assay. Results: Children with PH had approximately 50% lower IL-7 ( p < 0.01) and 59% lower VEGF-C plasma levels ( p < 0.001) in the SVC, PA, and AAO versus non-PH controls. IL-7 and VEGF-C concentrations negatively correlated with the pulmonary vascular resistance (PVR)/systemic vascular resistance (SVR) ratio (rho = -0.51 and r = -0.62, respectively). Central-venous IL-7 strongly positively correlated with VEGF-C ( r = 0.81). Most patients had a step down in ICAM-1 and VCAM-1 plasma concentrations across the pulmonary circulation and both ICAM-1 and VCAM-1 transpulmonary gradients negatively correlated with invasive hemodynamics. Conclusion: This manuscript is the first report on decreased circulating IL-7 and VEGF-C plasma concentrations in human PAH and their inverse correlations with invasive surrogates of PAH severity. Additional and larger studies are needed to explore the role of the immune-modulatory IL-7 and VEGF-C in pediatric and adult PAH., 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 © 2021 Diekmann, Legchenko, Chouvarine, Lichtinghagen, Bertram, Happel and Hansmann.)

Peroxisome proliferator-activated receptor gamma (PPARγ) is a type II nuclear receptor, initially recognized in adipose tissue for its role in fatty acid storage and glucose metabolism. It promotes lipid uptake and adipogenesis by increasing insulin sensitivity and adiponectin release. Later, PPARγ was implicated in cardiac development and in critical conditions such as pulmonary arterial hypertension (PAH) and kidney failure. Recently, a cluster of different papers linked PPARγ signaling with another superfamily, the transforming growth factor beta (TGFβ), and its receptors, all of which play a major role in PAH and kidney failure. TGFβ is a multifunctional cytokine that drives inflammation, fibrosis, and cell differentiation while PPARγ activation reverses these adverse events in many models. Such opposite biological effects emphasize the delicate balance and complex crosstalk between PPARγ and TGFβ. Based on solid experimental and clinical evidence, the present review summarizes connections and their implications for PAH and kidney failure, highlighting the similarities and differences between lung and kidney mechanisms as well as discussing the therapeutic potential of PPARγ agonist pioglitazone.

Total RNA sequencing allows capturing of long non-coding and circular RNA along with mRNA. Additional sequencing of micro RNA (miRNA), using libraries with shorter fragments, provides the means to characterize miRNA-driven transcriptional regulation. Here, we present a protocol for processing total RNA and miRNA sequencing data to quantify circular RNA, long non-coding RNA, mRNA, and miRNA. Further, the protocol combines the quantification data with miRNA target annotation to construct likely transcriptional regulatory networks, which can be validated in the subsequent studies. For complete details on the use and execution of this protocol, please refer to Chouvarine et al. (2021)., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Pulmonary arterial hypertension (PAH) is a progressive condition with an unmet need for early diagnosis, better monitoring, and risk stratification. The receptor for advanced glycation end products (RAGE) is activated in response to hypoxia and vascular injury, and is associated with inflammation, cell proliferation and migration in PAH. For the adult cohort, we recruited 120 patients with PAH, 83 with idiopathic PAH (IPAH) and 37 with connective tissue disease-associated PAH (CTD-PAH), and 48 controls, and determined potential plasma biomarkers by enzyme-linked immunoassay. The established heart failure marker NTproBNP and IL-6 plasma levels were several-fold higher in both adult IPAH and CTD-PAH patients versus controls. Plasma soluble RAGE (sRAGE) was elevated in IPAH patients (3044 ± 215.2 pg/mL) and was even higher in CTD-PAH patients (3332 ± 321.6 pg/mL) versus controls (1766 ± 121.9 pg/mL; p < 0.01). All three markers were increased in WHO functional class II+III PAH versus controls ( p < 0.001). Receiver-operating characteristic analysis revealed that sRAGE has diagnostic accuracy comparable to prognostic NTproBNP, and even outperforms NTproBNP in the distinction of PAH FC I from controls. Lung tissue RAGE expression was increased in IPAH versus controls (mRNA) and was located predominantly in the PA intima, media, and inflammatory cells in the perivascular space (immunohistochemistry). In the pediatric cohort, plasma sRAGE concentrations were higher than in adults, but were similar in PH (n = 10) and non-PH controls (n = 10). Taken together, in the largest adult sRAGE PAH study to date, we identify plasma sRAGE as a sensitive and accurate PAH biomarker with better performance than NTproBNP in the distinction of mild PAH from controls.

Loss-of-function mutations in the bone morphogenetic protein receptor 2 (BMPR2) gene are common in heritable or idiopathic pulmonary arterial hypertension (PAH), and can result in functional impairment of both endothelial and vascular smooth muscle cells. Here, we report 3 PAH patient-specific induced pluripotent stem cells (iPSC) lines from 3 unrelated patients harbouring different mutations in the BMPR2 gene: a heterozygous missense mutation in exon 12, a heterozygous frame shift deletion in exon 3, and a heterozygous missense mutation in exon 11. These cell lines will serve as a valuable resource to model PAH in vitro., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

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.

Right ventricular hypertrophy (RVH) occurs in high pressure afterload, e.g., tetralogy of Fallot/pulmonary stenosis (TOF/PS). Such RVH is associated with alterations in energy metabolism, neurohormonal and epigenetic dysregulation (e.g., microRNA), and fetal gene reprogramming in animal models. However, comprehensive expression profiling of competing endogenous RNA in human RVH has not been performed. Here, we unravel several previously unknown circular, long non-coding, and microRNAs, predicted to regulate expression of genes specific to human RVH in the non-failing heart (TOF/PS). These genes are significantly overrepresented in pathways related to regulation of glucose and lipid metabolism (SIK1, FABP4), cell surface interactions (THBS2, FN1), apoptosis (PIK3IP1, SIK1), extracellular matrix composition (CTGF, IGF1), and other biological events. This is the first unbiased RNA sequencing study of human compensated RVH encompassing coding and non-coding RNA expression and predicted sponging of miRNAs by non-coding RNAs. These findings advance our understanding of adaptive RVH and highlight future therapeutic targets., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)

Platelets are critically involved in murine patent ductus arteriosus (PDA) closure. To date, the clinical significance of these findings in human preterm infants with PDA is still controversial. We discuss the available study data on the role of platelets for PDA closure in preterm infants: Several mostly retrospective studies have yielded conflicting results on whether thrombocytopenia contributes to failed spontaneous ductal closure. The same applies to investigations on the role of thrombocytopenia as a risk factor for unsuccessful ductus arteriosus closure by pharmacological treatment with cyclooxygenase inhibitors. Nonetheless, recent meta-analyses have concluded that thrombocytopenia constitutes an independent risk factor for both failed spontaneous and pharmacological PDA closure in preterm infants. However, the available investigations differ in regard to patient characteristics, diagnostic strategies, and treatment protocols. Several studies suggest that impaired platelet function rather than platelet number is critically involved in failure of ductus arteriosus closure in the preterm infant. A recent randomized-controlled trial on platelet transfusions in preterm infants with PDA failed to show any benefit for liberal vs. restrictive transfusion thresholds on PDA closure rates. Importantly, liberal transfusions were associated with an increased rate of intraventricular hemorrhage, and thus should be avoided. In conclusion, the available evidence suggests that thrombocytopenia and platelet dysfunction contribute to failure of spontaneous and pharmacological PDA closure in preterm infants. However, these platelet effects on PDA seem to be of only moderate clinical significance. Furthermore, platelet transfusions in thrombocytopenic preterm infants in order to facilitate PDA closure appear to cause more harm than good., 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 © 2021 Sallmon, Timme, Atasay, Erdeve, Hansmann, Singh, Weber and Shelton.)

Bronchopulmonary dysplasia (BPD) is a major complication in prematurely born infants. Pulmonary hypertension (PH) associated with BPD (BPD-PH) is characterized by alveolar diffusion impairment, abnormal vascular remodeling, and rarefication of pulmonary vessels (vascular growth arrest), which lead to increased pulmonary vascular resistance and right heart failure. About 25% of infants with moderate to severe BPD develop BPD-PH that is associated with high morbidity and mortality. The recent evolution of broader PH-targeted pharmacotherapy in adults has opened up new treatment options for infants with BPD-PH. Sildenafil became the mainstay of contemporary BPD-PH therapy. Additional medications, such as endothelin receptor antagonists and prostacyclin analogs/mimetics, are increasingly being investigated in infants with PH. However, pediatric data from prospective or randomized controlled trials are still sparse. We discuss comprehensive diagnostic and therapeutic strategies for BPD-PH and briefly review the relevant differential diagnoses of parenchymal and interstitial developmental lung diseases. In addition, we provide a practical framework for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH from the 2018 World Symposium on Pulmonary Hypertension, and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies. Finally, current gaps of knowledge and future research directions are discussed. IMPACT: PH in BPD substantially increases mortality. Treatment of BPD-PH should be conducted by an interdisciplinary team and follow our new treatment algorithm while still kept tailored to the individual patient. We discuss recent developments in BPD-PH, make recommendations on diagnosis, monitoring and treatment of PH in BPD, and address current gaps of knowledge and potential research directions. We provide a practical framework, including a new treatment algorithm, for the management of children with BPD-PH, incorporating the modified definition and classification of pediatric PH (2018 WSPH) and the 2019 EPPVDN consensus recommendations on established and newly developed therapeutic strategies for BPD-PH.

While invasive assessment of hemodynamics and testing of acute vasoreactivity in the catheterization laboratory is the gold standard for diagnosing pulmonary hypertension (PH) and pulmonary vascular disease (PVD) in children, transthoracic echocardiography (TTE) serves as the initial diagnostic tool. International guidelines suggest several key echocardiographic variables and indices for the screening studies when PH is suspected. However, due to the complex anatomy and special physiological considerations, these may not apply to patients with congenital heart disease (CHD). Misinterpretation of TTE variables can lead to delayed diagnosis and therapy, with fatal consequences, or-on the other hand-unnecessary invasive diagnostic procedures that have relevant risks, especially in the pediatric age group. We herein provide an overview of the echocardiographic workup of children and adolescents with PH with a special focus on children with CHD, such as ventricular/atrial septal defects, tetralogy of Fallot or univentricular physiology. In addition, we address the use of echocardiography as a tool to assess eligibility for exercise and sports, a major determinant of quality of life and outcome in patients with PH associated with CHD.

This manuscript on drug repurposing incorporates the broad experience of members of the Pulmonary Vascular Research Institute's Innovative Drug Development Initiative as an open debate platform for academia, the pharmaceutical industry and regulatory experts surrounding the future design of clinical trials in pulmonary hypertension. Drug repurposing, use of a drug in a disease for which it was not originally developed, in pulmonary arterial hypertension has been a remarkable success story, as highlighted by positive large phase 3 clinical trials using epoprostenol, bosentan, iloprost, and sildenafil. Despite the availability of multiple therapies for pulmonary arterial hypertension, mortality rates have modestly changed. Moreover, pulmonary arterial hypertension patients are highly symptomatic and frequently end up on parental therapy and lung transplant waiting lists. Therefore, an unmet need for new treatments exists and drug repurposing may be an important avenue to address this problem., (© The Author(s) 2020.)

Postnatal ductal closure is stimulated by rising oxygen tension and withdrawal of vasodilatory mediators (prostaglandins, nitric oxide, adenosine) and by vasoconstrictors (endothelin-1, catecholamines, contractile prostanoids), ion channels, calcium flux, platelets, morphologic maturity, and a favorable genetic predisposition. A persistently patent ductus arteriosus (PDA) in preterm infants can have clinical consequences. Decreasing pulmonary vascular resistance, especially in extremely low gestational age newborns, increases left-to-right shunting through the ductus and increases pulmonary blood flow further, leading to interstitial pulmonary edema and volume load to the left heart. Potential consequences of left-to-right shunting via a hemodynamically significant patent ductus arteriosus (hsPDA) include increased risk for prolonged ventilation, bronchopulmonary dysplasia, necrotizing enterocolitis or focal intestinal perforation, intraventricular hemorrhage, and death. In the last decade, there has been a trend toward less aggressive treatment of PDA in preterm infants. However, there is a subgroup of infants who will likely benefit from intervention, be it pharmacologic, interventional, or surgical: (1) prophylactic intravenous indomethacin in highly selected extremely low gestational age newborns with PDA (<26 + 0/7 weeks' gestation, <750 g birth weight), (2) early targeted therapy of PDA in selected preterm infants at particular high risk for PDA-associated complications, and (3) PDA ligation, catheter intervention, or oral paracetamol may be considered as rescue options for hsPDA closure. The impact of catheter-based closure of hsPDA on clinical outcomes should be determined in future prospective studies. Finally, we provide a novel treatment algorithm for PDA in preterm infants that integrates the several treatment modalities in a staged approach., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

Background: Macitentan, a dual endothelin receptor antagonist (ERA), was approved in 2014 for the treatment of adults with idiopathic pulmonary arterial hypertension (PAH). Once-per-day dosing and low potential hepatic toxicity make macitentan an appealing therapeutic option for children with PAH, but reports on its use in pediatric patients are still lacking., Methods: Prospective observational study of 18 children [10 male; median age: 8.5, minimum (min.): 0.6, maximum (max.): 16.8 years] with pulmonary hypertension (PH). Four of these 18 patients were treatment-naïve and started on a de novo macitentan therapy. The remaining 14/18 children were already on a PH-targeted pharmacotherapy (sildenafil or bosentan as monotherapy or in combination). Nine children who were on bosentan were switched to macitentan. We analyzed the 6-minute walking distance (6MWD), NYHA functional class (FC)/modified ROSS score, invasive hemodynamics, echocardiographic variables and the biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP)., Results: The median follow up was 6 months (min.: 0.5, max.: 30). Macitentan treatment was associated with improvement of invasive hemodynamics, e.g., the ratio of mean pulmonary arterial pressure/mean systemic arterial pressure decreased from a median of 62% (min.: 30%, max.: 87%) to 49% (min.: 30%, max.: 69%), P<0.05; pulmonary vascular resistance index (PVRi) decreased from a median of 7.6 (min.: 3.3, max.: 11.5) to 4.8 Wood units × m 2 body surface area (min.: 2.5, max.: 10), P<0.05. The tricuspid annular plane systolic excursion (TAPSE) increased from a median of 1.4 (min.: 0.8, max.: 2.8) to 1.9 (min.: 0.8, max.: 2.7) cm, (P<0.05). NT-proBNP values decreased from a median of 272 (min.: 27, max.: 2,010) to 229 (min.: 23, max.: 814) pg/mL under macitentan therapy (P<0.05). The 6MWD and NYHA FC/modified ROSS score did not change significantly., Conclusions: This is the first prospective study of macitentan pharmacotherapy in infants and children with PH <12 years of age. Except in one patient, macitentan treatment was well tolerated and was associated with improvements in invasive hemodynamics, longitudinal systolic RV function (TAPSE) and serum NT-proBNP values., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt.2020.04.01). The series “Right Ventricular Dysfunction” was commissioned by the editorial office without any funding or sponsorship. AG reports grants from JNJ during the conduct of the study. Actelion/Johnson&Johnson had no influence on this publication, has not seen the data or the manuscript and had no role in the production of this manuscript. The authors are solely responsible for the design and conduction of this study, all study analyses, the drafting and editing of the paper and its final contents. The authors have no other conflicts of interest to declare., (2020 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Right ventricular (RV) dysfunction is the most important determinant of survival in patients with pulmonary hypertension (PH). The manifestations of RV dysfunction not only include changes in global RV systolic function but also abnormalities in the pattern of contraction and synchrony. The effects of PH on the right ventricle have been mainly studied in patients with pulmonary arterial hypertension (PAH). However, with the demographic shift towards an aging population, heart failure with preserved ejection fraction (HFpEF) has become an important etiology of PH in recent years. There are significant differences in RV mechanics, function and adaptation between patients with PAH and HFpEF (with or without PH), which are related to different patterns of remodeling and dysfunction. Due to the unique features of the RV chamber, its connection with the main pulmonary artery and the pulmonary circulation, an understanding of the mechanics of RV function and its clinical significance is mandatory for both entities. In this review, we describe the mechanics of the pressure overloaded right ventricle. We review the different mechanical components of RV dysfunction and ventricular dyssynchrony, followed by insights via analysis of pressure-volume loop, energetics and novel blood flow patterns, such as vortex imaging. We conduct an in-depth comparison of prevalence and characteristics of RV dysfunction in HFpEF and PAH, and summarize key outcome studies. Finally, we provide a perspective on needed and expected future work in the field of RV mechanics., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-479). The series “Right Ventricular Dysfunction” was commissioned by the editorial office without any funding or sponsorship. GH served as the unpaid Guest Editor of the series. GH reports grants from German Research Foundation (DFG; HA4348/2-2 and HA4348/6-2 KFO311), from Federal Ministry of Education and Research (BMBF ViP+ program-03VP08053; BMBF 01KC2001B), from European Pediatric Pulmonary Vascular Disease Network (www.pvdnetwork.org), outside the submitted work. AYD reports grants from Edwards (2019) research (equipment grant), outside the submitted work; and Speaker bureau and KOL for CAE Healthcare and Masimo. Dr. FSdM reports grants from The Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences (CVON-2012-08 PHAEDRA, CVON-2018-29 PHAEDRA-IMPACT, CVON-2017-10 Dolphin-Genesis), from The Netherlands Organization for Scientific Research (NWO-VIDI: 917.18.338), from The Dutch Heart Foundation Dekker senior post-doc grant (2018T059), outside the submitted work. The authors have no other conflicts of interest to declare., (2020 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Right ventricular (RV) function is important for clinical status and outcomes in children and adults with congenital heart disease (CHD). In the normal RV, longitudinal systolic function is the major contributor to global RV systolic function. A variety of factors contribute to RV failure including increased pressure- or volume-loading, electromechanical dyssynchrony, increased myocardial fibrosis, abnormal coronary perfusion, restricted filling capacity and adverse interactions between left ventricle (LV) and RV. We discuss the different imaging techniques both at rest and during exercise to define and detect RV failure. We identify the most important biomarkers for risk stratification in RV dysfunction, including abnormal NYHA class, decreased exercise capacity, low blood pressure, and increased levels of NTproBNP, troponin T, galectin-3 and growth differentiation factor 15. In adults with CHD (ACHD), fragmented QRS is independently associated with heart failure (HF) symptoms and impaired ventricular function. Furthermore, we discuss the different HF therapies in CHD but given the broad clinical spectrum of CHD, it is important to treat RV failure in a disease-specific manner and based on the specific alterations in hemodynamics. Here, we discuss how to detect and treat RV dysfunction in CHD in order to prevent or postpone RV failure., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-370). The series “Right Ventricular Dysfunction” was commissioned by the editorial office without any funding or sponsorship. GH and MK served as the unpaid Guest Editors of the series. GH reports grants from German Research Foundation, Federal Ministry of Education and Research and from European Pediatric Pulmonary Vascular Disease Network, outside the submitted work. MD reports grants from Actelion/Johnson & Johnson, grants and personal fees from Merck Sharp & Dohme, grants and personal fees from Glaxo Smith Kline, grants from United Therapeutics, and grants from Ferrer group, outside the submitted work. WB reports other from Abbott and Occlutech, outside the submitted work. The authors have no other conflicts of interest to declare., (2020 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Pulmonary arterial hypertension (PAH) is a rare, life-threatening condition characterized by dysregulated metabolism, pulmonary vascular remodeling, and loss of pulmonary vascular cross-sectional area due to a variety of etiologies. Right ventricular (RV) dysfunction in PAH is a critical mediator of both long-term morbidity and mortality. While combinatory oral pharmacotherapy and/or intravenous prostacyclin aimed at decreasing pulmonary vascular resistance (PVR) have improved clinical outcomes, there are currently no treatments that directly address RV failure in PAH. This is, in part, due to the incomplete understanding of the pathogenesis of RV dysfunction in PAH. The purpose of this review is to discuss the current understanding of key molecular mechanisms that cause, contribute and/or sustain RV dysfunction, with a special focus on pathways that either have led to or have the potential to lead to clinical therapeutic intervention. Specifically, this review discusses the mechanisms by which vessel loss and dysfunctional angiogenesis, sex hormones, and metabolic derangements in PAH directly contribute to RV dysfunction. Finally, this review discusses limitations and future areas of investigation that may lead to novel understanding and therapeutic interventions for RV dysfunction in PAH., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-404). The series “Right Ventricular Dysfunction” was commissioned by the editorial office without any funding or sponsorship. GH served as the unpaid Guest Editors of the series. TL reports personal fees from Bayer, Inc., outside the submitted work. GH reports patent “Compositions and method for treatment of pulmonary hypertension”, 12/2009 USPTO application no. 1289344, Stanford University (Inventors: Georg Hansmann, Roham T. Zamanian, Marlene Rabinovitch). ARH reports personal fees from Actelion, personal fees from Bayer, personal fees from Complexa, personal fees from PHPrecisionMed, personal fees from united therapeutics, outside the submitted work. The author has no other conflicts of interest to declare., (2020 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Producing excellent physician scientists starts with the active discovery of talent and dedication, supported by the strong belief that physician involvement in biomedical research is essential to make fundamental discoveries that improve human health. The revolution of surgical and interventional therapy of structural heart disease has had 'profoundly positive effects on survival and quality of life over the decades. (…) Small increments in clinical improvement will still be possible in the future, but for the most part, the potential for major advancement using these techniques has been exhausted' (Frank Hanley, MD; Stanford). Personalized medicine, rapid genetic diagnostics, RNA and extracellular vesicle biology, epigenetics, gene editing, gene and stem cell-derived therapy are exemplary areas where specialized training for paediatric/congenital cardiology physician scientists will be increasingly needed to further advance the field. About a decade ago, a series in Circulation discussed academic career models and highlighted the major challenges facing the cardiovascular 'clinician scientist' (syn. physician scientist), which have not abated since. To develop the skills and expertise in both clinical congenital cardiology and basic research, the training of fellows must be focused and integrated. The current pandemic COVID-19 puts additional pressure and hurdles on fellows-in-training (FIT) and early career investigators (ECI) who aim to establish, consolidate or expand their own research group. Here, we discuss the major challenges, opportunities and necessary changes for academic institutions to sustain and recruit physician scientists in paediatric/congenital cardiology in the years to come., (© 2020 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Right heart dysfunction and failure is the principal determinant of adverse outcomes in patients with pulmonary arterial hypertension (PAH). In addition to right ventricular (RV) dysfunction, systemic congestion, increased afterload and impaired myocardial contractility play an important role in the pathophysiology of RV failure. The behavior of the RV in response to the hemodynamic overload is primarily modulated by the ventricular interaction and its coupling to the pulmonary circulation. The presentation can be acute with hemodynamic instability and shock or chronic producing symptoms of systemic venous congestion and low cardiac output. The prognostic factors associated with poor outcomes in hospitalized patients include systemic hypotension, hyponatremia, severe tricuspid insufficiency, inotropic support use and the presence of pericardial effusion. Effective therapeutic management strategies involve identification and effective treatment of the triggering factors, improving cardiopulmonary hemodynamics by optimization of volume to improve diastolic ventricular interactions, improving contractility by use of inotropes, and reducing afterload by use of drugs targeting pulmonary circulation. The medical therapies approved for PAH act primarily on the pulmonary vasculature with secondary effects on the right ventricle. Mechanical circulatory support as a bridge to transplantation has also gained traction in medically refractory cases. The current review was undertaken to summarize recent insights into the evaluation and treatment of RV dysfunction and failure attributable to PAH., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-348). The series “Right Ventricular Dysfunction” was commissioned by the editorial office without any funding or sponsorship. GH, HJB and MK served as the unpaid Guest Editors of the series. Dr. RJT reports other from Actelion, other from Merck, other from Abiomed, personal fees and other from Medtronic, personal fees from United Therapeutics, personal fees from Arena Pharmaceuticals, personal fees from Aria Inc, outside the submitted work. IML reports grants and other from Actelion, grants and other from AOPOrphan Pharam, other from United Therapeutics, other from Ferrer, other from Astra Zeneca, outside the submitted work. HJB reports grants from Actelion, grants from Ferrer, outside the submitted work. GH reports grants from German Research Foundation, grants from The Federal Ministry of Education and Research, grants from European Pediatric Pulmonary Vascular Disease Network, outside the submitted work. ARH reports personal fees from actelion, personal fees from Bayer, personal fees from complexa, personal fees from PHPrecisionMed, personal fees from united therapeutics, outside the submitted work. The authors have no other conflicts of interest to declare., (2020 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Therapeutic options for right ventricular (RV) dysfunction and failure are strongly limited. Right heart failure (RHF) has been mostly addressed in the context of pulmonary arterial hypertension (PAH), where it is not possible to discern pulmonary vascular- and RV-directed effects of therapeutic approaches. In part, opposing pathomechanisms in RV and pulmonary vasculature, i.e., regarding apoptosis, angiogenesis and proliferation, complicate addressing RHF in PAH. Therapy effective for left heart failure is not applicable to RHF, e.g., inhibition of adrenoceptor signaling and of the renin-angiotensin system had no or only limited success. A number of experimental studies employing animal models for PAH or RV dysfunction or failure have identified beneficial effects of novel pharmacological agents, with most promising results obtained with modulators of metabolism and reactive oxygen species or inflammation, respectively. In addition, established PAH agents, in particular phosphodiesterase-5 inhibitors and soluble guanylate cyclase stimulators, may directly address RV integrity. Promising results are furthermore derived with microRNA (miRNA) and long non-coding RNA (lncRNA) blocking or mimetic strategies, which can target microvascular rarefaction, inflammation, metabolism or fibrotic and hypertrophic remodeling in the dysfunctional RV. Likewise, pre-clinical data demonstrate that cell-based therapies using stem or progenitor cells have beneficial effects on the RV, mainly by improving the microvascular system, however clinical success will largely depend on delivery routes. A particular option for PAH is targeted denervation of the pulmonary vasculature, given the sympathetic overdrive in PAH patients. Finally, acute and durable mechanical circulatory support are available for the right heart, which however has been tested mostly in RHF with concomitant left heart disease. Here, we aim to review current pharmacological, RNA- and cell-based therapeutic options and their potential to directly target the RV and to review available data for pulmonary artery denervation and mechanical circulatory support., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-592). The series “Right Ventricular Dysfunction” was commissioned by the editorial office without any funding or sponsorship. GH served as the unpaid Guest Editor of the series. LCN reports grants and personal fees from Abiomed, grants and personal fees from Cytosorbents, personal fees from Maquet, personal fees from Orion, personal fees from Abbott, personal fees from Zoll, personal fees from Bayer, non-financial support from Edwards, all outside the submitted work. AMKR reports grants from Medical Research Council (UK) and Wellcome Trust (206632/Z/17/Z), research support from Actelion, Novartis, Medtronic, Abbott, and personal fees and research support from SoniVie and Endotronix. SB reports personal fees from Actelion, personal fees from Janssen, personal fees from Allienaire, personal fees from morphic therapeutic, outside the submitted work. The other authors have no other conflicts of interest to declare., (2020 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Right heart failure may be the ultimate cause of death in patients with acute or chronic pulmonary hypertension (PH). As PH is often secondary to other cardiovascular diseases, the treatment goal is to target the underlying disease. We do however know, that right heart failure is an independent risk factor, and therefore, treatments that improve right heart function may improve morbidity and mortality in patients with PH. There are no therapies that directly target and support the failing right heart and translation from therapies that improve left heart failure have been unsuccessful, with the exception of mineralocorticoid receptor antagonists. To understand the underlying pathophysiology of right heart failure and to aid in the development of new treatments we need solid animal models that mimic the pathophysiology of human disease. There are several available animal models of acute and chronic PH. They range from flow induced to pressure overload induced right heart failure and have been introduced in both small and large animals. When initiating new pre-clinical or basic research studies it is key to choose the right animal model to ensure successful translation to the clinical setting. Selecting the right animal model for the right study is hence important, but may be difficult due to the plethora of different models and local availability. In this review we provide an overview of the available animal models of acute and chronic right heart failure and discuss the strengths and limitations of the different models., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-400). The series “Right Ventricular Dysfunction” was commissioned by the editorial office without any funding or sponsorship. GH and HJB served as the unpaid Guest Editors of the series. AA reports grants from Alfred Benzons Foundation, outside the submitted work. GH reports grants from German Research Foundation (DFG; HA4348/2-2 and HA4348/6-2 KFO311), grants from the Federal Ministry of Education and Research (BMBF ViP+ program-03VP08053; BMBF 01KC2001B), grants from the European Pediatric Pulmonary Vascular Disease Network (www.pvdnetwork.org), outside the submitted work. HJB reports grants from Dutch Cardiovascular Research Alliance, from null, outside the submitted work. The authors have no other conflicts of interest to declare., (2020 Cardiovascular Diagnosis and Therapy. All rights reserved.)