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The number of adults with congenital heart defects (ACHDs) is steadily increasing and is about 360,000 in Germany. Congenital heart defect (CHD) is often associated with pulmonary hypertension (PH), which sometimes develops early in untreated CHD. Despite timely treatment of CHD, PH not infrequently persists, redevelops in older age, and is associated with significant morbidity and lethality. The revised European Society of Cardiology (ESC)/European Respiratory Society (ERS) 2022 guidelines for the diagnosis and treatment of PH represent a significant contribution to the optimized care of those affected. However, the topic of "adults with congenital heart defects" is treated only relatively superficially in this context. In the present article, part I, therefore, this topic is commented on in detail from the perspective of congenital cardiology with a special focus on definition, epidemiology, classification, diagnostics, genetics, risk stratification and follow-up and gender aspects of PH in ACHDs. This paper consists of two parts. Part II will provide comments on the topics of supportive therapy, special situations like pregnancy, contraception, and non-cardiac surgery, targeted pharmacotherapy, organ transplantation, special management like shunt lesion, left ventricular disease, and univentricular hearts, interventions, intensive care, ACHDs follow-up and future perspective on PH in ACHDs. By examining these aspects in detail, this article aims to fill the gaps in the existing guidelines and provide a more thorough understanding from the perspective of congenital cardiology., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-148/coif). The series “Current Management Aspects of Adult Congenital Heart Disease (ACHD): Part VI” was commissioned by the editorial office without any funding or sponsorship. H.K. served as the unpaid Guest Editor of the series. H.K. received sponsorship and honoraria from Janssen/Jonson&Johnson, and Bristol Myers Squibb, and participated in the steering board of COMPERA International. G.P.D. has received honoraria and consulting fees from Janssen Pharmaceuticals. I.D. serves as an unpaid board member for Treasurer of the German Society for Pediatric Cardiology and Congenital Heart Disease. S.A. serves as board member for European Society of Cardiology, and Deutsche Herzstiftung. C.A.E. received honoraria for lectures and presentations from OMT and MSD, consulting fees from MSD. C.A.E. is co-inventor of the issued European patent “Gene panel specific for pulmonary hypertension and its uses” (EP3507380). E.G. has received research grants outside the submitted work from Actelion, Janssen, Bayer, MSD, Merck, Ferrer; research grants to the institution outside the submitted work from Acceleron, Actelion, Bayer, MSD, Janssen, Liquidia, United Therapeutics, OMT; consultancy fees outside the submitted work from Actelion, Janssen, Bayer, MSD, Merck, Ferrer; Speaker honoraria outside the submitted work from Actelion, Bayer/MSD, GSK, AOP, Janssen, phev, OMT, GEBRO, Ferrer, GWT; participation in AdBoards from MSD and Ferrer; unpaid board member for A DUE Steering committee and patient organisation phev. M.H. received consulting fees, honoraria, and travel support from Janssen. S.M. received Research Grant from German Center for Lung Research (DZL). A.U. received consulting fees from Medtronic. U.H. serves as an unpaid board member for Deutsche Gesellschaft für Kinderkardiologie und Angeborene Herzfehler, and Deutsche Gesellschaft für Kinder- und Jugendmedizin. C.A. received lecture and consulting fees from Janssen. The authors have no other conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

The number of adults with congenital heart defects (ACHDs) is steadily increasing and is about 360,000 in Germany. Congenital heart defect (CHD) is often associated with pulmonary hypertension (PH), which sometimes develops early in untreated CHD. Despite timely treatment of CHD, PH not infrequently persists, redevelops in older age, and is associated with significant morbidity and mortality. The revised European Society of Cardiology (ESC)/European Respiratory Society (ERS) 2022 guidelines for the diagnosis and treatment of PH represent a significant contribution to the optimized care of those affected. However, the topic of "adults with congenital heart defects" is treated only relatively superficially in this context. After the first part commenting on a broad range of topics like definition, epidemiology, classification, diagnostics, genetics, risk stratification and follow-up, and gender aspects, the second part focuses on supportive therapy, special situations (pregnancy, contraception, non-cardiac surgery), targeted pharmacotherapy, organ transplantation, special management [shunt lesion, left ventricular (LV) disease, univentricular hearts], interventions, intensive care, ACHD follow-up, and future perspective. In the present article, therefore, this topic is commented on from the perspective of congenital cardiology. By examining these aspects in detail, this article aims to fill the gaps in the existing guidelines and provide a more thorough understanding from the perspective of congenital cardiology., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cdt.amegroups.com/article/view/10.21037/cdt-24-167/coif). The series “Current Management Aspects of Adult Congenital Heart Disease (ACHD): Part VI” was commissioned by the editorial office without any funding or sponsorship. H.K. served as the unpaid Guest Editor of the series. H.K. received sponsorship and honoraria from Janssen/Jonson & Johnson, and Bristol Myers Squibb, and participated in the steering board of COMPERA International. G.P.D. has received honoraria and consulting fees from Janssen Pharmaceuticals. I.D. serves as an unpaid board member for Treasurer of the German Society for Pediatric Cardiology and Congenital Heart Disease. S.A. serves as board member for European Society of Cardiology, and Deutsche Herzstiftung. C.A.E. received honoraria for lectures and presentations from OMT and MSD, consulting fees from MSD. C.A.E. is co-inventor of the issued European patent “Gene panel specific for pulmonary hypertension and its uses” (EP3507380). E.G. has received research grants outside the submitted work from Actelion, Janssen, Bayer, MSD, Merck, Ferrer; research grants to the institution outside the submitted work from Acceleron, Actelion, Bayer, MSD, Janssen, Liquidia, United Therapeutics, OMT; consultancy fees outside the submitted work from Actelion, Janssen, Bayer, MSD, Merck, Ferrer; Speaker honoraria outside the submitted work from Actelion, Bayer/MSD, GSK, AOP, Janssen, phev, OMT, GEBRO, Ferrer, GWT; participation in AdBoards from MSD and Ferrer; unpaid borard member for A DUE Steering committee and patient organization phev. M.H. received consulting fees, honoraria, and travel support from Janssen. S.M. received Research Grant from German Center for Lung Research (DZL). A.U. received consulting fees from Medtronic. U.H. serves as an unpaid board member for Deutsche Gesellschaft für Kinderkardiologie und Angeborene Herzfehler, and Deutsche Gesellschaft für Kinder- und Jugendmedizin. C.A. received lecture and consulting fees from Janssen. The authors have no other conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Aim of the Study:  Esophageal atresia (EA) is associated with impaired motor development, cardiopulmonary function, and physical activity (PA). Despite missing scientific evidence, this fact is often attributed to associated congenital heart disease (CHD). The aim of this study was to investigate PA in EA patients without CHD compared with CHD patients and healthy controls., Methods:  In this multicenter study, EA patients aged 6 through 17 years were included. Moderate-to-vigorous PA (MVPA, minutes per week) was assessed using the standardized and validated questionnaire Motorik-Modul Physical Activity Questionnaire. EA patients were randomly matched 1:4 for gender and age with patients with CHD ( n  = 1,262) and healthy controls ( n  = 6,233). Patients born with both EA and CHD were excluded. Means and 95% confidence intervals (95% CIs) were calculated. To identify associated factors, Spearman's correlation was performed., Main Results:  Overall, 69 EA patients were matched with 276 CHD patients and 276 controls (57% male, 43% female, mean age 10,3 years, 95% CI: 9.5-11.1). Mean MVPA was reduced in EA (492 minutes, 95% CI: 387-598) and CHD patients (463 minutes, 95% CI: 416-511) compared with controls (613 minutes, 95% CI: 548-679). In subgroup analysis, MVPA was reduced further in females and older age groups with EA and CHD. For EA patients, there was no statistical association between Gross type, current symptoms, surgical approaches, and MVPA., Conclusion:  Isolated EA and CHD were associated with reduced PA, especially in females and teenagers. To avoid additional morbidity associated with sedentary behavior, PA should be promoted during follow-up., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Malnutrition and poor weight gain has been reported in infants with congenital heart defects (CHDs); however data in older children with CHDs are limited. In order to obtain representative data on the nutritional status, dietary behavior, and potential influencing factors in school-aged children with CHDs, we performed a nationwide online survey. Methods: Patients aged 6 to 17 years registered in the German National Register for CHDs were asked to participate in this study by completing the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) eating study questionnaire in order to assess their self-reported dietary habits. The use of the same questionnaire enabled a comparison with a representative subset of 4569 participants of the KiGGS study. Results: A total of 894 patients (mean age 12.5 ± 3.0 years; 47.2% female) were enrolled. Patients were allocated according to anatomic complexity into simple (23.8%), moderate (37.8%), and complex CHDs (38.4%). The consumption of sugar-containing food ( p < 0.001) and fast food ( p < 0.05) was significantly lower among the CHD patients than in the healthy children. Children with CHDs showed significantly lower body mass index (BMI) percentiles ( p < 0.001) compared with their healthy peers, while children with complex and moderate CHDs had the lowest BMI. While in CHD patients, the BMI percentiles were not related to unhealthy food, there was a strong correlation with the CHD severity and number of previous interventions ( p < 0.01). Conclusions: According to this nationwide survey, school-aged children with complex CHD are at risk of undernutrition, which is not due to dietary habits but to CHD severity and repeated surgery.

The number of adults with congenital heart defects (CHD) is steadily rising and amounts to approximately 360,000 in Germany. CHD is often associated with pulmonary hypertension (PH), which may develop early in untreated CHD. Despite timely treatment of CHD, PH not infrequently persists or recurs in older age and is associated with significant morbidity and mortality.The revised European Society of Cardiology/European Respiratory Society 2022 guidelines for the diagnosis and treatment of PH represent a significant contribution to the optimized care of those affected. However, the topic of "adults with congenital heart disease" is addressed only relatively superficial in these guidelines. Therefore, in the present article, this topic is commented in detail from the perspective of congenital cardiology., Competing Interests: Harald Kaemmerer: Unabhängig von diesem Manuskript Sponsorship and honoraria Janssen/Johnson & Johnson; Bristol Myers Squibb. Steering Board COMPERA International.Gerhard Paul Diller: Advisory consultancy work for Janssen/Johnson & Johnson.Ingo Dähnert: Proctortätigkeit für Occlutech und Medtronic, Studien für Janssen und Novartis, Advisory Board für Actelion/Janssen.Christina A. Eichstaedt: C. A. E. ist Miterfinderin des europäischen Patents (EP3507380) “Gene panel specific for pulmonary hypertension and its uses”. CAE hat von msd Vortragshonorare erhalten, unabhängig von dieser Arbeit.Andreas Eicken: Keine Interessenkonflikte.Annika Freiberger: Keine Interessenkonflikte.Sebastian Freilinger: Keine Interessenkonflikte.Ralf Geiger: Keine Interessenkonflikte.Matthias Gorenflo: Advisory Board für Janssen.Ekkehard Grünig: E. G. hat Honorare für Vorträge/Konsultationen von Bayer/MSD, Ferrer, GEBRO, GSK, Janssen und OMT erhalten. Forschungsförderung für klinische Studien wurde von Acceleron, Actelion, BayerHealthCare, MSD, Bellerophon, GossamerBio, Janssen, Novartis, OMT, Pfizer, REATE und United Therapeutics erhalten.Alfred Hager: Unabhängig von diesem Manuskript erhielt A. H. Reisekostenerstattungen von Actelion, Pfizer, GlaxoSmithKline, Lilly und OMT; Rednergelder von Encysive, Pfizer, Actelion, Medtronic, Schiller, GlaxoSmithKline, OMT, AOP Orphan und Janssen; Autorenvergütungen von Actelion; Beraterhonorare von Actelion, Bayer, Ethypharm und GlaxoSmithKline; er hält Aktien von Merck Inc., Merck KGaA, Johnson & Johnson, Pfizer und Abbott.Michael Huntgeburth: Honorare Advisory-Board Janssen-Cilag, Johnson & Johnson.Ann-Sophie Kaemmerer-Suleiman: Keine Interessenkonflikte.Rainer Kozlik-Feldmann: Teaching-Kurse für Occlutech, Proktortätigkeit für Abbott (Amplatzer).Astrid E. Lammers: CEC chair and advisory consultancy work for Janssen/Johnson & Johnson.Nicole Nagdyman: Keine Interessenkonflikte.Sebastian Michel: Keine Interessenkonflikte.Kai Helge Schmidt: Vortragshonorare von Janssen, MSD und Abbott.Anselm Uebing: Keine Interessenkonflikte.Fabian von Scheidt: Keine Interessenkonflikte.Christian Apitz: Honorare für Vortragstätigkeit und Advisory Board für Janssen., (Thieme. All rights reserved.)

Dilated cardiomyopathy (DCM) is a severe condition, characterised by left ventricular dilation and systolic dysfunction, necessitating heart transplantation when all other treatment options fail. This case report describes a 2-year-old girl initially presenting with oedema, listlessness, and severe iron deficiency anaemia. She was diagnosed with DCM. Extensive diagnostic workup ruled out other causes, leading to the suspicion of DCM due to alimentary iron deficiency. This was confirmed by the parents' report that the girl was fed almost exclusively with low-fat cow's milk. Prompt treatment, including packed red cell transfusion, iron supplementation, and heart failure medications (diuretics, ACE inhibitors, beta blockers, and aldosterone antagonists), resulted in significant improvement in cardiac function within days. This report demonstrates the potential risks of alimentary iron deficiency, the most common cause of microcytic hypochromic anaemia in young children, which might even result in the development of life-threatening cardiac dysfunction in extreme cases.

Purpose: RNF213, encoding a giant E3 ubiquitin ligase, has been recognized for its role as a key susceptibility gene for moyamoya disease. Case reports have also implicated specific variants in RNF213 with an early-onset form of moyamoya disease with full penetrance. We aimed to expand the phenotypic spectrum of monogenic RNF213-related disease and to evaluate genotype-phenotype correlations., Methods: Patients were identified through reanalysis of exome sequencing data of an unselected cohort of unsolved pediatric cases and through GeneMatcher or ClinVar. Functional characterization was done by proteomics analysis and oxidative phosphorylation enzyme activities using patient-derived fibroblasts., Results: We identified 14 individuals from 13 unrelated families with (de novo) missense variants in RNF213 clustering within or around the Really Interesting New Gene (RING) domain. Individuals presented either with early-onset stroke (n = 11) or with Leigh syndrome (n = 3). No genotype-phenotype correlation could be established. Proteomics using patient-derived fibroblasts revealed no significant differences between clinical subgroups. 3D modeling revealed a clustering of missense variants in the tertiary structure of RNF213 potentially affecting zinc-binding suggesting a gain-of-function or dominant negative effect., Conclusion: De novo missense variants in RNF213 clustering in the E3 RING or other regions affecting zinc-binding lead to an early-onset syndrome characterized by stroke or Leigh syndrome., Competing Interests: Conflict of Interest A.S. is supported by the BONFOR program of the Medical Faculty, University of Bonn (O-149.0134). All other authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht.

The number of adults with congenital heart disease (CHD) is steadily rising and amounts to approximately 360,000 in Germany. CHD is often associated with pulmonary arterial hypertension (PAH), which may develop early in untreated CHD. Despite timely treatment of CHD, PAH often persists or recurs in older age and is associated with significant morbidity and mortality.The revised European Society of Cardiology/European Respiratory Society 2022 guidelines for the diagnosis and treatment of PH represent a significant contribution to the optimized care of those affected. However, the topic of "adults with congenital heart defects" is addressed only relatively superficially in these guidelines. Therefore, this article addresses the perspective of congenital cardiology in greater depth., Competing Interests: Harald Kaemmerer: Unabhängig von diesem Manuskript Sponsorship and honoraria Janssen/Johnson & Johnson; Bristol Myers Squibb. Steering Board COMPERA International.Gerhard Paul Diller: Advisory consultancy work for Janssen/Johnson & Johnson.Ingo Dähnert: Proctortätigkeit für Occlutech und Medtronic, Studien für Janssen und Novartis, Advisory Board für Actelion/Janssen.Christina A. Eichstaedt: C.A.E. ist Miterfinderin des europäischen Patents (EP3507380) “Gene panel specific for pulmonary hypertension and its uses”. CAE hat von msd Vortragshonorare erhalten, unabhängig von dieser Arbeit.Andreas Eicken: keine Interessenkonflikte.Annika Freiberger: keine Interessenkonflikte.Sebastian Freilinger: keine Interessenkonflikte.Ralf Geiger: keine Interessenkonflikte.Matthias Gorenflo: Advisory Board für Janssen.Ekkehard Grünig: E.G. hat Honorare für Vorträge/Konsultationen von Bayer/MSD, Ferrer, GEBRO, GSK, Janssen und OMT erhalten. Forschungsförderung für klinische Studien wurde von Acceleron, Actelion, BayerHealthCare, MSD, Bellerophon, GossamerBio, Janssen, Novartis, OMT, Pfizer, REATE und United Therapeutics erhalten.Alfred Hager: Unabhängig von diesem Manuskript erhielt A.H. Reisekostenerstattungen von Actelion, Pfizer, GlaxoSmithKline, Lilly und OMT; Rednergelder von Encysive, Pfizer, Actelion, Medtronic, Schiller, GlaxoSmithKline, OMT, AOP Orphan und Janssen; Autorenvergütungen von Actelion; Beraterhonorare von Actelion, Bayer, Ethypharm und GlaxoSmithKline; er hält Aktien von Gilead, Merck Inc., Merck KGaA, Johnson &Johnson, Pfizer, Abbvie und Takeda.Ulrike Herberg: keine Interessenkonflikte.Michael Huntgeburth: Honorare Advisory-Board Janssen-Cilag, Johnson & Johnson.Ann-Sophie Kaemmerer: keine Interessenkonflikte.Rainer Kozlik-Feldmann: Teaching Kurse für Occlutech, Proktortätigkeit für Abbott (Amplatzer).Astrid E. Lammers: CEC chair and advisory consultancy work for Janssen/Johnson & Johnson.Nicole Nagdyman: keine Interessenkonflikte.Sebastian Michel: keine Interessenkonflikte.Kai Helge Schmidt: Vortragshonorare von Janssen, MSD und Abbott.Anselm Uebing: keine Interessenkonflikte.Fabian von Scheidt: keine Interessenkonflikte.Christian Apitz: Honorare Janssen., (Thieme. All rights reserved.)

Pulmonary hypertension (PH) in childhood differs from that of adulthood particularly in the specific pathophysiology of congenital heart disease-associated pulmonary arterial hypertension, the presence of developmental lung disease, and the frequent association with chromosomal, genetic, and syndromal abnormalities. Treatment of children with PH requires a modified diagnostic algorithm tailored to childhood, as well as pathophysiologically oriented therapeutic strategies. In the current 2022 ERS/ESC-PH guidelines, the specific features of PH in children are highlighted in its own chapter and commented on by the authorship group in this article., Competing Interests: C.A.: Honorare für Referenten- und Beratertätigkeit für Fa. Janssen.R.K.-F.: Honarare für Vortragstätigkeit für Fa. Occlutech (Atrial Flow Regulator).C.A.E.: Mit-Erfinderin des europäischen Patents (EP3507380) “Gene panel specific for pulmonary hypertension and its uses”. Vortragshonorare von MSD, unabhängig von dieser Arbeit.M.G.: Honorare für Referenten- und Beratertätigkeit für Fa. Janssen und Bayer Schering.A.E.L.: Advisory consultant und CEC chair für Actelion/Johnson & Johnson.R.G.: Honorare für Referententätigkeit für Fa. Janssen und AOP Orphan Pharmaceuticals GmbH., (Thieme. All rights reserved.)

Background: Thyroid dysfunction may have adverse effects on Fontan hemodynamics. Data on thyroid function in pediatric Fontan patients with or without protein-losing enteropathy (PLE) are limited., Methods: This retrospective multicenter study included 67 Fontan patients (median age 10.9 years; 35.8% female; 28.4% PLE) in whom thyroid function testing was performed., Results: Subclinical hypothyroidism (SHT) was present in 16 (23.9%) patients. Subjects with SHT had significantly lower systolic blood pressure (p = 0.014) and body weight z-score (p = 0.006), were in a worse New York Heart Association (NYHA) functional class (p = 0.004), were more often pacing dependent (p = 0.007), and were more likely to have PLE (p = 0.033, 8/19 (42.1%) patients). Serum thyroid stimulating hormone (TSH) levels were significantly higher in patients with NYHA class ≥ II (p = 0.005), significant atrioventricular valve regurgitation (p = 0.023), elevated serum natriuretic peptides (p = 0.031), and in those with PLE (p = 0.002). Patients with active PLE had significantly higher TSH levels than those in remission (p = 0.003). A strong inverse relationship was found between lower free triiodothyronine (fT3) levels and natriuretic peptides (r: -0.599, p = 0.040). Using binary logistic regression analysis we found that worse NYHA class was an independent predictor of SHT (OR 4.2; 95% CI 1.1-16.1, p = 0.036)., Conclusions: Subclinical thyroid dysfunction is common in Fontan, particularly in patients with hemodynamic derangements and PLE. Future studies are needed to address the prognostic implications of thyroid dysfunction in the Fontan population., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Markus Khalil reports financial support was provided by Stiftung KinderHerz, Essen, Germany., (© 2023 The Authors.)

Background In patients after heart transplantation, systemic arterial hypertension and enhanced central aortic stiffness contribute to increased ventricular afterload, which might lead to graft dysfunction. The aim of our study was to characterize systemic arterial elastance and its impact on left ventricular function and ventriculo-arterial coupling in a cohort of children, adolescents, and young adults after heart transplantation using invasive conductance catheter technique. Methods and Results Thirty patients who had heart transplants (age, 20.0±6.5 years, 7 female) underwent invasive cardiac catheterization including pressure-volume loop analysis. Load-independent parameters of systolic (ventricular elastance [Ees]) and diastolic (ventricular compliance) function as well as systemic arterial elastance (Ea, end-systolic pressure/stroke volume) and ventriculo-arterial coupling (Ea/Ees) were assessed at baseline level and during dobutamine infusion (10 μg/kg/min). Ees showed an appropriate increase under inotropic stimulation from 0.43 (0.11-2.52) to 1.00 (0.20-5.10) mm Hg/mL/m 2 ( P <0.0001), whereas ventricular compliance remained rather unchanged (0.16±0.10 mm Hg/mL/m 2 to 0.12±0.07 mm Hg/mL/m 2 ; P =0.10). Ventriculo-arterial coupling Ea/Ees was abnormal at rest and did not improve significantly under dobutamine (1.7 [0.6-6.7] to 1.3 [0.5-4.9], P =0.70) due to a simultaneous rise in Ea from 0.71 (0.37-2.82) to 1.10 (0.52-4.03) mm Hg/mL/m 2 ( P <0.0001). Both Ees and ventricular compliance were significantly associated with Ea at baseline and under dobutamine infusion. Conclusions Patients who underwent heart transplantation show impaired ventriculo-arterial coupling at rest and under inotropic stimulation despite preserved left ventricular contractile reserve. An abnormal response in vascular function resulting in increased afterload seems to represent an important factor that may play a role for the development of late graft failure.

Background: Physical activity is important for children with congenital heart defects (CHD), not only for somatic health, but also for neurologic, emotional, and psychosocial development. Swimming is a popular endurance sport which is in general suitable for most children with CHD. Since we have previously shown that children with CHD are less frequently physically active than their healthy peers, we hypothesized that the prevalence of non-swimmers is higher in CHD patients than in healthy children., Methods: To obtain representative data, we performed a nationwide survey in collaboration with the German National Register of Congenital Heart Defects (NRCHD) and the Institute for Sport Sciences of the Karlsruhe Institute for Technology (KIT). The questionnaire included questions capturing the prevalence of swimming skills and the timing of swim learning and was part of the "Motorik-Modul" (MoMo) from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS). A representative age-matched subset of 4569 participants of the MoMo wave two study served as a healthy control group., Results: From 894 CHD-patients (mean age of 12.5 ± 3.1 years), the proportion of non-swimmers in children with CHD was significantly higher (16% versus 4.3%; p < 0.001) compared to healthy children and was dependent on CHD severity: Children with complex CHD had an almost five-fold increased risk (20.4%) of being unable to swim, whereas in children with simple CHD, the ability to swim did not differ significantly from their healthy reference group (5.6% vs. 4.3% non-swimmers ( p = not significant)., Conclusions: According to our results, one in five patients with complex CHD are non-swimmers, a situation that is concerning in regard of motoric development, inclusion and integration, as well as prevention of drowning accidents. Implementation of swim learning interventions for children with CHD would be a reasonable approach.

Objective: Children with congenital heart defects (CHD) are at high risk for cardiovascular disease in addition to their congenital disease, so it is important to motivate this group of patients to live a physically active lifestyle. A potential influencing determinant of younger children's physical performance is the physical self-concept. The objective of the present study was first to evaluate the correlation between the physical self-concept (PSC) and the participation in physical activities (PA) of a representative group of children with congenital heart disease (CHD), and second to point out differences in comparison to their healthy peer group., Methods: Using the database of PA of the S-BAHn-Study we focused on physical self-concept assessed by the German version of the Physical Self-Description Questionnaire. We compare the obtained data of children with CHD to a representative age-matched sample of 3.385 participants of the Motorik Modul Study., Results: N = 1.198 complete datasets could be included in the analyses. The mean age of patients was 11.6 ± 3.1 years. For the total cohort of patients with CHD and the reference group, PA correlated significantly with a positive PSC ( p < 0.001). PA was significantly reduced in all groups of patients despite the severity of their heart defect ( p < 0.001). Remarkably, PSC did not differ statistically significantly in patients with simple CHD from the reference collective ( p > 0.24)., Conclusions: According to this representative survey, there is a clear relation between PA and PSC in the cohort of healthy children and the group of children with CHD throughout the severity of their heart defects. Although PSC did not differ in patients with simple CHD and their healthy peer group, PA was significantly reduced. This gap invites us to reflect on how we could break new ground to promote a physically active lifestyle in children with CHD regardless of the severity of their cardiac defects.

Children and adolescents with congenital heart disease (CHD) should be encouraged to adopt a physically active lifestyle, ideally by participating in sports activities at school and sports clubs. Children with complex CHD or other risk factors (for example, pacemakers, cardioverter-defibrillators, channelopathies) may, however, need specific individualized training programs. This review article summarizes the current knowledge regarding the clinical effects of sports and exercise training on CHD and its pathophysiologic mechanisms. An evidence-based approach based on a literature search, using PubMed, Medline, CINHAL, Embase, and the Cochrane Library was conducted, last completed on 30 December 2021. In studies with 3256 CHD patients in total, including 10 randomized controlled trials, 14 prospective interventional trials, 9 observational trials, and 2 surveys, exercise training has been shown to improve exercise capacity and physical activity, motoric skills, muscular function, and quality of life. Sports and exercise training appears to be effective and safe in CHD patients. Despite being cost-efficient, training programs are currently scarcely reimbursed; therefore, support from healthcare institutions, commissioners of healthcare, and research-funding institutions is desirable. There is a strong need to establish specialized rehabilitation programs for complex CHD patients to enhance these patients' access to this treatment intervention. Further studies may be desirable to confirm these data to investigate the impact on risk profiles and to identify the most advantageous training methodology and underlying pathophysiological mechanisms.

Background: Non-invasive cardiac imaging has a growing role in diagnosis, differential diagnosis, therapy planning, and follow-up in children and adolescents with congenital and acquired cardiac diseases. This review is based on a systematic analysis of international peer-reviewed articles and additionally presents own clinical experiences. It provides an overview of technical advances, emerging clinical applications, and the aspect of artificial intelligence., Main Body: The main imaging modalities are echocardiography, CT, and MRI. For echocardiography, strain imaging allows a novel non-invasive assessment of tissue integrity, 3D imaging rapid holistic overviews of anatomy. Fast cardiac CT imaging new techniques-especially for coronary assessment as the main clinical indication-have significantly improved spatial and temporal resolution in adjunct with a major reduction in ionizing dose. For cardiac MRI, assessment of tissue integrity even without contrast agent application by mapping sequences is a major technical breakthrough. Fetal cardiac MRI is an emerging technology, which allows structural and functional assessment of fetal hearts including even 4D flow analyses. Last but not least, artificial intelligence will play an important role for improvements of data acquisition and interpretation in the near future., Conclusion: Non-invasive cardiac imaging plays an integral part in the workup of children with heart disease. In recent years, its main application congenital heart disease has been widened for acquired cardiac diseases., (© 2022. The Author(s).)

Background Childhood cancer survivors (CCSs) show relevant cardiac morbidity and mortality throughout life. Early detection is key for optimal support of patients at risk. The aim of this study was to evaluate 2-dimensional speckle-tracking echocardiography strain analysis during semisupine exercise stress in CCSs for detection of subclinical left ventricular dysfunction after cancer treatment. Methods and Results Seventy-seven CCSs ≥1-year postchemotherapy were prospectively examined at rest, low, and submaximal stress level and compared with a cohort of healthy adolescents and young adults (n=50). Global longitudinal strain (GLS), short axis circumferential strain, and corresponding strain rates were analyzed using vendor-independent software. CCSs at median 7.8 years postchemotherapy showed comparable left ventricular GLS, circumferential strain, and strain rate values at all stress stages to healthy controls. Yet, prevalence of abnormal GLS (defined as <2 SD of controls reference) in CCSs was 1.3% at rest, 2.7% at low, and 8.6% at submaximal stress. In CCSs, relative change of circumferential strain from rest to submaximal stress was lower than in healthy controls, median 16.9 (interquartile range [IQR], 3.4; 28.8) % versus 23.3 (IQR, 11.3; 33.3) %, P =0.03, most apparent in the subgroups of CCSs after high-dose anthracycline treatment and cancer diagnosis before the age of 5 years. Conclusions In this prospective 2-dimensional speckle tracking echocardiography strain study, prevalence of abnormal left ventricular GLS increased with stress level reflecting impaired cardiac adaptation to exercise stress in some CCSs. However, relatively early after last chemotherapy, this did not result in significant differences of mean GLS-, circumferential strain-, and strain rate values between CCSs and controls at any stress level.

Riociguat, a soluble guanylate cyclase stimulator, is approved for treatment of adults with pulmonary arterial hypertension (PAH). The safety, tolerability, and pharmacokinetics (PK) of oral riociguat in a pediatric population with PAH was assessed in PATENT-CHILD (NCT02562235), a multicenter, single-arm, 24-week, open-label, Phase 3 study. Patients aged 6-17 years in World Health Organization functional class (WHO-FC) I-III treated with stable endothelin receptor antagonists and/or prostacyclin analogs received riociguat equivalent to 0.5-2.5 mg three times daily in adults, as either oral pediatric suspension or tablets, based on bodyweight. Primary outcomes were safety, tolerability, and PK of riociguat. Twenty-four patients (mean age 12.8 years), 18 of whom were in WHO-FC II, were enrolled. Adverse events (AEs), mostly mild or moderate, were reported in 20 patients (83%). Four patients (17%) experienced a serious AE; all resolved by study end and two (8%) were considered study-drug related. Hypotension was reported in three patients and hemoptysis in one (all mild/moderate intensity). Riociguat plasma concentrations in pediatric patients were consistent with those published in adult patients. From baseline to Week 24, mean ± standard deviation increase in 6-minute walking distance was 23 ± 69 m ( n  = 19), and mean decrease in NT-proBNP was -66 ± 585 pg/ml ( n  = 14). There was no change in WHO-FC. Two patients experienced clinical worsening events of hospitalization for right heart failure. PK results confirmed a suitable riociguat dosing strategy for pediatric patients with PAH. The data suggest an acceptable safety profile with potential efficacy signals., Competing Interests: H. G. A. reports fees for lectures and member of advisory boards for Bayer and Janssen. D. D. I. reports the University of Colorado contracts with Acceleron, Actelion/Janssen, Altavant, Bayer, Eli Lilly, GlaxoSmithKline, and United Therapeutics for D. D. I. to be a consultant and perform clinical trials. S. M. reports consultancy from Actelion/Janssen and GlaxoSmithKline. J. P. reports fees for lectures and/or consultancy from Actelion/Janssen. T. P. reports fees for lectures, member of advisory boards, and research grants from Actelion/Janssen, Bayer, GlaxoSmithKline, and Pfizer. H. Y. reports research grants and lecture fees from Actelion, AbbVie, and Teijin Pharma; research grants from Tanabe‐Mitsubishi; lecture fees from Bayer, GE Healthcare Japan, Merck Sharp and Dohme, Novo Nordisk, Nihon Seiyaku, Nihon Shinyaku, Pfizer, and Termo. G. C., M. G., S. L., A. R., S. S., S. W., G. W. are employees and stockholders of Bayer AG. D. B. is a steering committee member for Eli Lilly and Company, and steering committee and advisory board member for Actelion Pharmaceuticals, Bayer, and Novartis. M. B. reports fees for lectures and/or consultancy from Acceleron, Actelion/Janssen, AOP, Bayer, Eli Lilly, GlaxoSmithKline, and Gossamer; unrestricted research grants from Actelion and Bayer. The remaining authors declare no conflict of interest., (© 2022 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Background: Long-term course after atrial switch operation is determined by increasing right ventricular (RV) insufficiency. The aim of our study was to investigate subtle functional parameters by invasive measurements with conductance technique and noninvasive examinations with cardiac magnetic resonance imaging (CMR)., Methods: We used invasive (pressure-volume loops under baseline conditions and dobutamine) and noninvasive techniques (CMR with feature tracking [FT] method) to evaluate RV function. All patients had cardiopulmonary exercise testing (CPET)., Results: From 2011 to 2013, 16 patients aged 28.2 ± 7.3 (22-50) years after atrial switch surgery (87.5% Senning and 12.5% Mustard) were enrolled in this prospective study. All patients were in New York Heart Association (NYHA) class I to II and presented mean peak oxygen consumption of 30.1 ± 5.7 (22.7-45.5) mL/kg/min. CMR-derived end-diastolic volume was 110 ± 22 (78-156) mL/m 2 and RV ejection fraction 41 ± 8% (25-52%). CMR-FT revealed lower global systolic longitudinal, radial, and circumferential strain for the systemic RV compared with the subpulmonary left ventricle. End-systolic elastance (Ees) was overall reduced (compared with data from the literature) and showed significant increase under dobutamine (0.80 ± 0.44 to 1.89 ± 0.72 mm Hg/mL, p ≤ 0.001), whereas end-diastolic elastance (Eed) was not significantly influenced (0.11 ± 0.70 to 0.13 ± 0.15 mm Hg/mL, p  = 0.454). We found no relevant relationship between load-independent conductance indices and strain or CPET parameters. Conductance analysis revealed significant mechanical dyssynchrony, higher during diastole (mean 30 ± 4% baseline, 24 ± 6% dobutamine) than during systole (mean 17 ± 6% baseline, 19 ± 7% dobutamine)., Conclusions: Functional assessment of a deteriorating systemic RV remains demanding. Conductance indices as well as the CMR-derived strain parameters showed overall reduced values, but a significant relationship was not present (including CPET). Our conductance analysis revealed intraventricular and predominantly diastolic RV dyssynchrony., Competing Interests: On behalf of all authors, the corresponding author states that there is no conflict of interest., (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/).)

Background: Pulmonary arterial hypertension (PAH) is common in congenital heart disease (CHD). Because clinical-trial data on PAH associated with CHD (PAH-CHD) remain limited, registry data on the long-term course are essential. This analysis aimed to update information from the COMPERA-CHD registry on management strategies based on real-world data., Methods: The prospective international pulmonary hypertension registry COMPERA has since 2007 enrolled more than 10,000 patients. COMPERA-CHD is a sub-registry for patients with PAH-CHD., Results: A total of 769 patients with PAH-CHD from 62 specialized centers in 12 countries were included into COMPERA-CHD from January 2007 through September 2020. At the last follow-up in 09/2020, patients [mean age 45.3±16.8 years; 512 (66%) female] had either post-tricuspid shunts (n=359; 46.7%), pre-tricuspid shunts (n=249; 32.4%), complex CHD (n=132; 17.2%), congenital left heart or aortic valve or aortic disease (n=9; 1.3%), or miscellaneous CHD (n=20; 2.6%). The mean 6-minute walking distance was 369±121 m, and 28.2%, 56.0%, and 3.8% were in WHO functional class I/II, III or IV, respectively (12.0% unknown). Compared with the previously published COMPERA-CHD data, after 21 months of follow-up, the number of included PAH-CHD patients increased by 91 (13.4%). Within this group the number of Eisenmenger patients rose by 39 (16.3%), the number of "Non-Eisenmenger PAH" patients by 45 (26.9%). Currently, among the 674 patients from the PAH-CHD group with at least one follow-up, 450 (66.8%) received endothelin receptor antagonists (ERA), 416 (61.7%) PDE-5 inhibitors, 85 (12.6%) prostacyclin analogues, and 36 (5.3%) the sGC stimulator riociguat. While at first inclusion in the COMPERA-CHD registry, treatment was predominantly monotherapy (69.3%), this has shifted to favoring combination therapy in the current group (53%). For the first time, the nature, frequency, and treatment of significant comorbidities requiring supportive care and medication are described., Conclusions: Analyzing "real life data" from the international COMPERA-CHD registry, we present a comprehensive overview about current management modalities and treatment concepts in PAH-CHD. There was an trend towards more aggressive treatment strategies and combination therapies. In the future, particular attention must be directed to the "Non-Eisenmenger PAH" group and to patients with complex CHD, including Fontan patients., Trial Registration: www.clinicaltrials.gov, study identifier: Clinicaltrials.gov NCT01347216., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/cdt-21-351). The series “Current Management Aspects in Adult Congenital Heart Disease (ACHD): Part IV” was commissioned by the editorial office without any funding or sponsorship. Dr. DH reports non-financial support from Actelion, Boehringer-Ingelheim, and Shire, outside the submitted work; Dr. DP reports personal fees from Actelion, Biogen, Aspen, Bayer, Boehringer Ingelheim, Daiichi Sankyo, and Sanofi, outside the submitted work; Dr. MD reports personal fees from Actelion, Bayer, GSK and MSD, outside the submitted work; Dr. HAG reports personal fees from Actelion, Bayer, Gilead, GSK, MSD, Pfizer and United Therapeutics, outside the submitted work; Dr. MG reports personal fees from Actelion, Bayer and GSK, outside the submitted work; Dr. MMH reports personal fees from Acceleron, Actelion, Bayer, MSD and Pfizer, outside the submitted work; Dr. CDV reports personal fees from Actelion, Bayer, GSK, MSD, Pfizer, and United Therapeutics, outside the submitted work; Dr. RE reports personal fees from Actelion, Boehringer Ingelheim, OMT, Bayer, and Berlin Chemie; grants from Actelion and Boehringer Ingelheim, outside the submitted work; Dr. MH reports grants and personal fees from Actelion, personal fees from Bayer, Berlin Chemie, Boehringer Ingelheim, GSK, Janssen, Novartis and MSD, outside the submitted work; Dr. MH reports personal fees from Acceleron, Actelion, AstraZeneca, Bayer, BERLIN CHEMIE, GSK, MSD, Novartis and OMT, outside the submitted work; Dr. HW reports personal fees from Action, Bayer, Biotest, Boehringer, GSK, Pfizer, and Roche, outside the submitted work; Dr. DS reports personal fees from Actelion, Bayer, and GSK, outside the submitted work; Dr. LS reports personal fees from Actelion, Bayer, and MSD, outside the submitted work; Dr. SU reports grants from Swiss National Science Foundation, Zurich Lung, Swiss Lung, and Orpha Swiss, grants and personal fees from Actelion SA/Johnson & Johnson, Switzerland, and MSD Switzerland, outside the submitted work; Dr. TJL reports personal fees from Actelion, Janssen-Cilag, BMS, MSD, and OMT GmbH, outside the submitted work; Dr. LB reports personal fees from Actelion, outside the submitted work; Dr. MC reports personal fees from Boehringer Ingelheim Pharma GmbH, Roche Pharma, and Boehringer Ingelheim, outside the submitted work; Dr. HW reports personal fees from Boehringer Ingelheim, and Roche, outside the submitted work. Dr. EG reports personal fees from Actelion, Janssen, Bayer, MSD, Bial, OrPha Swiss GmbH, OMT and Medscape, outside the submitted work; Dr. SR reports personal fees from Actelion, Bayer, GSK, Pfizer, Novartis, Gilead, MSD, and United Therapeutics, outside the submitted work. The authors have no other conflicts of interest to declare., (2021 Cardiovascular Diagnosis and Therapy. All rights reserved.)

The heart should not be divided in right and left, whether in health nor in disease. However, the morphological and functional differences between the right and left ventricle should be known and the impact of the ventricle's position considered. Further, the parameters beyond heart rate, contractility, pre- and afterload guaranteeing a sufficient systemic cardiac output have to be integrated in therapeutic measures; preferentially the influence of interventricular mechanics. Despite of recent developments of specific drug therapies, heart failure is associated with a high rate of morbidity and mortality in children. During the progression of heart failure, pulmonary vascular disease is the consequence or the reason for further failing. Clinical symptoms are associated with congestion and low cardiac output at rest or exercise. Improved understanding of the pathophysiological mechanisms particularly of ventricular failure has resulted in the development of innovative therapies that target atrial/ventricular/arterial interactions. Recent advances in interventional and surgical approaches provide promising new strategies to deal with right and left ventricular deterioration. These techniques may delay listing for heart and (heart-) lung transplantation or even make redundant in individual cases. The beneficial effects of these ventricular interaction strategies are mainly based on the mechanics of the interventricular septum and improvement of systolic and diastolic ventricular performance., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-347). The series “Pediatric Pulmonary Hypertension” was commissioned by the editorial office without any funding or sponsorship. CA served as the unpaid Guest Editor of the series. The authors have no other conflicts of interest to declare., (2021 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Moyamoya disease (MD) is a rare vaso-occlusive disorder that primarily affects intracranial cerebral arteries. The involvement of extracranial vessels is unusual. However, there are previous reports suggesting MD to be a systemic disorder, causing disease manifestations in vessels of other parts of the body. We report the case of a female patient with MD and multiple episodes of ischemic strokes followed by bypass surgery of cerebral arteries during infancy. Due to corresponding ischemic lesions the girl showed global retardation of psychomotor development and central right sided movement disorder. At the age of 10 years the girl was admitted to our hospital with recurrent syncope. While cranial MRI excluded any newly added ischemic lesions, electrocardiography revealed evidence of right ventricular hypertrophy, and subsequent echocardiography then indicated pulmonary hypertension, which was confirmed by cardiac catheterization. Despite an upfront combination pulmonary vasodilating therapy, the pulmonary vascular disease appeared to be progressive. Genetic analysis showed heterozygous c.12341C>T mutation in the RNF213 gene. This case presentation demonstrates that pulmonary arterial hypertension is a rare comorbidity in patients with MD, especially in patients with genetic predictors such as the RNF213 mutation. Thus, regular echocardiographic screening for early signs of pulmonary arterial hypertension in patients with MD should be part of regular clinical work-up. Early detection and treatment of pulmonary arterial hypertension in MD might help to improve the long-term outcome in the individual patient., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-249). The series “Pediatric Pulmonary Hypertension” was commissioned by the editorial office without any funding or sponsorship. CA served as the unpaid Guest Editor of the series. CA reports personal fees from Actelion, outside the submitted work. JK reports Speaker honoraria from Sanofi, Biomarin and Shire-Takeda. The authors have no other conflicts of interest to declare., (2021 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Pediatric pulmonary arterial hypertension (PAH) is a progressive life-threatening disease of the pulmonary vasculature and is defined as an elevation of the mean pulmonary arterial pressure. Before the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018, pulmonary hypertension (PH) used to be defined as a mean pulmonary artery pressure (mPAP) of ≥25 mmHg. On the WSPH a revised hemodynamic definition of PH was introduced lowering the threshold for a normal mPAP from <25 to <21 mmHg. The Pediatric Task Force chose to follow this newly proposed definition of PH in order to speak a uniform language and facilitate transition to adult services. In this opinion paper we discuss the rationale behind the new PH definition and the impact on pediatric PH. We conclude, that to date, there is no evidence in children, suggesting that this decrease of threshold for PH warrants any further measures than clinical outpatient-follow-up. Hitherto, the new definition does not impact on currently applicable treatment strategies in children with PH., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-412). The series “Pediatric Pulmonary Hypertension” was commissioned by the editorial office without any funding or sponsorship. Both authors served as the unpaid Guest Editors of the series. AEL received remuneration for advisory consultancy for Actelion, outside the submitted work. CA reports lecture fees from Actelion, outside the submitted work. The authors have no other conflicts of interest to declare., (2021 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Systemic sclerosis (SSc) is a rare disease in childhood and is characterized by a combination of vasculopathy, inflammation, autoimmunity, and fibrogenesis with individually varying expression pattern. Pulmonary arterial hypertension (PAH) is a serious complication of SSc and affects approximately 10% of SSc patients. SSc-PAH is complex and difficult to diagnose, as symptoms are non-specific and may be complicated by other SSc-associated diseases such as interstitial lung disease or left heart disease. SSc-PAH patients can deteriorate rapidly, and disease progression can occur even in patients with mild PAH symptoms at diagnosis. Therefore, interdisciplinary care of SSc patients is essential, and treating physicians must be aware of the association between SSc and PAH. In order to detect PAH early, children with SSc should be regularly screened for PAH by pediatric cardiologists. If PAH is detected, a systematic diagnostic approach by trained PH specialists including careful phenotyping of PAH is required. Relevant interstitial lung disease and left heart disease should be ruled out in the differential diagnosis of SSc-PAH before starting any targeted therapy. Due to the progressive character of SSc-PAH known from adult studies, it appears appropriate to initiate targeted PAH-therapy in juvenile SSc-PAH early. Adapted from adult treatment algorithms, combination therapy regimens (addressing at least two pathophysiological pathways) are increasingly used for pediatric PAH patients, and there is growing evidence to support this approach also in SSc-PAH patients., Competing Interests: Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-901). The series “Pediatric Pulmonary Hypertension” was commissioned by the editorial office without any funding or sponsorship. Dr. Apitz served as the unpaid Guest Editor of the series. Dr. Apitz reports personal fees from Actelion, outside the submitted work. The authors have no other conflicts of interest to declare., (2021 Cardiovascular Diagnosis and Therapy. All rights reserved.)

While the current definition of pulmonary hypertension (PH) is still based on haemodynamic variables, transthoracic echocardiography is the most important diagnostic clinical tool for the first assessment and evaluation of a patient, in whom PH is suspected. In addition, it is the most important clinical modality in long term follow-up and the utility of echocardiography has widely been demonstrated in patients with PH. Echocardiography not only reveals the underlying cardiac morphology and diagnosis of any associated cardiac defects. In most patients with PH right ventricular (RV) pressure estimation is feasible. In addition, ventricular systolic and diastolic function, as well as ventricular-ventricular interactions of both ventricles can be assessed by using echocardiography. Maximizing the use of echocardiography by reporting several measures to gain information and quantitatively describe the parameters, that are linked to prognosis, seem particularly appealing in these children, in whom other advanced imaging modalities requiring anaesthesia is associated with a considerable risk. Herein we provide a practical approach and a concise and clinically applicable echocardiographic guidance and present basic variables, which should be obtained at any assessment. Moreover, we present additional advanced echocardiographic measures, that can be applied in a research or clinical setting when progressive PH needs a deeper insight to assess heart function, estimation of pulmonary artery pressures among others, by echocardiography. Finally, clinically relevant studies in view of the prognostic properties with a focus on the most important echocardiographic variables in pediatric PH are summarized., Competing Interests: Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/cdt-21-119). The series “Pediatric Pulmonary Hypertension” was commissioned by the editorial office without any funding or sponsorship. Drs. AEL and CA served as the unpaid Guest Editors of the series. Dr. AEL reports consultancy work for Actelion Pharmaceuticals/Johnson & Johnson. The authors have no other conflicts of interest to declare., (2021 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Significant progress in the understanding of the etiology, epidemiology, pathobiology and prognosis of pulmonary hypertension (PH) has been made over the last years. Especially in the pediatric patient population the etiology of PH is very heterogeneous. Nevertheless, the most recent change of the definition of PH to a mean pulmonary artery pressure (mPAP) >20 mmHg has been accepted by pediatricians for uniformity and concordance with adult physicians. Based on the diverse underlying medical conditions leading to PH, a comprehensive and systematic approach for diagnosis and treatment is mandatory. Cardiac catheterization remains the gold standard for invasive assessment and acute vasoreactivity testing (AVT) additionally providing detailed information about nature of PH. In most patients repeat cardiac catheterization may be helpful for evaluation of response to targeted PH treatment, risk stratification and indication for lung transplantation. However, the information and results taken from cardiac catheterization should be interpreted by experienced investigators only who are familiar with confounding factors that may influence the results. Here we provide an overview of current recommendations for invasive hemodynamic evaluation in pediatric PH. We point out different patient scenarios and provide a structured approach for AVT and response interpretation., Competing Interests: Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-395). The series “Pediatric Pulmonary Hypertension” was commissioned by the editorial office without any funding or sponsorship. CA and AEL served as the unpaid Guest Editors of the series. CA reports lecture fees from Actelion, outside the submitted work. AEL reports personal fees from Actelion, outside the submitted work. The author has no other conflicts of interest to declare., (2021 Cardiovascular Diagnosis and Therapy. All rights reserved.)

Background: Pulmonary arterial hypertension (PAH) is often associated with cardiac autonomic dysfunction, and heart rate variability (HRV) as marker of cardiac autonomic function is even related to disease severity. Knowledge about the effects of physical activity on HRV is limited in these patients. We aimed to assess whether HRV parameters can be influenced by a supervised exercise training program and whether respective changes are related to levels of activity., Methods: Six children and adolescents with moderate PAH (3 female, mean age 15.0±4.4 years; mean pulmonary to systemic arterial pressure ratio 0.5±0.2) performed supervised endurance and resistance training for 16 weeks. PAH-specific targeted medication remained unchanged during the study period. HRV was assessed before training and after 16 weeks of training by the use of ECG Move accelerometers. HRV indices included: standard deviation of normal-to-normal (NN) intervals (SDNN), square root of the mean of the sum of the squares of differences between successive NN-intervals (RMSSD), proportion of the number of pairs of successive normal-to-normal intervals that differ by more than 50 ms divided by total number of normal-to-normal interval (pNN50), and the Baevsky stress index (BSI) calculated by the histogram method., Results: Before and after the training program, SDNN, RMSSD and pNN50 correlated with the level of physical activity. Mean values of SDNN, RMSSD and pNN50 did not change significantly due to the training program. Notably, activity level depending SDNN increased markedly after the exercise program (during activity +12.4%, at rest +6.6% and reclining +8.1%, Hedge's g of 0.28, 0.14 and 0.27, respectively). BSI decreased during activity due to the training program reflecting a reduction of stress level (Hedge's g -0.87 indicating an effect of clinical relevance)., Conclusions: According to the experience of this pilot study a workout program of 16 weeks revealed an activity level dependent effect on parameters of autonomic cardiac function in children and adolescents with PAH. This mechanism might contribute to the positive effects of exercise training in patients with PAH., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/cdt-20-263). The series “Pediatric Pulmonary Hypertension” was commissioned by the editorial office without any funding or sponsorship. CA served as the unpaid Guest Editor of the series. The authors have no other conflicts of interest to declare., (2021 Cardiovascular Diagnosis and Therapy. All rights reserved.)