Dilated Cardiomyopathy Due to Alimentary Iron Deficiency.

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.

De novo variants in RNF213 are associated with a clinical spectrum ranging from Leigh syndrome to early-onset stroke.

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.

[New aspects in pediatric pulmonary hypertension - Commented 2022ERS/ESC-PH guidelines]. / Neue Aspekte bei der pulmonalen Hypertonie im Kindesalter ­ kommentierte 2022ERS/ESC-PH-Guidelines.

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.

[Pulmonary arterial hypertension in congenital heart disease - Part I]. / Pulmonale arterielle Hypertonie bei Erwachsenen mit angeborenen Herzfehlern ­ Teil I.

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.

Left Ventricular Physiology and Ventricular-Vascular Interactions in Young Patients After Heart Transplantation.

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/m2 (P<0.0001), whereas ventricular compliance remained rather unchanged (0.16±0.10 mm Hg/mL/m2 to 0.12±0.07 mm Hg/mL/m2; 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/m2 (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.

Nationwide Survey Reveals High Prevalence of Non-Swimmers among Children with Congenital Heart Defects.

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.

Physical Self-Concept and Physical Activity in Children with Congenital Heart Defects-Can We Point Out Differences to Healthy Children to Promote Physical Activity?

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.

Effects of Sports, Exercise Training, and Physical Activity in Children with Congenital Heart Disease-A Review of the Published Evidence.

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.

Non-invasive pediatric cardiac imaging-current status and further perspectives.

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.

Riociguat in children with pulmonary arterial hypertension: The PATENT-CHILD study.

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.

Left Ventricular Strain Analysis During Submaximal Semisupine Bicycle Exercise Stress Echocardiography in Childhood Cancer Survivors.

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.

Effects of exercise training on heart rate variability in children and adolescents with pulmonary arterial hypertension: a pilot study.

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.

Hemodynamic and prognostic impact of the diastolic pulmonary arterial pressure in children with pulmonary arterial hypertension-a registry-based analysis.

BACKGROUND: Diastolic pulmonary arterial pressure (dPAP) is regarded to be less sensitive to flow metrics as compared to mean PAP (mPAP), and was therefore proposed for the assessment of a precapillary component in patients with postcapillary pulmonary hypertension (PH). To analyze the diagnostic and prognostic impact of dPAP in patients with pure precapillary PH, we purposed to compare the correlation between dPAP and mPAP, as well as hemodynamically-derived calculations [ratio of PAP to systemic arterial pressure (PAP/SAP), pulmonary vascular resistance index (PVRI), transpulmonary gradient (TPG)], using both dPAP and mPAP, at rest and during acute vasoreactivity testing (AVT) in children with idiopathic or heritable pulmonary arterial hypertension (IPAH/HPAH). Furthermore, we aimed to assess the association of these metrics (at baseline and changes after AVT) with transplant-free survival. METHODS: We conducted a retrospective analysis of the TOPP (Tracking Outcomes and Practice in Pediatric Pulmonary Hypertension) registry including 246 IPAH/HPAH patients. Of these, 45 children (18.3%) died, and 13 (5.3%) received lung transplantation during the observation period. RESULTS: dPAP and mPAP-derived variables showed almost linear relationship. Higher mPAP/mSAP, and dPAP-/mPAP-derived PVRI at rest was associated with time to death/transplantation. At maximum AVT-response, the decrease of dPAP and mPAP, diastolic pulmonary gradient (DPG) and TPG, as well as dPAP/dSAP and mPAP/mSAP was associated with time to death/transplantation, showing higher significance than corresponding baseline values. Remarkably, no predictive value was found for PVRI-reduction during AVT, neither dPAP- nor mPAP-derived. CONCLUSIONS: There is a strong relationship between dPAP and mPAP-derived variables. According to our results, hemodynamics during AVT (irrespectively of dPAP- or mPAP-derived) may have more prognostic implications than resting hemodynamics in children with IPAH/HPAH, except for PVRI.

Update from the World Symposium on Pulmonary Hypertension 2018: does the new hemodynamic definition of pediatric pulmonary hypertension have an impact on treatment strategies?

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.

Moyamoya disease associated with pediatric pulmonary hypertension-a case report.

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.

Heart failure therapy based on interventricular mechanics and cardio-vascular communications.

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.

Cardiac catheterization in pediatric pulmonary hypertension: a systematic and practical approach.

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.

Systemic sclerosis-associated pulmonary arterial hypertension in children.

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.