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.

[Pulmonary hypertension in adults with congenital heart disease in light of the 2022-ESC-PAH guidelines - Part II: Supportive therapy, special situations (pregnancy, contraception, non-cardiac surgery), targeted pharmacotherapy, organ transplantation, special management (shunt lesions, left ventricular disorders, univentricular hearts), interventions, intensive care, follow-up, future perspectives]. / Pulmonale Hypertonie bei Erwachsenen mit angeborenen Herzfehlern im Lichte der 2022-ESC-PAH-Leitlinien.

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.

[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.

A Comprehensive Functional Analysis in Patients after Atrial Switch Surgery.

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/m2 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.

Impact of the Right Ventricular Sokolow-Lyon Index in Children with Idiopathic Pulmonary Arterial Hypertension.

Right ventricular (RV) hypertrophy is regarded as the adaptation on chronic RV pressure load in pulmonary hypertension. As the RV Sokolow-Lyon index (RVSLI) is an electrocardiographic marker of RV hypertrophy, we hypothesized that RVSLI might be able to reflect RV pressure load. Therefore, the purpose of this study was to characterize the diagnostic impact of the RVSLI in children with idiopathic pulmonary arterial hypertension (IPAH) in order to assess disease severity and to evaluate its value for the prediction of worse outcome. Forty-two children (aged 3-17 years) with IPAH were included in this retrospective study. The follow-up after baseline examination was 59 ± 17 months. Receiver-operating characteristic (ROC) curves and Kaplan-Meier analysis were used to discriminate a cut-off value of RVSLI and to assess its predictive value regarding morbidity and mortality. In 12/42 patients (29%) severe cardiovascular events (defined as death, lung transplantation, or Potts shunt) were observed (time to event 20 ± 22 months). Patients with an event showed higher RVSLI values (3.6 ± 1.2 mV vs. 2.6 ± 1.6 mV; p < 0.05). ROC analysis discriminated an RVSLI of 2.1 as the best cut-off value (area under the ROC curve: 0.79, sensitivity: 0.91, specificity: 0.70, p < 0.05) to detect patients with high-risk PAH (mPAP/mSAP ratio > 0.75). Relative risk for a severe event with an index > 2.1 mV was 1.76 (95% CI 1.21-3.20). Relative risk for death with RVSLI > 2.1 mV was 2.01 (95% CI 1.61-4.80). Our study demonstrates a strong relationship between RVSLI and disease severity in children with IPAH. An RVSLI > 2.1 mV at the time of first diagnosis is a predictor for patients at risk for cardiac events. As an adjunct to the usual diagnostic assessment this parameter may therefore contribute to the initial prognostic estimation.

Diagnostics in Children and Adolescents with Suspected or Confirmed Pulmonary Hypertension.

We provide a practical approach on the initial assessment and diagnostic work-up of children and adolescents with pulmonary hypertension (PH). Transthoracic echocardiography (TTE) often serves as initial study tool before invasive cardiac catheterization. Misinterpretation of TTE variables may lead to missed or delayed diagnosis with devastating consequences, or unnecessary invasive diagnostics that have inherited risks. In addition to clinical and biochemical markers, serial examination of patients with PH using a standardized TTE approach, determining conventional and novel echocardiographic variables, may allow early diagnosis and treatment in paediatric PH. Cardiac magnetic resonance imaging and computed tomography represent important non-invasive imaging modalities, that together with TTE may enable comprehensive assessment of ventricular function and pulmonary hemodynamics. Invasive assessment of haemodynamics (ventricular, pulmonary) and testing of acute vasoreactivity in the catheterization laboratory is still the gold standard for the diagnosis of PH and pulmonary hypertensive vascular disease (PHVD) in children and for the initiation of specific PH therapy. We suggest the regular assessment of prognostic TTE variables as part of a standardized approach for initial diagnosis of children with PH. Overreliance on any single TTE variable should be avoided as it detracts from the overall diagnostic potential of a standardized TTE examination for PH.

Hemodynamic Evaluation of Children with Persistent or Recurrent Pulmonary Arterial Hypertension Following Complete Repair of Congenital Heart Disease.

Persistent or recurrent pulmonary arterial hypertension (PAH) following complete surgical repair of congenital heart disease (CHD) represents one of the largest group of PAH associated with CHD (PAH-CHD) in recent registry studies and seems to have a particularly poor prognosis. However, little is known about this fourth clinical subclass of PAH-CHD, especially in children. The purpose of this study was to assess specific characteristics of invasive hemodynamics of this disease in children, including acute vasodilator testing (AVT) and pulmonary endothelial function (PEF) and to compare to patients with idiopathic PAH (IPAH), who usually present with a similar fatal clinical course. Thirty-two children with PAH were included in the study, twelve of these patients had PAH-CHD subclass 4 (mean age 8.0 ± 3.4 years) and twenty children had IPAH (mean age 8.6 ± 4.4 years). Cardiac catheterization was performed in all children, including AVT and PEF. PEF was assessed by changes in pulmonary blood flow in response to acetylcholine (Ach) using Doppler flow measurements. Pulmonary flow reserve (PFR) was calculated as the ratio of pulmonary blood flow velocity in response to Ach relative to baseline values. At baseline, the ratio of mean PA pressure to mean systemic arterial pressure (mPAP/mSAP) was comparably high in both groups (0.78 ± 0.32 vs. 0.80 ± 0.22), while the indexed pulmonary vascular resistance (PVRI) was significantly lower in the PAH-CHD group (12.6 ± 6.8 WUxm2) compared to IPAH patients (19.9 ± 10.6 WUxm2) (p = 0.04). Cardiac index was significantly higher in the PAH-CHD group (4.19 ± 1.09 l/min/m2 vs. 3.23 ± 0.76) (p = 0.017). However, AVT revealed a significantly larger maximum response (percentage of fall of PVR/SVR ratio during AVT) in the IPAH group (37 ± 22%) compared to the PAH-CHD group (13 ± 23%) (p = 0.017). PEF showed no significant difference between both patient groups (PFR 1.69 ± 0.71 vs. 1.73 ± 0.68) (p = 0.76). Our study demonstrates significant pulmonary vascular disease in children with persistent or recurrent PAH following complete surgical repair of CHD similar to IPAH patients. Although baseline measures appeared to be more favorable, pulmonary vasoreactivity was markedly impaired in PAH-CHD subclass 4, which may contribute to its negative impact on the long-term outcome of this patient group.

Home Exercise Training in Children and Adolescents with Pulmonary Arterial Hypertension: A Pilot Study.

Pulmonary arterial hypertension (PAH) is often associated with impaired exercise capacity. It has been shown that supervised training can improve exercise capacity in adult patients with PAH. The objective of this prospective study was to assess the feasibility of a home exercise training program in children with PAH. Nine children and adolescents (mean age 15.2 ± 3.8 years) with low-risk PAH (defined as mean pulmonary to systemic arterial pressure ratio <0.75; WHO functional class I and II) performed home-based exercise training for 16 weeks. Cardiopulmonary exercise testing and health-related quality of life was evaluated before and after 16 weeks of training. The amount of training at home and patients' well-being was supervised by periodical phone calls and online-questionnaires. Home exercise training was well tolerated in all patients, and no adverse events occurred. After 16 weeks of training, patients significantly improved their exercise capacity [treadmill running distance increased from 589.5 ± 153.9 to 747.9 ± 209.2 m (p = 0.036)]. Oxygen consumption at the anaerobic threshold increased from 1307.8 (±417) to 1406.4 (±418) ml (p = 0.028). Chronotropic index improved from 0.77 ± 0.12 to 0.82 ± 0.11 (p = 0.004) and was slightly related to the increase in running distance (r = 0.62; p = 0.07). Home exercise training is feasible in children and adolescents with low-risk PAH, and the preliminary results of this pilot study indicate beneficial effects. The observed increase in exercise capacity was accompanied by an improved chronotropic competence and increased oxygen consumption at the anaerobic threshold. Future research is needed to investigate the safety and efficacy of home exercise training in a larger population of children with PAH including also patients in WHO functional class III or IV.

Effect of Inhaled Nitric Oxide on Blood Flow Dynamics in Patients After the Fontan Procedure Using Cardiovascular Magnetic Resonance Flow Measurements.

Invasive hemodynamic studies have shown that nitric oxide (NO), a selective pulmonary vasodilator, can lower pulmonary vascular resistance in Fontan patients. Because oximetry-derived flow quantification may be unreliable, we sought to detect changes in blood flow within the Fontan circulation after inhalation of NO using cardiovascular magnetic resonance (CMR). Thirty-three patients (mean age 12.8 ± 7.0 years) after the Fontan procedure underwent CMR as part of their routine clinical assessment. Standard two-dimensional blood flow measurements were performed in the Fontan tunnel, superior vena cava (SVC) and ascending aorta (AAO) before and after inhalation of 40 ppm NO for 8-10 min. Systemic-to-pulmonary collateral (SPC) flow was calculated as AAO - (SVC + tunnel). Heart rate (82 ± 18 to 81 ± 18 bpm; p = 0.31) and transcutaneous oxygen saturations (93 ± 4 to 94 ± 3 %; p = 0.13) did not change under NO inhalation. AAO flow (3.23 ± 0.72 to 3.12 ± 0.79 l/min/m(2); p = 0.08) decreased, tunnel flow (1.58 ± 0.40 to 1.65 ± 0.46 l/min/m(2); p = 0.032) increased, and SVC flow (1.01 ± 0.39 to 1.02 ± 0.40 l/min/m(2); p = 0.50) remained unchanged resulting in higher total caval flow (Qs) (2.59 ± 0.58 to 2.67 ± 0.68 l/min/m(2); p = 0.038). SPC flow decreased significantly from 0.64 ± 0.52 to 0.45 ± 0.51 l/min/m(2) (p = 0.002) and resulted in a significant decrement of the Qp/Qs ratio (1.23 ± 0.23 to 1.15 ± 0.23; p = 0.001). Inhalation of NO in Fontan patients results in significant changes in pulmonary and systemic blood flow. The reduction in SPC flow is accompanied by a net increase in effective systemic blood flow suggesting beneficial effects of pulmonary vasodilators on cardiac output, tissue perfusion and exercise capacity.

Focal myocardial fibrosis assessed by late gadolinium enhancement cardiovascular magnetic resonance in children and adolescents with dilated cardiomyopathy.

BACKGROUND: Different patterns of late gadolinium enhancement (LGE) including mid-wall fibrosis using cardiovascular magnetic resonance (CMR) have been reported in adult patients presenting with non-ischemic dilated cardiomyopathy (DCM). In these studies, LGE was associated with pronounced LV remodelling and predicted adverse cardiac outcomes. Accordingly, the purpose of our study was to determine the presence and patterns of LGE in children and adolescents with DCM. METHODS: Patients <18 years of age presenting with severe congestive heart failure who were admitted for evaluation of heart transplantation at our centre underwent CMR examination which consisted of ventricular functional analysis and assessment of LGE for detection of myocardial fibrosis. Ischemic DCM was excluded by coronary angiography, and right ventricular endomyocardial biopsies ruled out acute myocarditis. RESULTS: Thirty-one patients (mean age 2.1 ± 4.2 years) with severe LV dilatation (mean indexed LVEDV 136 ± 48 ml/m(2)) and LV dysfunction (mean LV-EF 23 ± 8%) were examined. LGE was detected in 5 of the 31 patients (16%) appearing in various patterns characterized as mid-wall (n = 1), focal patchy (n = 1), RV insertion site (n = 1) and transmural (n = 2). Based on histopathological analysis, 4 of the 5 LGE positive patients had lymphocytic myocarditis, whereas one patient was diagnosed with idiopathic DCM. CONCLUSIONS: In children and adolescents with DCM, focal histologically proven myocardial fibrosis is rarely detected by LGE CMR despite marked LV dilatation and severely depressed LV function. LGE occurred in various patterns and mostly in patients with inflammatory cardiomyopathy. It remains unclear whether myocardial fibrosis in childhood DCM reflects different endogenous repair mechanisms that enable favourable reverse remodelling. Larger trials are needed to assess the prognostic implications of LGE in childhood DCM.

Transcatheter Closure of Perimembranous Ventricular Septal Defects with Left Ventricular to Right Atrial Shunt.

During the development of so-called aneurysmal transformation of perimembranous ventricular septal defects (pmVSD), tricuspid valve (TV) morphology and function may be altered resulting in left ventricular (LV) to right atrial (RA) shunting. The feasibility and outcome of interventional closure of these pmVSD has not been investigated so far. Interventional closure of pmVSD associated with mild to moderate LV-to-RA shunt was performed in four patients (aged 6.5-12.5 years). pmVSD were closed under fluoroscopic guidance by establishing an arteriovenous wire loop via a femoral artery and advancing the delivery sheath from a femoral vein. Before device release (or withdrawal if necessary), residual shunting across the device and TV valve function was investigated by transthoracic echocardiography and LV angiography. pmVSD sizes of 4, 5.5, 8 and 8.5 mm were closed with a 4/4 and 6/6 Amplatzer duct occluder II and an 8- and 10-mm Amplatzer muscular VSD occluder device, respectively. There were no or only minor residual postinterventional LV-to-RA shunts. No atrioventricular blocks were observed during a mean follow-up of 12.5 months (range 6.5-17 months). Transthoracic echocardiography indicated that the elimination of the VSD jet pushing the antero-superior TV leaflet open is the key mechanism for LV-to-RA shunt reduction after transcatheter pmVSD closure. Interventional closure in pmVSD associated with mild to moderate indirect LV-to-RA shunting is feasible and results in significant reduction in or elimination of LV-to-RA shunting.

Fifteen-year single center experience with the "Giessen Hybrid" approach for hypoplastic left heart and variants: current strategies and outcomes.

Presented is a retrospective outcome study of a 15-year single institutional experience with a contemporary cohort of patients with hypoplastic left heart syndrome and complex that underwent a "Giessen Hybrid" stage I as initial palliation. Hybrid approach consisting of surgical bilateral pulmonary artery banding and percutaneous duct stenting with or without atrial septum manipulation was developed from a rescue approach to a first-line procedure. Comprehensive Aristotle score defined pre-operative condition. Fifteen-year follow-up mortality is reported as occurring within the staged univentricular palliation or before and after biventricular repair. Hybrid stage I was performed in 154 patients; 107 should be treated by single ventricle palliation, 33 by biventricular repair (BVR), 7 received heart transplantation, and 7 were treated by comfort care, respectively. Overall 34 children died. The Aristotle score (mean value 18.2 ± 3) classified for univentricular circulations in newborns did not have statistical impact on the outcome. Two patients died during stage I (1.2%), and the interstage I mortality was 6.7%, and stage II mortality 9%, respectively. Stage III was up to now performed in 57 patients without mortality. At 1 year, the overall unadjusted survival of HLHS and variants was 84% and following BVR 89%, respectively. The Fifteen-year survival rate for HLHS and variants was 77%, with no significant impact of birth weight of less than 2.5 kg. In conclusion, Hybrid stage I fulfilled the criteria of life-saving approach. In our institution, Hybrid procedure replaced Norwood-staged palliation with a considerable mid- and long-term survival rate. Considering interstage mortality close surveillance is mandatory.

Pulmonary arterial hypertension associated with impaired lysosomal endothelin-1 degradation.

We report on a boy with severe pulmonary arterial hypertension associated with mucolipidosis, a rare lysosomal storage disorder. During diagnostic catheterisation, we found increased endothelin-1 levels, but normal big endothelin-1-levels (the precursor form of endothelin-1), which suggests impaired degradation of endothelin-1 rather than increased synthesis. As endothelin-1 degradation takes place in the lysosome, it appears likely that lysosomal dysfunction caused by the underlying disease contributes to the development of pulmonary arterial hypertension in this patient.

Upgraded heart failure therapy leads to an improved outcome of dilated cardiomyopathy in infants and toddlers.

OBJECTIVE: Dilated cardiomyopathy is a leading cause of cardiac death in children. Approximately 30% of children die or need cardiac transplantation in the first year after establishing the diagnosis. New strategies are needed to improve the outcome in this high-risk patient population. METHOD AND RESULTS: We present our experience in 38 patients below the age of three years, who were diagnosed with dilated cardiomyopathy and who were treated at our institution between 2006 and 2012. The treatment strategy involved institution of ß-blockers and angiotensin-converting enzyme inhibitors as soon as feasible. In selected cases, pulmonary artery banding or intracoronary autologous bone marrow-derived cell therapy was performed. The median age at presentation was six months (range 1-26 months). The median follow-up age was 16 months (range 2-80 months). Kaplan-Meier analysis of survival after dilated cardiomyopathy diagnosis revealed a one-year survival of 97% and a five-year survival of 86%. The rate of freedom from death or heart transplantation was 82% at one year and 69% at five years. Surviving patients who were free of transplantation, at the follow-up at 25 months (3-80 months), showed a significant improvement in left ventricular ejection fraction (from 19±11 to 46±16%) and left ventricular end-diastolic diameter (z-score from 4.6±2.4 to 1.4±1.6). In addition, the levels of B-type natriuretic peptide improved significantly (from 3330±3840 to 171±825 pg/ml). CONCLUSION: Our data suggest that the clinical approach described here may result in a markedly improved medium-term outcome in young children with dilated cardiomyopathy. Further studies are required to evaluate whether these approaches reduce end-points such as transplantation or death.

Cardiovascular magnetic resonance assessment of ventricular function and myocardial scarring before and early after repair of anomalous left coronary artery from the pulmonary artery.

BACKGROUND: In patients with anomalous left coronary artery from the pulmonary artery (ALCAPA) left ventricular (LV) dilatation and dysfunction evolves due to diminished myocardial perfusion caused by coronary steal phenomenon. Using late gadolinium enhanced cardiovascular magnetic resonance (LGE-CMR) imaging, myocardial scarring has been shown in ALCAPA patients late after repair, however the incidence of scarring before surgery and its impact on postoperative course after surgical repair remained unknown. METHODS: 8 ALCAPA-patients (mean age 10.0 ± 5.8 months) underwent CMR before and early after (mean 4.9 ± 2.5 months) coronary reimplantation procedures. CMR included functional analysis and LGE for detection of myocardial scars. RESULTS: LV dilatation (mean LVEDVI 171 ± 94 ml/m2) and dysfunction (mean LV-EF 22 ± 10 %) was present in all patients and improved significantly after surgery (mean LVEDV 68 ± 42 ml/m2, p=0.02; mean LV-EF 58 ± 19 %, p<0.001). Preoperative CMR revealed myocardial scarring in 2 of the 8 patients and did not predict postoperative course. At follow-up CMR, one LGE-positive patient showed delayed recovery of LV function while myocardial scarring was still present in both patients. In two patients new-onset transmural scarring was found, although functional recovery after operation was sufficient. One of them showed a stenosis of the left coronary artery and required resurgery. CONCLUSIONS: Despite diminished myocardial perfusion and severely compromised LV function, myocardial scarring was preoperatively only infrequently present. Improvement of myocardial function was independent of new-onset scarring while the impact of preoperative scarring still needs to be defined.

Systemic arterial endothelial function in children and young adults with idiopathic pulmonary arterial hypertension: is there a relation to pulmonary endothelium-dependent relaxation?

Pulmonary arterial endothelial function is known to be affected in patients with idiopathic pulmonary arterial hypertension (IPAH). Current reports also detected peripheral systemic arterial dysfunction in IPAH patients. The purpose of this study was to assess whether there is a relation between pulmonary arterial and systemic arterial endothelial function. Pulmonary arterial endothelium-dependent relaxation was assessed by changes in pulmonary blood flow in response to acetylcholine which were determined using intravascular Doppler flow measurements. Pulmonary flow reserve (PFR) was calculated as the ratio of pulmonary blood flow velocity in response to acetylcholine relative to baseline values. Systemic arterial endothelial function was assessed by the vascular response to reactive hyperemia, and was recorded non-invasively by peripheral arterial finger tonometry under standardized conditions. Thirteen children and young adults [mean age 16.7 (±5.6) years] with IPAH and 13 age-/gender-matched controls were included in the study. Digital reactive hyperemic index (RHI) of the IPAH patients was 1.54 (±0.69), and of the controls was 1.67 (±0.66) [p = 0.64]. The mean baseline flow velocity in the segmental pulmonary artery of all patients was 18.5 (±5.5) cm/s, increasing to 27.4 (±12.3) cm/s (p = 0.003) during acetylcholine infusion. The calculated mean PFR was 1.48 (±0.4). There was no significant correlation between the PFR and RHI (r = 0.19; p = 0.54). According to our results, systemic arterial endothelial function assessed by peripheral arterial finger tonometry was not significantly impaired in children and young adults with IPAH compared with age-/gender-matched controls. There was no correlation between systemic arterial and pulmonary arterial endothelial function, suggesting that different mechanisms may contribute to their pathogenesis and progression.

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.

Adverse biventricular remodeling in isolated right ventricular hypertension is mediated by increased transforming growth factor-ß1 signaling and is abrogated by angiotensin receptor blockade.

The pressure-loaded right ventricle (RV) adversely affects left ventricular (LV) function. We recently found that these ventricular-ventricular interactions lead to LV myocardial fibrosis through transforming growth factor-ß1 (TGF-ß1) signaling. We investigated the mechanisms mediating biventricular fibrosis in RV afterload and their potential modification by angiotensin receptor blockade. An adjustable pulmonary artery band (PAB) was placed in rabbits. In sham-operated control rabbits, the band was left uninflated (n = 6). In the RV afterload group, the PAB was sequentially inflated to generate systemic RV pressure at 28 days (n = 8). In a third group, the PAB was inflated to systemic levels, and the angiotensin receptor blocker losartan was added (n = 6). Five weeks after surgery, the animals were killed for assessments of biventricular hypertrophy, fibrosis, apoptosis, and the components of their signaling pathways. PAB animals developed biventricular hypertrophy, fibrosis, and apoptosis, versus sham rabbits, in which these conditions were decreased with losartan. RV and LV TGF-ß1, connective tissue growth factor (CTGF) (CCN2), endothelin-1 (ET-1), endothelin receptor B, and matrix metalloproteinase 2/9 mRNA levels were increased in PAB animals versus sham animals, and decreased with losartan. Given the marked biventricular CTGF up-regulation in PAB and down-regulation with losartan, we investigated CTGF signaling. RV and LV Smad 2/3/4 protein levels and LV RhoA mRNA levels were increased with PAB and reduced with losartan. In conclusion, isolated RV afterload induces biventricular fibrosis and apoptosis, which are reduced by angiotensin receptor blockade. Adverse ventricular-ventricular interactions induced by isolated RV afterload appear to be mediated through TGF-ß1-CTGF and ET-1 pathways.