The aim of this 4D flow cardiovascular magnetic resonance (CMR) follow-up study was to investigate longitudinal changes in aortic hemodynamics in adolescent patients with Marfan syndrome (MFS). 4D flow CMR for the assessment of in-vivo 3D blood flow with full coverage of the thoracic aorta was performed twice (baseline scan t1/follow-up scan t2) in 19 adolescent MFS patients (age at t1: 12.7 ± 3.6 years, t2: 16.2 ± 4.3 years) with a mean follow-up duration of 3.5 ± 1.2 years. Ten healthy volunteers (24 ± 3.8 years) served as a control group. Data analysis included aortic blood flow visualization by color-coded 3D pathlines, and grading of flow patterns (helices/vortices) on a 3-point scale (none, moderate, severe; blinded reading, 2 observers). Regional aortic peak systolic velocities and systolic 3D wall shear stress (WSS) along the entire aortic wall were quantified. Z-Scores of the aortic root and proximal descending aorta (DAo) were assessed. Regional systolic WSS was stable over the follow-up duration, except for a significant decrease in the proximal inner DAo segment (p = 0.02) between t1 and t2. MFS patients revealed significant lower mean systolic WSS in the proximal inner DAo compared with volunteers (0.78 ± 0.15 N/m2) at baseline t1 (0.60 ± 0.18 N/m2; p = 0.01) and follow-up t2 (0.55 ± 0.16 N/m2; p = 0.001). There were significant relationships (p < 0.01) between the segmental WSS in the proximal inner DAo, DAo Z-scores (r = −0.64) and helix/vortex pattern grading (r = −0.55) at both t1 and t2. The interobserver agreement for secondary flow patterns assessment was excellent (Cohen’s k = 0.71). MFS patients have lower segmental WSS in the inner proximal DAo segment which correlates with increased localized aberrant vortex/helix flow patterns and an enlarged diameter at one of the most critical sites for aortic dissection. General aortic hemodynamics are stable but these subtle localized DAo changes are already present at young age and tend to be more pronounced in the course of time.

Introduction: Pulmonary hypertension (PH) is a common complication in patients with congenital heart disease (CHD), aggravating the natural, post-operative, or post-interventional course of the underlying anomaly. The various CHDs differ substantially in characteristics, functionality, and clinical outcomes among each other and compared with other diseases with pulmonary hypertension. Objective: To describe current management strategies and outcomes for adults with PH in relation to different types of CHD based on real-world data. Methods and results: COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) is a prospective, international PH registry comprising, at the time of data analysis, >8200 patients with various forms of PH. Here, we analyzed a subgroup of 680 patients with PH due to CHD, who were included between 2007 and 2018 in 49 specialized centers for PH and/or CHD located in 11 European countries. At enrollment, the patients’ median age was 44 years (67% female), and patients had either pre-tricuspid shunts, post-tricuspid shunts, complex CHD, congenital left heart or aortic disease, or miscellaneous other types of CHD. Upon inclusion, targeted therapies for pulmonary arterial hypertension (PAH) included endothelin receptor antagonists, PDE-5 inhibitors, prostacyclin analogues, and soluble guanylate cyclase stimulators. Eighty patients with Eisenmenger syndrome were treatment-naïve. While at inclusion the primary PAH treatment for the cohort was monotherapy (70% of patients), with 30% of the patients on combination therapy, after a median observation time of 45.3 months, the number of patients on combination therapy had increased significantly, to 50%. The use of oral anticoagulants or antiplatelets was dependent on the underlying diagnosis or comorbidities. In the entire COMPERA-CHD cohort, after follow-up and receiving targeted PAH therapy (n = 511), 91 patients died over the course of a 5-year follow up. The 5-year Kaplan–Meier survival estimate for CHD associated PH was significantly better than that for idiopathic PAH (76% vs. 54%; p < 0.001). Within the CHD associated PH group, survival estimates differed particularly depending on the underlying diagnosis and treatment status. Conclusions: In COMPERA-CHD, the overall survival of patients with CHD associated PH was dependent on the underlying diagnosis and treatment status, but was significantly better as than that for idiopathic PAH. Nevertheless, overall survival of patients with PAH due to CHD was still markedly reduced compared with survival of patients with other types of CHD, despite an increasing number of patients on PAH-targeted combination therapy.

Numerous genetic studies have established a role for rare genomic variants in Congenital Heart Disease (CHD) at the copy number variation (CNV) and de novo variant (DNV) level. To identify novel haploinsufficient CHD disease genes, we performed an integrative analysis of CNVs and DNVs identified in probands with CHD including cases with sporadic thoracic aortic aneurysm. We assembled CNV data from 7,958 cases and 14,082 controls and performed a gene-wise analysis of the burden of rare genomic deletions in cases versus controls. In addition, we performed variation rate testing for DNVs identified in 2,489 parent-offspring trios. Our analysis revealed 21 genes which were significantly affected by rare CNVs and/or DNVs in probands. Fourteen of these genes have previously been associated with CHD while the remaining genes (FEZ1, MYO16, ARID1B, NALCN, WAC, KDM5B and WHSC1) have only been associated in small cases series or show new associations with CHD. In addition, a systems level analysis revealed affected protein-protein interaction networks involved in Notch signaling pathway, heart morphogenesis, DNA repair and cilia/centrosome function. Taken together, this approach highlights the importance of re-analyzing existing datasets to strengthen disease association and identify novel disease genes and pathways.

Supravalvular aortic stenosis is associated with the Williams–Beuren syndrome, but it also occurs in a non-syndromatic congenital form. Anelastingene mutation of chromosome 7q11.23 is responsible in both cases. The vascular features are identical. These patients have a higher risk of sudden death, particularly when undergoing diagnostic or surgical procedures. We report the account of a family with a new mutation in theelastingene. Screening over three generations revealed eight affected individuals. The cardiac and vascular malformations ranged from mild asymptomatic supravalvular aortic stenosis and isolated dysplastic atrioventricular valves to diffuse arterial hypoplasia. Two infants presented arteries affected at multiple locations, including the left coronary artery. Both died of sudden cardiac death and myocardial ischaemia, one while under general anaesthesia for cardiac catheterisation, and the other perioperatively. We discuss the pathophysiological aspects in these patients that deserve consideration before any general anaesthesia is administered.

Recessive dystrophic epidermolysis bullosa (RDEB) is a skin fragility disorder characterised by life-long mechanically induced skin blistering, fibrosis-driven pseudosyndactyly, and multi-organ involvement. Preclinical studies have suggested mitigated progression by angiotensin II type I receptor blockade through losartan. We aimed to determine the safety and tolerability of systemic losartan treatment among children with RDEB, and to obtain initial data on its clinical benefit. We conducted an open-label, single-arm, phase 1/2 trial at the Medical Center-University of Freiburg, Germany. Children with molecularly-confirmed RDEB, aged 2-16 years (starting from the 25th month of life) were eligible. Key exclusion criteria comprised anaemia with haemoglobin <8 g/dl; hypotension (defined as age-related systolic blood pressure under the 5th percentile); cardiologic contraindications, requirement for any medications that are likely to cause interactions with losartan; renal artery stenosis or renal insufficiency with creatinine clearance <30 ml/min; severe liver failure; severe, untreated electrolyte disturbances; history of cancer or chronic viral infections; hypersensitivity to losartan or any of the excipients and known or persistent abuse of medication, drugs, or alcohol. Treatment duration with losartan comprised 10 months, encompassing 16 weeks up-dosing of losartan, 24 weeks full dose losartan (final target dose of 1.4 mg/kg), and 4 weeks losartan tapering, followed by 12 weeks follow-up without losartan. The primary endpoint was occurrence of a serious safety concern, defined as one of the following side effects of losartan: clinically relevant severe hypotension, immediate hypersensitivity reactions to the drug or clinical relevant severe hypo- and hyperkalaemia. EB-specific scores (the EBDASI activity and damage score, Birmingham Epidermolysis Bullosa Severity Score (BEBS)) and other clinical outcome parameters were evaluated at five clinical visits as secondary outcomes: pain (Wong-Baker FACES Scale for pain), quality of life (Quality Of Life in EB [QOLEB] questionnaire and Children's Dermatology Life Quality Index [CDLQI]), itch (Itch Assessment Scale for the Paediatric Burn Patients), dysphagia (Mayo Dysphagia Questionnaire-day 30 [MDQ-30]), pseudosyndactyly progression (our own morphometric scoring instrument), and hand function (Score of Colville and Terrill). All analyses (safety and efficacy) were performed in the safety population, defined as participants who received at least one dose of trial medication with losartan. This trial is registered with EudraCT, 2015-003670-32. Between Jul 28, 2017, and Feb 12, 2021, 29 children were enrolled. Of those 27 received the full treatment. Losartan was well tolerated, no treatment-related severe complications leading to a serious safety concern occurred. The patients revealed improvement in the RDEB clinical scores, namely a mean reduction at week 40 of -7.36 points (95%-CI: -16.13 to 1.41) in the EBDASI activity score and -10.50 points (95%-CI: -20.81 to -0.19) in the EBDASI damage score, while the Children's Dermatology Life Quality Index rose by 2.64 points (95%-CI: -4.55 to -0.90). Similar to the EBDASI score, the BEBS showed a mean reduction of -3 points, 95%-CI: -0.21 to -5,79, P = 0.036). In the Wong-Baker FACES Scale for Pain an improvement of at least one level was identified for 9 of 28 patients between baseline and at month 9 (95%-CI: 15.9%-52.4%; P = 0.57). Regarding the Quality of Life in EB Score, five of 28 patients showed an improvement in the total scale of at least one level at month 9 (95%-CI: 6.1%-36.9%; P = 0.71). With the Itch assessment scale for the paediatric burn patients an improvement of at least one level could be observed in 12 of 28 patients (95%-CI: 24.5%-62.8%; P = 0.24). The MDQ-30 showed no relevant difference at 9 months after treatment start, as compared to baseline. We observed improvement of finger span with our own morphometric scoring instrument of pseudosyndactyly progression, revealing an increase of the maximal distance between thumb and index finger at month 9 by 6.92 mm, 95%-CI [3.48, 10.37] P = 0.0009. With the Hand function assessment score of Colville and Terrill, an improvement of at least one level was documented for 3 of 28 patients, i.e., 10.7% (95%-CI: 2.3%-28.2%; P = 0.63). Our results suggest that losartan was well tolerated by children with RDEB, and provide preliminary evidence that it may reduce disease burden. Further research with larger sample sizes and longer durations is needed to establish the treatment's long-term efficacy and safety. Debra International, the Department of Dermatology, Medical Center-University of Freiburg (Berta-Ottenstein Advanced Clinician Scientist Program of the Medical Faculty), and the German Research Foundation.