TAD boundary deletion causes PITX2-related cardiac electrical and structural defects.

While 3D chromatin organization in topologically associating domains (TADs) and loops mediating regulatory element-promoter interactions is crucial for tissue-specific gene regulation, the extent of their involvement in human Mendelian disease is largely unknown. Here, we identify 7 families presenting a new cardiac entity associated with a heterozygous deletion of 2 CTCF binding sites on 4q25, inducing TAD fusion and chromatin conformation remodeling. The CTCF binding sites are located in a gene desert at 1 Mb from the Paired-like homeodomain transcription factor 2 gene (PITX2). By introducing the ortholog of the human deletion in the mouse genome, we recapitulate the patient phenotype and characterize an opposite dysregulation of PITX2 expression in the sinoatrial node (ectopic activation) and ventricle (reduction), respectively. Chromatin conformation assay performed in human induced pluripotent stem cell-derived cardiomyocytes harboring the minimal deletion identified in family#1 reveals a conformation remodeling and fusion of TADs. We conclude that TAD remodeling mediated by deletion of CTCF binding sites causes a new autosomal dominant Mendelian cardiac disorder.

Health-related quality of life in children and adolescents with Marfan syndrome or related disorders: a controlled cross-sectional study.

BACKGROUND: This cross-sectional controlled study aims to assess health-related quality of life (HRQoL) of children and adolescents with a molecular diagnosis of Marfan syndrome (MFS) or related disorders and to evaluate the factors associated with HRQoL in this population. Sixty-three children with MFS and 124 age- and sex-matched healthy children were recruited. HRQoL was assessed using the Pediatric Quality of Life Inventory (PedsQL™) generic questionnaire. The correlation between HRQoL scores and the different continuous parameters (age, body mass index, disease severity, systemic score, aortic sinus diameter, and aerobic physical capacity) was evaluated using Pearson's or Spearman's coefficient. A multiple linear regression analysis was performed on the two health summary self-reported PedsQL™ scores (physical and psychosocial) to identify the factors associated with HRQoL in the MFS group. RESULTS: Except for emotional functioning, all other domains of HRQoL (psychosocial and physical health, social and school functions) were significantly lower in children with MFS compared to matched healthy children. In the MFS group, the physical health summary score was significantly lower in female than in male patients (self-report: absolute difference [95%CI] = -8.7 [-17.0; -0.47], P = 0.04; proxy-report: absolute difference [95%CI] = -8.6 [-17.3; 0.02], P = 0.05) and also negatively correlated with the systemic score (self-report: R = -0.24, P = 0.06; proxy-report: R = -0.29, P = 0.03) and with the height Z-score (proxy-report: R = -0.29, P = 0.03). There was no significant difference in the physical health summary scores between the different genetic subgroups. In the subgroup of 27 patients who performed a cardiopulmonary exercise test, self- and proxy-reported physical health summary scores were highly correlated with their aerobic physical capacity assessed by peak oxygen consumption (VO2max) and ventilatory anaerobic threshold (VAT). In the multivariate analysis, the most important independent predictors of decreased physical health were increased height, decreased body mass index, decreased VAT and use of prophylactic therapy. CONCLUSIONS: This study reports an impaired HRQoL in children and adolescents with MFS or related conditions, in comparison with matched healthy children. Educational and rehabilitation programs must be developed and evaluated to improve exercise capacity and HRQoL in these patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03236571 . Registered 28 July 2017.

Early hybrid cardiac rehabilitation in congenital heart disease: the QUALIREHAB trial.

BACKGROUND AND AIMS: Cardiopulmonary fitness in congenital heart disease (CHD) decreases faster than in the general population resulting in impaired health-related quality of life (HRQoL). As the standard of care seems insufficient to encourage and maintain fitness, an early hybrid cardiac rehabilitation programme could improve HRQoL in CHD. METHODS: The QUALIREHAB multicentre, randomized, controlled trial evaluated and implemented a 12-week centre- and home-based hybrid cardiac rehabilitation programme, including multidisciplinary care and physical activity sessions. Adolescent and young adult CHD patients with impaired cardiopulmonary fitness were randomly assigned to either the intervention (i.e. cardiac rehabilitation) or the standard of care. The primary outcome was the change in HRQoL from baseline to 12-month follow-up in an intention-to-treat analysis. The secondary outcomes were the change in cardiovascular parameters, cardiopulmonary fitness, and mental health. RESULTS: The expected number of 142 patients was enroled in the study (mean age 17.4 ± 3.4 years, 52% female). Patients assigned to the intervention had a significant positive change in HRQoL total score [mean difference 3.8; 95% confidence interval (CI) 0.2; 7.3; P = .038; effect size 0.34], body mass index [mean difference -0.7 kg/m2 (95% CI -1.3; -0.1); P = .022; effect size 0.41], level of physical activity [mean difference 2.5 (95% CI 0.1; 5); P = .044; effect size 0.39], and disease knowledge [mean difference 2.7 (95% CI 0.8; 4.6); P = .007; effect size 0.51]. The per-protocol analysis confirmed these results with a higher magnitude of differences. Acceptability, safety, and short-time effect of the intervention were good to excellent. CONCLUSIONS: This early hybrid cardiac rehabilitation programme improved HRQoL, body mass index, physical activity, and disease knowledge, in youth with CHD, opening up the possibility for the QUALIREHAB programme to be rolled out to the adult population of CHD and non-congenital cardiac disease.

Usefulness of perioperative transoesophageal echocardiography during paediatric cardiac surgery.

BACKGROUND: Paediatric transoesophageal echocardiography probes allow perioperative evaluation during paediatric congenital heart disease surgery. AIM: To assess the usefulness of perioperative transoesophageal echocardiography in evaluating the severity of residual lesions, based on the type of congenital heart disease repaired in paediatric patients. METHODS: A retrospective analysis was conducted on paediatric patients who underwent open-heart surgery at our tertiary centre over a four-year period. Perioperative transoesophageal echocardiography studies were performed, and residual lesions were classified as mild, moderate or severe. RESULTS: Overall, 323 procedures involving 310 patients with a median age of 13.8 (0.07-214.4) months and a median weight of 8.2 (2-96) kg at intervention were enrolled in the study. Twenty-one (6.5%) residual lesions led to immediate reintervention: severe right ventricular outflow tract obstruction (n=12); severe aortic regurgitation (n=3); superior vena cava stenosis (n=2); moderate residual ventricular septal defect (n=2); severe mitral regurgitation (n=1); and severe mitral stenosis (n=1). Three (0.9%) neonates had ventilation difficulties caused by the transoesophageal echocardiography probe having to be removed, but experienced no sequelae. CONCLUSION: Perioperative transoesophageal echocardiography is a safe procedure, providing information on severe residual lesions, leading to the immediate revision of several paediatric congenital heart disease cases.

Advancing paediatric cardiac imaging: a comprehensive analysis of the feasibility and accuracy of a novel 3D paediatric transoesophageal probe.

Aims: Pediatric transoesophageal echocardiography (TOE) probes have remained two-dimensional (2D) limiting their use compared to adults. While critical in pediatrics for interventions and post-surgery assessments, technological advancements introduced a three-dimensional (3D) pediatric TOE probe. This study assessed the new 3D pediatric TOE probe (GE 9VT-D) for feasibility, handling, and imaging quality. Methods and results: At Children's Hospital of Toulouse, 2-month prospective study enrolled children undergoing TOE with the new probe. All imaging modalities were rated by 2 operators using a 5-point Likert-type scale from 1 (very poor) to 5 (very good) quality. Forty-five children, median age 3.7 (range: 2 months-14.7 years) median weight 7.8 kg (range: 4.3-48 kg) underwent 60 TOEs: 25% pre-surgery, 45% post-surgery, 28% during percutaneous procedures, and 2% in intensive care. Probe handling was "very easy" in all cases without adverse events. The median score of 2D, 2D colour, pulsed Doppler and 3D were noted 5 out of 5 and continuous Doppler and 3D colour 4 out of 5. The 3D image quality remained consistent irrespective of the patient weighing above or below 7.8 kg (p = 0.72). Postoperative TOEs identified two cases needing further interventions, emphasizing its value in evaluating surgical outcomes and also for guiding percutaneous interventions. Conclusion: Our comprehensive evaluation demonstrates that the new 3D pediatric TOE probe is feasible and provides high-quality imaging in pediatric patients. The successful integration of this novel probe into clinical practice has the potential to enhance diagnostic accuracy and procedural planning, ultimately optimizing patient outcomes in pediatric cardiac care.

Primary Non-Aortic Lesions Are Not Rare in Marfan Syndrome and Are Associated with Aortic Dissection Independently of Age.

PURPOSE: The study sought to estimate the prevalence of primary non-aortic lesions (PNAL) unrelated to extension of aortic dissection (AD) in a cohort of patients with Marfan syndrome (MFS). METHODS: Adult patients presenting with pathogenic FBN1 mutations and an available pan-aortic contrast-enhanced CTA in eight French MFS clinics from April to October 2018 were included. Clinical and radiological data, particularly the presence of aortic lesions and PNAL (including aneurysm and ectasia), were retrospectively analyzed. RESULTS: Out of 138 patients, 28 (20.3%) had PNAL. In total, 27 aneurysms in 13 patients and 41 ectasias in 19 patients were reported mainly in the subclavian, iliac, and vertebral segments. Four patients (31%) with aneurysms and none with ectasia required prophylactic intervention during follow-up (median: 46 months). In multivariate analysis, factors associated with PNAL were history of AD (OR = 3.9, 95%CI: 1.3-12.1, p = 0.018), history of previous descending aortic surgery (OR = 10.3, 95%CI: 2.2-48.3, p = 0.003) and age (per 10 years OR = 1.6, 95%CI: 1.1-2.4, p = 0.008). CONCLUSION: PNAL is not rare in MFS patients with evolutive aortic disease. Natural history may differ between aneurysms and ectasia, emphasizing the need for standardized definitions and systematic screening for PNAL.

Radiation dose during catheter ablation in children using a low fluoroscopy frame rate.

BACKGROUND: Catheter ablation (CA) in children using fluoroscopy carries risks inherent to ionizing radiation exposure. AIMS: The objective of this study was to demonstrate the feasibility of using low frames rate during ablation in children to maximally decrease radiation dose. METHODS: Hundred sixty eight successive patients<18 years of age undergoing CA performed under a 3.75 frames/second rate were retrospectively included. Demographics, procedural and dosimetry data were analysed. The effective dose (ED) was evaluated in a subgroup of 14 patients. RESULTS: Median age and weight were 15 years and 54kg, 72% had WPW, 10% AV node reentrant tachycardia, 10% ventricular tachycardia (atrial tachycardia, flutter and atrial fibrillation for the other cases). Acute success was achieved in 98.5% without any complication. Median procedure and fluoroscopy duration were 120 and 16minutes. Median Dose Area Product (DAP) and Air Kerma were 2.46Gy.cm2 and 18 mGy respectively (2Gy.cm2 and 15 mGy for WPW ablation). A significant reduction of median DAP was noted over the years for WPW, from 3.1Gy.cm2 in 2011 to 1.4 in 2019. Median estimated ED was 0.19 mSv (0.03 to 1.64), falling into the range of yearly normal natural irradiation or caused by leasure or professional activity. CONCLUSION: Low frame rate fluoroscopy is a highly effective and safe approach in decreasing radiation exposure during CA in children without altering the success rate of the procedure. ED is low, similar to natural/leisure irradiation. This approach can be considered a good alternative to 3D-based procedures in terms of efficiency and radiation issues, at least for WPW ablations.

Impact of 3D-printed models in meetings with parents of children undergoing interventional cardiac catheterisation.

Background: Paediatric interventional catheterisation has consistently improved in recent decades, with often highly successful outcomes. However, progress is still required in terms of the information delivered to parents and how parental anxiety is managed. Aim: To investigate the impact of cardiac printed models on improving parental understanding and alleviating anxiety before interventional catheterisation. Methods: The parents of children undergoing interventional cardiac catheterisation were prospectively enrolled in the study. A questionnaire highlighting knowledge and understanding of the condition and cardiac catheterisation per se was scored on a scale of 1-30. The State-Trait Anxiety Inventory (STAI), which generates current anxiety scores, was also used before and after the pre-catheterisation meeting. The "printing group" received an explanation of catheterisation using the device and a three-dimensional (3D) model, while the "control group" received an explanation using only the device and a manual drawing. Results: In total, 76 parents of 50 children were randomly assigned to a "control group" (n = 38) or "printing group" (n = 38). The groups were comparable at baseline. The level of understanding and knowledge improved after the "control group" and "printing group" meetings (+5.5±0.8 and +10.2±0.8; p < 0.0001 and p < 0.0001, respectively). A greater improvement was documented in the "printing group" compared to the "control group" (p < 0.0001). The STAI score also improved after the explanation was given to both groups (-1.8±0.6 and -5.6±1.0; p < 0.0001 and p < 0.0001). The greatest improvement was noted in the "printing group" (p = 0.0025). Most of the parents (35/38 from the "printing group") found the models to be extremely useful. Conclusion: 3D-printed models improve parental knowledge and understanding of paediatric cardiac catheterisation, thereby reducing anxiety levels.

A +3 variant at a donor splice site leads to a skipping of the MYH11 exon 32, a recurrent RNA defect causing Heritable Thoracic Aortic Aneurysm and Dissection and/or Patent Ductus Arteriosus.

BACKGROUND: Pathogenic variants in MYH11 are associated with either heritable thoracic aortic aneurysm and dissection (HTAAD), patent ductus arteriosus (PDA) syndrome, or megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS). METHODS AND RESULTS: We report a family referred for molecular diagnosis with HTAAD/PDA phenotype in which we found a variant at a non-conserved position of the 5' donor splice site of intron 32 of MYH11 potentially altering splicing (NM_002474.3:c.4578+3A>C). Although its cosegregation with disease was observed, it remained of unknown significance. Later, aortic surgery in the proband gave us the opportunity to perform a transcript analysis. This showed a skipping of the exon 32, an RNA defect previously reported to be translated to an in-frame loss of 71 amino acids and a dominant-negative effect in the smooth muscle myosin rod. This RNA defect is also reported in 3 other HTAAD/PDA pedigrees. CONCLUSION: This report confirms that among rare variants in MYH11, skipping of exon 32 is recurrent. This finding is of particular interest to establish complex genotype-phenotype correlations where some alleles are associated with autosomal dominant HTAAD/PDA, while others result in recessive or dominant visceral myopathies.

The usefulness of 3D printed heart models for medical student education in congenital heart disease.

BACKGROUND: Three-dimensional (3D) printing technology enables the translation of 2-dimensional (2D) medical imaging into a physical replica of a patient's individual anatomy and may enhance the understanding of congenital heart defects (CHD). We aimed to evaluate the usefulness of a spectrum of 3D-printed models in teaching CHD to medical students. RESULTS: We performed a prospective, randomized educational procedure to teach fifth year medical students four CHDs (atrial septal defect (ASD, n = 74), ventricular septal defect (VSD, n = 50), coarctation of aorta (CoA, n = 118) and tetralogy of Fallot (ToF, n = 105)). Students were randomized into printing groups or control groups. All students received the same 20 min lecture with projected digital 2D images. The printing groups also manipulated 3D printed models during the lecture. Both groups answered an objective survey (Multiple-choice questionnaire) twice, pre- and post-test, and completed a post-lecture subjective survey. Three hundred forty-seven students were included and both teaching groups for each CHD were comparable in age, sex and pre-test score. Overall, objective knowledge improved after the lecture and was higher in the printing group compared to the control group (16.3 ± 2.6 vs 14.8 ± 2.8 out of 20, p < 0.0001). Similar results were observed for each CHD (p = 0.0001 ASD group; p = 0.002 VSD group; p = 0.0005 CoA group; p = 0.003 ToF group). Students' opinion of their understanding of CHDs was higher in the printing group compared to the control group (respectively 4.2 ± 0.5 vs 3.8 ± 0.4 out of 5, p < 0.0001). CONCLUSION: The use of 3D printed models in CHD lectures improve both objective knowledge and learner satisfaction for medical students. The practice should be mainstreamed.

Health-related quality of life and physical activity in children with inherited cardiac arrhythmia or inherited cardiomyopathy: the prospective multicentre controlled QUALIMYORYTHM study rationale, design and methods.

BACKGROUND: Advances in paediatric cardiology have improved the prognosis of children with inherited cardiac disorders. However, health-related quality of life (QoL) and physical activity have been scarcely analysed in children with inherited cardiac arrhythmia or inherited cardiomyopathy. Moreover, current guidelines on the eligibility of young athletes with inherited cardiac disorders for sports participation mainly rely on expert opinions and remain controversial. METHODS: The QUALIMYORYTHM trial is a multicentre observational controlled study. The main objective is to compare the QoL of children aged 6 to 17 years old with inherited cardiac arrhythmia (long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, or arrhythmogenic right ventricular dysplasia), or inherited cardiomyopathy (hypertrophic, dilated, or restrictive cardiomyopathy), to that of age and gender-matched healthy subjects. The secondary objective is to assess their QoL according to the disease's clinical and genetic characteristics, the level of physical activity and motivation for sports, the exercise capacity, and the socio-demographic data. Participants will wear a fitness tracker (ActiGraph GT3X accelerometer) for 2 weeks. A total of 214 children are required to observe a significant difference of 7 ± 15 points in the PedsQL, with a power of 90% and an alpha risk of 5%. DISCUSSION: After focusing on the survival in children with inherited cardiac disorders, current research is expanding to patient-reported outcomes and secondary prevention. The QUALIMYORYTHM trial intends to improve the level of evidence for future guidelines on sports eligibility in this population. Trial registration ClinicalTrials.gov Identifier: NCT04712136, registered on January 15th, 2021 ( https://clinicaltrials.gov/ct2/show/NCT04712136 ).

Echocardiographic Parameters Predictive of Poor Outcome in Persistent Pulmonary Hypertension of the Newborn (PPHN): Preliminary Results.

The aim is to conduct a pilot study to prospectively describe echocardiographic parameters in neonates with pulmonary hypertension (PH) managed according to current recommendations and to identify those parameters that could predict worsening of short-term outcomes. All neonates less than 28 days old with a diagnosis of PH were prospectively enrolled in a tertiary care center for 1 year. Two echocardiograms were performed by a trained neonatologist. The first echocardiogram was performed at the time of diagnosis, whereas the second was performed just after basic therapeutic optimization. The cohort included 27 neonates. Mean gestational age at birth was 36.1 weeks gestational age (WGA) (SD: 4) and mean birth weight was 2658 g (SD: 907). Six neonates (22%) died before day 28, with a median age at death of 48 h (IQR [33; 89]). Although the first echocardiogram showed no difference, the second highlighted a strong link between the persistence of right-to left-shunt and death (p = 0.002). We showed a link between right-to-left shunt and a poor outcome (death or morbidity) after therapeutic optimization among premature and full-term neonates suffering from PH. We recommend repeating echocardiography after basic therapeutic optimization and for prognostic purposes, taking into account only the second examination. Larger cohorts are needed to confirm these results.

Feasibility and accuracy of printed models of complex cardiac defects in small infants from cardiac computed tomography.

BACKGROUND: Three-dimensional (3-D) printed models are increasingly used to enhance understanding of complex anatomy in congenital heart disease. OBJECTIVE: To assess feasibility and accuracy of 3-D printed models obtained from cardiac CT scans in young children with complex congenital heart diseases. MATERIALS AND METHODS: We included children with conotruncal heart anomalies who were younger than 2 years and had a cardiac CT scan in the course of their follow-up. We used cardiac CT scan datasets to generate 3-D models. To assess the models' accuracy, we compared four diameters for each child between the CT images and the printed models, including the largest diameters (Dmax) of ventricular septal defects and aortic annulus and their minimal diameters (Dmin). RESULTS: We obtained images from 14 children with a mean age of 5.5 months (range 1-24 months) and a mean weight of 6.7 kg (range 3.4-14.5 kg). We generated 3-D models for all children. Mean measurement difference between CT images and 3-D models was 0.13 mm for Dmin and 0.12 mm for Dmax for ventricular septal defect diameters, and it was 0.16 mm for Dmin and -0.13 mm for Dmax for aortic annulus diameter, indicating a non-clinically significant difference. CONCLUSION: Three-dimensional printed models could be feasibly generated from cardiac CT scans in a small pediatric population with complex congenital heart diseases. This technique is highly accurate and reliably reflects the same structural dimensions when compared to CT source images.

Impact of a transition education program on health-related quality of life in pediatric patients with congenital heart disease: study design for a randomised controlled trial.

BACKGROUND: Recent advances in the field of congenital heart disease (CHD) led to an improved prognosis of the patients and in consequence the growth of a new population: the grown up with congenital heart disease. Until recently, more than 50% of these patients were lost to follow up because of the lack of specialized structures. The critical moment is the transition between paediatric and adult unit. Therapeutic education is crucial to solve this issue by helping patients to become independent and responsible. The TRANSITION-CHD randomized trial aims to assess the impact of a transition education program on health-related quality of life (HRQoL) of adolescents and young adults with CHD. METHODS: Multicentre, randomised, controlled, parallel arm study in CHD patients aged from 13 to 25 years old. Patients will be randomised into 2 groups (education program vs. no intervention). The primary outcome is the change in self-reported HRQoL between baseline and 12-month follow-up. A total of 100 patients in each group is required to observe a significant increase of the overall HRQoL score of 7 ± 13.5 points (on 100) with a power of 80% and an alpha risk of 5%. The secondary outcomes are: clinical outcomes, cardiopulmonary exercise test parameters (peak VO2, VAT, VE/VCO2 slope), level of knowledge of the disease using the Leuven knowledge questionnaire for CHD, physical and psychological status. DISCUSSION: As the current research is opening on patient related outcomes, and as the level of proof in therapeutic education is still low, we sought to assess the efficacy of a therapeutic education program on HRQoL of CHD patients with a randomized trial. TRIAL REGISTRATION: This study was approved by the National Ethics Committee (South-Mediterranean IV 2016-A01681-50) and was registered on Clinicaltrials.gov (NCT03005626).

Parental mosaicism in Marfan and Ehlers-Danlos syndromes and related disorders.

Marfan syndrome (MFS) is a heritable connective tissue disorder (HCTD) caused by pathogenic variants in FBN1 that frequently occur de novo. Although individuals with somatogonadal mosaicisms have been reported with respect to MFS and other HCTD, the overall frequency of parental mosaicism in this pathology is unknown. In an attempt to estimate this frequency, we reviewed all the 333 patients with a disease-causing variant in FBN1. We then used direct sequencing, combined with High Resolution Melting Analysis, to detect mosaicism in their parents, complemented by NGS when a mosaicism was objectivized. We found that (1) the number of apparently de novo events is much higher than the classically admitted number (around 50% of patients and not 25% as expected for FBN1) and (2) around 5% of the FBN1 disease-causing variants were not actually de novo as anticipated, but inherited in a context of somatogonadal mosaicisms revealed in parents from three families. High Resolution Melting Analysis and NGS were more efficient at detecting and evaluating the level of mosaicism compared to direct Sanger sequencing. We also investigated individuals with a causal variant in another gene identified through our "aortic diseases genes" NGS panel and report, for the first time, on an individual with a somatogonadal mosaicism in COL5A1. Our study shows that parental mosaicism is not that rare in Marfan syndrome and should be investigated with appropriate methods given its implications in patient's management.

Impact of Sophrology on cardiopulmonary fitness in teenagers and young adults with a congenital heart disease: The SOPHROCARE study rationale, design and methods.

BACKGROUND: Recent advances in the field of congenital heart disease (CHD) have significantly improved the overall prognosis. Now more attention is being given to health-related quality of life (HRQoL) and promotion of physical activity. Non-invasive relaxation therapy may be effective in cardiac patients concerned with exercise-induced dyspnoea. The SOPHROCARE randomised trial aims to assess the impact of Caycedian Sophrology on cardiopulmonary fitness in adolescents and young adults with CHD. METHODS: The SOPHROCARE trial is a nationwide, multicentre, randomised, controlled study in CHD patients aged from 13 to 25 years old. Patients will be randomised into 2 groups (8 Sophrology group sessions vs. no intervention). The primary outcome is the change in percent predicted maximum oxygen uptake (VO2max) between baseline and 12-month follow-up. A total of 94 patients in each group is required to observe a significant increase of 10% in VO2max with a power of 80% and an alpha risk of 5%. The secondary outcomes are: clinical outcomes, cardiopulmonary exercise test parameters (VE/VCO2 slope, ventilatory anaerobic threshold, oxygen pulse, respiratory response to hypercapnia), health-related quality of life score (PedsQL), physical and psychological status. CONCLUSION: After focusing on the survival in CHD, current research is opening on secondary prevention and patient-related outcomes. We sought to assess in the SOPHROCARE trial, if a Sophrology program, could improve exercise capacity and quality of life in youth with CHD. TRIAL REGISTRATION: Clinicaltrials.gov (NCT03999320).

Clinical and genetic data of 22 new patients with SMAD3 pathogenic variants and review of the literature.

BACKGROUND: Pathogenic SMAD3 variants are responsible for a cardiovascular phenotype, mainly thoracic aortic aneurysms and dissections. Precocious identification of the vascular risk such as aortic dilatation in mutated patients has a major impact in terms of management, particularly to avoid dissection and sudden death. These vascular damages are classically associated with premature osteoarthritis and skeletal abnormalities. However, variable expressivity and incomplete penetrance are common with SMAD3 variants. METHODS: To investigate the clinical variability observed within SMAD3 patients, we reviewed the phenotypic and genetic data of 22 new patients from our Centre and of 133 patients reported in the literature. From this cohort of 155 mutated individuals, we first aimed to delineate an estimated frequency of the main clinical signs associated with SMAD3 pathogenic variants and, then, to look for genotype-phenotype correlations, mainly to see if the aortic phenotype (AP) could be predicted by the SMAD3 variant type. RESULTS: We showed, herein, the absence of correlation between the SMAD3 variant type and the occurrence of an AP in patients. CONCLUSION: Therefore, this report brings additional data for the genotype-phenotype correlations of SMAD3 variants and the need to explore in more detail the effects of genetic modifiers that could influence the phenotype.

Incidence of cardiovascular events and risk markers in a prospective study of children diagnosed with Marfan syndrome.

BACKGROUND: Little is known about the incidence of cardiovascular events (CVEs) and their associated risk markers in children with Marfan syndrome (MFS). AIMS: To assess the incidence of CVEs and determine risk markers in a cohort diagnosed with Marfan syndrome during childhood and followed for several years. METHODS: From a French multicentre nationwide database, 462 patients with MFS diagnosed during childhood were included prospectively. Patients' files were screened for a period of 20 years (1993-2013). CVEs (e.g. death, aortic dissection, cardiac valve or aortic root surgery) were assessed during the prospective follow-up. RESULTS: Median (interquartile range) age at the end of follow-up was 17.2 (11.1-21.3) years. CVEs were reported for 35 participants (7.6%; 95% confidence interval [CI] 5.3-10.4%). First CVEs were prophylactic aortic root surgery (n=29), aortic dissection (n=4; two aged <18 years) and death (n=2). Kaplan-Meier cumulative incidence of CVEs was 5.3% (95% CI 3.3-8.7%) during childhood (aged≤18 years) and 19.4% (95% CI 13.3-27.9%) at 25years of age. The cumulative rate of CVEs was higher in case of Valsalva sinus Z-score increase of≥0.1 per year (P=0.0003), maximal Valsalva sinus diameter growth speed ≥5mm per year (P=0.03), aortic regurgitation≥2 (P=0.0005) and maximal Valsalva sinus Z-score≥3 before 16 years of age (P<0.0001). In a multivariable Cox proportional analysis, the Valsalva sinus Z-score remained significantly related to outcome. Considering aortic root evolution, aortic regurgitation, age at diagnosis and beta-blocker therapy were related to Valsalva sinus Z-score evolution during follow-up. CONCLUSIONS: CVEs in children with MFS are mainly related to prophylactic aortic root surgery. Aortic dissections are rarely observed in children. The Valsalva sinus Z-score is a strong indicator of subsequent CVEs in children with MFS. Attention to follow-up and beta-blocker observance may be warranted in high-risk children.