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.

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).

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 ).

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.

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.

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.

Genetic diversity and pathogenic variants as possible predictors of severity in a French sample of nonsyndromic heritable thoracic aortic aneurysms and dissections (nshTAAD).

PURPOSE: Heritable thoracic aortic aneurysms and dissections (hTAAD) are life-threatening complications of well-known syndromic diseases or underdiagnosed nonsyndromic heritable forms (nshTAAD). Both have an autosomal dominant transmission and are genetically heterogeneous. Our objective was to describe the relevance of molecular diagnosis in these patients and the contribution of each gene in nshTAAD. METHODS: Two hundred twenty-six consecutive nshTAAD probands, either young (<45 years) sporadic or familial cases were included. A next-generation sequencing capture panel comprising 23 known disease-causing genes was performed. RESULTS: Class 4 or 5 variants were identified in 18% of the nshTAAD probands, while class 3 variants were found in 10% of them. The yield in familial cases was greater than in sporadic cases. SMAD3 and FBN1 genes were the major disease-causing genes. Unexpectedly, no premature termination codon variant was identified in the FBN1 gene. Furthermore, we report for the first time that aortic dissection or surgery occurred significantly more often and earlier in probands with a class 4 or 5 pathogenic variant. CONCLUSION: This study indicates that genetic screening using NGS is efficient in young and familial nshTAAD. The presence of a pathogenic variant has a possible predictive value, which needs to be further investigated because it may influence care.

MFAP5 loss-of-function mutations underscore the involvement of matrix alteration in the pathogenesis of familial thoracic aortic aneurysms and dissections.

Thoracic aortic aneurysm and dissection (TAAD) is an autosomal-dominant disorder with major life-threatening complications. The disease displays great genetic heterogeneity with some forms allelic to Marfan and Loeys-Dietz syndrome, and an important number of cases still remain unexplained at the molecular level. Through whole-exome sequencing of affected members in a large TAAD-affected family, we identified the c.472C>T (p.Arg158(∗)) nonsense mutation in MFAP5 encoding the extracellular matrix component MAGP-2. This protein interacts with elastin fibers and the microfibrillar network. Mutation screening of 403 additional probands identified an additional missense mutation of MFAP5 (c.62G>T [p.Trp21Leu]) segregating with the disease in a second family. Functional analyses performed on both affected individual's cells and in vitro models showed that these two mutations caused pure or partial haploinsufficiency. Thus, alteration of MAGP-2, a component of microfibrils and elastic fibers, appears as an initiating mechanism of inherited TAAD.

Image of a left atrial mass after a cardiopulmonary bypass in a child.

Invagination of an appendage into the left atrium is a rare complication. It occurs spontaneously or after open-heart surgery. In our case, a postoperative transesophageal echocardiogram, after closure of a ventricular septal defect in a 5-month-old infant, revealed a large mass in the left atrium. A diagnosis of a left appendage inversion was confirmed after external examination of the heart. Herein, we provide echocardiographic images before, during, and after manual reversion of the left appendage. Misdiagnosis of this complication could have led to an additional unnecessary surgical procedure that could have impacted on the patient's morbidity.

Marfan Sartan: a randomized, double-blind, placebo-controlled trial.

AIMS: To evaluate the benefit of adding Losartan to baseline therapy in patients with Marfan syndrome (MFS). METHODS AND RESULTS: A double-blind, randomized, multi-centre, placebo-controlled, add on trial comparing Losartan (50 mg when <50 kg, 100 mg otherwise) vs. placebo in patients with MFS according to Ghent criteria, age >10 years old, and receiving standard therapy. 303 patients, mean age 29.9 years old, were randomized. The two groups were similar at baseline, 86% receiving ß-blocker therapy. The median follow-up was 3.5 years. The evolution of aortic diameter at the level of the sinuses of Valsalva was not modified by the adjunction of Losartan, with a mean increase in aortic diameter at the level of the sinuses of Valsalva of 0.44 mm/year (s.e. = 0.07) (-0.043 z/year, s.e. = 0.04) in patients receiving Losartan and 0.51 mm/year (s.e. = 0.06) (-0.01 z/year, s.e. = 0.03) in those receiving placebo (P = 0.36 for the comparison on slopes in millimeter per year and P = 0.69 for the comparison on slopes on z-scores). Patients receiving Losartan had a slight but significant decrease in systolic and diastolic blood pressure throughout the study (5 mmHg). During the study period, aortic surgery was performed in 28 patients (15 Losartan, 13 placebo), death occurred in 3 patients [0 Losartan, 3 placebo, sudden death (1) suicide (1) oesophagus cancer (1)]. CONCLUSION: Losartan was able to decrease blood pressure in patients with MFS but not to limit aortic dilatation during a 3-year period in patients >10 years old. ß-Blocker therapy alone should therefore remain the standard first line therapy in these patients.

Three-dimensional printing of a complex CHD to plan surgical repair.

We used three-dimensional printing technology to create an anatomical three-dimensional model of a very rare and complex cyanotic CHD in a newborn, consisting of double-outlet left ventricle, ventricular septal defect, and pulmonary stenosis. This case demonstrates how this new innovative technology allows better understanding of the anatomy in complex CHDs and permits to better plan the surgical repair.

Endothelial Function and Vascular Properties in Children with Sickle Cell Disease.

BACKGROUND: Sickle cell disease (SCD) is an inherited disorder characterized by recurrent painful crises with ischemia resulting from vascular occlusion. Adults with SCD have increased arterial stiffness and reduced flow-mediated dilation (FMD), due to impaired release of substances such as nitric oxide. AIM: We aimed to assess the vascular properties of carotid and brachial arteries in children with SCD compared with a control group without cardiovascular risk factors. METHODS: Thirty patients with SCD, mean age 12.3 ± 4.5 years, were prospectively enrolled. A control group was made up of 30 age- and gender-matched healthy subjects. Carotid intima-media thickness (IMT), cross-sectional compliance (CSC), cross-sectional distensibility (CSD), diastolic wall stress (DWS), incremental elastic modulus (Einc), and FMD were determined in both groups. RESULTS: There was no significant difference in FMD between the two groups (8.2 ± 5.0% in the SCD group vs. 9.3 ± 4.2% in the control group, P = 0.15). There was no significant correlation between FMD and age, hemoglobin, LDH level, or transcranial Doppler findings. CSD was significantly elevated in the SCD group (0.96 ± 0.44 vs. 0.59 ± 0.21, P = 0.0002), whereas DWS and Einc were significantly lower in the SCD group. CSC did not differ significantly between the two groups. CONCLUSIONS: Children with SCD have no marked endothelial dysfunction or change in arterial stiffness. These manifestations may be related to disease severity and duration. Changes may become evident later in life as the disease progresses.

Bedside right ventricle quantification using three-dimensional echocardiography in children with congenital heart disease: A comparative study with cardiac magnetic resonance imaging.

BACKGROUND: Accurate quantification of right ventricular (RV) volumes and function is crucial for the management of congenital heart diseases. AIMS: We aimed to assess the feasibility and accuracy of bedside analysis using new RV quantification software from three-dimensional transthoracic echocardiography in children with or without congenital heart disease, and to compare measurements with cardiac magnetic resonance imaging. METHODS: We included paediatric patients with congenital heart disease (106 patients) responsible for RV volume overload and a control group (30 patients). All patients underwent three-dimensional transthoracic echocardiography using a Vivid E95 ultrasound system. RV end-diastolic and end-systolic volumes and RV ejection fraction were obtained using RV quantification software. Measurements were compared between RV quantification and cardiac magnetic resonance imaging in 27 patients. RESULTS: Bedside RV quantification analysis was feasible in 133 patients (97.8%). Manual contour adjustment was necessary in 126 patients (93%). The mean time of analysis was 62±42s. RV end-diastolic and end-systolic volumes were larger in the congenital heart disease group than the control group: median 85.0 (interquartile range 29.5) mL/m2 vs 55.0 (interquartile range 20.5) mL/m2 for RV end-diastolic volume and 42.5 (interquartile range 15.3) mL/m2 vs 29.0 (interquartile range 11.8) mL/m2 for RV end-systolic volume, respectively. Good agreement for RV end-diastolic and end-systolic volumes and RV ejection fraction was found between RV quantification and magnetic resonance imaging measurements. RV quantification software underestimated RV end-diastolic volume/body surface area by 3mL/m2 and RV ejection fraction by 2.1%, and overestimated RV end-systolic volume/body surface area by 0.2mL/m2. CONCLUSIONS: We found good feasibility and accuracy of bedside RV quantification analysis from three-dimensional transthoracic echocardiography in children with or without congenital heart disease. RV quantification could be a reliable and non-invasive method for RV assessment in daily practice, facilitating appropriate management and follow-up care.

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.

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.

Efficacy of a Transition Program in Adolescents and Young Adults With Congenital Heart Disease: The TRANSITION-CHD Randomized Controlled Trial.

PURPOSE: Currently, nearly 90% of patients with congenital heart disease (CHD) reach adulthood in relatively good health. Structured transition programs have emerged to support adolescents and young adults in transitioning to adult care structures, improve their autonomy, and limit healthcare ruptures. The TRANSITION-CHD randomized controlled trial aimed to assess the impact of a transition program on health-related quality of life (HRQoL) in adolescents and young adults with CHD. METHODS: From January 2017 to February 2020, 200 subjects with a CHD, aged 13-25 years, were enrolled in a prospective, controlled, multicenter study and randomized in two balanced groups (transition program vs. standard of care). The primary outcome was the change in PedsQL self-reported HRQoL score between baseline and 12-month follow-up, using an intention-to-treat analysis. The secondary outcomes were the change in disease knowledge, physical health (cardiopulmonary fitness, physical activity), and mental health (anxiety, depression). RESULTS: The change in HRQoL differed significantly between the transition group and the control group (mean difference = 3.03, 95% confidence interval (CI) = [0.08; 5.98]; p = .044; effect size = 0.30), in favor of the intervention group. A significant increase was also observed in the self-reported psychosocial HRQoL (mean difference = 3.33, 95% CI = [0.01; 6.64]; p = .049; effect size = 0.29), in the proxy-reported physical HRQoL (mean difference = 9.18, 95% CI = [1.86; 16.51]; p = .015; effect size = 0.53), and in disease knowledge (mean difference = 3.13, 95% CI = [1.54; 4.72]; p < .001; effect size = 0.64). DISCUSSION: The TRANSITION-CHD program improved HRQoL and disease knowledge in adolescents and young adults with CHD, supporting the generalization and systematization of similar preventive interventions in pediatric and congenital cardiology.

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.

Parental electrocardiographic screening identifies a high degree of inheritance for congenital and childhood nonimmune isolated atrioventricular block.

BACKGROUND: The origin of congenital or childhood nonimmune isolated atrioventricular (AV) block remains unknown. We hypothesized that this conduction abnormality in the young may be a heritable disease. METHODS AND RESULTS: A multicenter retrospective study (13 French referral centers, from 1980-2009) included 141 children with AV block diagnosed in utero, at birth, or before 15 years of age without structural heart abnormalities and without maternal antibodies. Parents and matched control subjects were investigated for family history and for ECG screening. In parents, a family history of sudden death or progressive cardiac conduction defect was found in 1.4% and 11.1%, respectively. Screening ECGs from 130 parents (mean age 42.0 ± 6.8 years, 57 couples) were compared with those of 130 matched healthy control subjects. All parents were asymptomatic and in sinus rhythm, except for 1 with undetected complete AV block. Conduction abnormalities were more frequent in parents than in control subjects, found in 50.8% versus 4.6%, respectively (P<0.001). A long PR interval was found in 18.5% of the parents but never in control subjects (P<0.0001). Complete or incomplete right bundle-branch block was observed in 39.2% of the parents and 1.5% of the control subjects (P<0.0001). Complete or incomplete left bundle-branch block was found in 15.4% of the parents and 3.1% of the control subjects (P<0.0006). Estimated heritability for isolated conduction disturbances was 91% (95% confidence interval, 80%-100%). SCN5A mutation screening identified 2 mutations in 2 patients among 97 children. CONCLUSIONS: ECG screening in parents of children affected by idiopathic AV block revealed a high prevalence of conduction abnormalities. These results support the hypothesis of an inheritable trait in congenital and childhood nonimmune isolated AV block.

Characteristics and long-term outcome of non-immune isolated atrioventricular block diagnosed in utero or early childhood: a multicentre study.

AIMS: The natural history of congenital or childhood non-immune, isolated atrioventricular (AV) block is poorly defined. METHODS AND RESULTS: We retrospectively studied 141 children with isolated, non-immune AV block diagnosed in utero, or up to 15 years of age, at 13 French medical centres, between 1980 and 2009. Patients with structural heart disease or maternal antibodies were excluded. Atrioventricular block was asymptomatic in 119 (84.4%) and complete in 100 (70.9%) patients. There was progression to complete AV block in 29/41 (70.7%) patients with incomplete AV block over 2.8 ± 3.4 years (1-155 months), but all patients with incomplete AV block may not have been included in the study. Narrow QRS complex was present in 18 of 26 patients (69.2%) with congenital, and 106 of 115 (92.2%) with childhood AV block. Pacemakers were implanted in 112 children (79.4%), during the first year of life in 18 (16.1%) and before 10 years of age in 90 (80.4%). The mean interval between diagnosis of AV block and pacemaker implants was 2.6 ± 3.9 years (0-300 months). The pacing indication was prophylactic in 70 children (62.5%). During a mean follow-up of 11.6 ± 6.7 years (1-32 years), no patient died or developed dilated cardiomyopathy (DCM). The long-term follow-up was uncomplicated in 127 children (90.1%). CONCLUSION: In this large multicentre study, the long-term outcome of congenital or childhood non-immune, isolated AV block was favourable, regardless of the patient's age at the time of diagnosis. No patient died or developed DCM, and pacemaker-related complications were few.

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.