Yves Dulac

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 β-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. β-Blocker therapy alone should therefore remain the standard first line therapy in these patients.

Rationale and design of a randomized clinical trial (Marfan Sartan) of angiotensin II receptor blocker therapy versus placebo in individuals with Marfan syndrome

BACKGROUND Recent studies have demonstrated that blockade of the angiotensin II type 1 receptor with losartan decreases aortic damage in an animal model of Marfan syndrome (a KI mouse model with a pathogenic mutation in the gene coding for fibrillin-1). AIMS To demonstrate a beneficial effect of losartan on aortic dilatation when added to optimal therapy in patients with Marfan syndrome. METHODS This is a multicentre, randomized, placebo-controlled, double-blind, clinical trial with a 2-year inclusion period and a 3-year follow-up period. Aortic root diameter will be measured using two-dimensional echocardiography. Secondary endpoints will include incidence of aortic dissection, aortic root surgery, death, quality of life, tolerance and compliance with treatments. We aim to enroll a total of 300 patients aged > or =10 years who fulfil the Ghent criteria for Marfan syndrome. Analyses will be based on intention to treat. CONCLUSION The results of this clinical trial could lead to profound modification of the management of aortic risk and complications in patients with Marfan syndrome and possibly in patients with thoracic aortic aneurysms of other aetiologies.

Impact of clinical and genetic findings on the management of young patients with Brugada syndrome

BACKGROUND Brugada syndrome (BrS) is an arrhythmogenic disease associated with sudden cardiac death (SCD) that seldom manifests or is recognized in childhood. OBJECTIVES The objectives of this study were to describe the clinical presentation of pediatric BrS to identify prognostic factors for risk stratification and to propose a data-based approach management. METHODS We studied 106 patients younger than 19 years at diagnosis of BrS enrolled from 16 European hospitals. RESULTS At diagnosis, BrS was spontaneous (n = 36, 34%) or drug-induced (n = 70, 66%). The mean age was 11.1 ± 5.7 years, and most patients were asymptomatic (family screening, (n = 67, 63%; incidental, n = 13, 12%), while 15 (14%) experienced syncope, 6(6%) aborted SCD or symptomatic ventricular tachycardia, and 5 (5%) other symptoms. During follow-up (median 54 months), 10 (9%) patients had life-threatening arrhythmias (LTA), including 3 (3%) deaths. Six (6%) experienced syncope and 4 (4%) supraventricular tachycardia. Fever triggered 27% of LTA events. An implantable cardioverter-defibrillator was implanted in 22 (21%), with major adverse events in 41%. Of the 11 (10%) patients treated with hydroquinidine, 8 remained asymptomatic. Genetic testing was performed in 75 (71%) patients, and SCN5A rare variants were identified in 58 (55%); 15 of 32 tested probands (47%) were genotype positive. Nine of 10 patients with LTA underwent genetic testing, and all were genotype positive, whereas the 17 SCN5A-negative patients remained asymptomatic. Spontaneous Brugada type 1 electrocardiographic (ECG) pattern (P = .005) and symptoms at diagnosis (P = .001) were predictors of LTA. Time to the first LTA event was shorter in patients with both symptoms at diagnosis and spontaneous Brugada type 1 ECG pattern (P = .006). CONCLUSION Spontaneous Brugada type 1 ECG pattern and symptoms at diagnosis are predictors of LTA events in the young affected by BrS. The management of BrS should become age-specific, and prevention of SCD may involve genetic testing and aggressive use of antipyretics and quinidine, with risk-specific consideration for the implantable cardioverter-defibrillator.

Live 3D Echocardiography with the Pediatric Matrix Probe

Three‐dimensional echocardiography (3DE) enables new views of heart valves and the septa to be imaged. While the previous 3DE system was cumbersome, the recent introduction of live 3DE allowed for routine use of the technique in adult patients. Here, we report our initial experiences in adapting live 3DE and the adult matrix probe to the pediatric population. Thirty‐four 3DE examinations were performed on children, aged 1 day to 12 years (n = 23; median 4 years) and fetuses 20–33 weeks in gestation (n = 11; median 25 weeks), many of whom had various congenital heart diseases. The pediatric matrix probe (2–7 MHz) was used for 2D, Doppler, and 3DE. New modalities of the Vision 2007 (Philips) were applied: live, full volume, thick slice, 3D color Doppler, the QLAB system for navigation, and cropping. The pediatric matrix probe allows for complete 2D and 3D echocardiography, and new acoustic windows are now available to perform live 3DE. The higher frequency of the probe increases the 3D image resolution obtained in neonates and fetuses. This advancement allows new views of the aorta, pulmonary valve, septa and intra cardiac anatomy to be captured. Real time 3DE is a feasible method in addition to conventional 2D echocardiography for evaluating congenital heart disease.

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 patients age at the time of diagnosis. No patient died or developed DCM, and pacemaker-related complications were few.

Outcome of coronary artery bypass grafting performed in young children

OBJECTIVES The long-term patency rate of coronary artery bypass grafting for which arterial grafts are used is known to be high in the pediatric population. However, this issue remains uncertain in children under 3 years of age. Here, we report the outcome in this specific population. METHODS From July 1988 to July 2007, 18 children less than 3 years of age (age at operation, 0.1-35 months; median, 4 months) underwent 20 coronary artery bypass graft operations using an arterial graft. Indications for bypass grafting were coronary artery complications related to the arterial switch operation for transposition of the great arteries in 12 patients (coronary obstruction in 8 patients, peroperative coronary anomalies precluding coronary transfer in 4 patients), congenital anomalies of the coronary arteries in 4 patients, and Kawasaki disease in 2 patients. RESULTS After a mean follow-up of 55 months (range, 1-176 months; median, 41 months), patency of 19 bypass grafts was assessed. One was occluded and 2 have necessitated a percutaneous procedure. Two patients died suddenly (1 with an occluded graft and 1 with a patent graft and hypertrophic myocardiopathy) 3.5 and 4.6 months, respectively, after bypass grafting. CONCLUSIONS Coronary artery bypass grafting should be considered as a possible alternative for coronary revascularization in young children. Although our series shows quite a good patency rate, this procedure remains a technical challenge and requires careful follow-up.

Cardiovascular abnormalities in Turner's syndrome: what prevention?

Cardiovascular complications in Turners syndrome are the most common cause of excess early mortality, with a life expectancy that may be reduced by more than 10 years. Congenital cardiac abnormalities are described in approximately one third of patients. These abnormalities are mostly left heart obstructions, the most common of which are bicuspid aortic valve (16%) and coarctation of the aorta (11%). Dilatations of the ascending aorta are often described and may occur in isolation from any heart disease, suggesting a vasculopathy specific to the syndrome, probably predisposed to by extracardiac risk factors such as oestrogen deficiency, diabetes, dysplidaemia and overweight. The most feared complication is aortic dissection with around a 100 cases, described at average age of approximately 35-years-old. This is believed to complicate 2% of induced pregnancies. Hypertension (HBP) usually essential, affects up to 50% of patients with Turners syndrome. This is an important risk factor for cardiovascular complications and justifies aggressive treatment. On the other hand, retrospective studies have not demonstrated adverse cardiological effects due to growth hormone treatments. Patients with Turners syndrome merit regular cardiology follow-up from childhood onwards, particularly if they have treated heart disease. The merits of preventative treatments for aortic dilatation have not been demonstrated in Turners syndrome and justify prospective trials.

Transthoracic three-dimensional echocardiography prior to closure of atrial septal defects in children.

AIMS Our aims were to use transthoracic three-dimensional echocardiography to assess the morphology of atrial septal defects in children prior to closure, and to compare the three-dimensional echocardiographic data with transcatheter and surgical findings. METHODS AND RESULTS We used transthoracic three-dimensional echocardiography in 62 consecutive patients, aged from 2 to 18 years, with atrial septal defects, measuring the maximal diameter and the extent of the rims. Subsequent to the study, we referred 42 patients for transcatheter closure, the rims being measured at greater than 4 mm. We found a good correlation between the maximal diameter of the defect as measured at transthoracic three-dimensional echocardiography and using a balloon (y = 3.45 - 0.73x; r = 0.78; p < 0.0001), the mean difference between the measurements being 2.4 +/- 2.8 mm. Successful closure with the Amplatzer septal occluder, having a mean size of 22 +/- 4 mm, was achieved in 95% of the patients. Of the original cohort, 20 patients were referred for surgical closure. In these patients, the inferior rim had been deemed insufficient in 5, the postero-superior rim in 6, and the postero-inferior rim in 9. Complete agreement was found when the deficiency of the rim as judged using transthoracic three-dimensional echocardiography was compared with intraoperative findings. The correlation between measurements of the deficiency of the rim achieved by transthoracic three-dimensional echocardiography and at surgery was excellent (y = 0.2 + 0.98x; r = 0.93; p < 0.0001), the mean difference between the measurements being no more than 0.6 +/- 0.4 mm. CONCLUSIONS Transthoracic three-dimensional echocardiography proved accurate in measuring the maximal diameter and rims of atrial septal defects within the oval fossa. This non-invasive method will be valuable in selecting children for transcatheter or surgical closure of such defects.

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.

Assessment of proximal isovelocity surface area (PISA) shape using three-dimensional echocardiography in a paediatric population with mitral regurgitation or ventricular shunt

BACKGROUND The proximal isovelocity surface area (PISA) method is validated to quantify mitral regurgitation (MR) and ventricular shunt (VS). However, the two-dimensional echocardiography (2DE) PISA method assumes a hemispherical distribution of velocity factors proximal to the MR or VS orifice. AIM To assess the PISA shape by three-dimensional echocardiography (3DE) in a paediatric population with MR or VS. According to the true PISA shape, we suggest different models to calculate the MR or VS volume by the 3DE PISA method. METHODS Thirty-one paediatric patients (aged 1month to 20years, median 69months) were included: 17 had MR and 14 had VS. The orifice area and volume of MR and VS were evaluated by 2DE. 3DE acquired the entire PISA volume at orifice level. The PISA shape was estimated according to three diameters as being hemispherical, prolate hemispheroid, oblate hemispheroid and hemiellipsoid. RESULTS Data from 28patients were analysed. The PISA shape was variable: hemispherical, 11%; prolate hemispheroid, 43%; oblate hemispheroid, 32%; hemiellipsoid, 14%. Oblate hemispheroids occurred more frequently in the MR group (47%), whereas prolate hemispheroids occurred more frequently in the VS group (62%); hemispheres were scarce in both groups (10%). The mean MR or VS orifices and volumes measured by 2DE and 3DE were significantly different (0.123cm(2) versus 0.094cm(2) and 13.2mL versus 10.1mL, respectively; p=0.019). CONCLUSIONS 3DE describes the true surface of the PISA shape. In a paediatric population with MR or VS, the PISA is rarely hemispherical but is more often prolate or oblate hemispheroid.