Corinne Ducreux

A de novo Mutation of the Beta Cardiac Myosin Heavy Chain Gene in an Infantile Restrictive Cardiomyopathy

Here we report the first pediatric case of restrictive cardiomyopathy secondary to a de novo mutation in the cardiac myosin heavy chain gene MYH7. The clinical course is characterized by an early onset of disease, mild hypertrophy of the left ventricle and a very short evolution to death. Because of the location of the mutation in the hinge region between the rod part and the globular head of the myosin molecule, it is possible that restrictive cardiomyopathy resulted from an impairment of flexion/extension of myosin heads during the contraction/relaxation cycle.

A systematic variant screening in familial cases of congenital heart defects demonstrates the usefulness of molecular genetics in this field

The etiology of congenital heart defect (CHD) combines environmental and genetic factors. So far, there were studies reporting on the screening of a single gene on unselected CHD or on familial cases selected for specific CHD types. Our goal was to systematically screen a proband of familial cases of CHD on a set of genetic tests to evaluate the prevalence of disease-causing variant identification. A systematic screening of GATA4, NKX2-5, ZIC3 and Multiplex ligation-dependent probe amplification (MLPA) P311 Kit was setup on the proband of 154 families with at least two cases of non-syndromic CHD. Additionally, ELN screening was performed on families with supravalvular arterial stenosis. Twenty-two variants were found, but segregation analysis confirmed unambiguously the causality of 16 variants: GATA4 (1 ×), NKX2-5 (6 ×), ZIC3 (3 ×), MLPA (2 ×) and ELN (4 ×). Therefore, this approach was able to identify the causal variant in 10.4% of familial CHD cases. This study demonstrated the existence of a de novo variant even in familial CHD cases and the impact of CHD variants on adult cardiac condition even in the absence of CHD. This study showed that the systematic screening of genetic factors is useful in familial CHD cases with up to 10.4% elucidated cases. When successful, it drastically improved genetic counseling by discovering unaffected variant carriers who are at risk of transmitting their variant and are also exposed to develop cardiac complications during adulthood thus prompting long-term cardiac follow-up. This study provides an important baseline at dawning of the next-generation sequencing era.

Extracoronary echocardiographic findings as predictors of coronary artery lesions in the initial phase of Kawasaki disease

Objective To describe the significance of pericardial effusion (PE), mitral regurgitation (MR) and impaired systolic function in predicting coronary artery lesions (CAL) at diagnosis and follow-up in Kawasaki disease (KD). Design Echocardiographic records on admission, at 1–3 weeks of illness, and at 6–8 weeks of illness were retrospectively retrieved in children with acute KD treated by intravenous immunoglobulins. Setting, patients The study included 194 consecutive children (113 male; median age 2.1 years) in a paediatric cardiology tertiary care centre, from 1988 to 2007. Results Overall, children with CAL (64/194) were more likely to have PE (OR=3.00, CI 1.34 to 6.72) and MR (OR=2.51, CI 1.22 to 5.16) at diagnosis; PE was the sole echocardiographic abnormality associated with CAL in multivariable analysis. These abnormalities were predictive of the presence of CAL at the first echocardiography in the acute phase of the disease only. MR, systolic dysfunction and PE were not associated with persistence of CAL in the convalescent phase. Male gender, CAL size and resistance to immunoglobulin treatment were independent factors predictive of the persistence of CAL. Conclusions Children with MR or PE should undergo careful assessment of coronary status at diagnosis. However, PE or MR at diagnosis is not predictive of persistent CAL at follow-up.

TRPM4 non-selective cation channel variants in long QT syndrome

BackgroundLong QT syndrome (LQTS) is an inherited arrhythmic disorder characterized by prolongation of the QT interval, a risk of syncope, and sudden death. There are already a number of causal genes in LQTS, but not all LQTS patients have an identified mutation, which suggests LQTS unknown genes.MethodsA cohort of 178 LQTS patients, with no mutations in the 3 major LQTS genes (KCNQ1, KCNH2, and SCN5A), was screened for mutations in the transient potential melastatin 4 gene (TRPM4).ResultsFour TRPM4 variants (2.2% of the cohort) were found to change highly conserved amino-acids and were either very rare or absent from control populations. Therefore, these four TRPM4 variants were predicted to be disease causing. Furthermore, no mutations were found in the DNA of these TRPM4 variant carriers in any of the 13 major long QT syndrome genes. Two of these variants were further studied by electrophysiology (p.Val441Met and p.Arg499Pro). Both variants showed a classical TRPM4 outward rectifying current, but the current was reduced by 61 and 90% respectively, compared to wild type TRPM4 current.ConclusionsThis study supports the view that TRPM4 could account for a small percentage of LQTS patients. TRPM4 contribution to the QT interval might be multifactorial by modulating whole cell current but also, as shown in Trpm4−/− mice, by modulating cardiomyocyte proliferation. TRPM4 enlarges the subgroup of LQT genes (KCNJ2 in Andersen syndrome and CACNA1C in Timothy syndrome) known to increase the QT interval through a more complex pleiotropic effect than merely action potential alteration.

0532: Features and outcomes of acute myocarditis in children

This study was to assess features and outcomes of children with acute myocarditis. Methods Patients 10y). Results 72 patients were included (1983 to 2012), 30males, aged 4.1±5.1y (med1.5y): 43 in group I, 17 in II and 12 in III. Heart failure was present at onset in 57(78%): 8 cardiogenic shock (12%), 30 severeHF (44%) were more frequent in I (56%) and II (46%) than in III (17%, p in 3). Nine patients died (13%) within 2months post-diagnosis (2days to 8.6months), 1 was transplanted (3rdmonth), 19 have sequellae (27.5%), 40 recovered (58%), at FU= 5.5±5.6y. Inotrope was needed in 34(47%):51%, 59% and 16% of groups I, II and III respectively (p Download : Download full-size image Abstract 0254 - Figure: Increase in HMDP heart retention after 16months. Conclusion Acute myocarditis in children has favourable outcomes despite early mortality. Myocardial dysfunction and heart failure are less frequent in patients > 10years. Mechanical circulatory support lessens mortality. Myocardial contractility progressively improves within the first 6months after onset.

0531: Long-term experience with heart transplantation in children and patients with congenital heart disease

This study assessed the long-term outcome of heart (HTx) and heart-lung transplantation (HLTx) in patients with congenital heart disease (CHD) and children with non-congenital cardiac or pulmonary disease. Methods Retrospective single-centre analysis of long-term posttransplant outcome, with chart collection of clinical and paraclinical data. Results From 1984 to 2013, 111 first-HTx, 5 HLTx and 6 re-HTx were performed (62 males), in patients aged 11.7±8.2y: 96(79%) aged 5th year in non-compliant teenagers. Overall 33 patients died (27%), 3.5±4.6y postTx (1 day to 16.4y, med 1.5 months), due to early multivisceral failure in 6 (18%), pulmonary hypertension in 3 (9%), acute rejection in 7 (21%), graft coronary disease in 6 (18%), sepsis in 5 (15%) and miscellaneous in 6. Graft coronary disease occurred in 15(12.4%): 4 had re-HTx, 6 died and 5 are alive. Five lymphoma occurred, 4 months to 14y after HTx, cured in 4 (1died). Patient’s survival was 85% at 1y, 81% at 5y, 70% at 10y and 61% at 20y post-transplant. Graft survival rates were respectively 82%, 68% and 52% at 5y, 10y and 20y post-transplant. Survival did not differ with pretransplant disease, age, gender, pretransplant mechanical support. Mortality was higher in patients with coronary disease (40%) than those free from (25%). Conclusion long-term prognosis after HTx and HLTx is favourable. Graft coronary disease is the main cause of failure, less frequent than in the adult non-CHD heart-transplanted population.

296: ExtraCorporeal Membrane Oxygenator support in the perioperative course of pediatric heart surgery

The aim of this study was to assess the results of ECMO as a perioperative support in children with congenital heart disease (CHD) during and after open-heart surgery. Material and methods All patients aged Results Twenty-seven patients (19 males) (i.e. 0.5% of total pediatric cardiac surgical procedures performed per year), aged 3days to 18years (mean 1.6years) were placed on ECMO, per-operatively in 10 (37%, for failure to wean off bypass) or during the early postoperative course in 17 (8 24th hour) for cardiac arrest (33%) or low cardiac output (30%). Surgical repair included: severe form of tetralogy of Fallot (4), complex arterial switch operation (7), complex left heart obstruction (5), Rastelli (4), ALCAPA (1), cavopulmonary anastomosis (3) and miscellaneaous (3). Twelve cases were in-hospital preoperatively, of whom 7 were dependent on mechanical ventilatory support. Five patients died while on ECMO because of multi organ failure (4) or pulmonary hypertension (1). Main complications during support included hemorrhages (15 cases), renal failure requiring peritoneal dialysis (14), hemolysis (13), canulas thrombosis (6), and strokes (4). Only 3 cases were free from complication. Duration of ECMO was 5.4±3.6days (1 to 16, median 5), of CICU stay 26±16days (10 to 69, median 22). Survival to ECMO was 81.5% (22 patients) and overall survival was 59% (16). Significant predictive factors for mortality were: preoperative clinical status (in-hospital: 25% in alive patients versus 73% in deceased cases, p= 0.01), lactates level at onset of ECMO (mean 6 versus 10, p= 0.004) and duration of aortic clamp (mean 70 versus 110mn, p= 0.05). Conclusion This study shows that post-cardiotomy ECMO in children is a valuable therapeutic option as a bridge to recovery, despite high frequency of complications on support.

Long-term follow-up after heart transplantation in very young children

January 2002 to December 2011 were included: 1258 (59%) in-born neonates whose delivery was planned in our institution, 799 (38%) terminations of pregnancy, and 73 (3%) foetal deaths. For in-born, planned delivery was classified as ‘certainly justified’ for 899 (71%) for the following reasons: Rashkind atrioseptotomy in 344 cases, risk of aortic coarctation in 272 cases, ductal patency needed for pulmonary flow in 107 cases, ductal patency needed for systemic flow in 93 cases, need for an immediate intervention in 83 cases. For the remaining 359 in-born, planned delivery was classified as ‘potentially justified’ for the following reasons: possible need for ductal patency for pulmonary flow in 156 cases, for systemic flow in 35 cases (3%), incomplete congenital heart disease diagnosis in 94 cases, need to monitor neonatal tolerance of the defect in 51 cases. In these 359 in-born at risk, rationale for planned delivery was reviewed after birth. A posteriori, it was not necessary for 249 in-born (20%) in whom no intervention was needed during the first week, and confirmed to be necessary for 110 in-born (9%) — 32 in whom diagnosis was different with a direct influence on management and with 78 who needed an intervention during the first week. Conclusions.— Our study demonstrates that only one fifth of foetal congenital heart diseases delivered in a tertiary reference centre appears to be unnecessary. Conversely, one third of in-borns with only possible post-natal risk of cardiac complication were appropriately delivered in our institution, as they needed immediate specialized management.

Infective endocarditis in adults with congenital heart disease

The aim of this retrospective study was to describe features ofinfective endocarditis (IE) in adults with congenital heart disease (CHD). Methods The records of all episodes of IE diagnosed from 1974, in patients with CHD and more than 18 years of age at diagnosis, were retrospectively reviewed. Results Fourty-four episodes of IE occurred, 36 after 1990 (81.8%), 28 males (63.6%). Age at diagnosis was 30.3±9years (median 28years). Ten were recurrent episodes (22.7%). CHD was previously repared in 15 cases (34%), palliated in 7 (16%) and non-operated in 22 (50%). Dental causes were predominant (34%), followed by cutaneous causes (25%) ; others were postoperative (4.5%), miscellaneous (7%) or unknown causes (29.5%). A microbial agent as identified in 95.4% of the cases : oral streptococcus and staphylococcus aureus were the leading causative agents (respectively 41% and 36%). Left heart locations were predominant (75%). Severe clinical cardiac complication occurred in 10 cases (23%), an echocardiographic complication in 18 (40%). Twenty-four patients experienced embolic events (54.5%) ; early surgical treatment was required in 25% of the cases. Three patients died due to IE (6.8%). Antibiotic prophylaxis had been neglicted despite known risk in 41% of the cases. Conclusion IE is an ongoing life-threatening complication in adults with CHD, with a significant morbidity, a high rate of prophylaxis negligence and of recurrence.

317 Cardiac features of Kawasaki Disease in France: a single-center esperience

Little is known about Kawasaki Disease (KD) features in France. The aims of this retrospective single-center study were to assess the characteristics of a French KD population over a long period of time, and to describe cardiac lesions. Methods We retrospectively reviewed the medical records of 417 patients referred to echocardiography for KD suspicion between August 1983 and April 2007. Results 210 patients met criteria for diagnosis of KD, at the age of 2.7±2.5years (median 2). Fever was present in all patients. Time to diagnosis was 7±4.6days (median 6days), time to hospitalization 5.7±4.3days (median 5days). Time to first echocardiography was 11.4±7.8days (median 9days), shorter in more recent period. Median time to IVIG administration was 8 days (1 to 39). At initial evaluation, 63.8% were free from cardiac lesions, 23.8% (52 cases) had coronary lesions (aneurisms : 25, dilatation : 27) and 12.4% had « hyperechogen » coronary arteries. Among 52 cases with abnormal coronary arteries, 40 were 8mm (giant aneurisms): one third localized on one coronary vessel, one third on 2 and one third one all 3 coronary arteries. Echographic pericarditis was found in 31 patients, mitral insufficiency in 20 and aortic insufficiency in 2. All patients recovered, except 1 who died from cardiogenic shock due to ruptured chordae. Coronary lesions resolved in 17 of 52 cases (32.6%) and persisted in 35 (67.4%, i.e. 16.7% of all patients): 14 with aneurisms and 19 with dilatations. No patient developped significant long-term coronary artery stenosis. The incidence of aneurisms was lower over the past decade (7.2%). Conclusion In our experience, the occurrence of coronary lesions in KD have lessened over time and long-term cardiac outcome is favourable despite persistent coronary lesions.