A. Bozio

Gain-of-Function Mutations in TRPM4 Cause Autosomal Dominant Isolated Cardiac Conduction Disease

Background—Isolated cardiac conduction block is a relatively common condition in young and elderly populations. Genetic predisposing factors have long been suspected because of numerous familial case reports. Deciphering genetic predisposing factors of conduction blocks may give a hint at stratifying conduction block carriers in a more efficient way. Methods and Results—One Lebanese family and 2 French families with autosomal dominant isolated cardiac conduction blocks were used for linkage analysis. A maximum combined multipoint lod score of 10.5 was obtained on a genomic interval including more than 300 genes. After screening 12 genes of this interval for mutation, we found a heterozygous missense mutation of the TRPM4 gene in each family (p.Arg164Trp, p.Ala432Thr, and p.Gly844Asp). This gene encodes the TRPM4 channel, a calcium-activated nonselective cation channel of the transient receptor potential melastatin (TRPM) ion channel family. All 3 mutations result in an increased current density. This gain of function is due to an elevated TRPM4 channel density at the cell surface secondary to impaired endocytosis and deregulation of Small Ubiquitin MOdifier conjugation (SUMOylation). Furthermore, we showed by immunohistochemistry that TRPM4 channel signal level is higher in atrial cardiomyocytes than in common ventricular cells, but is highest in Purkinje fibers. Small bundles of highly TRPM4-positive cells were found in the subendocardium and in rare intramural bundles. Conclusions—the TRPM4 gene is a causative gene in isolated cardiac conduction disease with mutations resulting in a gain of function and TRPM4 channel being highly expressed in cardiac Purkinje fibers.

Current patterns of infective endocarditis in congenital heart disease

Objective: To assess the changing profile of infective endocarditis in patients with congenital heart disease. Methods: All cases diagnosed from 1966 to 2001 (revised Duke criteria) were retrospectively reviewed and categorised in periods I (< 1990) and II (⩾ 1990). Results: 153 episodes occurred, 81 in period I and 72 in period II. Mean age of affected patients was higher in period II. Non-operated ventricular septal defect, Rastelli correction and palliated cyanotic heart disease increased. Infective endocarditis in corrective surgery changed to patients with prosthetic material. Post-surgical cases decreased. Dental problems were the leading cause (period I 20% v II 33% of cases) with a large variety of pathological organisms (multiple species of Streptococcus). Cutaneous causative infections increased (5% to 17%) with different species of Staphylococcus. Negative blood cultures lessened (20% to 7%, p  =  0.03). Streptococci were the most common causative organisms in both periods. Severe heart failure and cardiac complications lessened (20% to 4% and 31% to 18% during periods I and II, respectively). Early surgery was more frequent in period II (32% v 18.5%, p  =  0.02). One- and 10-year survival was 91% v 97% in period I and 89% v 97% in period II, respectively (NS). Conclusion: Current targets include complex cyanotic disease, congenital heart disease corrected with prosthetic material and small ventricular septal defect. Postoperative cases lessened; dental and cutaneous causes increased. Survival was unchanged. Prophylactic measures targeted at dental and cutaneous sources should be emphasised.

Rabbit antithymocyte globulin as induction immunotherapy in pediatric heart transplantation.

Background. There is little published data on the use of antithymocyte globulins in children. This retrospective study describes the use of Thymoglobulin (Imtix, SangStat, Lyon, France) in pediatric cardiac transplantation over a 13-year period in a single center that adjusted the dose of Thymoglobulin according to platelet count monitoring and examines the short-term hematological effects as well as longer-term outcomes. Methods. Data for all children who received a heart transplant at the Hôpital Cardiologique at Lyon from 1984 to 2001 and who were given Thymoglobulin as part of their immunosuppressive protocol were extracted. The dose of Thymoglobulin given depended on baseline platelet count and was 2, 1.5, or 1 mg/kg per day over 5 days for the following platelet count groups: greater than 150,000/mm3 (normal group), 100 to 150,000/mm3 (mild thrombocytopenia group), and 50 to 100,000/mm3 (moderate thrombocytopenia group). Results. Thirty children of median age 14.2 years were given a median cumulative dose of Thymoglobulin of 8 mg/kg per patient; the moderate thrombocytopenia subgroup was given significantly less (6.4 mg/kg) (P =0.032). Immediate tolerability of Thymoglobulin was good, with no cases of first-dose syndrome, anaphylaxis, or serum sickness. The platelet count decreased at the start of therapy, but recovered after discontinuation, and did not give rise to clinical concern. Patients were followed up for a median of 6.3 years (7 days–15.5 years); actuarial survival was 90%, 86%, and 74.5%, respectively, at 1, 5, and 10 years. In the first year, 50% of patients suffered an episode of rejection. The overall incidence of infection in the month following transplantation was 40%. One lymphoma occurred at 5 months. Conclusions. The use of Thymoglobulin in pediatric heart-transplant patients as part of an immunosuppressive protocol, with dose adjustment according to platelet levels, has been shown to be effective in terms of rejection rate and patient survival and safe in terms of the incidence of infections and malignancy.

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.

Non-invasive detection of coronary artery disease by dobutamine-stress echocardiography in children after heart transplantation

BACKGROUND Coronary vasculopathy is the main cause of cardiac graft failure. Because yearly coronary angiography is invasive in children, a non-invasive method for detecting graft vasculopathy is needed. The aim of this study was to test dobutamine-stress echocardiography in a pediatric population to determine its feasibility, safety and reliability in the detection of graft coronary artery disease. METHODS Eighteen patients, aged 2 days to 16.8 years at transplantation (mean 8.4 years), underwent 44 dobutamine-stress echocardiography (DSE) exams, at a follow-up of 1.1 to 11.8 years (mean 5.1 years). Selective coronary angiography was performed for comparison. Echocardiographic recordings were obtained in 4 standard views of the left ventricle and measurements carried out within the frames of a 16-segment model. Segmental scores of contractility were obtained for each segment and a total segmental contractility index was calculated at each stage. RESULTS All patients reached the maximum dose stage. Maximum heart rate was 57% to 90% of predicted maximum. Maximum systolic blood pressure reached 190 mmHg. Segmental scores were normal in 37 and abnormal in 7 cases. Echographic results were concordant with angiography in 82% and discordant in 18% of the cases (4 negative DSEs with minor angiographic lesions, 2 positive DSEs with normal angiography), but there was no significant angiographic lesion with normal DSE. CONCLUSIONS DSE is a safe and highly feasible non-invasive technique in transplanted children. A normal DSE study successfully predicts the absence of significant coronary artery disease in the post-transplant population.

The challenge of renal function in heart transplant children

Renal dysfunction may occur after pediatric heart transplantation and impacts on long-term prognosis. This study aims to review the incidence and mechanisms of chronic nephropathy following heart transplantation, and suggest therapeutic directions. The proportion of pediatric heart-transplant recipients with impaired renal function varies from 22 to 57%, and end-stage renal failure from 3 to 10%, depending on the method used for estimating the glomerular filtration rate. The pathophysiology of renal dysfunction is in part due to calcineurin inhibitor-induced renal vasoconstriction, through activation of the intrarenal renin-angiotensin system, TGF-β1 upregulation and TGF-β1 gene polymorphisms. Overproduction of angiotensin II, associated with angiotensin-converting-enzyme genotype, might be associated with poor prognosis and pharmacological factor gene polymorphisms, and may contribute to variation of calcineurine inhibitor exposure in the kidney. Strategies to prevent renal dysfunction include reducing calcineurine inhibitor exposure or delaying calcineurine inhibitor administration from the early post-transplant period. Calcium channel blockers and angiotensin-converting-enzyme inhibitors, blockade of angiotensin II, or anti-TGF-β1 antibodies might limit nephrotoxicity. No accurate marker can predict the potential of renal lesions to develop. Lowering calcineurine inhibitors levels with immunosuppressive agents that are either less nephrotoxic or non-nephrotoxic should be formally studied. Of high interest is the impact of genetic polymorphism on the development of renal dysfunction.

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.

La prévention de l'endocardite infectieuse chez l'enfant. Situation et protocoles actuels

Summary Infective endocarditis remains a severe, potentially lethal disease, which justifies a rigourous prevention schedule. Children with cyanotic congenital heart disease, mitroaortic valvulopathies, prosthetic valve and uncorrected ventricular septal defect are the most susceptible. Dental care is the main cause of bacterial graft, followed by upper respiratory tract and cutaneous infections. Prevention is mainly based upon antibiotic prophylaxis but patient education and good dental hygiene are also important.

0524: Experience with foetal supraventricular arrhythmias

This study was to review experience and outcomes of supraventricular (SV) arrhythmias in fetus Methods: Cases were divided in groups: SVPB= premature SV beats, NSSVT= non-sustained SV tachycardia, SSVT= sustained SV tachycardia, and AF= atrial flutter. Heart failure (HF) was defined as foetal hydrops or isolated effusion (pericardial or pleural or ascitis). Outcome was favourable if arrhythmia resolved or stabilized until full-term birth, not-favourable if premature birth or foetal death occurred. Results 188 fetuses were included:89 in SVPB(47.3%), 31 in NSSVT(16.5%), 60 in SSVT(31.9%), 8 in AF(4.3%), aged at diagnosis 30.8±4.5weeks (no difference between groups). Foetus HR at diagnosis was 241±30bpm in SSVT vs 226±26 in AF. Antiarrhytmic therapy was administered in sustained tachycardia (83% of SSVT and 71% AF): 28 had 1 medication, 25: 2 medications, 2: 3 medications. Complication occurred in 29 cases, all in SSVT and AF (29 of 68= 43%): 18 hydrops, 5 ascitis, 4 pericarditis, 1 pleural effusion and 1 LVdysfunction+MR, was more frequent in SSVT (86%: hydrops in 30%) than AF (51%: no hydrops), p= 0.08. Fetal HF was associated with HR at diagnosis: 251±25bpm in hydrops vs 228±31bpm in nohydrops (p=0.025). Outcome was favourable in SVPB and NSSVT, in 45 of SSVT+AF (79%). Tachycardia resolved in 36, more frequently in SSVT (57%) than AF (25%). HR only decreased in 9cases. Premature birth occurred in 10, foetal death in 2. Outcome was not associated with HR or weeks of gestation at diagnosis. Defavourable outcome was more frequent in hydrops or isolated effusion (57%) than in uncomplicated cases (10%, p= 0.0002). Resolution occurred in 45% hydrops vs 66% of non-hydrops cases. Digoxine decreased from 79% of cases before 2000 to 33% after 2000, while flecaine increased from 14% to 48.5%. There was no relationship between therapy or number of medications and outcomes. Conclusion Fetal SSVT more frequently resolves but has worse outcome than AF, especially if HR at diagnosis is high and hydrops occurs. Larger scale prospective studies are needed to evaluate the efficacy of flecaine compared to digoxine therapy.

0534: Antenatal echocardiographic parameters to predict postnatal outcome of neonates with Ebstein anomaly

Ebstein tricuspide valve anomaly is a rare CHD with uncertain postnatal prognosis. Criteria to predict outcome are still a matter of debate. The aim of this study was to determine antenatal echocardiographic predictive parameters. Methods Retrospective multicentric analysis of fetus with diagnosis of Ebstein anomaly. Echocardiographic measurements of ventricles, atria, great vessels and tricuspid regurgitation were collected. Comparisons were made between group I (poor outcome= death occurred in utero or within the first 3 months of life) and group II (favourable outcome: postnatal survival >3 months). Results 16 fetuses were included in the study: 10 in group I (62.5%: 2 TOP, 2 fetal deaths, 6 postnatal deaths) and 6 in group II (37.5%). Mean gestationnal age at diagnosis was 29weeks (22 to 38). The mean number of echocardiographic records per patient was 2 (1 to 6). LV to RV ratio, tricuspid valve regurgitation grade and retrograde or anterograde ductal flow did not differ between the 2 groups. Significative differences were found between groups I and II regarding the presence of pulmonary flow (none or mild RV to PA flow: 8 of 9 cases died= 89%), AO to PA ratio (75% death if > 97°p vs 25% if 3-97°p), RA diameter (77.3% death if > 97°p vs 0%), PA diameter (100% death if Conclusion This small sample size study showed that the absence of RV to PA flow and/ or pulmonary valve opening, increased AO to PA ratio, RA and decreased PA diameter and the presence of pericardial effusion might represent prognosis factors in fetus with Ebstein anomaly. These results should be confirmed by large scale prospective study.