Lympho-hematopoietic malignancies risk after exposure to low dose ionizing radiation during cardiac catheterization in childhood.

Pediatric patients with congenital heart disease (CHD) often undergo low dose ionizing radiation (LDIR) from cardiac catheterization (CC) for the diagnosis and/or treatment of their disease. Although radiation doses from a single CC are usually low, less is known about the long-term radiation associated cancer risks. We aimed to assess the risk of lympho-hematopoietic malignancies in pediatric CHD patients diagnosed or treated with CC. A French cohort of 17,104 children free of cancer who had undergone a first CC from 01/01/2000 to 31/12/2013, before the age of 16 was set up. The follow-up started at the date of the first recorded CC until the exit date, i.e., the date of death, the date of first cancer diagnosis, the date of the 18th birthday, or the 31/12/2015, whichever occurred first. Poisson regression was used to estimate the LDIR associated cancer risk. The median follow-up was 5.9 years, with 110,335 person-years. There were 22,227 CC procedures, yielding an individual active bone marrow (ABM) mean cumulative dose of 3.0 milligray (mGy). Thirty-eight incident lympho-hematopoietic malignancies were observed. When adjusting for attained age, gender and predisposing factors to cancer status, no increased risk was observed for lympho-hematopoietic malignancies RR/mGy = 1.00 (95% CI: 0.88; 1.10). In summary, the risk of lympho-hematopoietic malignancies and lymphoma was not associated to LDIR in pediatric patients with CHD who undergo CC. Further epidemiological studies with greater statistical power are needed to improve the assessment of the dose-risk relationship.

Cardiovascular events in perimembranous ventricular septal defect with left ventricular volume overload: a French prospective cohort study (FRANCISCO).

The long-term prospective multi-centre nationwide (French) observational study FRANCISCO will provide new information on perimembranous ventricular septal defect with left ventricular overload but no pulmonary hypertension in children older than 1 year. Outcomes will be compared according to treatment strategy (watchful waiting, surgical closure, or percutaneous closure) and anatomic features of the defect. The results are expected to provide additional guidance about the optimal treatment of this specific population, which is unclear at present. BACKGROUND: The management of paediatric isolated perimembranous ventricular septal defect (pmVSD) with left ventricle (LV) volume overload but no pulmonary arterial hypertension (PAH) remains controversial. Three therapeutic approaches are considered: watchful waiting, surgical closure, and percutaneous closure. We aim to investigate the long-term outcomes of these patients according to anatomic pmVSD characteristics and treatment strategy. METHODS: The Filiale de Cardiologie Pediatrique et Congénitale (FCPC) designed the FRANCISCO registry, a long-term prospective nationwide multi-centre observational cohort study sponsored by the French Society of Cardiology, which enrolled, over 2 years (2018­2020), patients older than 1 year who had isolated pmVSD with LV volume overload. Prevalent complications related to pmVSD at baseline were exclusion criteria. Clinical, echocardiographic, and functional data will be collected at inclusion then after 1, 5, and 10 years. A core lab will analyse all baseline echocardiographic data to depict anatomical pmVSD features. The primary outcome is the 5-year incidence of cardiovascular events (infective endocarditis, sub-aortic stenosis, aortic regurgitation, right ventricular outflow tract stenosis, tricuspid regurgitation, PAH, arrhythmia, stroke, haemolysis, heart failure, or death from a cardiovascular event). We plan to enrol 200 patients, given the 10% estimated 5-year incidence of cardiovascular events with a 95% confidence interval of ±5%. Associations linking anatomical pmVSD features and treatment strategy to the incidence of complications will be assessed. CONCLUSIONS: The FRANSCICO study will provide the long-term incidence of complications in patients older than 1 year with pmVSD and LV volume overload. The results are expected to improve guidance for treatment decisions.

Exposure to low-dose ionising radiation from cardiac catheterisation and risk of cancer: the COCCINELLE study cohort profile.

PURPOSE: The COCCINELLE study is a nationwide retrospective French cohort set up to evaluate the risk of cancer in patients who undergone cardiac catheterisation (CC) procedures for diagnosis or treatment of congenital heart disease during childhood. PARTICIPANTS: Children who undergone CC procedures from 1 January 2000 to 31 December 2013, before the age of 16 in one of the 15 paediatric cardiology departments which perform paediatric CC in mainland France were included. The follow-up started at the date of the first recorded CC procedure until the exit date, that is, the date of death, the date of first cancer diagnosis, the date of the 18th birthday or the 31 December 2015, whichever occurred first. The cohort was linked to the National Childhood Cancer Registry to identify patients diagnosed with cancer and with the French National Directory for the Identification of Natural Persons to retrieve the patients' vital status. FINDINGS TO DATE: A total of 17 104 children were included in the cohort and followed for 110 335 person-years, with 22 227 CC procedures collected. Among the patients, 81.6% received only one procedure. Fifty-nine cancer cases were observed in the cohort. Standardised incidence ratios (SIRs) were increased for all-cancer (SIR=3.8, 95% CI: 2.9 to 4.9), leukaemia (SIR=3.3, 95% CI: 2.0 to 5.4), lymphoma (SIR=14.9, 95% CI: 9.9 to 22.5) and solid cancers excluding central nervous system (CNS) tumours (SIR=3.3, 95% CI: 2.0 to 5.5) compared with the general population. FUTURE PLANS: Dose reconstruction is currently underway to estimate individual cumulative doses absorbed to relevant organs, including red bone marrow and brain for respectively haematologic disorders and CNS tumours risk estimation. A dose-response analysis will be conducted with consideration to confounding factors such as age at exposure, gender, predisposing factors to cancer and other sources of medical diagnostic low-dose ionising radiation.

Increased expression of blood muscarinic receptors in patients with reflex syncope.

AIMS: Pathophysiology of reflex syncope is not fully understood but a vagal overactivity might be involved in this syncope. Previously, overexpression of muscarinic M2 receptors and acetylcholinesterase was found in particular in the heart and in lymphocytes of rabbits with vagal overactivity as well as in hearts of Sudden Infant Death Syndromes. The aim of this present study was to look at M2 receptor expression in blood of patients with reflex syncope. The second objective was to measure acetylcholinesterase expression in these patients. METHODS AND RESULTS: 136 subjects were enrolled. This monocenter study pooled 45 adults exhibiting recurrent reflex syncope compared with 32 healthy adult volunteers (18-50 years) and 38 children exhibiting reflex syncope requiring hospitalization compared with 21 controls (1-17 years). One blood sample was taken from each subject and blood mRNA expression of M2 receptors was assessed by qRT-PCR. Taking into account the non-symmetric distributions of values in both groups, statistical interferences were assessed using bayesian techniques. A M2 receptor overexpression was observed in adult and pediatric patients compared to controls. The medians [q1;q3] were 0.9 [0.3;1.9] in patients versus 0.2 [0.1;1.0] in controls; the probability that M2 receptor expression was higher in patients than in controls (Pr[patients>controls]) was estimated at 0.99. Acetylcholinesterase expression was also increased 0.7 [0.4;1.6] in patients versus 0.4 [0.2;1.1] in controls; the probability that acetylcholinesterase expression was higher in patients than in controls (Pr[patients>controls]) was estimated at 0.97. Both in adults and children, the expression ratio of M2 receptors over acetylcholinesterase was greater in the patient group compared with the control group. CONCLUSION: M2 receptor overexpression has been detected in the blood of both, adults and children, exhibiting reflex syncope. As in our experimental model, i.e. rabbits with vagal overactivity, acetylcholinesterase overexpression was associated with M2 receptor overexpression. For the first time, biological abnormalities are identified in vagal syncope in which only clinical signs are, so far, taken into account for differential diagnosis and therapeutic management. Further work will be needed to validate potential biomarkers of risk or severity associated with the cholinergic system.

Peculiar Clinical Presentation of Coxsackievirus B4 Infection: Neonatal Restrictive Cardiomyopathy.

Introduction Restrictive cardiomyopathy in fetuses and neonates is extremely rare and has a poor outcome. Its etiology in neonates is elusive: metabolic diseases (e.g., Gaucher, Hurler syndrome), neuromuscular disorders (e.g., muscular dystrophies, myofibrillar myopathies), or rare presentation of genetic syndromes (e.g., Coffin-Lowry syndrome) account for a minority of the cases, the majority remaining idiopathic. Case Study We report the case of a 17-day-old male infant presenting cardiogenic shock following a restrictive dysfunction of the left ventricle. Postmortem investigations revealed coxsackievirus B4 myocarditis with histological lesions limited to the left heart. However, polymerase chain reaction (PCR) for coxsackievirus B4 was positive in the left as well as in the right ventricular samples. Conclusion In conclusion, coxsackievirus myocarditis is a cause of restrictive cardiomyopathy, and its diagnosis should involve PCR screening as a more sensitive technique.

Next-generation sequencing (NGS) as a fast molecular diagnosis tool for left ventricular noncompaction in an infant with compound mutations in the MYBPC3 gene.

Left ventricular noncompaction (LVNC) is a clinically heterogeneous disorder characterized by a trabecular meshwork and deep intertrabecular myocardial recesses that communicate with the left ventricular cavity. LVNC is classified as a rare genetic cardiomyopathy. Molecular diagnosis is a challenge for the medical community as the condition shares morphologic features of hypertrophic and dilated cardiomyopathies. Several genetic causes of LVNC have been reported, with variable modes of inheritance, including autosomal dominant and X-linked inheritance, but relatively few responsible genes have been identified. In this report, we describe a case of a severe form of LVNC leading to death at 6 months of life. NGS sequencing using a custom design for hypertrophic cardiomyopathy panel allowed us to identify compound heterozygosity in the MYBPC3 gene (p.Lys505del, p.Pro955fs) in 3 days, confirming NGS sequencing as a fast molecular diagnosis tool. Other studies have reported neonatal presentation of cardiomyopathies associated with compound heterozygous or homozygous MYBPC3 mutations. In this family and in families in which parental truncating MYBPC3 mutations are identified, preimplantation or prenatal genetic screening should be considered as these genotypes leads to neonatal mortality and morbidity.

Effect of angiotensin-converting enzyme inhibition on skeletal muscle oxidative function and exercise capacity in streptozotocin-induced diabetic rats.

Since exercise capacity is related to the mitochondrial respiration rate in skeletal muscle and both parameters are potentially modulated by the onset of diabetes and by inhibition of the angiotensin-converting enzyme (ACE), we investigated whether skeletal muscle oxidative functions and exercise capacities are impaired in chronic streptozotocin-induced diabetic (STZ) rats and whether ACE inhibition could reverse such abnormalities. The ACE inhibitor perindopril (2 mg kg(-1) day(-1)) was given for a period of 5 weeks to 7-month-old STZ rats (DIA-PE, n = 8) whose haemodynamic function, skeletal muscle mitochondrial function and exercise capacity were compared with those of untreated diabetic (DIA, n = 8) and control rats (CONT, n = 8). Increased arterial blood pressure (157 +/- 12 versus 130 +/- 6 mmHg, P < 0.05) and reduced exercise capacity (29 +/- 2 versus 91 +/- 2 min, respectively, P < 0.01) were observed in DIA compared with CONT. The oxidative capacity of the gastrocnemius muscle was significantly reduced in DIA compared with CONT rats (5.4 +/- 0.5 versus 10.6 +/- 0.7 micromol O(2) min(-1)(g dry weight)(-1), respectively, P < 0.001). Moreover, the coupling between oxidation and phosphorylation was significantly impaired in DIA (-52%, P < 0.001). Angiotensin-converting enzyme inhibition (ACEi) normalized blood pressure without improving mitochondrial function (4.3 +/- 0.8 micromol O(2) min(-1) (g dry weight)(-1) in DIA-PE rats) but reduced exercise capacity to even lower levels (10 +/- 1 min, P < 0.01). Exercise capacity correlated positively with blood pressure in DIA-PE (r = 0.79, P < 0.05). In experimental type 1 diabetic rats, both skeletal muscle mitochondrial respiration and exercise capacity are impaired. The ACEi failed to restore the muscular function and worsened exercise capacity. Further studies will be useful to determine whether an inadequate muscular blood flow secondary to the reduction in mean systemic blood pressure can explain these results.

The influence of peritoneal surface area on dialysis adequacy.

In children, the prescription of peritoneal dialysis is based mainly on the choice of the peritoneal dialysis fluid, the intraperitoneal fill volume (mL/m2 body surface area (BSA)], and the contact time. The working mode of the peritoneal membrane as a dialysis membrane is more related to a dynamic complex structure than to a static hemodialyzer. Thus, the peritoneal surface area impacts on dialysis adequacy. In fact, the peritoneal surface area may be viewed as composed of three exchange entities: the anatomic area, the contact area, and the vascular area. First, in infants, the anatomic area appears to be two-fold larger than in adults when expressed per kilogram body weight. On the other hand, the anatomic area becomes independent of age when expressed per square meter BSA. Therefore, scaling of the intraperitoneal fill volume by BSA (m2) is necessary to prevent a too low ratio of fill volume to exchange area, which would result in a functional "hyperpermeable" peritoneal exchange. Second, the contact area, also called the wetted membrane, is only a portion of the anatomic area, representing 30% to 60% of this area in humans, as measured by computed tomography. Both posture and fill volume may affect the extent of recruitment of contact area. Finally, the vascular area is influenced by the availability of both the anatomic area and the recruited contact area. This surface is governed essentially by both peritonealvascular perfusion, represented by the mesenteric vascular flow and, hence, by the number of perfused capillaries available for exchange. This vascular area is dynamically affected by different factors, such as composition of the peritoneal fluid, the fill volume, and the production of inflammatory agents. Peritoneal dialysis fluids that will be developed in the future for children should allow an optimization of the fill volume owing to a better tolerance in terms of lower achieved intraperitoneal pressure for a given fill volume. Moreover, future peritoneal dialysis fluids should protect the peritoneal membrane from hyperperfusion (lower glucose degradation products).

Daily on-line haemodiafiltration: a pilot trial in children.

BACKGROUND: Despite major improvements in paediatric dialysis over the last two decades, cardiovascular outcome is often poor. As France gives priority to kidney transplantation over dialysis, children in chronic haemodialysis are generally pre-adolescents or adolescents with long medical histories and low compliance. In them, the usual weekly schedule of dialysis is often unsuitable. We conducted a study of conversion to daily dialysis, which allowed an enhanced dialysis dose, a gentle ultrafiltration rate and achievement of dry body weight. METHODS: In this single-centre, observational, prospective, non-randomized study, five oligoanuric dialysis patients (mean age: 13.8 +/- 3.2 years) were converted from standard on-line haemodiafiltration (S-OL-HDF) (4 h, three times/week) to daily on-line haemodiafiltration (D-OL-HDF) (3 h, six times/week). Patient selection was based on both the presence of uraemic cardiomyopathy (left ventricular hypertrophy and reduced fractional shortening) and their reduced therapeutic compliance. The D-OL-HDF parameters were the same as for the S-OL-HDF. RESULTS: Increasing the number of sessions from three to six weekly positively impacted the weekly dialysis dose. On D-OL-HDF, mean arterial blood pressure decreased significantly (from 95 +/- 15 to 82 +/- 13 and 87 +/- 9 mmHg at 6 and 12 months, respectively). Left ventricular hypertrophy decreased and its fractional shortening improved markedly (from 26.6 +/- 17% to 31 +/- 14% and 46.6 +/- 15% at 6 and 12 months, respectively). Pre-dialytic plasma phosphorus also decreased markedly (from 1.87 +/- 0.23 to 1.43 +/- 0.22 and 1.28 +/- 0.29 mmol/l at 6 and 12 months, respectively), as did the calcium-phosphorus product. The post-dialytic recovery time disappeared and so did perception of fatigue. Fasting the day before dialysis to avoid excess weight gain (necessitating longer dialysis) disappeared. Combined with an improved appetite, these changes resulted in higher caloric and protein intake (nPCR), from 1.28 +/- 0.23 to 1.43 +/- 0.24 g/kg at 6 months, and school attendance became regular. The only pre-pubertal child included showed catch-up growth. CONCLUSIONS: Increasing dialysis frequency to daily sessions without shortening the durations of sessions excessively allowed us to overcome the "free diet" imposed on these paediatric, very uncompliant patients. This strategy led to a reduction in blood pressure and an improvement of left ventricular size and function, normalization of pre-dialytic plasma phosphorus and improvements in general well-being and dialysis acceptance. Long-term, however, this protocol is only acceptable for the children if associated with the potential of clinical recovery allowing inscription on the kidney transplantation waiting list.

The peritoneal membrane: a dynamic dialysis membrane in children.

Peritoneal dialysis prescription in children should be individualized--based not only on numerical targets (Kt/Vurea, Kcreat), but also on consideration of the peritoneal membrane, a dynamic dialysis membrane. In fact, the effective peritoneal surface area is at least a triple entity: an anatomic area, a contact area, and an exchange area. The anatomic area appears to be twice as large in infants as in adults if expressed per kilogram of body weight (BW), although the area is independent of age if expressed per square meter of body surface area (BSA). Therefore, scaling of the intraperitoneal fill volume (IPV) by BSA in square meters is necessary to avoid a low IPV/area ratio, which results in a functionally "hyperpermeable" peritoneal exchange. The contact area (the wetted membrane) is only a fraction of the anatomic area--that is, 30%-60% in humans (by computed tomography). Contact area depends on a variety of factors, such as posture and fill volume, that affect the degree of recruitment of membrane contact area. The exchange area is influenced by both the anatomic are and the contact area. However, it is mainly governed by the specific vascular area as determined by the peritoneal vascular perfusion and the capillaries available for exchange. Vascular area is dynamically affected by a variety of factors, such as the composition of the peritoneal dialysis fluid, the fill volume, and possible inflammatory agents.