Isabelle Szezepanski

Arterial stiffness and endothelial dysfunction in HIV-infected children

Background: The role of antiretroviral therapy in acceleration of atherosclerosis in HIV-infected adults is controversial, partly because of the confounding effects of the involvement of classic cardiovascular risk factors. Objective: To study vascular function in HIV-infected children. Design: Cross-sectional study of 49 HIV-infected children (34 receiving antiretroviral therapy and 15 never treated) and if 24 age- and sex-matched controls. Methods: Automatic, computerized, ultrasonic procedure evaluation of geometric and mechanical properties of the common carotid artery, and of the endothelium-dependent dilation and endothelium-independent dilation. Results: Relative systolodiastolic variations in diameter of the carotid artery in HIV-infected children were significantly lower than those in controls, but there was no significant difference in intima-media thickness. Cross-sectional compliance and distensibility were also significantly lower. Wall stiffness, assessed as the incremental elastic modulus, was larger in HIV-infected children. Endothelium-dependent dilation was lower in HIV-infected children but non-endothelium-dependent dilation was similar to that in controls. We did not find differences for any of the vascular variables between HIV-infected children receiving antiretroviral therapy and those never treated. All arterial variables were similar in children with and without dyslipidemia. Conclusions: HIV-infected children had a vascular dysfunction in the absence of cardiovascular risk factors. In this short series, no additional detrimental effects were observed after a mean of 5 years of antiretroviral therapy.

Noninvasive Assessment of Arterial Stiffness and Risk of Atherosclerotic Events in Children

Noninvasive assessment of vascular dysfunction in the pediatric population has taken advantage of the development of high-resolution ultrasound techniques. The most frequently used methods are the quantification of flow-mediated endothelium-dependent dilation of the brachial artery and measurement of the intima-media thickening of the carotid artery. Both reduced flow-mediated dilation and increased intima-media thickness have been proven to correlate with late cardiovascular events and/or mortality in adults. As these noninvasive methods can easily be applied in children, there have been recent investigations in high-risk pediatric patients harboring classical cardiovascular risk factors. Endothelial dysfunction and increased thickness of the intima media are currently observed in children with familial hypercholesterolemia, obesity, and type 1 diabetes mellitus. The association of early vascular dysfunction with a known risk factor is an important issue as these anomalies precede the formation of atherosclerotic plaques. Therefore, they may help in stratification of the risk for cardiovascular event and to better tailor therapeutic interventions in at risk children. Finally, these methods have been applied in specific pediatric populations, such as children with end-stage renal disease, chronic parenteral nutrition, HIV infection, and coarctation of the aorta. In these conditions, endothelial dysfunction and vascular remodeling are also present early in life and these data raise new possibilities in the understanding of the pathogenesis of atherosclerosis in these populations.

Patent Ductus Arteriosus Stenting (Transcatheter Potts Shunt) for Palliation of Suprasystemic Pulmonary Arterial Hypertension A Case Series

Idiopathic pulmonary arterial hypertension (IPAH) continues to be a progressive and fatal disease.1 Patients with congenital heart disease and PAH constitute a separate subset with Eisenmenger syndrome where the life expectancy is significantly better than patients with IPAH. Prior surgical series have reported improved survival after converting severe and refractory IPAH into an Eisenmenger physiology using a Potts shunt with direct side-to-side anastomosis.2–4 We describe a similar approach using a transcatheter technique by stenting residual or probe-patent ductus arteriosus (PDA) to establish a stable communication between descending thoracic aorta and left pulmonary artery in patients with severe suprasystemic PAH. During the past 5 years, we have performed cardiac catheterization in 28 IPAH patients and found 4 with a small or probe-patent PDA. One of these patients had infrasystemic PA pressures and did not undergo PDA stenting. The other 3 patients, whose data are summarized in the Table, had the PDA stented. Patient 1 was diagnosed with idiopathic PAH at the age of 6 months. Transthoracic echocardiography at the time of the diagnosis showed an atrial septal defect with left-to-right shunt and a small PDA. He remained stable on oral medications until 9.7 years of age when he presented with recurrent syncope. Severe right ventricular dilatation and bowing of the interventricular septum to the left were noted on transthoracic echocardiogram. Cardiac catheterization confirmed suprasystemic PAH and the presence of a small PDA shunting right-to-left with significant restriction (Figure 1). Figure 1. Angiographic views from the first case. A , Aortography in lateral view, showing …

Microsatellite DNA markers detects 95% of chromosome 22q11 deletions

Cono-truncal cardiac malformations account for some 50% of congenital heart defects in newborn infants. Recently, hemizygosity for chromosome 22q11.2 was reported in patients with the DiGeorge/Velo-cardio-facial syndromes (DGS/VCFS) and causally related disorders. We have explored the potential use of microsatellite DNA markers for rapid detection of 22q11 deletions in 19 newborn infants referred for cono-truncal heart malformations with associated DGS/VCFS anomalies. A failure of parental inheritance was documented in 84.2% of cases (16/19). PCR-based genotyping using microsatellite DNA markers located within the commonly deleted region allowed us either to confirm or reject a 22q11 microdeletion in 94.3% of cases (18/19) within 24 hours. This test is now currently performed in the infants referred to us for a cono-truncal heart malformation as a first intention screening for 22q11 microdeletion.

Endothelial-dependent vasodilation is impaired in children with sickle cell disease

Impairment of endothelial-dependent vasodilation has been demonstrated in adults with sickle cell anemia (SCA). We enrolled 21 SCA children, mean age 10.4±3.3 yrs, and 23 Afro-Caribbean controls. We examined flow-mediated (FMD) and nitroglycerine-mediated (GTNMD) dilation of the brachial artery, using echotracking techniques, and measured intima-media thickness (IMT) and mechanical properties of the common carotid artery. FMD was significantly decreased in SCA children vs controls (5.6±0.2 vs 8.0±0.2%, p=0.008), while IMT, stiffness of the common carotid artery, and GTNMD were comparable. In conclusion, endothelial dysfunction is present as early as childhood in SCA patients.

Kinetics of the utilization of dietary arginine for nitric oxide and urea synthesis: insight into the arginine–nitric oxide metabolic system in humans

BACKGROUND The systemic availability of oral/dietary arginine and its utilization for nitric oxide (NO) synthesis remains unknown and may be related to a competitive hydrolysis of arginine into urea in the splanchnic area and systemic circulation. OBJECTIVES We investigated the kinetics and dose-dependency of dietary arginine utilization for NO compared with urea synthesis and studied the characteristics of the arginine-NO metabolic system in healthy humans. DESIGN We traced the metabolic fate and analyzed the utilization dynamics of dietary arginine after its ingestion at 2 nutritional amounts in healthy humans (n = 9) in a crossover design by using [(15)N-(15)N-(guanido)]-arginine, isotope ratio mass spectrometry techniques, and data analysis with a compartmental modeling approach. RESULTS Whatever the amount of dietary arginine, 60 ± 3% (±SEM) was converted to urea, with kinetics indicative of a first-pass splanchnic phenomenon. Despite this dramatic extraction, intact dietary arginine made a major contribution to the postprandial increase in plasma arginine. However, the model identified that the plasma compartment was a very minor (~2%) precursor for the conversion of dietary arginine into NO, which, in any case, was small (<0.1% of the dose). The whole-body and plasma kinetics of arginine metabolism were consistent with the suggested competitive metabolism by the arginase and NO synthase pathways. CONCLUSIONS The conversion of oral/dietary arginine into NO is not limited by the systemic availability of arginine but by a tight metabolic compartmentation at the systemic level. We propose an organization of the arginine metabolic system that explains the daily maintenance of NO homeostasis in healthy humans.

Genetic analyses in a cohort of children with pulmonary hypertension.

The prevalence of germline mutations in paediatric pulmonary hypertension (PH) is poorly documented. The objective of this study was to determine the mutation frequency in PH genes in a paediatric cohort and describe the clinical characteristics of mutation carriers. The study involved 66 index cases with PH: 35 children with idiopathic pulmonary arterial hypertension (IPAH); five children with familial PAH (FPAH); three children with pulmonary veno-occlusive disease (PVOD); and 23 children with PAH associated with congenital heart disease (APAH-CHD). No mutations were found in the 23 children with APAH-CHD. In the 40 children with IPAH or FPAH, 12 mutations were found: five on BMPR2; four on ACVRL1; and three on TBX4. In the three PVOD cases, two carried the EIF2AK4 mutation. Mutation carriers had a more severe disease at diagnosis and more aggressive first-line therapy was required. The three patients with PVOD had a very severe disease at diagnosis and required a lung transplantation. The genetic architecture of paediatric PAH is enriched in ACVRL1 and TBX4 mutations compared to adult PAH, but further studies are required to confirm these results. Childhood-onset PAH in children carrying a mutation in one of the genes tested has a more severe presentation at diagnosis but a similar outcome to that observed in non-carriers. Paediatric pulmonary hypertension has a specific genetic architecture http://ow.ly/54yP301hCQi

Do tertiary paediatric hospitals deal with the same spectrum of paediatric pulmonary hypertension as multicentre registries

To the Editor: Although national [1–5] and international paediatric registries for pulmonary hypertension (PH) [6, 7] have been published recently, inclusion criteria and, therefore, the distribution of aetiologies and severity of cases have not always been comparable [8]. In order to determine possible differences between registries, we have compared the aetiologies of confirmed PH of prevalent versus incident cases of PH in our own large database (in a tertiary paediatric hospital), and compared these to recently reported large multinational registries. According to pre-specified protocols, any children with clinical symptoms or at risk of PH at our centre were referred for echocardiography. If tricuspid regurgitation velocity was >2.8 m·s−1, right heart catheterisation was performed and the diagnosis of PH was confirmed if mean pulmonary artery pressure was ≥25 mmHg. The Dana Point classification was used [1, 9]. A standardised diagnostic work-up was used in PH cases: thoracic computed tomography scan, hepatic echography, lung function tests, genetic screening, screening for systemic diseases, and HIV serology were used when appropriate. At the beginning of our study, our database included 86 prevalent PH patients. Over the next 3 yrs, 126 incident PH patients were referred. Median age at inclusion was 2.4 yrs (range 0.5–15 …

0462: Chest CT findings in idiopathic and heritable pediatric pulmonary arterial hypertension

Objectives To describe CT findings in paediatric idiopathic pulmonary arterial hypertension (PAH). Methods Lung and cardiac CT of 30 children with idiopathic PAH or heritable PAH (median age 7.5 years (range 11 months - 15.5 years)) were compared to 30 children without cardiac or lung disease matched for age. PAH diagnosis was always confirmed by a right heart catheterization. All patients were considered as having idiopathic or heritable PAH after a complete diagnostic work-up according to the Nice international recommandations. Seven/ 30 patients had mutations in one of the known PAH genes (BMPR2, Alk1, TBX4, EIF2AK4). Results CT findings were significant increase of the ratio of main pulmonary artery/ascending aorta (median 1.5 [1- 1.9] versus 0.98 [0.7-1.1] in controls and of right ventricle/left ventricle (median 1.4 [0.9-3] versus 0.8 [0.6-1]). Mediastinal adenopathies were observed in 9 cases. Parenchymal anomalies were present in 25/30 patients with mosaic pattern of attenuation in 9, ground glass nodules in 17, micronodules in 12, interlobular septal thickening in 13, consolidation in 3, and distal pulmonary arteries anomalies in 16. No correlation was found between CT findings and WHO functional class or hemodynamic characteristics of patients. Veno-occlusive disease was diagnosed at CT in 3 patients and confirmed subsequently either genetically or histologically. Two/4 diagnosis of Rendu-Osler (ALK1 mutations) were diagnosed at CT before genetic confirmation. Conclusion CT is a valuable tool in the diagnostic work-up of PAH in children. Specific parenchymal anomalies are highly suggestive of EIF2AK4 or ALK1 mutations and may orientate genetic confirmation of the disease.

280: Circulating endothelial cell levels decrease after vasodilator therapy and are a biomarker of deterioration in pediatric pulmonary hypertension

Background Pulmonary vasodilators in general and prostacyclin therapy in particular have markedly improved the outcome of patients with pulmonary arterial hypertension (PAH). Endothelial dysfunction is a key feature of PAH and we previously described that circulating endothelial cells (CECs) could be used as a biomarker of endothelial dysfunction in PAH. We now hypothesized that PAH-specific vasodilator therapy might decrease CEC numbers. Methods We quantified CECs in peripheral blood from children with idiopathic PAH (iPAH, n =30) or PAH secondary to congenital heart disease (PAH-CHD, n =30), before and after treatment and during follow up. CEC were enumerated by immunomagnetic separation with mAb CD146-coated beads. Results CEC counts were significantly decreased in children after treatment with oral endothelin antagonists and/or PDE5 inhibitors. In 10 children with refractory PAH despite combination oral therapies, SC treprostinil was added and we found a further significant decrease in CEC count during the first month of treatment in every patient. We quantified CEC during 6 to 36 months follow-up after initiation of SC treprostinil and found that CEC count is modified according to clinical status. Conclusions CEC counts fall with vasodilatator therapy in PAH and could also be used as biomarker of deterioration in refractory pediatric pulmonary hypertension treated with SC treprostinil.