Effects of Respiration on Left Ventricular Diastolic Function in Healthy Children

Pulsed Doppler echocardiographic indices of mitral valve filling were measured in 20 healthy children, between 3 and 125 years old, in order to evaluate the effects of spontaneous respiration on left ventricular diastolic filling patterns. There were significant respiratory variations in four parameters of left ventricular diastolic function: The peak early filling velocity, the ratio of early to late peak filling velocity, and the ratio of early to late diastolic velocity-time integral decreased significantly during inspiration (mean decrease 7%, P<0·05; 16%, P<0·01; and 12%, P<0·05, respectively). On the other hand there was a significant increase in late peak filling velocity with inspiration (10% increase, P<0·05). Other variables of left ventricular diastolic filling were unchanged with inspiration. These results suggest that assessment of left ventricular diastolic function in children should be standardized with regard to respiratory phases in any clinical application. (Eur Heart J 1996; 17: 453%456)Scopu

New hyperekplexia mutations provide insight into glycine receptor assembly, trafficking, and activation mechanisms

Hyperekplexia is a syndrome of readily provoked startle responses, alongside episodic and generalized hypertonia, that presents within the first month of life. Inhibitory glycine receptors are pentameric ligand-gated ion channels with a definitive and clinically well stratified linkage to hyperekplexia. Most hyperekplexia cases are caused by mutations in the α1 subunit of the human glycine receptor (hGlyR) gene (GLRA1). Here we analyzed 68 new unrelated hyperekplexia probands for GLRA1 mutations and identified 19 mutations, of which 9 were novel. Electrophysiological analysis demonstrated that the dominant mutations p.Q226E, p.V280M, and p.R414H induced spontaneous channel activity, indicating that this is a recurring mechanism in hGlyR pathophysiology. p.Q226E, at the top of TM1, most likely induced tonic activation via an enhanced electrostatic attraction to p.R271 at the top of TM2, suggesting a structural mechanism for channel activation. Receptors incorporating p.P230S (which is heterozygous with p.R65W) desensitized much faster than wild type receptors and represent a new TM1 site capable of modulating desensitization. The recessive mutations p.R72C, p.R218W, p.L291P, p.D388A, and p.E375X precluded cell surface expression unless co-expressed with α1 wild type subunits. The recessive p.E375X mutation resulted in subunit truncation upstream of the TM4 domain. Surprisingly, on the basis of three independent assays, we were able to infer that p.E375X truncated subunits are incorporated into functional hGlyRs together with unmutated α1 or α1 plus β subunits. These aberrant receptors exhibit significantly reduced glycine sensitivity. To our knowledge, this is the first suggestion that subunits lacking TM4 domains might be incorporated into functional pentameric ligand-gated ion channel receptors

Haemodynamic characterisation and heart catheterisation complications in children with pulmonary hypertension: Insights from the Global TOPP Registry (tracking outcomes and practice in paediatric pulmonary hypertension)

Background: The TOPP Registry has been designed to provide epidemiologic, diagnostic, clinical, and outcome data on children with pulmonary hypertension (PH) confirmed by heart catheterisation (HC). This study aims to identify important characteristics of the haemodynamic profile at diagnosis and HC complications of paediatric patients presenting with PH. Methods and results: HC data sets underwent a blinded review for confirmation of PH (defined as mean pulmonary arterial pressure >= 25 mm Hg, pulmonary capillary wedge pressure 3 WU x m(2)). Of 568 patients enrolled, 472 who fulfilled the inclusion criteria and had sufficient data from HC were analysed. A total of 908 diagnostic and follow-up HCs were performed and complications occurred in 5.9% of all HCs including five (0.6%) deaths. General anaesthesia (GA) was used in 53%, and conscious sedation in 47%. Complications at diagnosis were more likely to occur if GA was used (p=0.04) and with higher functional class (p = 0.02). Mean cardiac index (CI) was within normal limits at diagnosis when analysed for the entire group (3.7 L/min/m(2); 95% confidence interval 3.4-4.1), as was right atrial pressure despite a severely increased PVRI (16.6 WU x m(2), 95% confidence interval 15.6-17.76). However, 24% of the patients had a CI of <2.5 L/min/m(2) at diagnosis. A progressive increase in PVRI and decrease in CI was observed with age (p < 0.001). Conclusion: In TOPP, haemodynamic assessment was remarkable for preserved CI in the majority of patients despite severely elevated PVRI. HC-related complication incidence was 5.9%, and was associated with GA and higher functional clas