Cardiac electrophysiological adaptations in the equine athlete-Restitution analysis of electrocardiographic features.

Exercising horses uniquely accommodate 7-8-fold increases in heart rate (HR). The present experiments for the first time analysed the related adaptations in action potential (AP) restitution properties recorded by in vivo telemetric electrocardiography from Thoroughbred horses. The horses were subjected to a period of acceleration from walk to canter. The QRS durations, and QT and TQ intervals yielded AP conduction velocities, AP durations (APDs) and diastolic intervals respectively. From these, indices of active, λ = QT/(QRS duration), and resting, λ0 = TQ/(QRS duration), AP wavelengths were calculated. Critical values of QT and TQ intervals, and of λ and λ0 at which plots of these respective pairs of functions showed unity slope, were obtained. These were reduced by 38.9±2.7% and 86.2±1.8%, and 34.1±3.3% and 85.9±1.2%, relative to their resting values respectively. The changes in λ were attributable to falls in QT interval rather than QRS duration. These findings both suggested large differences between the corresponding critical (129.1±10.8 or 117.4±5.6 bpm respectively) and baseline HRs (32.9±2.1 (n = 7) bpm). These restitution analyses thus separately identified concordant parameters whose adaptations ensure the wide range of HRs over which electrophysiological activation takes place in an absence of heart block or arrhythmias in equine hearts. Since the horse is amenable to this in vivo electrophysiological analysis and displays a unique wide range of heart rates, it could be a novel cardiac electrophysiology animal model for the study of sudden cardiac death in human athletes

Childhood outcomes after low-grade intraventricular haemorrhage: A systematic review and meta-analysis

Aim: To undertake a systematic review and meta-analysis exploring school-age neurodevelopmental outcomes of children after low-grade intraventricular haemorrhage (IVH). Method: The published and grey literature was extensively searched to identify observational comparative studies exploring neurodevelopmental outcomes after IVH grades 1 and 2. Our primary outcome was neurodevelopmental impairment after 5 years of age, which included cognitive, motor, speech and language, behavioural, hearing, or visual impairments. Results: This review included 12 studies and over 2036 infants born preterm with low grade IVH. Studies used 30 different neurodevelopmental tools to determine outcomes. There was conflicting evidence of the composite risk of neurodevelopmental impairment after low-grade IVH. There was evidence of an association between low-grade IVH and lower IQ at school age (−4.23, 95% confidence interval [CI] –7.53, −0.92, I2 = 0%) but impact on school performance was unclear. Studies reported an increased crude risk of cerebral palsy after low-grade IVH (odds ratio [OR] 2.92, 95% CI 1.95, 4.37, I2 = 41%). No increased risk of speech and language impairment or behavioural impairment was found. Few studies addressed hearing and visual impairment. Interpretation: This systematic review presents evidence that low-grade IVH is associated with specific neurodevelopmental impairments at school age, lending support to the theory that low-grade IVH is not a benign condition

Atrial Transcriptional Profiles of Molecular Targets Mediating Electrophysiological Function in Aging and Pgc-1β Deficient Murine Hearts

BackgroundDeficiencies in the transcriptional co-activator, peroxisome proliferative activated receptor, gamma, coactivator-1β are implicated in deficient mitochondrial function. The latter accompanies clinical conditions including aging, physical inactivity, obesity, and diabetes. Recent electrophysiological studies reported that Pgc-1β-/- mice recapitulate clinical age-dependent atrial pro-arrhythmic phenotypes. They implicated impaired chronotropic responses to adrenergic challenge, compromised action potential (AP) generation and conduction despite normal AP recovery timecourses and background resting potentials, altered intracellular Ca2+ homeostasis, and fibrotic change in the observed arrhythmogenicity.ObjectiveWe explored the extent to which these age-dependent physiological changes correlated with alterations in gene transcription in murine Pgc-1β-/- atria.Methods and ResultsRNA isolated from murine atrial tissue samples from young (12–16 weeks) and aged (>52 weeks of age), wild type (WT) and Pgc-1β-/- mice were studied by pre-probed quantitative PCR array cards. We examined genes encoding sixty ion channels and other strategic atrial electrophysiological proteins. Pgc-1β-/- genotype independently reduced gene transcription underlying Na+-K+-ATPase, sarcoplasmic reticular Ca2+-ATPase, background K+ channel and cholinergic receptor function. Age independently decreased Na+-K+-ATPase and fibrotic markers. Both factors interacted to alter Hcn4 channel activity underlying atrial automaticity. However, neither factor, whether independently or interactively, affected transcription of cardiac Na+, voltage-dependent K+ channels, surface or intracellular Ca2+ channels. Nor were gap junction channels, β-adrenergic receptors or transforming growth factor-β affected.ConclusionThese findings limit the possible roles of gene transcriptional changes in previously reported age-dependent pro-arrhythmic electrophysiologial changes observed in Pgc-1β-/- atria to an altered Ca2+-ATPase (Atp2a2) expression. This directly parallels previously reported arrhythmic mechanism associated with p21-activated kinase type 1 deficiency. This could add to contributions from the direct physiological outcomes of mitochondrial dysfunction, whether through reactive oxygen species (ROS) production or altered Ca2+ homeostasis

Molecular basis of arrhythmic substrate in ageing murine peroxisome proliferator-activated receptor γ co-activator deficient hearts modelling mitochondrial dysfunction.

INTRODUCTION: Ageing and chronic metabolic disorders are associated with mitochondrial dysfunction and cardiac pro-arrhythmic phenotypes which were recently attributed to slowed atrial and ventricular action potential (AP) conduction in peroxisome proliferator-activated receptor γ co-activator deficient (Pgc-1β-/-) mice. METHODS: We compared expression levels of voltage-gated Na+ channel (NaV1.5) and gap junction channels, Connexins 40 and 43 (Cx40 and Cx43) in the hearts of young and old, and wild-type (WT) and Pgc-1β-/- mice. This employed Western blotting (WB) for NaV1.5, Cx40 and Cx43 in atrial/ventricular tissue lysates, and immunofluorescence (IF) from Cx43 was explored in tissue sections. Results were analysed using two-way analysis of variance (ANOVA) for independent/interacting effects of age and genotype. RESULTS: In atria, increased age and Pgc-1β-/- genotype each independently decreased both Cx40 and Cx43 expression without interacting effects. In IF experiments, both age and Pgc-1β deletion independently reduced Cx43 expression. In ventricles, age and genotype exerted interacting effects in WB studies of NaV1.5 expression. Young Pgc-1β-/- then showed greater NaV1.5 expression than young WT ventricles. However, neither age nor Pgc-1β deletion affected Cx43 expression, independently or through interacting effects in both WB and IF studies. CONCLUSION: Similar pro-arrhythmic atrial/ventricular phenotypes arise in aged/Pgc-1β-/- from differing contributions of altered protein expression and functional effects that may arise from multiple acute mechanisms

The effects of ageing and adrenergic challenge on electrocardiographic phenotypes in a murine model of long QT syndrome type 3.

Long QT Syndrome 3 (LQTS3) arises from gain-of-function Nav1.5 mutations, prolonging action potential repolarisation and electrocardiographic (ECG) QT interval, associated with increased age-dependent risk for major arrhythmic events, and paradoxical responses to β-adrenergic agents. We investigated for independent and interacting effects of age and Scn5a+/ΔKPQ genotype in anaesthetised mice modelling LQTS3 on ECG phenotypes before and following β-agonist challenge, and upon fibrotic change. Prolonged ventricular recovery was independently associated with Scn5a+/ΔKPQ and age. Ventricular activation was prolonged in old Scn5a+/ΔKPQ mice (p = 0.03). We associated Scn5a+/ΔKPQ with increased atrial and ventricular fibrosis (both: p < 0.001). Ventricles also showed increased fibrosis with age (p < 0.001). Age and Scn5a+/ΔKPQ interacted in increasing incidences of repolarisation alternans (p = 0.02). Dobutamine increased ventricular rate (p < 0.001) and reduced both atrioventricular conduction (PR segment-p = 0.02; PR interval-p = 0.02) and incidences of repolarisation alternans (p < 0.001) in all mice. However, in Scn5a+/ΔKPQ mice, dobutamine delayed the changes in ventricular repolarisation following corresponding increases in ventricular rate. The present findings implicate interactions between age and Scn5a+/ΔKPQ in prolonging ventricular activation, correlating them with fibrotic change for the first time, adding activation abnormalities to established recovery abnormalities in LQTS3. These findings, together with dynamic electrophysiological responses to β-adrenergic challenge, have therapeutic implications for ageing LQTS patients

Ageing in Pgc-1β-/- mice modelling mitochondrial dysfunction induces differential expression of a range of genes regulating ventricular electrophysiology.

Mice deficient in mitochondrial promoter peroxisome proliferator activated receptor-γ co-activator-1β (Pgc-1β-/- ) is a valuable model for metabolic diseases and has been found to present with several pathologies including ventricular arrhythmia. In the present study, our aim was to shed light on the molecular mechanisms behind the observed arrhythmic substrate by studying how the expression of selected genes critical for cardiac function differs in wild-type (WT) compared with Pgc-1β knockout mice and young compared with aged mice. We found that a clear majority of genes are down-regulated in the Pgc-1β-/- ventricular tissue compared with the WT. Although most individual genes are not significantly differentially expressed, a pattern is apparent when the genes are grouped according to their functional properties. Genes encoding proteins relating to ATPase activity, potassium ion channels relating to repolarisation and resting membrane potential, and genes encoding proteins in the cAMP pathway are found to be significantly down-regulated in the Pgc-1β deficient mice. On the contrary, the pacemaker channel genes Hcn3 and Hcn4 are up-regulated in subsets of the Pgc-1β deficient tissue. Furthermore, we found that with age, especially in the Pgc-1β-/- genotype, most genes are up-regulated including genes relating to the resting membrane potential, calcium homeostasis, the cAMP pathway, and most of the tested adrenoceptors. In conclusion, we here demonstrate how a complex pattern of many modest changes at gene level may explain major functional differences of the action potential related to ageing and mitochondrial dysfunction

Cardiac Potassium Channels: Physiological Insights for Targeted Therapy.

The development of novel drugs specifically directed at the ion channels underlying particular features of cardiac action potential (AP) initiation, recovery, and refractoriness would contribute to an optimized approach to antiarrhythmic therapy that minimizes potential cardiac and extracardiac toxicity. Of these, K(+) channels contribute numerous and diverse currents with specific actions on different phases in the time course of AP repolarization. These features and their site-specific distribution make particular K(+) channel types attractive therapeutic targets for the development of pharmacological agents attempting antiarrhythmic therapy in conditions such as atrial fibrillation. However, progress in the development of such temporally and spatially selective antiarrhythmic drugs against particular ion channels has been relatively limited, particularly in view of our incomplete understanding of the complex physiological roles and interactions of the various ionic currents. This review summarizes the physiological properties of the main cardiac potassium channels and the way in which they modulate cardiac electrical activity and then critiques a number of available potential antiarrhythmic drugs directed at them

A rare case of paediatric astroblastoma with concomitant MN1 ‐ GTSE1 and EWSR1 ‐ PATZ1 gene fusions altering management

Funder: Great Ormond Street Children’s CharityFunder: The Brain Tumour Charity; Id: http://dx.doi.org/10.13039/501100002203Funder: National Institute for Health Research; Id: http://dx.doi.org/10.13039/501100000272Funder: Olivia Hodson Cancer FundFunder: CHILDREN with CANCER UK; Id: http://dx.doi.org/10.13039/501100001273Funder: Cancer Research UK; Id: http://dx.doi.org/10.13039/501100000289Funder: Wellcome Trust; Id: http://dx.doi.org/10.13039/100010269Funder: Medical Research Council; Id: http://dx.doi.org/10.13039/50110000026

GLP-1 agonists for obesity and type 2 diabetes in children: Systematic review and meta-analysis.

Pharmacological options for management of obesity and type 2 diabetes mellitus (T2DM) in children are limited. We aimed to synthesize published randomized controlled trial (RCT) evidence on the efficacy of glucagon-like peptide-1 (GLP-1) agonists in T2DM, pre-diabetes, and obesity in children aged <18 years. Inclusion criteria were RCTs of any GLP-1 agonist, solely or in conjunction with other drugs, for the treatment of obesity, pre-diabetes, and/or T2DM in children aged <18 years old. Nine studies met the inclusion criteria (two for T2DM, one for pre-diabetes, and six for obesity without diabetes). In total, 286 children were allocated to GLP-1 agonist therapy. Compared with controls, GLP-1 agonist therapy reduced HbA1c by -0.30% (95% confidence interval [CI] -0.57, -0.04) with a larger effect in children with (pre-)diabetes (-0.72%; 95% CI -1.17, -0.28; three studies) than in children with obesity (-0.08%; 95% CI -0.13, -0.02; four studies). Conversely, GLP-1 agonist therapy reduced body weight more in children with obesity (-2.74 kg; 95% CI -3.77, -1.70; six studies) than in children with T2DM (-0.97 kg; 95% CI -2.01, 0.08; two studies). Adverse effects included gastrointestinal symptoms and minor hypoglycemic episodes, but not severe hypoglycemia. GLP-1 agonists are efficacious in treating children with obesity and/or T2DM. Effect sizes are comparable with those reported in adults.TSC and KKO are supported by the Medical Research Council (Unit programme MC_UU_12015/2