Hypertrophic cardiomyopathy (HCM) is an inherited cardiac disorder affecting one in 500 of the general population. Atrial fibrillation (AF) is the most common arrhythmia in patients with HCM. We sought to characterize the atrial electrophysiological and structural substrate in young and aging Gly203Ser cardiac troponin-I transgenic (HCM) mice. At 30 weeks and 50 weeks of age (n = 6 per strain each group), the left atrium was excised and placed on a multi-electrode array (MEA) for electrophysiological study; subsequent histological analyses and plasma samples were analyzed for biomarkers of extracellular matrix remodeling and cell adhesion and inflammation. Wild-type mice of matched ages were included as controls. Young HCM mice demonstrated significantly shortened atrial action potential duration (APD), increased conduction heterogeneity index (CHI), increased myocyte size, and increased interstitial fibrosis without changes in effective refractory periods (ERP), conduction velocity (CV), inflammatory infiltrates, or circulating markers of extracellular matrix remodeling and inflammation. Aging HCM mice demonstrated aggravated changes in atria electrophysiology and structural remodeling as well as increased circulating matrix metalloproteinases (MMP)-2, MMP-3, and VCAM-1 levels. This model of HCM demonstrates an underlying atrial substrate that progresses with age and may in part be responsible for the greater propensity for AF in HCM.

Intrauterine growth restriction (IUGR) and subsequent neonatal catch-up growth are implicated in programming of insulin resistance later in life. Spontaneous IUGR in the guinea pig, due to natural variation in litter size, produces offspring with asymmetric IUGR and neonatal catch-up growth. We hypothesized that spontaneous IUGR and/or accelerated neonatal growth would impair insulin sensitivity in adult guinea pigs. Insulin sensitivity of glucose metabolism was determined by hyperinsulinemic-euglycemic clamp (HEC) in 38 (21 male, 17 female) young adult guinea pigs from litters of two-to-four pups. A subset (10 male, 8 female) were infused with d-[3-3H]glucose before and during the HEC to determine rates of basal and insulin-stimulated glucose utilization, storage, glycolysis, and endogenous glucose production. n males, the insulin sensitivity of whole body glucose uptake ( r = 0.657, P = 0.002) and glucose utilization ( r = 0.884, P = 0.004) correlated positively and independently with birth weight, but not with neonatal fractional growth rate (FGR10-28). In females, the insulin sensitivity of whole body and partitioned glucose metabolism was not related to birth weight, but that of endogenous glucose production correlated negatively and independently with FGR10-28 ( r = -0.815, P = 0.025). Thus, perinatal growth programs insulin sensitivity of glucose metabolism in the young adult guinea pig and in a sex-specific manner; impaired insulin sensitivity, including glucose utilization, occurs after IUGR in males and impaired hepatic insulin sensitivity after rapid neonatal growth in females.

Decades of focus on selective ion channel blockade has been dismissed as an effective approach to antiarrhythmic drug development. In that context many older antiarrhythmic drugs lacking ion channel selectivity may serve as tools to explore mixed ion channel blockade producing antiarrhythmic activity. This study investigated the non-clinical electrophysiological and antiarrhythmic actions of bisaramil and penticainide using in vitro and in vivo methods. In isolated cardiac myocytes both drugs directly block sodium currents with IC50 values of 13μM (bisaramil) and 60μM (penticainide). Both drugs reduced heart rate but prolonged the P-R, QRS and Q-T intervals of the ECG (due to sodium and potassium channel blockade) in intact rats. They reduced cardiac conduction velocity in isolated rat hearts, increased the threshold currents for capture and fibrillation (indices of sodium channel blockade) and reduced the maximum following frequency as well as prolonged the effective refractory period (indices of potassium channel blockade) of electrically stimulated rat hearts. Both drugs reduced ventricular arrhythmias and eliminated mortality due to VF in ischemic rat hearts. The index of cardiac electrophysiological balance (iCEB) did not change significantly over the dose range evaluated; however, different drug effects resulted when changes in BP and HR were considered. While bisaramil is a more potent sodium channel blocker compared to penticainide, both produce a spectrum of activity against ventricular arrhythmias due to mixed cardiac ion channel blockade. Antiarrhythmic drugs exhibiting mixed ion channel blockade may serve as tools for development of safer mixed ion channel blocking antiarrhythmic drugs.

Background: RSD921, the R,R enantiomer of the kappa (kappa) agonist PD117,302, lacks significant activity on opioid receptors. Methods: The pharmacological and toxicological actions were studied with reference to cardiovascular, cardiac, antiarrhythmic, toxic and local anaesthetic activity. Results: In rats, dogs and baboons, RSD921 dose-dependently reduced blood pressure and heart rate. In a manner consistent with sodium channel blockade it prolonged the PR and QRS intervals of the ECG. Furthermore, in rats and NHP, RSD921 increased the threshold currents for induction of extra-systoles and ventricular fibrillation (VFt), and prolonged effective refractory period (ERP). In rats, RSD921 was protective against arrhythmias induced by electrical stimulation and coronary artery occlusion. Application of RSD921 to voltage-clamped rat cardiac myocytes blocked sodium currents. RSD921 also blocked transient (i(to)) and sustained (I-Ksus) outward potassium currents, albeit with reduced potency relative to sodium current blockade. Sodium channel blockade due to RSD921 in myocytes and isolated hearts was enhanced under ischaemic conditions (low pH and high extracellular potassium concentration). When tested on the cardiac, neuronal and skeletal muscle forms of sodium channels expressed in Xenopus laevis oocytes, RSD921 produced equipotent tonic block of sodium currents, enhanced channel block at reduced pH (6.4) and marked use-dependent block of the cardiac isoform. RSD921 had limited but quantifiable effects in subacute toxicology studies in rats and dogs. Pharmacokinetic analyses were performed in baboons. Plasma concentrations producing cardiac actions in vivo after intravenous administration of RSD921 were similar to the concentrations effective in the in vitro assays utilized. Conclusions: RSD921 primarily blocks sodium currents, and possesses antiarrhythmic and local anaesthetic activity.

The guinea pig is an alternate small animal model for the study of metabolism, including insulin sensitivity. However, only one study to date has reported the use of the hyperinsulinemic euglycemic clamp in anesthetized animals in this species, and the dose response has not been reported. We therefore characterized the dose-response curve for whole body glucose uptake using recombinant human insulin in the adult guinea pig. Interspecies comparisons with published data showed species differences in maximal whole body responses (guinea pig ≈ human < rat < mouse) and the insulin concentrations at which half-maximal insulin responses occurred (guinea pig > human ≈ rat > mouse). In subsequent studies, we used concomitant d-[3-3H]glucose infusion to characterize insulin sensitivities of whole body glucose uptake, utilization, production, storage, and glycolysis in young adult guinea pigs at human insulin doses that produced approximately half-maximal (7.5 mU·min-1·kg-1) and near-maximal whole body responses (30 mU·min-1·kg-1). Although human insulin infusion increased rates of glucose utilization (up to 68%) and storage and, at high concentrations, increased rates of glycolysis in females, glucose production was only partially suppressed (~23%), even at high insulin doses. Fasting glucose, metabolic clearance of insulin, and rates of glucose utilization, storage, and production during insulin stimulation were higher in female than in male guinea pigs (P < 0.05), but insulin sensitivity of these and whole body glucose uptake did not differ between sexes. This study establishes a method for measuring partitioned glucose metabolism in chronically catheterized conscious guinea pigs, allowing studies of regulation of insulin sensitivity in this species.

Cardiac ischaemic-reperfusion injury (IRI) remains the primary cause of mortality throughout the developed world. Molecular mechanisms underlying IRI are complex and are often interlinked with each other driving a synergistic response. Toll-like receptor 4 (TLR4), an immunosurveillance receptor, is known to enhance tissue injury during IRI by enhancing the inflammatory response. The release of endogenous components during IRI bind onto TLR4 leading to the activation of multiple signalling kinases. Once this event occurs these proteins are defined as danger associated molecular patterns molecules (DAMPs) or alarmins. Examples include heat shock proteins, high mobility group box one (HMGB1) and extracellular matrix proteins, all of which are involved in IRI. However, literature in the last two decades suggests that transient stimulation of TLR4 may suppress IRI and thus improve cardiac recovery. Furthermore, it remains to be seen what role TLR4 plays during ischaemic-preconditioning where acute bouts of ischaemia, preceding a harmful bout of ischaemic-reperfusion, is cardioprotective. The other question which also needs to be considered is that if transient TLR4 signalling drives a preconditioning response then what are the ligands which drive this? Hence the second part of this review explores the possible TLR4 ligands which may promote cardioprotection against IRI.

Hypertrophic cardiomyopathy (HCM) is a common heritable cardiac disorder with diverse clinical outcomes including sudden death, heart failure, and stroke. Depressed heart rate variability (HRV), a measure of cardiac autonomic regulation, has been shown to predict mortality in patients with cardiovascular disease. Cardiac autonomic remodelling in animal models of HCM are not well characterised. This study analysed Gly203Ser cardiac troponin-I transgenic (TG) male mice previously demonstrated to develop hallmarks of HCM by age 21 weeks. 33 mice aged 30 and 50 weeks underwent continuous electrocardiogram (ECG) recording for 30 min under anaesthesia. TG mice demonstrated prolonged P-wave duration (P < 0.001) and PR intervals (P < 0.001) compared to controls. Additionally, TG mice demonstrated depressed standard deviation of RR intervals (SDRR; P < 0.01), coefficient of variation of RR intervals (CVRR; P < 0.001) and standard deviation of heart rate (SDHR; P < 0.001) compared to controls. Additionally, total power was significantly reduced in TG mice (P < 0.05). No significant age-related difference in either strain was observed in ECG or HRV parameters. Mice with HCM developed slowed atrial and atrioventricular conduction and depressed HRV. These changes were conserved with increasing age. This finding may be indicative of atrial and ventricular hypertrophy or dysfunction, and perhaps an indication of worse clinical outcome in heart failure progression in HCM patients.

Introduction: Ischaemic-reperfusion injury remains problematic in the clinical setting. Investigating the properties of ischaemic-preconditioning has assisted in treating ischaemic-reperfusion injury, however, its ability to manipulate inflammation remains poorly defined. (+)-Naloxone and (+)-naltrexone, are novel non-opioid receptor antagonists with anti-inflammatory properties. This study investigates the effects of these drugs on ischaemic-preconditioning. Method: Balb/c (12 weeks) hearts were studied using the isolated heart technique (n=8). Non-preconditioned (NPC) hearts were given 35 mins of ischaemia (LTI-35m) and 40 mins of reperfusion. Ischaemic-preconditioned (IPC) hearts were given 3 bouts 2.5 mins of ischaemia and reperfusion before LTI-35m. (+)-naloxone or (+)-naltrexone were infused for 15 mins in NPC hearts (20 μM) before LTI-35m. In IPC hearts, drug infusion (20 μM) started 10 mins before IPC and during the 1st and 2nd bouts of reperfusion. Western blots analyses on left ventricular homogenate for cytosolic Il-1β, cardiac-FABP and HMGB1 levels was performed. Data was analysed using multiway ANOVAs and post-hoc Tukey HSDs. Results: Left ventricular develop pressure measurements taken post-ischaemia (LVDP%) revealed that IPCs (82.9±2.53%) were protected against LTI-35m (NPC: 57.5±5.62%) (P<0.05). LVPD% recovery was reduced in (+)-naltrexone-IPC (68.3±4.13%) and (+)-naloxone-IPC (71.1±3.96%) groups compared to IPCs (P<0.05). Neither drugs affected the LVDP recovery in NPC hearts (P>0.05). A conditioning and treatment effect was observed (P<0.05) in hearts treated with (+)-naloxone, but not (+)-naltrexone, when cytosolic C-FABP & HMGB1 was examined. No significance in Il-1β was observed between groups. Conclusion: (+)-Naltrexone & (+)-naloxone at 20 μM blocks early LVDP recovery after ischaemia. (+)-naloxone alters cytosolic C-FABP and HMGB1 levels.

Intrauterine growth restriction (IUGR) and subsequent neonatal catch-up growth are implicated in the programming of increased appetite, adiposity and cardiometabolic diseases. Guinea pigs provide an alternate small animal model to rodents to investigate mechanisms underlying prenatal programming, being relatively precocial at birth, with smaller litter sizes and undergoing neonatal catch-up growth after IUGR. The current study, therefore, investigated postnatal consequences of spontaneous IUGR due to varying litter size in this species. Size at birth, neonatal, juvenile (post-weaning, 30-60 days) and adolescent (60-90 days) growth, juvenile and adolescent food intake, and body composition of young adults (120 days) were measured in 158 male and female guinea pigs from litter sizes of one to five pups. Compared with singleton pups, birth weight of pups from litters of five was reduced by 38%. Other birth size measures were reduced to lesser degrees with head dimensions being relatively conserved. Pups from larger litters had faster fractional neonatal growth and faster absolute and fractional juvenile growth rates (P<0.005 for all). Relationships of post-weaning growth, feed intakes and adult body composition with size at birth and neonatal growth rate were sex specific, with neonatal growth rates strongly and positively correlated with adiposity in males only. In conclusion, spontaneous IUGR due to large litter sizes in the guinea pig causes many of the programmed sequelae of IUGR reported in other species, including human. This may therefore be a useful model to investigate the mechanisms underpinning perinatal programming of hyperphagia, obesity and longer-term metabolic consequences.

Introduction: The electroanatomical influence of type I diabetes (T1DM) on the cardiac myocardium is not well understood. Methods: Zucker lean rats (3 months) underwent an i.p injection of saline (control, n=10) or 30mg/kg Streptozotocin (T1DM, n=10). At 6 months of age, the atria were excised and placed with the epicardial surface in contact with a 9x10 multi-electrode array (0.5mm inter-electrode spacing). A 100MΩ aluminosilicate microelectrode was inserted into the endocardial surface during a standard S1-S2 pacing protocol to record intracellular action potentials (AP). AP duration (APD) at 90%, 50% and 20% of repolarisation, effective refractory period (ERP), body weight, blood glucose levels and systolic blood pressure measurements were obtained. Plasma serum samples were collected, and, tissue samples weighed and stored for immunohistochemical and histological analyses respectively. Results: No significant differences were found in body (p=0.07) and chamber weights (p>0.05) between groups. T1DM had significantly elevated and reduced levels of ICAM-1 (p=0.03) and MCP-1 (p=0.03) respectively. In T1DM animals, fasting blood glucose (p=0.04) and systolic blood pressure levels were elevated (p=0.04) compared to controls. APD20,50,90 were significantly prolonged across all pacing cycle lengths (RA and LA p< 0.0001), whilst the ERP shortened (LA and RA p<0.0001) in T1DM compared to controls. Cardiomyocytes were larger in T1DM atria (LA and RA both p<0.0001) and fibrosis was enhanced in T1DM animals compared to controls (LA p<0.05; RA p<0.01). Conclusion: T1DM may have an important role in mediating atrial structural and electrophysiological changes to facilitate the presence of a vulnerable substrate for atrial fibrillation.

Background/objectives: Amitriptyline (AMY) is a tricyclic anti-depressant that has recently been shown to have anti-inflammatory properties. We investigated whether AMY is cardioprotective against reperfusion injury in ex-vivo rat hearts.Methods: Thirty adult Sprague-Dawley rat hearts were perfused ex-vivo in a Langendorff apparatus. All hearts except SHAM (n=6, perfused for 110 min.) received 30 min no-flow ischemia followed by 40 min reperfusion (I-R). One group (n=6) was untreated before I-R (non-preconditioned; NPC), another non-preconditioned group was perfused with 10 mu M amitriptyline for 30 min before I-R (NPC-AMY, n=6). One group was preconditioned with 3 x 5-minute periods of ischemia before I-R (PC, n=6) and a fifth group was preconditioned in the presence of 10 mu M amitriptyline (PC-AMY, n=6). p38 phosphorylation and HMGB1 levels were quantified using Western blots. Data was analysed using multiway ANOVAs with Tukey HSD and linear regression models with Sobel mediator tests.Results: NPC hearts recovered poorly (LVDP recovered to 26.5 +/- 10.5% of pre-ischemic values, compared to PC hearts (82.8 +/- 14.9%: P < 0.05)). PC-AMY (69.9 +/- 6.16%) and NPC-AMY (90.3 +/- 10.0%) groups both recovered well (P < 0.05). The Sobel mediator test suggested that p38 activity may be indirectly involved in the amitriptyline induced cardioprotection (P < 0.05). HMGB1 was lower in amitriptyline treated hearts compared to the non-preconditioned hearts (P < 0.05) but the multiway ANOVA test suggests that HMGB1 was not involved in amitriptyline induced protection.Conclusions: Amitriptyline at 10 mu M protects hearts against ischemic-reperfusion injury which may be partially mediated through p38 phosphorylation. Crown Copyright (C) 2015 Published by Elsevier Ireland Ltd. All rights reserved.

Introduction: Diabetes is a major risk factor of atrial fibrillation. Methods: The atria of zucker lean (Control n=12) and obese (T2DM n=9) rats (12 weeks) were placed with the epicardial surface in contact with a 9x10 multi-electrode array (0.5mm inter-electrode spacing). A 100MΩ aluminosilicate microelectrode was inserted into the endocardial surface during a standard S1-S2 pacing protocol to record intracellular action potentials (AP). AP duration (APD) at 90%, 50% and 20% of repolarisation, effective refractory period (ERP), body weight, blood glucose levels and systolic blood pressure measurements were obtained. Pre-experiments, plasma serum was collected to determine levels of pro-inflammatory biomarkers. Post-experiments, tissues were weighed and stored for histological analyses. Results: T2DM animals were significantly heavier (p<0.0001), had elevated systolic blood pressures (p<0.0001), plasma glucose levels (p<0.0001) and larger chamber weights (RA, LA and LV p<0.02) than controls. ERP was prolonged in the RA (p<0.001) but reduced in the LA (p<0.05) of T2DM animals compared to controls. APD was significantly prolonged in T2DM animals in the RA (APD20,50,90 and cycle lengths (CL) p<0.0001). This was significant only at CL of 400 and 300ms in the LA (both p=0.02). No significant differences were observed between groups for the proinflammatory biomarkers studied (p>0.05). T2DM animals had larger cardiomyocyte diameters in the RA and LA (both p<0.0001), and a significantly higher degree of fibrosis in the RA (p=0.01) and LA (p=0.0004) compared to controls. Conclusion: Early onset T2DM is associated with both electrophysiological and structural changes in cardiac myocardium. This may partly explain the increased risk of AF in patients with T2DM.

OBJECTIVE:This study aims to investigate the impact of upper airway obstruction (UAO) in children by measuring thoracoabdominal asynchrony (TAA) during periods of sleep apnea/hypopnea and during scored-event-free (SEF) breathing periods.METHODS:Respiratory inductive plethysmographic signals were extracted from polysomnographic data, recorded before and after adenotonsillectomy in 40 children with UAO and 40 healthy, matched children at equivalent time points. Thoracoabdominal asynchrony was computed using a Hilbert transform-based phase difference estimation method in SEF periods during stage 2, stage 4 non-rapid eye movement (NREM), and rapid eye movement (REM) sleep and compared between the groups.RESULTS:At baseline, in the UAO group, TAA during obstructions were significantly higher than TAA during SEF periods in both stage 2 and REM sleep. Compared to controls, children with UAO had a significantly higher TAA during SEF periods in stage 2, stage 4 sleep, and REM sleep. This between-group difference was not significant post adenotonsillectomy. UAO group showed a significant decrease in TAA compared to their baseline during SEF stage 2 and 4 NREM, but not in REM.CONCLUSION:Upper airway obstruction in children is associated with increased TAA during SEF periods, indicative of continuous partial obstruction of the upper airway. Adenotonsillectomy decreased this effect significantly in non-REM sleep as evidenced by reduced asynchrony levels post-surgery. TAA assessment during sleep may therefore provide additional diagnostic information.

Introduction: Hypertrophic cardiomyopathy (HCM) is a common heritable cardiac disease with a diverse disease spectrum including sudden death, progressive heart failure, and chronic and/or paroxysmal atrial fibrillation. Depressed heart rate variability (HRV), a measure of autonomic function, has been demonstrated to predict for mortality risk in various cardiac disorders such as heart failure and myocardial infarction. It is unknown if HRV is altered in Gly203Ser cardiac troponin-I (TnI) transgenic (TG) mice, a murine model of HCM. Methods: Upon reaching 30 or >50 weeks of age, TG and WT mice were anaesthetised and underwent 30 minutes of 3-lead electrocardiography recording using PowerLab and LabChart Pro (ADInstruments). HRV was calculated using 2 minute ECG tracings for time- and frequency-domain methods of HRV analysis. Electrogram (ECG) parameters were calculated in 100 successive beats from each tracing, with averages generated for each group of successively occurring 4 beats. Results: No significant age-related differences were observed in any HRV and ECG parameters of both mice strains. TG mice demonstrated similar heart rates, increased PR interval and P wave duration (P<0.01 and P<0.0001 respectively), and similar QRS, QT and QTc intervals as compared to controls. Time-domain HRV analysis revealed decreased standard deviation of RR intervals (SDRR), coefficient variance of RR intervals (CVRR), and standard deviation of heart rate (SD rate) in TG mice (all P<0.05). Total power, power spectrum of low frequency (LF), of high frequency (HF), and LF/HF ratio were not significantly altered in TG mice. Conclusions: No age-related differences in ECG and HRV were observed in the current study. Mice with the TnI gene mutation demonstrating phenotypic features of human HCM demonstrated slowed atrial and atrioventricular conduction, and decreased HRV compared to WT mice.

These studies examined the opioid and non-opioid in vivo and in vitro actions of PD117,302 (((±)-trans-N-methyl-N-[2-(l-pyrrolidinyl)-cyclohexyl]benzo[b]thiophene-4-acetamide), a kappa (κ)-opioid receptor agonist. PD117,302 selectively labeled the κ-opioid receptor in guinea pig cerebellar membranes and in mice the ED50 for analgesia was 2.3µmol/kg. A non opioid cardiovascular assessment of PD117,302 showed that it dose-dependently increased left-ventricular peak systolic pressure in rat isolated perfused hearts but reduced heart rate and blood pressure in anaesthetized rats. Over the concentration range 0.3-30µM in vitro, and dose-range 0.25-4µmol/kg in vivo, PD117,302 dose-dependently prolonged the P-R interval, QRS width and Q-T interval of the rat heart ECG. Naloxone (either 1µM or 8µmol/kg) did not antagonize the observed ECG effects of PD117,302. Cardiac electrical stimulation studies in anesthetized rats showed that threshold currents for capture and fibrillation were increased and effective refractory period (ERP) prolonged. In rats subject to coronary artery occlusion PD117,302 reduced arrhythmia incidence. Intracellular cardiac action potential studies qualified the ECG changes produced by PD117,302 such that there was a dose-dependent reduction in the maximum rate of depolarization of phase 0 (dV/dtmax) and prolongation of the action potential duration (APD). In isolated cardiac myocytes PD117,302 dose-dependently (1-100µM) reduced peak Na(+) current and produced a hyperpolarizing shift in the inactivation curve. Transient outward and sustained outward K(+) currents were blocked by PD117,302. Thus, the ECG changes and antiarrhythmic effects observed in vivo result from direct blockade of multiple cardiac ion channels.

We describe a novel approach for simultaneously determining regional differences in action potential (AP) morphology and tissue electrophysiological properties in isolated atria. The epicardial surface of rat atrial preparations was placed in contact with a multi-electrode array (9 × 10 silver chloride electrodes, 0.1 mm diameter and 0.1 mm pitch). A glass microelectrode (100 MΩ) was simultaneously inserted into the endocardial surface to record intracellular AP from either of 2 regions (A, B) during pacing from 2 opposite corners of the tissue. AP duration at 80% of repolarisation and its restitution curve was significantly different only in region A (p < 0.01) when AP was initiated at different stimulation sites. Alternans in AP duration and AP amplitude, and in conduction velocity were observed during 2 separate arrhythmic episodes. This approach of combining microelectrode array and intracellular membrane potential recording may provide new insights into arrhythmogenic mechanisms in animal models of cardiovascular disease.

Study Objective: To investigate respiratory cycle-related electroencephalographic changes (RCREC) in healthy children and in children with sleep disordered breathing (SDB) during scored event-free (SEF) breathing periods of sleep.Design: Interventional case-control repeated measurements design.Setting: Paediatric sleep laboratory in a hospital setting.Participants: Forty children with SDB and 40 healthy, age-and sex-matched children.Interventions: Adenotonsillectomy in children with SDB and no intervention in controls.Measurements and Results: Overnight polysomnography; electroencephalography (EEG) power variations within SEF respiratory cycles in the overall and frequency band-specific EEG within stage 2 nonrapid eye movement (NREM) sleep, slow wave sleep (SWS), and rapid eye movement (REM) sleep. Within both groups there was a decrease in EEG power during inspiration compared to expiration across all sleep stages. Compared to controls, RCREC in children with SDB in the overall EEG were significantly higher during REM and frequency band specific RCRECs were higher in the theta band of stage 2 and REM sleep, alpha band of SWS and REM sleep, and sigma band of REM sleep. This between-group difference was not significant postadenotonsillectomy.Conclusion: The presence of nonrandom respiratory cycle-related electroencephalographic changes (RCREC) in both healthy children and in children with sleep disordered breathing (SDB) during NREM and REM sleep has been demonstrated. The RCREC values were higher in children with SDB, predominantly in REM sleep and this difference reduced after adenotonsillectomy.

Citation: David A Saint. Finding a niche in a changing sociological, technological and scientific world—AIMS Biophysics[J]. AIMS Biophysics, 2014, 1(1): 49-50. doi: 10.3934/biophy.2014.1.49

STUDY OBJECTIVES To develop a measure of sleep fragmentation in children with upper airway obstruction based on survival curve analysis of sleep continuity. DESIGN Prospective repeated measures. SETTING Hospital sleep laboratory. PARTICIPANTS 92 children aged 3.0 to 12.9 years undergoing 2 overnight polysomnographic (PSG) sleep studies, 6 months apart. Subjects were divided into 3 groups based on their obstructive apnea and hypopnea index (OAHI) and other upper airway obstruction (UAO) symptoms: primary snorers (PS; n = 24, OAHI <1), those with obstructive sleep apnea syndrome (OSAS; n = 20, OAHI ≥1) and non-snoring controls (C; n = 48, OAHI <1). INTERVENTIONS Subjects in the PS and OSAS groups underwent tonsillectomy and adenoidectomy between PSG assessments. MEASUREMENTS AND RESULTS Post hoc measures of movement and contiguous sleep epochs were exported and analyzed using Kaplan-Meier estimates of survival to generate survival curves for the 3 groups. Statistically significant differences were found between these group curves for sleep continuity (P < 0.05) when using movement events as the sleep fragmenting event, but not if stage 1 NREM sleep or awakenings were used. CONCLUSION Using conventional indices of sleep fragmentation in survival curve analysis of sleep continuity does not provide a useful measure of sleep fragmentation in children with upper airway obstruction. However, when sleep continuity is defined as the time between gross body movements, a potentially useful clinical measure is produced.

We demonstrate the synergistic benefits of using multiple technologies to investigate complex multi-scale biological responses. The combination of reductionist and integrative methodologies can reveal novel insights into mechanisms of action by tracking changes of in vivo phenomena to alterations in protein activity (or vice versa). We have applied this approach to electrical and mechanical remodelling in right ventricular failure caused by monocrotaline-induced pulmonary artery hypertension in rats.We show arrhythmogenic T-wave alternans in the ECG of conscious heart failure animals. Optical mapping of isolated hearts revealed discordant action potential duration (APD) alternans. Potential causes of the arrhythmic substrate; structural remodelling and/or steep APD restitution and dispersion were observed, with specific remodelling of the Right Ventricular Outflow Tract. At the myocyte level, [Ca2+]i transient alternans were observed together with decreased activity, gene and protein expression of the sarcoplasmic reticulum Ca2+-ATPase (SERCA). Computer simulations of the electrical and structural remodelling suggest both contribute to a less stable substrate.Echocardiography was used to estimate increased wall stress in failure, in vivo. Stretch of intact and skinned single myocytes revealed no effect on the Frank-Starling mechanism in failing myocytes. In isolated hearts acute stretch-induced arrhythmias occurred in all preparations. Significant shortening of the early APD was seen in control but not failing hearts. These observations may be linked to changes in the gene expression of candidate mechanosensitive ion channels (MSCs) TREK-1 and TRPC1/6. Computer simulations incorporating MSCs and changes in ion channels with failure, based on altered gene expression, largely reproduced experimental observations. (C) 2014 The Authors. Published by Elsevier Ltd.