Electrophysiological and Structural Remodeling of the Atria in a Mouse Model of Troponin-I Mutation Linked Hypertrophic Cardiomyopathy: Implications for Atrial Fibrillation.

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.

Sex-specific programming of adult insulin resistance in guinea pigs by variable perinatal growth induced by spontaneous variation in litter size.

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.

Use of the hyperinsulinemic euglycemic clamp to assess insulin sensitivity in guinea pigs: dose response, partitioned glucose metabolism, and species comparisons.

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.

The role of Toll-like receptor 4 (TLR4) in cardiac ischaemic-reperfusion injury, cardioprotection and preconditioning.

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.

Simultaneous conduction mapping and intracellular membrane potential recording in isolated atria.

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.

Slowed atrial and atrioventricular conduction and depressed HRV in a murine model of hypertrophic cardiomyopathy.

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.

An examination of the cardiac actions of PD117,302, a κ-opioid receptor agonist.

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.

Increased thoracoabdominal asynchrony during breathing periods free of discretely scored obstructive events in children with upper airway obstruction.

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.

Heartbeat evoked potentials during sleep and daytime behavior in children with sleep-disordered breathing.

RATIONALE: Event-related brain potentials allow probing of cortical information processing, but when evoked with externally induced stimuli may disrupt sleep homeostasis and do not provide insight into intrinsic cortical information processing. To investigate if cortical processing of intrinsic information in children with sleep-disordered breathing (SDB) is different from healthy children and, if so, whether it resolves with treatment, we used heartbeat as a source of interoceptive event-related brain potentials. OBJECTIVES: To investigate heartbeat evoked potentials (HEP) during sleep in healthy children and in children with SDB before and after treatment and to explore if there are any associations between HEP and daytime behavioral deficits in children with SDB. METHODS: Heartbeat-aligned EEG was assessed for presence of HEP within stage 2, slow-wave sleep, and REM sleep in 40 children with primarily mild to moderate SDB before and after adenotonsillectomy and in 40 matched control subjects at similar time points. MEASUREMENTS AND MAIN RESULTS: In both groups, nonrandom HEP were present in all sleep stages analyzed; however, amplitude of HEP were significantly lower in children with SDB during non-REM sleep (stage 2: P = 0.03; slow-wave sleep: P = 0.001). This between-group difference was not significant post adenotonsillectomy. Significant negative associations between HEP and daytime behavioral scores were observed at baseline. CONCLUSIONS: Children with SDB displayed reduced HEP amplitude during sleep, which might be indicative of changes in afferent sensory inputs to the brain and/or signify differences in sensory gating of cardiac-related information in the insular cortex. Adenotonsillectomy appears to reverse this effect.

Respiratory cycle-related electroencephalographic changes during sleep in healthy children and in children with sleep disordered breathing.

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: Immanuel SA, Pamula Y, Kohler M, Martin J, Kennedy D, Saint DA, Baumert M. Respiratory cycle-related electroencephalographic changes during sleep in healthy children and in children with sleep disordered breathing.

Systems approach to the study of stretch and arrhythmias in right ventricular failure induced in rats by monocrotaline.

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, [Ca(2+)]i transient alternans were observed together with decreased activity, gene and protein expression of the sarcoplasmic reticulum Ca(2+)-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.

Effect of resistive inspiratory and expiratory loading on cardio-respiratory interaction in healthy subjects.

Resistive loading affects the breathing pattern and causes an increase in negative intrathoracic pressure. The aim of this paper was to study the influence inspiratory and expiratory loading on cardio-respiratory interaction. We recorded electrocardiogram (ECG) and respiratory inductance plethysmogram (RIP) in 11 healthy male subjects under normal and resistive loading conditions. The R-R time series were extracted from the ECG and respiratory phases were calculated from the ribcage and abdominal RIP using the Hilbert transform. Both the series were transformed into ternary symbol vectors based on the changes between two successive R-R intervals or respiratory phases, respectively. Subsequently, words of length `3 digits' were formed and the correspondence between words of the two series was determined to quantify cardio-respiratory interaction. Adding inspiratory and expiratory resistive loads resulted in an increase in inspiratory and expiatory time, respectively. Furthermore, we observed a significant increase in cardio-respiratory interaction during inspiratory resistive loading as compared to expiratory resistive loading (ribcage: 22.1±7.2 vs. 12.5±4.3 %, p<;0.0001; abdomen: 18.8±8.5 vs. 12.1±3.1 %, p<;0.05, respectively). Further studies may aid in better understanding the underlying physiological mechanisms and management of patients with breathing disorders.

Symbolic dynamics of respiratory cycle related sleep EEG in children with sleep disordered breathing.

Childhood sleep disordered breathing (SDB) is characterized by an increased work of breathing, restless night sleep and excessive daytime sleepiness and has been associated with cognitive impairment, behavioral disturbances and early cardiovascular changes. Compared to normal controls, children with SDB have elevated arousal thresholds and their sleep EEG may elicit cortical activation associated with arousals but often too subtle to be visually scored. The aim of this study was to assess EEG complexity throughout the respiratory cycle based on symbolic dynamics in children with SDB (n=40) and matched healthy controls. EEG amplitude values were symbolized based on the quartiles of their distribution and words of length 3 were formed and classed into 4 types based on their patterns. Children with SDB showed less complex EEG dynamics in non-REM sleep that was unrelated to the respiratory phase. In REM sleep normal children showed a respiratory phase-related reduction in EEG variability during the expiratory phase compared to inspiration, which was not apparent in children with SDB. In conclusion, respiratory cycle related EEG dynamics are altered in children with SDB during REM sleep and indicate changes in cortical activity.

Riluzole reduces arrhythmias and myocardial damage induced by coronary occlusion in anaesthetized pigs.

The cardiac persistent sodium current (IN aP ) presents a novel target for cardiac ischaemic protection. Herein we investigated the effects of the IN aP blocker riluzole in a pig model of regional myocardial ischaemia. Landrace or Large White pigs were subjected to 3 h ligation of the left anterior descending coronary artery (LAD). Pigs received either saline (500 mL/h, i.v.) throughout the experiment (control; n = 7) or riluzole (2 mg/kg in 2 mL propylene glycol in 100 mL saline, i.v.; RIL; n = 7) between 15 and 5 min prior to ligation. The arrhythmia score was calculated in 5 min epochs. Myocardial damage was assessed using epicardial image analysis and histological sectioning. In the control group, all seven pigs developed premature ventricular contractions (PVC), seven developed non-sustained arrhythmias and six of seven developed sustained arrhythmias. Of the sustained arrhythmias, 23 of 28 instances were initiated by R-on-T extrasytoles (extrasystoles within the vulnerable period that can trigger re-entrant arrhythmias). In the RIL group, all seven pigs developed PVC, six of seven developed non-sustained arrhythmias and only three developed sustained arrhythmias, of which two of five instances were R-on-T initiated. The riluzole-treated pigs exhibited less myocardial damage than pigs in the control group (65% smaller surface area (P = 0.008) on gross epicardial inspection, 51% less oedema (P = 0.01), 53% less fibre waviness (P = 0.029) assessed by haematoxylin and eosin staining and 79% fewer fragmented nuclei (P = 0.009) assessed by terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling). In conclusion, riluzole significantly reduced Phase 2 (the period associated with irreversible damage) ischaemic R-on-T triggered and non-R-on-T arrhythmias and myocardial damage occurring during the 3 h period of regional ischaemia.

Increased variability in respiratory parameters heralds obstructive events in children with sleep disordered breathing.

Sleep disordered breathing (SDB) is characterized by repeated episodes of central or obstructive apneas, disturbing respiratory patterns. The purpose of this study is to quantify respiratory variability associated with apneic/hypopneic events by computing respiratory parameters and thoraco-abdominal asynchrony (TAA) over sleep periods preceding the occurrence of obstructive events in children with SDB. One minute artifact-free epochs of ribcage (RC) and abdominal (AB) signals were extracted from the respiratory inductive plethysmograph (RIP) channel of the PSG prior to the onset of each obstruction. Breath-by-breath values of TAA were computed using a Hilbert transform based technique that measures the phase shift between the RC and AB signals. In addition, the following parameters were computed breath-by-breath from the RC signal: inspiratory time (Ti), expiratory time (Te), total time (Ttot), and the inspiratory duty cycle (DC=Ti/Ttot). Standard deviation of the parameters (SD_TAA, SD_Ti, SD_Te, SD_Ttot, SD_DC) over each 1 min epoch were calculated and averaged over each subject with respect to sleep stage. For comparison, similar measures were computed from within quiet breathing periods of each subject. We found that breaths immediately before apnea/hypopneas were associated with a high degree of variability in respiratory timing and TAA. The proposed variability analysis of RIP signals may be useful for detecting acute epochs of respiratory instability in children with SDB.

Atrial arrhythmia in ageing spontaneously hypertensive rats: unraveling the substrate in hypertension and ageing.

BACKGROUND: Both ageing and hypertension are known risk factors for atrial fibrillation (AF) although the pathophysiological contribution or interaction of the individual factors remains poorly understood. Here we aim to delineate the arrhythmogenic atrial substrate in mature spontaneously hypertensive rats (SHR). METHODS: SHR were studied at 12 and 15 months of age (n = 8 per group) together with equal numbers of age-matched normotensive Wistar-Kyoto control rats (WKY). Electrophysiologic study was performed on superfused isolated right and left atrial preparations using a custom built high-density multiple-electrode array to determine effective refractory periods (ERP), atrial conduction and atrial arrhythmia inducibility. Tissue specimens were harvested for structural analysis. RESULTS: COMPARED TO WKY CONTROLS, THE SHR DEMONSTRATED: Higher systolic blood pressure (p<0.0001), bi-atrial enlargement (p<0.05), bi-ventricular hypertrophy (p<0.05), lower atrial ERP (p = 0.008), increased atrial conduction heterogeneity (p = 0.001) and increased atrial interstitial fibrosis (p = 0.006) & CD68-positive macrophages infiltration (p<0.0001). These changes resulted in higher atrial arrhythmia inducibility (p = 0.01) and longer induced AF episodes (p = 0.02) in 15-month old SHR. Ageing contributed to incremental bi-atrial hypertrophy (p<0.01) and atrial conduction heterogeneity (p<0.01) without affecting atrial ERP, fibrosis and arrhythmia inducibility. The limited effect of ageing on the atrial substrate may be secondary to the reduction in CD68-positive macrophages. CONCLUSIONS: Significant atrial electrical and structural remodeling is evident in the ageing spontaneously hypertensive rat atria. Concomitant hypertension appears to play a greater pathophysiological role than ageing despite their compounding effect on the atrial substrate. Inflammation is pathophysiologically linked to the pro-fibrotic changes in the hypertensive atria.

Myocardial infarction and atrial fibrillation: importance of atrial ischemia.

BACKGROUND: Myocardial infarction (MI) is associated with the development of atrial fibrillation (AF). We aimed to characterize the atrial abnormalities because of MI and determine the role of ischemia to the AF substrate. METHODS AND RESULTS: Forty-four sheep were studied. MI was induced by occlusion of the left circumflex artery (LCX) or left anterior descending artery (LAD). Excluding 11 with fatal arrhythmias, equal groups of animals (LCX; LAD; and sham-operated) underwent sequential electrophysiology study for 45 minutes to determine atrial effective refractory periods, conduction velocity, conduction heterogeneity index, and AF inducibility. Postmortem evaluation was performed with 2,3,5 triphenyl tetrazolium chloride staining. MI resulted in greater left ventricular dysfunction (P<0.05), LA pressure (P<0.0003), and reduction in atrial effective refractory periods (P<0.0001) compared with control. 2,3,5 triphenyl tetrazolium chloride staining demonstrated that the left circumflex artery, and not the LAD, group had atrial infarction. The left circumflex artery group demonstrated the following compared with the LAD or control groups: greater slowing in atrial conduction velocity (P<0.0001 and P<0.001); increased absolute range of conduction phase delay (P<0.001 and P<0.001); increased conduction heterogeneity index (P<0.0001 and P<0.001); greater AF vulnerability (P<0.05 for both); and longer AF duration (P<0.05 for both). LAD group had modest but significant slowing in conduction velocity (P<0.01) but no change in conduction heterogeneity index or AF duration compared with control. CONCLUSIONS: Left ventricular infarction, which is known to result in atrial stretch, hemodynamic change, and neurohumoral activation, contributes partially to the atrial abnormalities in MI. Atrial ischemia/infarction results in greater atrial electrophysiological changes and propensity for AF forming the dominant substrate for AF in MI.

The Lambeth Conventions (II): guidelines for the study of animal and human ventricular and supraventricular arrhythmias.

The 'Lambeth Conventions' is a guidance document, written in 1987 (Walker et al., 1988), intended to be of practical value in the investigation of experimental arrhythmias induced by ischaemia, infarction, and reperfusion. This is an update, expanded to include guidance on the study of supraventricular arrhythmias, drug-induced arrhythmias, heritable arrhythmias, and advances in our knowledge in core areas since 1987. We have updated the guidance on the design and execution of experiments and the definition, classification, quantification, and analysis of all types of arrhythmias. Investigators are encouraged to adopt the conventions and test their validity in the hope that this will improve uniformity and interlaboratory comparisons, aid clinical research, facilitate antiarrhythmic drug discovery and safety assessment, and improve antiarrhythmic drug deployment for different cardiac conditions. We note that there is a gap between some definitions proposed here and their conventional clinical counterparts, and encourage the research necessary to bridge that translational gap. A web link offers the chance to vote and comment on the new conventions (https://bscr.wufoo.com/forms/z7x0x5/).

Respiratory timing and variability during sleep in children with sleep-disordered breathing.

Sleep-disordered breathing (SDB) in children is assessed by quantification of hypopnea and apnea events. Little is known, however, about respiratory timing and breath-to-breath variability during sleep. The aim of this study was to investigate respiratory parameters across sleep stages in children with SDB before and after treatment compared with healthy children. Overnight polysomnography (PSG) was conducted in 40 children with SDB prior to and 6 mo following adenotonsillectomy. For comparison, a control group of 40 healthy sex- and age-matched children underwent two PSGs at equivalent time points but without intervention. The following variables were measured breath by breath during obstruction-free periods in stage 2 nonrapid eye movement (NREM), stage 4 NREM, and REM sleep: inspiratory time (Ti), expiratory time (Te), total time (Ttotal), inspiratory duty cycle (DC; =Ti/Ttotal), respiratory frequency (fR), and SD of the parameters Ti, Te, fR, and DC. Variability in waveform morphology was also computed using the residue of respiratory patterns. The severity of SDB was relatively mild in the study cohort (obstructive apnea hypopnea index: baseline, 5.1 ± 9.4 vs. 0.1 ± 0.2, P < 0.001; follow-up, 0.3 ± 0.3 vs. 0.8 ± 1.0, P < 0.01). Compared with healthy controls, children with SDB showed significantly longer Ti and Te and a lower fR at the baseline study. These differences were not significant after adenotonsillectomy. Sleep stages were associated with significant differences in all of the respiratory measures in both groups of children. In conclusion, children with relatively mild SDB showed prolonged inspiration and expiration indicative of chronic narrowing of the upper airway. Treatment of SDB normalizes respiratory timing. Documentation of these parameters may aid in both understanding and management of children with SDB.

Increased mechanically-induced ectopy in the hypertrophied heart.

INTRODUCTION: Left ventricular hypertrophy (LVH) predisposes patients to arrhythmias, but the mechanism of these arrhythmias is unclear. Here we show that hearts from spontaneously hypertensive rats (SHR) have a lower threshold for induction mechanically induced arrhythmias compared to age matched Wistar-Kyoto (WKY). METHODS: Recordings were made from isolated hearts from nine month old SHR (n = 18) and WKY (n = 17) rats. A water filled balloon in the left ventricle had its volume controlled by a servo-driven syringe. LVEDP was abruptly increased in increments until an ectopic beat was detected by an epicardial MAP electrode. Alternatively, LVEDP was abruptly reduced back to 5 mm Hg from an elevated pressure. RESULTS: SHR hearts had a lower threshold for stretch induced ectopics (29.87 ± 2.79 mm Hg vs. 42.23 ± 2.33 mm Hg, p < 0.01) and for release induced ectopics (24.09 ± 1.40 vs. 37.23 ± 3.22, p < 0.01). Perfusion with 100 µM streptomycin increased threshold for stretch induced ectopics in both strains (from 49.4 ± 4.7 to 69.5 ± 6.9 mm Hg in WKY; p < 0.05 and from 21.2 ± 3.5 to 39.7 ± 9.0 mm Hg in SHR; p = 0.07). 100 µM streptomycin also increased threshold for release induced ectopics in SHR (from 23.5 ± 3.6 to 32.6 ± 4.9 mm Hg; p < 0.05) but not in WKY. Perfusion with 0.01 µM isoprenaline decreased the threshold for stretch induced ectopics in both strains (from 40.6 ± 5.0 to 22.6 ± 2.5 mm Hg in WKY; not significant at p < 0.05; p = 0.07 and from 31.0 ± 5.5 to 14.3 ± 2.5 mm Hg in SHR; p < 0.05). CONCLUSIONS: Hearts from SHR are more susceptible to both stretch-induced and release-induced arrhythmia.