Reverse fountain flow of phosphatidylinositol-3,4-bisphosphate polarizes migrating cells.

The ability of cells to polarize and move toward external stimuli plays a crucial role in development, as well as in normal and pathological physiology. Migrating cells maintain dynamic complementary distributions of Ras activity and of the phospholipid phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2). Here, we show that lagging-edge component PI(3,4)P2 also localizes to retracting leading-edge protrusions and nascent macropinosomes, even in the absence of phosphatidylinositol 3,4,5-trisphosphate (PIP3). Once internalized, macropinosomes break up into smaller PI(3,4)P2-enriched vesicles, which fuse with the plasma membrane at the rear of the cell. Subsequently, the phosphoinositide diffuses toward the front of the cell, where it is degraded. Computational modeling confirms that this cycle gives rise to stable back-to-front gradient. These results uncover a surprising "reverse-fountain flow" of PI(3,4)P2 that regulates polarity.

Low dose of propyl-pyrazole-triol, an agonist of estrogen receptor alpha, administration stimulates the Coolidge effect in fadrozole-treated male rats.

Estrogen receptor (ER) α is involved in male sexual function. Here, we aim to investigate how ERα activation influences sexual satiety and the Coolidge effect (i.e., when a rat, that has reached sexual satiety, experiences an increased arousal after exposure to a novel sexual partner) in estrogen-deprived male rats. Male rats (8 per group) were treated daily for 29 days with either saline (Control group) or fadrozole dissolved in saline (1 mg/kg/day) 1 h before mating. On Days 13 and 29, rats treated with fadrozole received either no additional treatment (fadrozole group) or a single injection of propyl-pyrazole-triol (ERα-agonist group, dissolved in sesame oil, 1 mg/kg). Rats mated until reaching sexual satiety on Days 13 and 29. In these sessions, the Control group displayed higher frequency of intromission and ejaculation than the other groups. The ERα-agonist group mounted more frequently but reached sexual satiety sooner than the Control group. On Day 29, when exposed to a new sexual partner, the fadrozole-treated rats were less likely to display intromission than the other groups, or ejaculation than the Control group, or mounting than the ERα-agonist group. The Control group showed more ejaculatory behavior and shorter ejaculation latency than the other groups. Body weights, testosterone levels, estradiol levels, and ERα-immunoreactive cell counts in brain regions for sexual behavior were comparable between groups after 29 days of treatments. Our data suggest that estrogen helps regulate sexual satiety and the Coolidge effect in male rats.

Characterization of cardiovascular profile of anti-influenza drug peramivir: A reverse-translational study using the isoflurane-anesthetized dog.

An injectable anti-influenza drug peramivir has been reported to induce QT-interval prolongation in some phase III studies, although its thorough QT/QTc study was negative. We investigated the discrepancy among those clinical studies using isoflurane-anesthetized beagle dogs (n = 4). Peramivir in doses of 1 mg/kg/10 min (sub-therapeutic dose) followed by 10 mg/kg/10 min (clinically-relevant dose) was intravenously administered. Peramivir prolonged QT interval/QTcV and Tpeak-Tend, and tended to delay ventricular repolarization in a reverse-frequency dependent manner, indicating IKr inhibition in vivo. Meanwhile, peramivir did not alter P-wave duration, PR interval or QRS width, indicating a lack of impact on cardiac conduction via Na+ or Ca2+ channel inhibition in vivo. Peramivir prolonged Tpeak-Tend and tended to prolong terminal repolarization period, which would develop substrates for initiating and maintaining spiral reentry, respectively. Meanwhile, peramivir did not prolong J-Tpeakc, which could not induce early afterdepolarization, a trigger inducing torsade de pointes. Thus, our results support that clinical dose exposure of peramivir can delay the ventricular repolarization in influenza patients. Peramivir has only a small potential to induce torsade de pointes in patients with the intact hearts, but caution should be paid on its use for patients formerly having the trigger for torsade de pointes.

Working memory involvement in action planning does not include timing initiation structure.

A fundamental limitation in the type of information that can be retained in working memory is identified in this theoretical / review article. The analysis is based on studies of skilled motor performance that were not initially conceived in terms of working memory. Findings from a long history of experimentation involving reaction time (RT) prior to making a brief motor response indicate that although the parameters representing the goal to be achieved by the response can be retained in working memory, the control code that implements timing of action components cannot. This lack of working memory requires that the "timing code" must be compiled immediately prior to the moment that it is to be utilized; it is not possible to be fully ready to respond earlier. This compiling process increases RT and may also underlie both the psychological refractory period effect and the difficulty of generating concurrent motor actions with independent timing. These conclusions extend, but do not conflict with, other models of working memory.

The Hodgkin-Huxley-Katz Prize Lecture: A Markov model with permeation-dependent gating that accounts for resurgent current of voltage-gated Na channels.

Many neurons that fire high-frequency action potentials express specialized voltage-gated Na channel complexes that not only conduct transient current upon depolarization, but also pass resurgent current upon repolarization. The resurgent current is associated with recovery of transient current, even at moderately negative potentials where fast inactivation is usually absorbing. The combined results of many experimental studies have led to the hypothesis that resurgent current flows upon repolarization when an endogenous blocking protein that occludes open channels at depolarized potentials is expelled by inwardly permeating Na ions. Additional observations have suggested that the position of the voltage sensor of domain IV regulates the affinity of the channel for the putative blocker. To test the effectiveness of a kinetic scheme incorporating these features, here we develop and justify a Markov model with states grounded in known Na channel conformations. Simulations were designed to investigate whether including a permeation-dependent unblocking rate constant and two open-blocked states, superimposed on conformations and voltage-sensitive movements present in all voltage-gated Na channels, is sufficient to account for the unusual gating of channels with a resurgent component. Optimizing rate constant parameters against a wide range of experimental data from cerebellar Purkinje cells demonstrates that a kinetic scheme for Na channels incorporating the novel aspects of a permeation-dependent unblock, as well as distinct high- and low-affinity blocked states, reproduces all the attributes of experimentally recorded Na currents in a physiologically plausible manner.

Do long-lasting effects of epidural polarization of afferent fibres depend on persistent sodium current?

Few attempts have so far been made to define the mechanisms underlying the hour-long effects of trans-spinal stimulation combined with epidural polarization. In the present study, we investigated the potential involvement of non-inactivating sodium channels in afferent fibres. To this end, riluzole, a blocker of these channels, was administered locally to the dorsal columns close to the site of the excitation of afferent nerve fibres by epidural stimulation in deeply anaesthetized rats in vivo. Riluzole did not prevent the induction of the polarization-evoked sustained increase in the excitability of dorsal column fibres but tended to weaken it. It likewise weakened but did not abolish the sustained polarization-evoked shortening of the refractory period of these fibres. These results lead to the conclusion that the persistent sodium current may contribute to the sustained post-polarization-evoked effects but is only partly involved in both the induction and the expression of these effects.

Cardiac contractility modulation: an effective treatment strategy for heart failure beyond reduced left ventricular ejection fraction?

Heart failure (HF) with preserved ejection fraction (HFpEF) causes a progressive limitation of functional capacity, poor quality of life (QoL) and increased mortality, yet unlike HF with reduced ejection fraction (HFrEF) there are no effective device-based therapies. Both HFrEF and HFpEF are associated with dysregulations in myocardial cellular calcium homeostasis and modifications in calcium-handling proteins, leading to abnormal myocardial contractility and pathological remodelling. Cardiac contractility modulation (CCM) therapy, based on a pacemaker-like implanted device, applies extracellular electrical stimulation to myocytes during the absolute refractory period of the action potential, which leads to an increase in cytosolic peak calcium concentrations and thereby the force of isometric contraction promoting positive inotropism. Subgroup analysis of CCM trials in HFrEF has demonstrated particular benefits in patients with LVEF between 35% and 45%, suggesting its potential effectiveness also in patients with higher LVEF values. Available evidence on CCM in HFpEF is still preliminary, but improvements in terms of symptoms and QoL have been observed. Future large, dedicated, prospective studies are needed to evaluate the safety and efficacy of this therapy in patients with HFpEF.

Prognostic value of right ventricular refractory period heterogeneity in Type-1 Brugada electrocardiographic pattern.

AIMS: To investigate the prognostic significance of heterogeneity in the refractoriness of right ventricular (RV) outflow tract (RVOT) and RV apex at the electrophysiological study (EPS) in Brugada syndrome (BrS). METHODS AND RESULTS: A cohort of BrS patients (primary prevention) from five Italian centres was retrospectively analysed. Patients with spontaneous or drug-induced Type-1 electrocardiogram (ECG) + symptoms were offered an EPS for prognostic stratification. The primary endpoint was a composite of sudden cardiac death (SCD), resuscitated cardiac arrest, or appropriate intervention by the implantable cardioverter-defibrillator (ICD). Three hundred and seventy-two patients with BrS were evaluated (44 ± 15 years, 69% males, 23% with ICD): 4 SCDs and 17 ICD interventions occurred at follow-up (median 48, interquartile range: 36-60 months). Family history of SCD, syncope, and a spontaneous Type-1 ECG pattern were univariate predictors of the primary endpoint in the whole population. In patients undergoing EPS (n = 198, 53%, 44 ± 12 years, 71% males, 39% with ICD), 3 SCD and 15 ICD interventions occurred at follow-up. In this subset, the primary endpoint was not only predicted by ventricular tachycardia/fibrillation inducibility but also by a difference in the refractory period between RVOT and RV apex (ΔRPRVOT-apex) >60 ms. ΔRPRVOT-apex > 60 ms remained an independent predictor of SCD/ICD shock at bivariate analysis, even when adjusted for the other univariate predictors, showing the highest predictive power at C-statistic analysis (0.75, 95% confidence interval 0.63-0.86). CONCLUSIONS: Heterogeneity of RV refractory periods is a strong, independent predictor of life-threatening arrhythmias in BrS patients, beyond VT/VF inducibility at EPS and common clinical predictors.

Transient cardiac electrophysiological changes in a rat model of subarachnoid haemorrhage: a brain-heart interaction.

AIMS: Subarachnoid haemorrhage (SAH) is one of the causes of sudden cardiac death (SCD). However, the time course of ventricular arrhythmias and potential mechanisms responsible for this effect after SAH remain unknown. OBJECTIVE: This study aims to investigate the effect of SAH on ventricular electrophysiological changes and its potential mechanisms in long-term phase. METHODS AND RESULTS: We examined the ventricular electrophysiological remodelling and potential mechanisms in a Sprague Dawley rat model of SAH at six time points (baseline, and Days 1, 3, 7, 14 and 28) and explored the potential mechanisms. We measured the ventricular effective refractory period (ERP), ventricular fibrillation threshold (VFT) and left stellate ganglion (LSG) activity at different time points before and after SAH. We also detected neuropeptide Y (NPY) levels in plasma and myocardial tissues by enzyme-linked immunosorbent assay, and quantified NPY 1 receptor (NPY1R) protein and mRNA expression levels by western blotting and quantitative real-time reverse transcription-polymerase chain reaction, respectively. Subarachnoid haemorrhage gradually prolonged QTc intervals, shortened ventricular ERP and reduced VFT during the acute phase, peaking at Day 3. However, no significant changes were observed from Days 14 to 28 compared to Day 0. Subarachnoid haemorrhage gradually increased LSG activity, increased NPY concentrations and up-regulated NPY1R expression in the acute phase of SAH, peaking at Day 3. However, no significant variations were found from Days 14 to 28 compared to Day 0. CONCLUSION: Subarachnoid haemorrhage increases the transient susceptibility of VAs in the acute phase, and the underlying mechanisms for this response included increased sympathetic activity and up-regulated NPY1R expression.

Characterization of electropharmacological profile of an anti-atrial fibrillatory drug vernakalant along with potential risk toward torsade de pointes: Translational studies using isoflurane-anesthetized dogs and isolated rat aortic preparations.

We simultaneously assessed electropharmacological effects of anti-atrial fibrillatory drug vernakalant and its potential risk toward torsade de pointes. Vernakalant hydrochloride in doses of 0.3 and 3 mg/kg/10 min was intravenously administered to isoflurane-anesthetized beagle dogs without (n = 5) and with (n = 4) α-adrenoceptor blockade. Its vascular effect was analyzed using the rat aortae (n = 12). Vernakalant increased total peripheral vascular resistance and preload to left ventricle, leading to transient elevation of mean blood pressure indirectly via non-adrenergic pathway. Vernakalant suppressed sinus automaticity, ventricular contractility and intra-atrial/atrioventricular nodal/intraventricular conductions, and decreased cardiac output. Moreover, vernakalant prolonged atrial/ventricular effective refractory period by 53/55 ms, respectively, whereas it delayed ventricular repolarization in a reverse frequency-dependent manner. The extent of prolongation in early/late ventricular repolarization and electrically vulnerable period was 26/32 and 9 ms, respectively when QT-interval prolongation was the greatest. We compared them with those of known anti-atrial fibrillatory drugs; ranolazine, amiodarone, dronedarone, dl-sotalol and bepridil. The magnitude of vernakalant to alter those variables was the greater among those drugs except that the atrial selectivity was the lesser of those. Thus, vernakalant is expected to be efficacious against atrial fibrillation, but caution should be excised on its use for patients having labile ventricular function and repolarization.

Nutrient availability contributes to a graded refractory period for regeneration in Xenopus tropicalis.

Xenopus tadpoles are a unique model for regeneration in that they exhibit two distinct phases of age-specific regenerative competence. In Xenopus laevis, young tadpoles fully regenerate following major injuries such as tail transection, then transiently lose regenerative competence during the "refractory period" from stages 45-47. Regenerative competence is then regained in older tadpoles before being permanently lost during metamorphosis. Here we show that a similar refractory period exists in X. tropicalis. Notably, tadpoles lose regenerative competence gradually in X. tropicalis, with full regenerative competence lost at stage 47. We find that the refractory period coincides closely with depletion of maternal yolk stores and the onset of independent feeding, and so we hypothesized that it might be caused in part by nutrient stress. In support of this hypothesis, we find that cell proliferation declines throughout the tail as the refractory period approaches. When we block nutrient mobilization by inhibiting mTOR signaling, we find that tadpole growth and regeneration are reduced, while yolk stores persist. Finally, we are able to restore regenerative competence and cell proliferation during the refractory period by abundantly feeding tadpoles. Our study argues that nutrient stress contributes to lack of regenerative competence and introduces the X. tropicalis refractory period as a valuable new model for interrogating how metabolic constraints inform regeneration.

Location and coupling interval of an ectopic excitation determine the initiation of atrial fibrillation from the pulmonary veins.

INTRODUCTION: Ectopic beats originating from the pulmonary vein (PV) trigger atrial fibrillation (AF). The purpose of this study was to clarify the electrophysiological determinant of AF initiation from the PVs. METHODS: Pacing studies were performed with a single extra stimulus mimicking an ectopic beat in the left superior PVs (LSPVs) in 62 patients undergoing AF ablation. Inducibility of AF, effective refractory period (ERP), and conduction properties within the PVs were analyzed. RESULTS: A single extra stimulus in LSPV induced AF in 20 patients (32% of all patients) at the mean coupling interval (CI) of 172 ms. A CI-dependent anisotropic conduction at the AF onset was visualized in a three-dimensional mapping. Onset of AF was site-specific with reproducibility in each individual. Mean ERP in LSPV in the AF-inducible group was shorter than that in the AF-noninducible group (182 ± 55 vs. 254 ± 51 ms, p < .0001). LSPV ERP dispersion was greater in the AF-inducible group than in the AF-noninducible group (45 ± 28 vs. 27 ± 19 ms, p < .01). Circumferential intra-PV conduction time (IPVCT) exhibited decremental properties in response to shortening of CI and the prolongation of IPVCT in the AF-inducible site was greater than that in the AF-noninducible site (p < .05) in each individual. CONCLUSIONS: Location and CI of an ectopic excitation ultimately determine the initiation of AF from the PVs. ERP dispersion and circumferential conduction delay may lead to anisotropic conduction and reentry within the PVs that initiate AF.

Simultaneous analyses of hemodynamic and electrophysiological effects of oseltamivir along with its pharmacokinetic profile using the canine paroxysmal atrial fibrillation model.

Since information of antiviral drug oseltamivir on the anti-atrial fibrillation (AF) property is still limited, we assessed it using the canine paroxysmal AF model. Oseltamivir in doses of 3 and 30 mg/kg/10 min was intravenously infused to the isoflurane-anesthetized, chronic atrioventricular block dogs (n = 6) with monitoring hemodynamic and electrophysiological variables, in which AF was induced by 10 s of burst pacing on atrial septum. Oseltamivir decreased AF incidence and AF duration, and prolonged AF cycle length in a dose-dependent manner. The low and high doses attained the peak plasma drug concentrations of 9.7 and 96.5 µg/mL, which were approximately 100 and 1000 times greater than those observed in human clinical cases, respectively. The low dose of oseltamivir decreased mean blood pressure without altering sinoatrial or idioventricular rate, whereas its high dose reduced each of them. Oseltamivir delayed inter-atrial conduction in dose- and frequency-dependent manners, whereas it prolonged atrial effective refractory period in dose-dependent but frequency-independent manners. The high dose prolonged ventricular effective refractory period, which was not detected with the low dose. These findings can be used for repurposing oseltamivir as an anti-AF drug candidate.

The role of alcohol consumption on echocardiographic and electrophysiologic changes in atrial fibrillation.

BACKGROUND: A wealth of evidence suggests that alcohol consumption is a risk factor for atrial fibrillation (AF); however, the mechanisms underlying this association are unclear. This makes it challenging to develop therapeutic strategies in patients with AF attributed to alcohol consumption. PURPOSE: To investigate the echocardiographic and electrophysiologic changes caused by alcohol consumption in patients with AF. METHODS: The study was registered in Chinese Clinical Trial Registry (Registration number ChiCTR2000041575). Data on 134 consecutive non-valvular AF patients who underwent radiofrequency catheter ablation in our center was collected from April 1, 2019 to June 30, 2020. Patients were divided into no-alcohol (72) and alcohol groups [categorized into light (34), moderate (11) and heavy (17) alcohol consumption]. All patients underwent echocardiographic and electrophysiologic examinations for the assessment of left atrial (LA) strain, inter-atrial conduction, intra-atrial conduction, and atrial effective refractory period (ERP). RESULTS: Overall, the mean age was 61 ± 11 years and 87 (65%) were males. Compared with the no-alcohol group, impaired peak LA longitudinal strain, obvious inter-atrial conduction delay and increasing ERP dispersion were observed in the alcohol group. Intra-atrial conduction delay and ERP dispersion increased with increasing amounts of alcohol consumption. CONCLUSION: Alcohol consumption was associated with substantial abnormal echocardiographic and electrophysiologic changes in AF patients. These changes may contribute to the occurrence and progression of AF attributed to alcohol consumption, which may help in the development of new strategies for the prevention and management of AF. However further investigation is required.

Atrial activation sequence changes during ventricular overdrive pacing: What is the mechanism?

We describe atrial activation sequence changes during ventricular overdrive pacing in a patient with a concealed left-sided accessory pathway and discuss its potential mechanism.

Glucocorticoid Induces Atrial Arrhythmogenesis via Modification of Ion Channel Gene Expression in Rats.

Excess psychological stress is one of the precipitating factors for paroxysmal atrial fibrillation (AF), although the involved mechanisms are still uncertain. To test a hypothesis that one of the stress-induced hormones, glucocorticoid, is involved in the pathogenesis of stress-induced AF, we investigated whether the glucocorticoid could alter the temporal profile of cardiac ion channels gene expression, thereby leading to atrial arrhythmogenesis.Dexamethasone (DEX, 1.0 mg/kg) was injected subcutaneously in Sprague-Dawley rats. At predetermined times after DEX injection (0, 1, 3, 6, 12, and 24 hours), the mRNA levels of cardiac ion channel genes (erg, KvLQT1, Kv4.3, Kv4.2, Kv2.1, Kv1.5, Kv1.4, Kv1.2, SUR2A, Kir6.2, Kir3.4, Kir3.1 Kir2.2, Kir2.1, SCN5A, and α1C) were determined using RNase protection assay. DEX induced immediate and transient increase in the mRNA level of Kv1.5 and Kir2.2 with peaks at 6 (5.0 fold) and 3 hours (3.3 fold) after DEX injection, respectively. Patch-clamp studies revealed a significantly increased current density of the corresponding current, IKur and IK1 at 6 hours after DEX injection. Simultaneously, electrophysiological study in isolated perfused hearts showed significantly increased number of repetitive atrial responses induced by single atrial extrastimulus (3.2 ± 2.4 to 26.7 ± 16.4, P = 0.004) with shorting of the refractory period (36.4 ± 4.6 to 27.4 ± 5.5 ms, P = 0.049) after DEX injection.Glucocorticoid immediately modified Kv1.5 and Kir2.2 gene expression at pretranslational levels, thus leading to effective refractory period shortening that could be arrhythmogenic. These results implied that transient glucocorticoid-induced biochemical modification of cardiac ion channels might be one of the mechanisms underlying the stress-induced paroxysmal AF.

A new implantable tool for repeated assessment of supraventricular electrophysiology and atrial fibrillation susceptibility in freely moving rats.

The complex pathophysiology of atrial fibrillation (AF) is governed by multiple risk factors in ways that are still elusive. Basic electrophysiological properties, including atrial effective refractory period (AERP) and conduction velocity, are major factors determining the susceptibility of the atrial myocardium to AF. Although there is a great need for affordable animal models in this field of research, in vivo rodent studies are limited by technical challenges. Recently, we introduced an implantable system for long-term assessment of AF susceptibility in ambulatory rats. However, technical considerations did not allow us to perform concomitant supraventricular electrophysiology measurements. Here, we designed a novel quadripolar electrode specifically adapted for comprehensive atrial studies in ambulatory rats. Electrodes were fabricated from medical-grade silicone, four platinum-iridium poles, and stainless-steel fixating pins. Initial quality validation was performed ex vivo, followed by implantation in adult rats and repeated electrophysiological studies 1, 4, and 8 wk postimplantation. Capture threshold was stable. Baseline AERP values (38.1 ± 2.3 and 39.5 ± 2.0 using 70-ms and 120-ms S1-S1 cycle lengths, respectively) confirmed the expected absence of rate adaptation in the unanesthetized state and validated our prediction that markedly higher values reported under anesthesia are nonphysiological. Evaluation of AF substrate in parallel with electrophysiological parameters validated our recent finding of a gradual increase in AF susceptibility over time and demonstrated that this phenomenon is associated with an electrical remodeling process characterized by AERP shortening. Our findings indicate that the miniature quadripolar electrode is a potent new tool, which opens a window of opportunities for better utilization of rats in AF research.NEW & NOTEWORTHY Rodents are increasingly used in AF research. However, technical challenges restrict long-term supraventricular electrophysiology studies in these species. Here, we developed an implantable electrode adapted for such studies in the rat. Our findings indicate that this new tool is effective for long-term follow-up of critical parameters such as atrial refractoriness. Obtained data shed light on the normal electrophysiology and on the increased AF susceptibility that develops in rats with implanted atrial electrodes over time.

Exploring Male Multiple Orgasm in a Large Online Sample: Refining Our Understanding.

BACKGROUND: The scientific literature on multiple orgasm in males is small. There is little consensus on a definition, and significant controversy about whether multiple orgasm is a unitary experience. AIMS: This study has 2 goals: (i) describing the experience of male multiple orgasm; (ii) investigating whether there are different profiles of multiple orgasm in men. METHODS: Data from a culturally diverse online convenience sample of 122 men reporting multiple orgasm were collected. Data reduction analyses were conducted using principal components analysis (PCA) on 13 variables of interest derived from theory and the existing literature. A K-means cluster analysis followed, from which a 4-cluster solution was retained. RESULTS: While the range of reported orgasms varied from 2 to 30, the majority (79.5%, N = 97) of participants experienced between 2 and 4 orgasms separated by a specific time interval during which further stimulation was required to achieve another orgasm. Most participants reported maintaining their erections throughout and ejaculating with every orgasm. Age was not a significant correlate of the multiple orgasm experience which occurred more frequently in a dyadic context. Four different profiles of multiorgasmic men were described. STRENGTHS & LIMITATIONS: This study constitutes a rare attempt to collect systematic self-report data concerning the experience of multiple orgasm in a relatively large sample. Limitations include the lack of validated measures, memory bias associated with self-reported data and retrospective designs, the lack of a control group and of physiological measurement. CONCLUSION: Our study suggests that multiple orgasm in men is not a unitary phenomenon and sets the stage for future self-report and laboratory study. Griffin-Mathieu G, Berry M, Shtarkshall RA, Amsel R, Binik YM, Gérard M. Exploring Male Multiple Orgasm in a Large Online Sample: Refining Our Understanding. J Sex Med 2021;XX:XXX-XXX.

Effects of genetic background, sex, and age on murine atrial electrophysiology.

AIMS: Genetically altered mice are powerful models to investigate mechanisms of atrial arrhythmias, but normal ranges for murine atrial electrophysiology have not been robustly characterized. METHODS AND RESULTS: We analyzed results from 221 electrophysiological (EP) studies in isolated, Langendorff-perfused hearts of wildtype mice (114 female, 107 male) from 2.5 to 17.7 months (mean 7 months) with different genetic backgrounds (C57BL/6, FVB/N, MF1, 129/Sv, Swiss agouti). Left atrial monophasic action potential duration (LA-APD), interatrial activation time (IA-AT), and atrial effective refractory period (ERP) were summarized at different pacing cycle lengths (PCLs). Factors influencing atrial electrophysiology including genetic background, sex, and age were determined. LA-APD70 was 18 ± 0.5 ms, atrial ERP was 27 ± 0.8 ms, and IA-AT was 17 ± 0.5 ms at 100 ms PCL. LA-APD was longer with longer PCL (+17% from 80 to 120 ms PCL for APD70), while IA-AT decreased (-7% from 80 to 120 ms PCL). Female sex was associated with longer ERP (+14% vs. males). Genetic background influenced atrial electrophysiology: LA-APD70 (-20% vs. average) and atrial ERP (-25% vs. average) were shorter in Swiss agouti background compared to others. LA-APD70 (+25% vs. average) and IA-AT (+44% vs. average) were longer in 129/Sv mice. Atrial ERP was longer in FVB/N (+34% vs. average) and in younger experimental groups below 6 months of age. CONCLUSION: This work defines normal ranges for murine atrial EP parameters. Genetic background has a profound effect on these parameters, at least of the magnitude as those of sex and age. These results can inform the experimental design and interpretation of murine atrial electrophysiology.

Cycle length statistics during human atrial fibrillation reveal refractory properties of the underlying substrate: a combined in silico and clinical test of concept study.

AIMS: The treatment of atrial fibrillation beyond pulmonary vein isolation has remained an unsolved challenge. Targeting regions identified by different substrate mapping approaches for ablation resulted in ambiguous outcomes. With the effective refractory period being a fundamental prerequisite for the maintenance of fibrillatory conduction, this study aims at estimating the effective refractory period with clinically available measurements. METHODS AND RESULTS: A set of 240 simulations in a spherical model of the left atrium with varying model initialization, combination of cellular refractory properties, and size of a region of lowered effective refractory period was implemented to analyse the capabilities and limitations of cycle length mapping. The minimum observed cycle length and the 25% quantile were compared to the underlying effective refractory period. The density of phase singularities was used as a measure for the complexity of the excitation pattern. Finally, we employed the method in a clinical test of concept including five patients. Areas of lowered effective refractory period could be distinguished from their surroundings in simulated scenarios with successfully induced multi-wavelet re-entry. Larger areas and higher gradients in effective refractory period as well as complex activation patterns favour the method. The 25% quantile of cycle lengths in patients with persistent atrial fibrillation was found to range from 85 to 190 ms. CONCLUSION: Cycle length mapping is capable of highlighting regions of pathologic refractory properties. In combination with complementary substrate mapping approaches, the method fosters confidence to enhance the treatment of atrial fibrillation beyond pulmonary vein isolation particularly in patients with complex activation patterns.