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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.

Heart failure (HF) post-myocardial infarction (MI) presents with increased vulnerability to monomorphic ventricular tachycardia (mmVT). To appropriately evaluate new therapies for infarct-mediated reentrant arrhythmia in the preclinical setting, chronologic characterization of the preclinical animal model pathophysiology is critical. This study aimed to evaluate the rigor and reproducibility of mmVT incidence in a rodent model of HF. We hypothesize a progressive increase in the incidence of mmVT as the duration of HF increases. Adult male Sprague-Dawley rats underwent permanent left coronary artery ligation or SHAM surgery and were maintained for either 6 or 10 wk. At end point, SHAM and HF rats underwent echocardiographic and invasive hemodynamic evaluation. Finally, rats underwent electrophysiologic (EP) assessment to assess susceptibility to mmVT and define ventricular effective refractory period (ERP). In 6-wk HF rats (n = 20), left ventricular (LV) ejection fraction (EF) decreased (P < 0.05) and LV end-diastolic pressure (EDP) increased (P < 0.05) compared with SHAM (n = 10). Ten-week HF (n = 12) revealed maintenance of LVEF and LVEDP (P > 0.05), (P > 0.05). Electrophysiology studies revealed an increase in incidence of mmVT between SHAM and 6-wk HF (P = 0.0016) and ERP prolongation (P = 0.0186). The incidence of mmVT and ventricular ERP did not differ between 6- and 10-wk HF (P = 1.0000), (P = 0.9831). Findings from this rodent model of HF suggest that once the ischemia-mediated infarct stabilizes, proarrhythmic deterioration ceases. Within the 6- and 10-wk period post-MI, no echocardiographic, invasive hemodynamic, or electrophysiologic changes were observed, suggesting stable HF. This is the necessary context for the evaluation of experimental therapies in rodent HF. NEW & NOTEWORTHY Rodent model of ischemic cardiomyopathy exhibits a plateau of inducible monomorphic ventricular tachycardia incidence between 6 and 10 wk postinfarction.

Antiarrhythmic drugs remain the mainstay therapy for patients with atrial fibrillation (AF). A major disadvantage of the currently available anti-AF agents is the risk of induction of ventricular proarrhythmias. Aiming to reduce this risk, several atrial-specific or -selective ion channel block approaches have been introduced for AF suppression, but only the atrial-selective inhibition of the sodium channel has been demonstrated to be valid in both experimental and clinical studies. Among the other pharmacological anti-AF approaches, “upstream therapy” has been prominent but largely disappointing, and pulmonary delivery of anti-AF drugs seems to be promising. Major contradictions exist in the literature about the electrophysiological mechanisms of AF (ie, reentry or focal?) and the mechanisms by which anti-AF drugs terminate AF, making the search for novel anti-AF approaches largely empirical. Drug-induced termination of AF may or may not be associated with prolongation of the atrial effective refractory period. Anti-AF drug research has been largely based on the “suppress reentry” ideology; however, results of the AF mapping studies increasingly indicate that nonreentrant mechanism(s) plays an important role in the maintenance of AF. Also, the analysis of anti-AF drug-induced electrophysiological alterations during AF, conducted in the current study, leans toward the focal source as the prime mechanism of AF maintenance. More effort should be placed on the investigation of pharmacological suppression of the focal mechanisms.

Increased late sodium current (INa) induces long QT syndrome 3 with increased risk of atrial fibrillation (AF). The role of atrial late INa in the induction of AF and in the treatment of AF was determined in this study. AF parameters were measured in isolated rabbit hearts exposed to late INa enhancer and inhibitors. Late INa from isolated atrial and ventricular myocytes were measured using whole-cell patch-clamp techniques. We found that induced-AF by programmed S1S2 stimulation and spontaneous episodes of AF were recorded in hearts exposed to either low (0.1-3 nM) or high (3-10 nM) concentrations of ATX-II (n = 10). Prolongations in atrial monophasic action potential duration at 90% completion of repolarization and effective refractory period by ATX-II (0.1-15 nM) were greater in hearts paced at slow than at fast rates (n = 5-10, P < 0.05). Both endogenous and ATX-II-enhanced late INa density were greater in atrial than that in ventricular myocytes (n = 9 and 8, P < 0.05). Eleclazine and ranolazine reduced AF window and AF burden in association with the inhibition of both endogenous and enhanced atrial late INa with half maximal inhibitory concentrations (IC50) of 1.14 and 9.78, and 0.94 and 8.31 μM, respectively. The IC50s for eleclazine and ranolazine to inhibit peak INa were 20.67 and 101.79 μM, respectively, in atrial myocytes. In conclusion, enhanced late INa in atrial myocytes increases the susceptibility for AF. Inhibition of either endogenous or enhanced late INa, with increased atrial potency of drugs is feasible for the treatment of AF.

Aims Systemic inflammation and increased activity of atrial NOX2-containing NADPH oxidases have been associated with the new onset of atrial fibrillation (AF) after cardiac surgery. In addition to lowering LDL-cholesterol, statins exert rapid anti-inflammatory and antioxidant effects, the clinical significance of which remains controversial. Methods and results We first assessed the impact of cardiac surgery and cardiopulmonary bypass (CPB) on atrial nitroso-redox balance by measuring NO synthase (NOS) and GTP cyclohydrolase-1 (GCH-1) activity, biopterin content, and superoxide production in paired samples of the right atrial appendage obtained before (PRE) and after CPB and reperfusion (POST) in 116 patients. The effect of perioperative treatment with atorvastatin (80 mg once daily) on these parameters, blood biomarkers, and the post-operative atrial effective refractory period (AERP) was then evaluated in a randomized, double-blind, placebo-controlled study in 80 patients undergoing cardiac surgery on CPB. CPB and reperfusion led to a significant increase in atrial superoxide production (74% CI 71–76%, n = 46 paired samples, P, Graphical Abstract

Development and progression of atrial fibrillation (AF) is driven by comorbidities such as arterial hypertension and diabetes mellitus. In animal models of chronic hyperglycaemia, progression of AF has been proposed to be triggered by oxidative stress, apoptosis and fibrosis. Acute glycosylation of CaMKII has been associated with increased susceptibility to arrhythmias in acute hyperglycaemia. However, the proarrhythmogenic effect of acute hyperglycaemia has not been investigated. Nine healthy, anesthetized pigs (54 ± 6 kg) were instrumented with electrophysiologic catheters and a multielectrode array on the epicardium of the left atrial anterior wall. Left and right atrial effective refractory periods (AERP), inducibility of AF and left atrial epicardial conduction velocities (CV) were measured at baseline (BL), increasing steps of blood glucose (200–500 mg/dL in steps of 100 mg/dL by glucose infusion) and repeated after normalisation of blood glucose levels (recovery). Serum electrolytes were kept constant during measurements by means of sodium and potassium infusion. There were no significant differences in AERP, CV or AF inducibility between BL and recovery. Heart rate remained constant regardless of blood glucose levels (BL: 103 ± 18 bpm, 500 mg/dL: 103 ± 18 bpm, r = 0.02, p = 0.346). Mean left as well as right AERP increased with higher glucose levels. CV increased with glucose levels (1.25 (1.04, 1.67) m/s at BL vs. 1.53 (1.22, 2.15) m/s at 500 mg/dL, r = 0.85, p = 0.034). Rate of AF inducibility in the left atrium remained constant throughout the whole protocol (AF episodes > 10 s: mean inducibility of 80% at BL vs. 69% at 500 mg/dL, p = 0.32, episodes > 30 s: 0% at BL vs. 0% at 500 mg/dL, p = 0.17). Our data imply that acute hyperglycaemia is associated with lower arrhythmogenic substrate and does not promote AF inducibility.

The ever-increasing incidence of obesity and related disorders impose serious challenges on public health worldwide. Brown adipose tissue (BAT) has strong capacity for promoting energy expenditure and has shown great potential in treating obesity. Exosomes are nanovesicles that share the characteristics of their donor cells. Whether BAT derived exosomes (BAT-Exos) might exert similar metabolic benefits on obesity is worthy of investigation. Methods: Obese mice were established by high-fat-diet (HFD) feeding and were treated with Seum-Exos or BAT-Exos isolated from young healthy mice. Blood glucose, glucose tolerance and blood lipids were tested in mice with indicated treatments. Histology examinations were performed on adipose tissue, liver and heart by HE staining and/or Oil Red O staining. Echocardiography was performed to evaluate cardiac function of mice. In vivo distribution of exosomes was analyzed by fluorescence labeling and imaging and in vitro effects of exosomes were evaluated by cell metabolism analysis. Protein contents of BAT-Exos were analyzed by mass spectrometry. Results: The results showed that BAT-Exos reduced the body weight, lowered blood glucose and alleviated lipid accumulation in HFD mice independently of food intake. Echocardiography revealed that the abnormal cardiac functions of HFD mice were significantly restored after treatment with BAT-Exos. Cell metabolism analysis showed that treatment with BAT-Exos significantly promoted oxygen consumption in recipient cells. Protein profiling of exosomes demonstrated that BAT-Exos were rich in mitochondria components and involved in catalytic processes. Conclusions: Collectively, our study showed that BAT-Exos significantly mitigated the metabolic syndrome in HFD mice. Detailed elucidation of the reactive molecules and mechanism of action would provide new insights in combating obesity and related disorders.

Surrogates for the shortest pre-excited R-R interval in atrial fibrillation (SPERRI) such as the accessory pathway effective refractory period (APERP) and shortest pre-excited paced cycle length (SPPCL) are flawed assessments of accessory pathway function in patients with WPW. Multi-extrastimulus pacing may have the theoretical advantage of more accurately mimicking the clinical reality of atrial fibrillation and thus may serve to better assess accessory pathway function. This cross-sectional study included 25 consecutive patients, aged ≤ 18 years, undergoing electrophysiology study for WPW. The longest S1S2, S2S3, S3S4 coupling intervals at which the antegrade AP refractoriness occurred, SPERRI, and SPPCL were recorded. Induction of atrial fibrillation was attempted in all patients and induced in 8 (32%, 4 SPERRIbaseline (265 ms ± 61 ms), 4 SPERRIIsuprel (258 ms ± 41 ms)). At baseline, the lower value of the S3ERP or S4ERP (274 ms ± 52 ms) was lower than the SPPCL (296 ms ± 54 ms, p

Introduction Intra-atrial conduction abnormalities are associated with the development of atrial fibrillation (AF) and cause morphological changes of the unipolar atrial electrogram (U-AEGM). This study examined the impact of different atrial programmed electrical stimulation (APES) protocols on U-AEGM morphology to identify the most optimal APES protocol provoking conduction abnormalities. Methods APES techniques (14 protocols) were applied in 30 patients referred for an electrophysiology study, consisting of fixed rate, extra, and decremental stimuli at different frequencies. U-AEGM morphologies including width, amplitude, and fractionation for patients without (control group) and with a history of AF (AF group) were examined during APES. In addition, sinus rhythm (SR) U-AEGMs preceding different APES protocols were compared to evaluate the morphology stability over time. Results U-AEGM morphologies during SR before the APES protocols were comparable (all P > .396). Atrial refractoriness was longer in the AF group compared to the control group (298 ± 48 vs 255 ± 33 ms; P ≤ .020), but did not differ between AF patients with and without amiodarone therapy (278 ± 48 vs 311 ± 40 ms; P ≥ .126). Compared to the initial SR morphology, U-AEGM width, amplitude, and fractionation changed significantly during the 14 different APES protocols, particularly in the AF group. In both groups, U-AEGM changes in morphology were most pronounced during fixed-rate stimulation with extra stimuli (8S1-S2 = 400-250 ms). Conclusion APES results in significant changes in U-AEGM morphology, including width, amplitude, and fractionation. The impact of APES differed between APES sequence and between patients with and without AF. These findings suggest that APES could be useful to identify AF-related conduction abnormalities in the individual patient.

To study patients with sporadic inclusion body myositis (sIBM) with muscle velocity recovery cycles (MVRC) to assess muscle membrane excitability, pathophysiological mechanisms and potential biomarkers of this disorder.MVRC were recorded from 20 individuals with sIBM from tibialis anterior (TA) and rectus femoris (RF) muscles. Excitability parameters were compared with MVRC data obtained from 22 normal controls50 years.Muscle relative refractory period was prolonged in both TA (6.4 ms vs 4.4 ms, P 0.001) and RF (7.1 ms vs 3.9 ms, P 0.001) of sIBM affected muscle when compared to controls. Early supernormality was reduced in both TA (3.6% vs 8.8% P = 0.001) and in RF (mean 5.4% vs 13% P 0.001). Late supernormality was only decreased significantly in sIBM affected TA (1.8% vs 3.6% P = 0.001) but not in RF. No consistent correlations between MVRC parameters and clinical markers of sIBM disease severity were found.The resting sarcolemmal muscle membrane potential of sIBM muscle is depolarized relative to that of normal controls, which may be related to intramuscular amyloid deposition in sIBM.Sarcolemmal depolarization may play a role in muscle dysfunction and weakness observed in sIBM patients.

So far, there is no consistent and convincing theory explaining the pathogenesis of migraines. Vascular disorders, the effect of oxidative stress on neurons, and the contribution of magnesium-calcium deficiencies in triggering cortical depression and abnormal glutaminergic neurotransmission are taken into account. However, there are no reliable publications confirming the role of dietary deficits of magnesium and latent tetany as factors triggering migraine attacks. The aim of the study was to evaluate the influence of latent magnesium deficiency assessed with the electrophysiological tetany test on the course of migraine. The study included: a group of 35 patients (29 women and six men, in mean age 41 years) with migraine and a control group of 24 (17 women and seven men, in mean age 39 years) healthy volunteers. Migraine diagnosis was based on the International Headache Society criteria, 3rd edition. All patients and controls after full general and neurological examination were subjected to a standard electrophysiological ischemic tetany test. Moreover, the level of magnesium in blood serum was tested and was in the normal range in all patients. Then, the incidence of a positive tetany EMG test results in the migraine group and the results in the subgroups with and without aura were compared to the results in the control group. Moreover, the relationship between clinical markers of spasmophilia and the results of the tetany test was investigated in the migraine group. As well as the relationship between migraine frequency and tetany test results. There was no statistically significant difference in the occurrence of the electrophysiological exponent of spasmophilia between the migraine and control group. Neither correlation between the occurrence of clinical symptoms nor the frequency of migraine attacks and the results of the tetany test was stated (p &gt, 0.05). However, there was an apparent statistical difference between the subgroup of migraine patients with aura in relation to the control group (p &lt, 0.05). The result raises hope to find a trigger for migraine attacks of this clinical form, the more that this factor may turn out to be easy to supplement with dietary supplementation.

Arrhythmogenic ingredients in our diet such as mushrooms, licorice, toxic honey, liquid protein drinks, etc. have long been recognized as rare but important considerations in the differential diagnosis of arrhythmias. Anecdotal reports of torsades de pointes (TdP), arrhythmias and/or sudden death and small studies in normal subjects have suggested that simple ingredients such as grapefruit juice or ingredients in energy drinks marketed as dietary supplements could have direct arrhythmogenic actions, especially in patients with congenital long QT syndrome (cLQTS). Two recent studies that employed the industry-standard "thorough QT" trial design leave no doubt that grapefruit juice and some energy drinks can prolong the QTc interval and to exceed 500 msec. in some patients with cLQTS, a threshold known to signal imminent danger. These reports raise numerous clinically important questions such as which other patients may be at risk of arrhythmias. For example, patients with multiple clinical risk factors for TdP (hypokalemia, bradycardia, female sex, etc.) may be at risk from these and possibly other dietary ingredients ingested by millions of people each day. It is essential that further research evaluate the safety of these and similar food products and that vulnerable patients, especially those with cLQTS, be warned of this serious and emerging threat.

BACKGROUND A diagnosis of silent paroxysmal atrial fibrillation (AF) is highly challenging due to its asymptomatic and intermittent nature. The goal of the present study was to clarify its asymptomaticity with the use of a comprehensive electrophysiological approach. METHODS We prospectively compared (a) 24-hour Holter monitoring data, (b) invasive cardiac electrophysiological properties, (c) AF inducibility, and (d) outcome of radiofrequency catheter ablation between patients with symptomatic paroxysmal AF and those with silent paroxysmal AF, defined as transient asymptomatic AF detected by chance. RESULTS Patients with silent paroxysmal AF (N = 57) were more likely than patients with symptomatic paroxysmal AF (N = 282) to be male (75.4% vs 56.7%; P = .009), and to have a previous stroke (17.5% vs 6.7%; P = .008), more prolonged atrio-His interval (114.9 ± 29.1 vs 105.5 ± 24.1 ms; P = .01), longer atrioventricular nodal effective refractory period (352.3 ± 103 vs 318.2 ± 77.2 ms; P = .007), slower Wenckebach cycle length (488.5 ± 83.9 vs 443.3 ± 74.9 ms; P

INTRODUCTION The sarcolemmal resting membrane potential (RMP) affects muscle excitability, contractility, and force generation. However, there are limited In vivo data on the normal RMP of the human sarcolemma between muscles. We hypothesize that the in vivo RMP may differ between human muscles with different physiological roles. METHODS Muscle velocity recovery cycles were recorded from a proximal antigravity muscle, the rectus femoris, and compared with paired recordings from a distal non-antigravity muscle, the tibialis anterior, in 34 normal individuals. RESULTS Significant differences in muscle relative refractory period (3.55 millseconds vs 3.87 milliseconds, P = .002), early supernormality (14.22% vs 10.50%, P

Ranolazine has been found to prevent ventricular arrhythmias (VAs) during acute myocardial infarction (AMI). This study aimed to investigate its efficacy on VAs induced several days post-MI. For this purpose, 13 anesthetized rabbits underwent coronary artery ligation. Ten of these animals that survived AMI were reanesthetized 3 to 7 days later for electrophysiologic testing. An endocardial monophasic action potential combination catheter was placed in the right ventricle for simultaneous pacing and recording. Monophasic action potential duration, ventricular effective refractory period (VERP), and VAs induced by programmed stimulation were assessed. Measurements were performed during control pacing, and following an intravenous infusion of either a low-dose ranolazine (2.4 mg/kg, R1) or a higher dose ranolazine (4.8 mg/kg cumulative dose, R2). During control stimulation, 2 animals developed primary ventricular fibrillation (VF), 6 sustained ventricular tachycardia (sVT), and 2 nonsustained VT (nsVT). R1 did not prevent the appearance of VAs in any of the experiments; in contrast, it aggravated nsVT into sVT and complicated sVT termination in 2 of 6 animals. Sustained ventricular tachycardia cycle length and VERP were only slightly decreased after R1 (112 ± 5 vs 110 ± 6 ms and 101 ± 11 vs 98 ± 10 ms, respectively). R2 suppressed inducibility of control nsVT, VF, and sVT in 2 animals. In 4 animals with still inducible sVT, R2 significantly prolonged VT cycle length by 150 ± 23 ms ( P < .01), and VERP by 120 ± 7 ms ( P < .001) versus control. In conclusion, R2 exerted antiarrhythmic efficacy against subacute-MI VAs, whereas R1 rather aggravated than prevented these arrhythmias. Ventricular effective refractory period prolongation could partially explain the antiarrhythmic action of R2 in this rabbit model.

Exploratory research OBJECTIVES: Cutaneous silent periods (CSPs) that reflect the inhibitory spinal cord reflex, can sensitively detect spinal cord dysfunction, and contribute to the diagnosis of degenerative cervical myelopathy (DCM). However, CSP changes after DCM surgery related to functional improvement have not been reported.University hospital in Nankoku, Japan METHODS: CSP recorded at four time points-before surgery, 3, 6, 12 months after surgery-were investigated in 31 hands of 16 DCM patients. CSPs were categorized as follows: normal, delayed onset latency, shortened duration, onset delay with shortened duration, and absent CSP. Myelopathic symptoms were evaluated by the Japanese Orthopaedic Association score (JOA score).Normal CSPs were observed in five hands (16%) before surgery and six hands (19%) twelve months after surgery (P 0.05). Either onset delay or shortened duration or both were observed in 18 hands (58%) before surgery and 16 hands (52%) twelve months after surgery (P 0.05). Absent CSPs were observed in eight hands (26%) before surgery and nine hands (29%) twelve months after surgery (P 0.05). Measured values of onset latency and duration also did not change throughout the study period (P 0.05). On the other hand, JOA scores improved after surgery. (P = 0.003).CSP abnormalities persisted after surgery in most cases, indicating irreversible damage of the intramedullary reflex circuit. JOA score recovery without CSP recovery provides insight into postoperative neural recovery in DCM.

Background The multiple wavelets and functional re-entry hypotheses are mechanistic theories to explain atrial fibrillation (AF). If valid, a chamber's ability to support AF should depend upon the left atrial size, conduction velocity (CV), and refractoriness. Measurement of these parameters could provide a new therapeutic target for AF. We investigated the relationship between left atrial effective conducting size (LAECS), a function of area, CV and refractoriness, and AF vulnerability in patients undergoing AF ablation. Methods and Results Activation mapping was performed in patients with paroxysmal (n = 21) and persistent AF (n = 18) undergoing pulmonary vein isolation. Parameters used for calculating LAECS were: (a) left atrial body area (A); (b) effective refractory period (ERP); and (c) total activation time (T). Global CV was estimated as √A/T. Effective atrial conducting size was calculated as LAECS = A/(CV × ERP). Post ablation, AF inducibility testing was performed. The critical LAECS required for multiple wavelet termination was determined from computational modeling. LAECS was greater in patients with persistent vs paroxysmal AF (4.4 ± 2.0 cm vs 3.2 ± 1.4 cm; P = .049). AF was inducible in 14/39 patients. LAECS was greater in AF-inducible patients (4.4 ± 1.8 cm vs 3.3 ± 1.7 cm; P = .035, respectively). The difference in LAECS between inducible and noninducible patients was significant in patients with persistent (P = .0046) but not paroxysmal AF (P = .6359). Computational modeling confirmed that LAECS > 4 cm was required for continuation of AF. Conclusions LAECS measured post ablation was associated with AF inducibility in patients with persistent, but not paroxysmal AF. These data support a role for this method in electrical substrate assessment in AF patients.

Objectives The mechanisms underlying age-related changes in speech perception are still unclear, most likely multifactorial and often can be difficult to parse out from the effects of hearing loss. Age-related changes in temporal resolution (i.e., the ability to track rapid changes in sounds) have long been associated with speech perception declines exhibited by many older individuals. The goals of this study were as follows: (1) to assess age-related changes in temporal resolution in cochlear implant (CI) users, and (2) to examine the impact of changes in temporal resolution and cognition on the perception of speech in noise. In this population, it is possible to bypass the cochlea and stimulate the auditory nerve directly in a noninvasive way. Additionally, CI technology allows for manipulation of the temporal properties of a signal without changing its spectrum. Design Twenty postlingually deafened Nucleus CI users took part in this study. They were divided into groups of younger (18 to 40 years) and older (68 to 82 years) participants. A cross-sectional study design was used. The speech processor was bypassed and a mid-array electrode was used for stimulation. We compared peripheral and central physiologic measures of temporal resolution with perceptual measures obtained using similar stimuli. Peripherally, temporal resolution was assessed with measures of the rate of recovery of the electrically evoked compound action potential (ECAP), evoked using a single pulse and a pulse train as maskers. The acoustic change complex (ACC) to gaps in pulse trains was used to assess temporal resolution more centrally. Psychophysical gap detection thresholds were also obtained. Cognitive assessment included two tests of processing speed (Symbol Search and Coding) and one test of working memory (Digit Span Test). Speech perception was tested in the presence of background noise (QuickSIN test). A correlational design was used to explore the relationship between temporal resolution, cognition, and speech perception. Results The only metric that showed significant age effects in temporal processing was the ECAP recovery function recorded using pulse train maskers. Younger participants were found to have faster rates of neural recovery following presentation of pulse trains than older participants. Age was not found to have a significant effect on speech perception. When results from both groups were combined, digit span was the only measure significantly correlated with speech perception performance. Conclusions In this sample of CI users, few effects of advancing age on temporal resolution were evident. While this finding would be consistent with a general lack of aging effects on temporal resolution, it is also possible that aging effects are influenced by processing peripheral to the auditory nerve, which is bypassed by the CI. However, it is known that cross-fiber neural synchrony is improved with electrical (as opposed to acoustic) stimulation. This change in neural synchrony may, in turn, make temporal cues more robust/perceptible to all CI users. Future studies involving larger sample sizes should be conducted to confirm these findings. Results of this study also add to the growing body of literature that suggests that working memory is important for the perception of degraded speech.

A post hoc analysis of the PALLAS trial suggested life-threatening interactions of digitalis and dronedarone. Thus, there is concern about an interplay between digitalis and other drugs that influence cardiac electrophysiology. We therefore investigated the interaction between digitalis and flecainide or ranolazine. Twenty-five rabbit hearts were Langendorff-perfused and treated with flecainide (2 µM, 12 hearts) or ranolazine (10 µM, 13 hearts). Infusion of flecainide prolonged mean action potential duration [APD90, from 153 ms (interquartile range (IQR): 29.7 ms) to 159 ms (IQR: 24.9 ms, p = 0.04)] and effective refractory period [ERP, 170 ms (IQR: 40 ms) vs. 200 ms (IQR: 32.5 ms, p

Knowledge of the refractory properties of auditory-nerve fibers (ANFs) is required for understanding the transduction of the graded membrane potential of the receptor cells into spike trains. The refractory properties inferred when ANFs are excited by electrical stimulation might differ from those present when ANFs are excited naturally by transmitter release from receptor cells. As a proxy for the latter, we investigated the recovery of spike amplitude with time since the previous spike in long extracellular recordings of the activity of individual ANFs from anesthetized Mongolian gerbils. Voltage traces were filtered minimally to avoid distortions of spike amplitude and timing. The amplitude of each spike was defined as the difference between its peak voltage and an extrapolated instantaneous reference voltage at the time of the peak. Spike amplitude was normalized to that of the previous spike to exclude effects of long-term changes in recording conditions. To ensure that the amplitude of the first spike in each pair was fully recovered, each spike pair was used only when preceded by an interspike interval of at least 5 ms. We find that the recovery of spike amplitude is well described by a short dead time followed by a double-exponential recovery function. Total recovery times were short (median: 0.85 ms; interquartile range: 0.74–1.00 ms) and independent of the ANF's characteristic frequency and spontaneous rate, but they increased weakly with increasing mean rate. We emphasize the differences between the recovery of spike amplitude, the recovery of spike probability from postsynaptic refractoriness, and the recovery of spike probability as reflected in the hazard-rate function. Our findings are inconsistent with the long refractory periods assumed in some models, but are consistent with the brief refractoriness assumed in the synapse model of Peterson and Heil (2018), which reproduces the stochastic properties of stationary spontaneous and sound-driven ANF spike trains.

The aim was to investigate the role of the α7nAChR-mediated cholinergic anti-inflammatory pathway in vagal nerve regulated atrial fibrillation (AF).18 beagles (standard dogs for testing) were used in this study, and the effective refractory period (ERP) of atrium and pulmonary veins and AF inducibility were measured hourly during rapid atrial pacing at 800 beats/minute for 6 hours in all beagles. After cessation of 3 hours of RAP, the low-level vagal nerve stimulation (LL-VNS) group (n = 6) was given LL-VNS and injection of salinne (0.5 mL/GP) into four GPs, the methyllycaconitine (MLA, the antagonist of α7nAChR) group (n = 6) was given LL-VNS and injection of MLA into four GPs, and the Control group (n = 6) was given saline into four GPs and the right cervical vagal nerve was exposed without stimulation. Then, the levels of the tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), acetylcholine (ACh), STAT3, and NF-κB proteins were measured. During the first 3 hours of RAP, the ERPs gradually decreased while the dispersion of ERPs (dERPs) and AF inducibility gradually increased in all three groups. During the last 3 hours of 6 hours' RAP in this study, the ERPs in the LL-VNS group were higher, while the dERPs and AF inducibility were significantly lower when compared with the Control and MLA groups at the same time points. The levels of ACh in the serum and atrium in the LL-VNS and MLA groups were higher than in the Control group, and the levels of TNF-α and IL-6 were higher in the Control and MLA groups than in the LL-VNS group. The concentrations of STAT3 in RA and LA tissues were higher in the LL-VNS group while those of NF-κB were lower.In conclusion, the cholinergic anti-inflammatory pathway mediated by α7nACh plays an important role in low-level vagal nerve-regulated AF.

Electrical stimulation of the enteric nervous system (ENS) is an attractive approach to modify gastrointestinal transit. Colonic motor complexes (CMCs) occur with a periodic rhythm, but the ability to elicit a premature CMC depends, at least in part, upon the intrinsic refractory properties of the ENS, which are presently unknown. The objectives of this study were to record myoelectric complexes (MCs, the electrical correlates of CMCs) in the smooth muscle and 1) determine the refractory periods of MCs, 2) inform and evaluate closed-loop stimulation to repetitively evoke MCs, and 3) identify stimulation methods to suppress MC propagation. We dissected the colon from male and female C57BL/6 mice, preserving the integrity of intrinsic circuitry while removing the extrinsic nerves, and measured properties of spontaneous and evoked MCs in vitro. Hexamethonium abolished spontaneous and evoked MCs, confirming the necessary involvement of the ENS for electrically evoked MCs. Electrical stimulation reduced the mean interval between evoked and spontaneous CMCs (24.6 ± 3.5 vs. 70.6 ± 15.7 s, P = 0.0002, n = 7). The absolute refractory period was 4.3 s (95% confidence interval (CI) = 2.8–5.7 s, R(2) = 0.7315, n = 8). Electrical stimulation applied during fluid distention-evoked MCs led to an arrest of MC propagation, and following stimulation, MC propagation resumed at an increased velocity (n = 9). The timing parameters of electrical stimulation increased the rate of evoked MCs and the duration of entrainment of MCs, and the refractory period provides insight into timing considerations for designing neuromodulation strategies to treat colonic dysmotility. NEW & NOTEWORTHY Maintained physiological distension of the isolated mouse colon induces rhythmic cyclic myoelectric complexes (MCs). MCs evoked repeatedly by closed-loop electrical stimulation entrain MCs more frequently than spontaneously occurring MCs. Electrical stimulation delivered at the onset of a contraction temporarily suppresses the propagation of MC contractions. Controlled electrical stimulation can either evoke MCs or temporarily delay MCs in the isolated mouse colon, depending on timing relative to ongoing activity.

Background Metoclopramide (MCP) is a dopamine D2 -receptor antagonist, mainly used to treat post-operative or chemotherapy-induced nausea. While it is very effective in the cure of gastric symptoms, MCP can cause severe neurologic side effects. Furthermore, there is growing evidence for severe arrhythmic side effects resulting from inhibitory effects on cardiac sodium and potassium channels. Methods and results Thirteen hearts of New Zealand white rabbits were retrogradely perfused, and electrophysiology studies were performed to obtain action potential duration (APD90 ) and effective refractory period (ERP). After generating baseline data, the hearts were perfused with increasing concentrations of metoclopramide (MCP 10 µM, MCP 50 µM, MCP 100 µM) and the standardized protocol was repeated for each concentration. Perfusion with MCP resulted in a significant prolongation of APD90 and QT interval. In parallel, the incidence of ventricular tachycardias was significantly increased by high doses of MCP. Conclusion This is the first experimental study that investigated the effect of increasing doses of metoclopramide on a sensitive whole-heart model of proarrhythmia. MCP led to a significant increase in action potential duration and QT interval; meanwhile, the number of ventricular tachycardias was significantly increased.

Patients diagnosed with the same subtype of atrial fibrillation according to our current classification system may differ in symptom severity, severity of the arrhythmogenic substrate, and response to antiarrhythmic therapy. Hence, there is a need for an electrical biomarker as an indicator of the arrhythmogenic substrate underlying atrial fibrillation enabling patient‐tailored therapy. The aim of this review is to investigate whether atrial refractoriness, a well‐known electrophysiological parameter that is affected by electrical remodeling, can be used as an electrical biomarker of the arrhythmogenic substrate underlying atrial fibrillation. We discuss methodologies of atrial effective refractory period assessment, identify which changes in refractoriness‐related parameters reflect different degrees of electrical remodeling, and explore whether these parameters can be used to predict clinical outcomes.

The contraction of myotubes using electrical pulse stimulation is a research tool used to mimic muscle contractile activity and exercise in rodents and humans. Most protocols employed in previous work used low-frequency twitch contractions. However, high-frequency tetanus contractions that are more physiologically relevant to muscle contractions in vivo are poorly characterized. In this report, the similarities and differences in acute responses and chronic adaptations with different contractile modes using twitches (2 Hz, continuous, 3 h) and tetanus (66 Hz, on: 5 s/off: 5 s, 3 h) were investigated. RNA sequencing-based transcriptome analysis and subsequent bioinformatics analysis suggest that tetanus may promote bioenergetic remodeling rather than twitch. Based on in silico analyses, metabolic remodeling after three contractile sessions of twitch and tetanus were investigated. Although twitch and tetanus had no significant effect on glycolysis, both types of contraction upregulated glucose oxidation capacity. Both twitch and tetanus qualitatively caused mitochondrial adaptations (increased content, respiratory chain enzyme activity, and respiratory function). The magnitude of adaptation was much greater under tetanus conditions. Our findings indicate that the contraction of myotubes by tetanus may be a useful experimental model, especially in the study of metabolic adaptations in C

Human ether-à-go-go related gene (hERG) K

Aims Hutchinson–Gilford progeria syndrome (HGPS) is an ultrarare laminopathy caused by expression of progerin, a lamin A variant, also present at low levels in non-HGPS individuals. HGPS patients age and die prematurely, predominantly from cardiovascular complications. Progerin-induced cardiac repolarization defects have been described previously, although the underlying mechanisms are unknown. Methods and results We conducted studies in heart tissue from progerin-expressing LmnaG609G/G609G (G609G) mice, including microscopy, intracellular calcium dynamics, patch-clamping, in vivo magnetic resonance imaging, and electrocardiography. G609G mouse cardiomyocytes showed tubulin-cytoskeleton disorganization, t-tubular system disruption, sarcomere shortening, altered excitation–contraction coupling, and reductions in ventricular thickening and cardiac index. G609G mice exhibited severe bradycardia, and significant alterations of atrio-ventricular conduction and repolarization. Most importantly, 50% of G609G mice had altered heart rate variability, and sinoatrial block, both significant signs of premature cardiac aging. G609G cardiomyocytes had electrophysiological alterations, which resulted in an elevated action potential plateau and early afterdepolarization bursting, reflecting slower sodium current inactivation and long Ca+2 transient duration, which may also help explain the mild QT prolongation in some HGPS patients. Chronic treatment with low-dose paclitaxel ameliorated structural and functional alterations in G609G hearts. Conclusions Our results demonstrate that tubulin-cytoskeleton disorganization in progerin-expressing cardiomyocytes causes structural, cardiac conduction, and excitation–contraction coupling defects, all of which can be partially corrected by chronic treatment with low dose paclitaxel., Graphical Abstract

The mechanisms underlying atrial-selective prolongation of effective refractory period (ERP) and suppression of atrial fibrillation (AF) by NS8593 and UCL1684, small conductance calcium-activated potassium (SK) channel blockers, are poorly defined. The purpose of the study was to confirm the effectiveness of these agents to suppress AF and to probe the underlying mechanisms. Transmembrane action potentials and pseudoelectrocardiograms were recorded from canine isolated coronary-perfused canine atrial and ventricular wedge preparations. Patch clamp techniques were used to record sodium channel current (INa) in atrial and ventricular myocytes and human embryonic kidney cells. In both atria and ventricles, NS8593 (3-10 µM) and UCL1684 (0.5 µM) did not significantly alter action potential duration, suggesting little to no SK channel inhibition. Both agents caused atrial-selective: (1) prolongation of ERP secondary to development of postrepolarization refractoriness, (2) reduction of Vmax, and (3) increase of diastolic threshold of excitation (all are sodium-mediated parameters). NS8593 and UCL1684 significantly reduced INa density in human embryonic kidney cells as well as in atrial but not in ventricular myocytes at physiologically relevant holding potentials. NS8593 caused a shift of steady-state inactivation to negative potentials in atrial but not ventricular cells. NS8593 and UCL1684 prevented induction of acetylcholine-mediated AF in 6/6 and 8/8 preparations, respectively. This anti-AF effect was associated with strong rate-dependent depression of excitability. The SK channel blockers, NS8593 and UCL1684, are effective in preventing the development of AF due to potent atrial-selective inhibition of INa, causing atrial-selective prolongation of ERP secondary to induction of postrepolarization refractoriness.

Background: Repolarization alternans (RA) has been implicated in the pathogenesis of ventricular arrhythmias and sudden cardiac death. Methods: We have developed a real-time, closed-loop system to record and analyze RA from multiple intracardiac leads, and deliver dynamically R-wave triggered pacing stimuli during the absolute refractory period. We have evaluated the ability of this system to control RA and reduce arrhythmia susceptibility, in vivo. Results: R-wave triggered pacing can induce RA, the magnitude of which can be modulated by varying the amplitude, pulse width, and size of the pacing vector. Using a swine model (n=9), we demonstrate that to induce a 1 µV change in the alternans voltage on the body surface, coronary sinus and left ventricle leads, requires a delivered charge of 0.04±0.02, 0.05±0.025, and 0.06±0.033 µC, respectively, while to induce a one unit change of the K score , requires a delivered charge of 0.93±0.73, 0.32±0.29, and 0.33±0.37 µC, respectively. For all body surface and intracardiac leads, both Δ(alternans voltage) and ΔK score between baseline and R-wave triggered paced beats increases consistently with an increase in the pacing pulse amplitude, pulse width, and vector spacing. Additionally, we show that the proposed method can be used to suppress spontaneously occurring alternans (n=7), in the presence of myocardial ischemia. Suppression of RA by pacing during the absolute refractory period results in a significant reduction in arrhythmia susceptibility, evidenced by a lower S rank score during programmed ventricular stimulation compared with baseline before ischemia. Conclusions: We have developed and evaluated a novel closed-loop method to dynamically modulate RA in a swine model. Our data suggest that suppression of RA directly reduces arrhythmia susceptibility and reinforces the concept that RA plays a critical role in the pathophysiology of arrhythmogenesis.

Background The tandem of P domains in a weak inward rectifying K+ channel (TWIK)‐related acid‐sensitive K + channel (TASK‐1; hK 2P 3.1) two‐pore–domain potassium channel was recently shown to regulate the atrial action potential duration. In the human heart, TASK ‐1 channels are specifically expressed in the atria. Furthermore, upregulation of atrial TASK ‐1 currents was described in patients suffering from atrial fibrillation ( AF ). We therefore hypothesized that TASK ‐1 channels represent an ideal target for antiarrhythmic therapy of AF . In the present study, we tested the antiarrhythmic effects of the high‐affinity TASK ‐1 inhibitor A293 on cardioversion in a porcine model of paroxysmal AF . Methods and Results Heterologously expressed human and porcine TASK ‐1 channels are blocked by A293 to a similar extent. Patch clamp measurements from isolated human and porcine atrial cardiomyocytes showed comparable TASK ‐1 currents. Computational modeling was used to investigate the conditions under which A293 would be antiarrhythmic. German landrace pigs underwent electrophysiological studies under general anesthesia. Paroxysmal AF was induced by right atrial burst stimulation. After induction of AF episodes, intravenous administration of A293 restored sinus rhythm within cardioversion times of 177±63 seconds. Intravenous administration of A293 resulted in significant prolongation of the atrial effective refractory period, measured at cycle lengths of 300, 400 and 500 ms, whereas the surface ECG parameters and the ventricular effective refractory period lengths remained unchanged. Conclusions Pharmacological inhibition of atrial TASK ‐1 currents exerts antiarrhythmic effects in vivo as well as in silico , resulting in acute cardioversion of paroxysmal AF . Taken together, these experiments indicate the therapeutic potential of A293 for AF treatment.

While vanoxerine (GBR-12909) is a synaptosomal dopamine uptake inhibitor, it also suppresses IKr, INa and ICa,L in vitro. Based on these profiles on ionic currents, vanoxerine has been developed as a candidate compound for treating atrial fibrillation. To investigate electropharmacological profiles, vanoxerine dihydrochloride was intravenously administered at 0.03 and 0.3 mg/kg to halothane-anesthetized dogs (n = 4), possibly providing subtherapeutic and therapeutic concentrations, respectively. The low dose increased the heart rate and cardiac output, whereas it prolonged the ventricular refractoriness. The high dose decreased the heart rate but increased the total peripheral vascular resistance, whereas it delayed the ventricular repolarization and increased the atrial refractoriness in addition to further enhancing the ventricular refractoriness. The extent of increase in the refractoriness in the atrium was 0.8 times of that in the ventricle. The high dose also prolonged the early and late repolarization periods of the ventricle as well as the terminal repolarization period. Meanwhile, no significant change was detected in the mean blood pressure, ventricular contraction, preload to the left ventricle, or the intra-atrial, intra-ventricular or atrioventricular conductions. The high dose can be considered to inhibit IKr, but it may not suppress INa or ICa in the in situ heart, partly explaining its poor atrial selectivity for increasing refractoriness. The prolongation of early repolarization period may reflect enhancement of net inward current, providing potential risk for intracellular Ca2+ overload. Thus, vanoxerine may provide both trigger and substrate toward torsade de pointes, which would make the drug less promising as an anti-atrial fibrillatory drug.

To compare the effects of class III antiarrhythmic agents (amiodarone vs. ibutilide) on ventricular fibrillation (VF) and hemodynamic status in a canine heart failure (HF) model.A total of 12 beagles were used to establish the HF model by rapid pacing for 4 consecutive weeks. These canines were randomly divided into two groups based on the administration of ibutilide and amiodarone. A 12 × 12 unipolar electrode plaque was used for ventricular epicardial mapping, and a 6-electrode plunge needle was inserted for ventricular transmural mapping. The restitution curve was estimated from activation recovery intervals (ARIs) by pacing from the plaque electrodes before and after drug administration. The defibrillation threshold (DFT) and VF activation patterns, including the activation rate, cycle length (VF-CL) and the transmural dispersion of the activation rate, were evaluated and the hemodynamic parameters were mearsured and compared before and after drug administration.Compared to HF baseline, ibutilide administration has markedly decreased the DFT by 28% (18 ± 2 J vs. 13 ± 2.7 J, P 0.01) without affecting the canine's hemodynamics (mean arterial pressure 91 ± 15 mmHg vs. 92 ± 17 mmHg, P 0.05). Furthermore, VF activation pattern became more organized, and spontaneous termination was observed only after ibutilide administration. Conversely, amiodarone has significantly compromised the hemodynamic status (mean arterial pressure 92 ± 6.1 mmHg vs. 52 ± 11.6 mmHg, P 0.05), but did not alter the DFT (17 ± 2.3 J vs. 16 ± 2.0 J, P 0.05). Compared to pre-medication, both ibutilide and amiodarone have significantly prolonged the VERP (178 ± 9.6 ms vs. 208 ± 8.9 ms, P 0.05; 185 ± 10.5 ms vs. 202 ± 7.5 ms, P 0.05, respectively) and reduced the dispersion of refractoriness, the maximal slope of restitution curve, and the epicardial dispersion during pacing. Additionally, both drugs have significantly increased the VF-CL and reduced the transmural dispersion of the VF activation rate.Ibutilide had potential antifibrillatory properties, which was shown by decreasing the DFT and organizing the VF activation in HF, and with no apparent impact on the hemodynamic status. In contrast, intravenous amiodarone administration demonstrated prominent negative effects on the hemodynamic status possibly by affecting the myocardial contractility before and after defibrillation but did not alter the DFT.

BACKGROUND Low-intensity focused ultrasound (LIFU) has been shown to be a beneficial tool for autonomic nervous system modulation, but its effect on the left stellate ganglion (LSG) remains unknown. OBJECTIVE To seek the effect of LIFU on myocardial infarction (MI)-induced LSG activation and ventricular arrhythmias (VAs). METHODS In this study, 20 dogs were included and randomly divided into the LIFU (LIFU & MI, n = 8), Sham (sham LIFU & MI, n = 8), and Control group (sham LIFU & sham MI, n = 4). For each LIFU intervention (1.0-2.0 W, 10 minutes) of the LSG, the LSG function, ventricular effective refractory period (ERP), and temperature were tested pre-intervention and postintervention. Thereafter, MI was induced by left anterior artery ligation and VAs were recorded for 1 hour. At the end, both the LSG and the heart were extracted for biomedical and histological analysis. RESULTS In the Sham group, no significant change was shown in ventricular ERP or LSG function for any intensity settings of sham LIFU intervention when compared with the group baseline. In the LIFU group, however, both 1.5 and 2.0 W LIFU modulation of LSG resulted in significant prolongation of ERP and attenuation of LSG function. Furthermore, the incidence of VAs was significantly attenuated in the LIFU group compared with the Sham group. Moreover, histological analysis showed that no damage or apoptosis was observed in LSG although a statistically significant increase was shown in temperature (maximal increase

cAMP is a positive regulator tightly involved in certain types of synaptic plasticity and related memory functions. However, its spatiotemporal roles at the synaptic and neural circuit levels remain elusive. Using a combination of a cAMP optogenetics approach and voltage-sensitive dye (VSD) imaging with electrophysiological recording, we define a novel capacity of postsynaptic cAMP in enabling dentate gyrus long-term potentiation (LTP) and depolarization in acutely prepared murine hippocampal slices. To manipulate cAMP levels at medial perforant path to granule neuron (MPP-DG) synapses by light, we generated transgenic (Tg) mice expressing photoactivatable adenylyl cyclase (PAC) in DG granule neurons. Using these Tg(CMV-Camk2a-RFP/bPAC)3Koka mice, we recorded field excitatory postsynaptic potentials (fEPSPs) from MPP-DG synapses and found that photoactivation of PAC during tetanic stimulation enabled synaptic potentiation that persisted for at least 30 min. This form of LTP was induced without the need for GABA receptor blockade that is typically required for inducing DG plasticity. The paired-pulse ratio (PPR) remained unchanged, indicating the cAMP-dependent LTP was likely postsynaptic. By employing fast fluorescent voltage-sensitive dye (VSD: di-4-ANEPPS) and fluorescence imaging, we found that photoactivation of the PAC actuator enhanced the intensity and extent of dentate gyrus depolarization triggered following tetanic stimulation. These results demonstrate that the elevation of cAMP in granule neurons is capable of rapidly enhancing synaptic strength and neuronal depolarization. The powerful actions of cAMP are consistent with this second messenger having a critical role in the regulation of synaptic function.

Background Coronary microembolization (CME) has a poor prognosis, with ventricular arrhythmia being the most serious consequence. Understanding the underlying mechanisms could improve its management. We investigated the effects of granulocyte colony-stimulating factor (G-CSF) on connexin-43 (Cx43) expression and ventricular arrhythmia susceptibility after CME. Methods Forty male rabbits were randomized into four groups (n = 10 each): Sham, CME, G-CSF, and AG490 (a JAK2 selective inhibitor). Rabbits in the CME, G-CSF, and AG490 groups underwent left anterior descending (LAD) artery catheterization and CME. Animals in the G-CSF and AG490 groups received intraperitoneal injection of G-CSF and G-CSF + AG490, respectively. The ventricular structure was assessed by echocardiography. Ventricular electrical properties were analyzed using cardiac electrophysiology. The myocardial interstitial collagen content and morphologic characteristics were evaluated using Masson and hematoxylin-eosin staining, respectively. Results Western blot and immunohistochemistry were employed to analyze the expressions of Cx43, G-CSF receptor (G-CSFR), JAK2, and STAT3. The ventricular effective refractory period (VERP), VERP dispersion, and inducibility and lethality of ventricular tachycardia/fibrillation were lower in the G-CSF than in the CME group (P P P P Conclusion G-CSF might attenuate myocardial remodeling via JAK2-STAT3 signaling and thereby reduce ventricular arrhythmia susceptibility after CME.

AVE0118, an inhibitor of IKur, Ito and IK,ACh, was in the drug pipeline for atrial fibrillation. To investigate the limitation of AVE0118 as an anti-atrial fibrillatory drug, we studied its electropharmacological effects particularly focusing on the anti-atrial fibrillatory action as reverse translational research. We adopted the chronic atrioventricular block beagle dogs (n = 4), having a pathophysiology of bradycardia-associated, volume overload-induced chronic heart failure, in which the atrial fibrillation was induced by 10 s of burst pacing on atrial septum. AVE0118 in doses of 0.24 and 1.2 mg/kg, i.v. over 10 min hardly altered electrophysiological variables. Meanwhile, AVE0118 in a dose of 6 mg/kg, i.v. over 10 min delayed the inter-atrial conduction in a frequency-dependent manner and prolonged the atrial effective refractory period in a reverse frequency-dependent manner, whereas it did not significantly alter the duration of atrial fibrillation or its cycle length. The increment of atrial effective refractory period was 3.3 times greater compared with that of ventricular one at a basic cycle length of 400 ms. Torsade de pointes was not induced during the experimental period. Thus, AVE0118 may possess a favorable cardiac safety pharmacological profile, but its weak anti-atrial fibrillatory effect would indicate the limitation of atrial repolarization-delaying agents for suppressing atrial fibrillation.

Since deuterium replacement has a potential to modulate pharmacodynamics, pharmacokinetics and toxicity, we developed deuterated dronedarone; poyendarone, and assessed its cardiovascular effects. Poyendarone hydrochloride in doses of 0.3 and 3 mg/kg over 30 s was intravenously administered to the halothane-anesthetized dogs (n = 4), which provided peak plasma concentrations of 108 ± 10 and 1120 ± 285 ng/mL, respectively. The 0.3 mg/kg shortened the ventricular repolarization period. The 3 mg/kg transiently increased the heart rate at 5 min but decreased at 45 min, and elevated the total peripheral vascular resistance and left ventricular preload, whereas it reduced the mean blood pressure at 5 min, left ventricular contractility and cardiac output. The transient tachycardic action is considered to be induced by the hypotension-induced, reflex-mediated increase of sympathetic tone. The 3 mg/kg delayed both intra-atrial and intra-ventricular conductions, indicating Na+ channel inhibitory action. Moreover, the 3 mg/kg transiently shortened the ventricular repolarization period at 5 min. No significant change was detected in the late repolarization by poyendarone, indicating it might not hardly significantly alter rapidly activating delayed-rectifier K+ current (IKr). Poyendarone prolonged the atrial effective refractory period greater than the ventricular parameter. When compared with dronedarone, poyendarone showed similar pharmacokinetics of dronedarone, but reduced β-adrenoceptor blocking activity as well as the cardio-suppressive effect. Poyendarone failed to inhibit IKr and showed higher atrial selectivity in prolonging the effective refractory period of atrium versus ventricle. Thus, the deuteration may be an effective way to improve the cardiovascular profile of dronedarone. Poyendarone is a promising anti-atrial fibrillatory drug candidate.

Dynamic signaling on branching axons is critical for rapid and efficient communication between neurons in the brain. Efficient signaling in axon arbors depends on a trade-off between the time it takes action potentials to reach synaptic terminals (temporal cost) and the amount of cellular material associated with the wiring path length of the neuron’s morphology (material cost). However, where the balance between structural and dynamical considerations for achieving signaling efficiency is, and the design principle that neurons optimize to preserve this balance, is still elusive. In this work, we introduce a novel analysis that compares morphology and signaling dynamics in axonal networks to address this open problem. We show that in Basket cell neurons the design principle being optimized is the ratio between the refractory period of the membrane, and action potential latencies between the initial segment and the synaptic terminals. Our results suggest that the convoluted paths taken by axons reflect a design compensation by the neuron to slow down signaling latencies in order to optimize this ratio. Deviations in this ratio may result in a breakdown of signaling efficiency in the cell. These results pave the way to new approaches for investigating more complex neurophysiological phenomena that involve considerations of neuronal structure-function relationships.

Increased excitability of motor neurons in patients with amyotrophic lateral sclerosis (ALS) may be a relevant factor leading to motor neuron damage. This randomized, double-blind, three-way crossover, placebo-controlled study evaluated peripheral motor nerve excitability testing as a biomarker of hyperexcitability and assessed the effects of riluzole and retigabine in 18 patients with ALS. We performed excitability testing at baseline, and twice after participants had received a single dose of either 100 mg riluzole, 300 mg retigabine, or placebo. Between- and within-day repeatability was at least acceptable for 14 out of 18 recorded excitability variables. No effects of riluzole on excitability testing were observed, but retigabine significantly decreased strength-duration time-constant (9.2%) and refractoriness at 2 ms (10.2) compared to placebo. Excitability testing was shown to be a reliable biomarker in patients with ALS, and the acute reversal of previously abnormal variables by retigabine justifies long-term studies evaluating the impact on disease progression and survival.

Obstructive sleep apnea, which involves chronic intermittent hypoxia (CIH), is a major risk factor for developing atrial fibrillation (AF). Whether or not CIH alone alters cardiac mechanisms to support AF is unknown. This study investigated the effects of CIH on atrial electrophysiology and arrhythmia vulnerability and evaluated the role of autonomics in CIH promotion of AF. Adult male Sprague-Dawley rats were exposed to 8 h/day of CIH or normoxia for 7 days. After exposure, rats were anesthetized for intracardiac electrophysiological experiments. Atrial effective refractory periods (AERPs) and AF inducibility were determined using programmed electrical stimulation and burst pacing in the absence and presence of autonomic receptor agonists and antagonists. Western blot analysis measured atrial protein expression of muscarinic M2, M3, and β1-adrenergic receptors. Compared with normoxia-exposed control rats, CIH-exposed rats had enhanced AF vulnerability using both programmed electrical stimulation and burst pacing, accompanied by greater AERP responses to carbachol and propranolol, lesser responses to isoproterenol, and higher atrial M2 receptor protein levels. Enhanced atrial vulnerability was accentuated by carbachol and abolished by atropine, indicating that the AF-promoting effects of CIH depended principally on parasympathetic activation. Enhancement of atrial vulnerability and AERP shortening with cholinergic agonists in CIH-exposed rats is consistent with sensitivity to parasympathetic activation. Higher responses to adrenergic receptor blockade in CIH-exposed rats is consistent with sympathetic potentiation. These findings implicate CIH as an important mediator of enhanced AF susceptibility in obstructive sleep apnea and provide novel insights into the underlying mechanisms. NEW & NOTEWORTHY Our study demonstrates, for the first time, that chronic intermittent hypoxia alone enhances vulnerability to atrial arrhythmia induction, which depends principally on parasympathetic activation. Enhanced atrial vulnerability was accompanied by heightened electrophysiological responses of the atrial myocardium to carbachol and isoproterenol, dampened responses to propranolol, and increased atrial M2 receptor protein levels.

The cardiac sympathetic nerves distribute across cardiac tissues with uneven density. Yet, to what extent this anatomical heterogeneity affects electrical activity of the left ventricle is largely unknown. Dogs were randomized into non-stimulation control (NC), posterior basal-stimulation (PB), anterior superior-stimulation (AS), apical part-stimulation (AP) group. The epicardial sympathetic nerves at different sites along their distribution were with electrical stimulation (ES) for 4 hours except in the NC group. The myocardial effective refractory period (ERP), ventricular fibrillation threshold (VFT) and density of sympathetic nerves were recorded. Compared with ES at other places, the stimulation at PB site significantly shortened ERP (left ventricular anterior and posterior walls; PB group, 118 ± 4 ms, 106 ± 2 ms; Versus NC group, 155 ± 3.5 ms, 160 ± 3 ms; p p

Background Studies have shown that left stellate ganglion (LSG) suppression protects against ventricular arrhythmias (VAs). Optogenetics is a novel technique to reversibly regulate the activity of the targeted neurons. Objectives This study aimed to investigate whether an optogenetically silenced LSG could protect against VAs induced by myocardial ischemia. Methods Adeno-associated virus (AAV) was used as the vector to deliver ArchT, an inhibitory light-sensitive opsin, to the LSG neurons. Twenty male beagles were randomized into the optogenetics group (n = 10, AAV2/9-CAG-ArchT-GFP microinjected into LSG) and control group (n = 10, AAV2/9-CAG-GFP microinjected into LSG). After 4 weeks, the LSG function and neural activity, heart rate variability, ventricular action potential duration, and effective refractory period were measured in the absence or presence of a light-emitting diode illumination (565 nm). Myocardial ischemia was induced by left anterior coronary artery ligation and 1 h of electrocardiography was recorded for VAs analysis. Results ArchT was successfully expressed in all dogs. Transient light-emitting diode illumination significantly suppressed the LSG function, LSG neural activity, and sympathetic nerve indices of heart rate variability as well as prolonged left ventricular effective refractory period and APD90 only in the optogenetics group. Thirty-minute illumination further enhanced these changes in the optogenetics group. Importantly, all of these changes returned to baseline within 2 h after illumination was turned off. Moreover, the ischemia-induced VAs were significantly suppressed by illumination only in the optogenetics group. Conclusions Optogenetic modulation could reversibly inhibit the neural activity of LSG, thereby increasing electrophysiological stability and protecting against myocardial ischemia–induced VAs.

Item does not contain fulltext BACKGROUND: Arrhythmias in horses may require long-term anti-arrhythmic therapy. Unfortunately, oral anti-arrhythmic drugs for use in horses are currently scarce. In human patients and small animals, sotalol, a beta-blocker with class III anti-arrhythmic properties, is often used for long-term treatment. OBJECTIVES: To determine the pharmacokinetics of sotalol at multiple oral dosages in unfasted horses, as well as the effects on electro- and echocardiographic measurements, right atrial and ventricular monophasic action potential (MAP) and effective refractory period (ERP). STUDY DESIGN: Placebo controlled, double-blinded experiment. MATERIALS AND METHODS: Six healthy, unfasted Warmblood horses were given either 0, 2, 3 or 4 mg/kg bodyweight (bwt) sotalol orally (PO) twice daily (bid) for 9 days in a randomised cross-over design. Echocardiography and surface electrocardiography were performed and plasma concentrations of sotalol and right atrial and right ventricular MAPs and ERPs were determined at steady-state conditions. Statistical analysis was performed using a repeated measures univariate analysis with post hoc Bonferroni corrections. RESULTS: Calculated mean steady-state plasma concentrations determined by nonlinear mixed-effect modelling were 287 (range 234-339), 409 (359-458) and 543 (439-646) ng/mL for 2, 3 and 4 mg/kg bwt sotalol PO bid respectively. Sotalol significantly increased the QT interval and ERPs, but, despite increasing plasma concentrations, higher dosages did not result in a progressive increase in QT interval or ERPs. Echocardiographic and other electrocardiographic measurements did not change significantly. MAP durations at 90% repolarisation were not significantly different during sotalol treatment. Besides transient local sweating, no side effects were noted. MAIN LIMITATIONS: Study size and ad libitum feeding of hay. CONCLUSIONS: Sotalol at a dose of 2, 3 and 4 mg/kg bwt PO bid increases the QT interval and ERP and might be a useful drug for long-term anti-arrhythmic therapy in horses.

In this study we aim to resolve the contributions of facilitation and refractoriness at very short pulse intervals. Measurements of the refractory properties of the electrically evoked compound action potential (ECAP) of the auditory nerve in cochlear implant (CI) users at inter pulse intervals below 300 μs are influenced by facilitation and recovery effects. ECAPs were recorded using masker pulses with a wide range of current levels relative to the probe pulse levels, for three suprathreshold probe levels and pulse intervals from 13 to 200 μs. Evoked potentials were measured for 21 CI patients by using the masked response extraction artifact cancellation procedure. During analysis of the measurements the stimulation current was not used as absolute value, but in relation to the patient's individual ECAP threshold. This enabled a more general approach to describe facilitation as a probe level independent effect. Maximum facilitation was found for all tested inter pulse intervals at masker levels near patient's individual ECAP threshold, independent from probe level. For short inter pulse intervals an increased N1P1 amplitude was measured for subthreshold masker levels down to 120 CL below patient's individual ECAP threshold in contrast to the recreated state. ECAPs recorded with inter pulse intervals up to 200 μs are influenced by facilitation and recovery. Facilitation effects are most pronounced for masker levels at or below ECAP threshold, while recovery effects increase with higher masker levels above ECAP threshold. The local maximum of the ECAP amplitude for masker levels around ECAP threshold can be explained by the mutual influence of maximum facilitation and minimal refractoriness.